recent journal articles: psychiatry




Recent Articles in Archives of General Psychiatry

McNally RJ
Trauma in childhood.
Arch Gen Psychiatry. 2007 Dec;64(12):1451. [Abstract]

Saddichha S, Kumar D
Is psychosocial management effective?
Arch Gen Psychiatry. 2007 Dec;64(12):1451; author reply 1452-3. [Abstract]

Dickerson BC, Sperling RA, Hyman BT, Albert MS, Blacker D
Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment.
Arch Gen Psychiatry. 2007 Dec;64(12):1443-50.
OBJECTIVE: To determine whether clinical assessment methods that grade the severity of impairments within the spectrum of mild cognitive impairment (MCI) can predict clinical course, particularly among very mildly impaired individuals who do not meet formal MCI criteria as implemented in clinical trials. DESIGN: Cohort. SETTING: Community volunteers. PARTICIPANTS: From a longitudinal study of normal (Clinical Dementia Rating [CDR] = 0; n = 77) and mildly impaired (CDR = 0.5; n = 167) participants with 5 or more annual clinical assessments, baseline level of cognitive impairment in daily life was graded using CDR sum of boxes (CDR-SB) and level of cognitive performance impairment was graded using neuropsychological test scores. MAIN OUTCOME MEASURES: Five-year outcome measures included (1) probable Alzheimer disease (AD) diagnosis and (2) clinical "decline" (CDR-SB increase > or = 1.0). Logistic regression models were used to assess the ability of baseline measures to predict outcomes in the full sample and separately in the subjects who did not meet formal MCI criteria as implemented in a multicenter clinical trial (n = 125; "very mild cognitive impairment" [vMCI]). RESULTS: The presence of both higher CDR-SB and lower verbal memory and executive function at baseline predicted greater likelihood of probable AD and decline. Five-year rates of probable AD and decline in vMCI (20%, AD; 49%, decline) were intermediate between normal participants (0%, AD; 28%, decline) and participants with MCI (41%, AD; 62%, decline). Within vMCI, likelihood of probable AD was predicted by higher CDR-SB and lower executive function. CONCLUSIONS: Even in very mildly impaired individuals who do not meet strict MCI criteria as implemented in clinical trials, the degree of cognitive impairment in daily life and performance on neuropsychological testing predict likelihood of an AD diagnosis within 5 years. The clinical determination of relative severity of impairment along the spectrum of MCI may be valuable for trials of putative disease-modifying compounds, particularly as target populations are broadened to include less impaired individuals. [Abstract]

Reed PL, Anthony JC, Breslau N
Incidence of drug problems in young adults exposed to trauma and posttraumatic stress disorder: do early life experiences and predispositions matter?
Arch Gen Psychiatry. 2007 Dec;64(12):1435-42.
CONTEXT: Most estimated associations of posttraumatic stress disorder (PTSD) with DSM-IV drug dependence and abuse are from cross-sectional studies or from prospective studies of adults that generally do not take into account suspected causal determinants measured in early childhood. OBJECTIVE: To estimate risk for incident drug disorders associated with prior DSM-IV PTSD. DESIGN: Multiwave longitudinal study of an epidemiologic sample of young adults first assessed at entry to first grade of primary school in the fall semesters of 1985 and 1986, with 2 young adult follow-up assessments. SETTING: Mid-Atlantic US urban community. PARTICIPANTS: Young adults (n = 988; aged 19-24 years) free of clinical features of DSM-IV drug use disorders at the first young adult assessment and therefore at risk for newly incident drug use disorders during the 1-year follow-up period. MAIN OUTCOME MEASURES: During the 12-month interval between the 2 young adult follow-up assessments, newly incident (1) DSM-IV drug abuse or dependence; (2) DSM-IV drug abuse; (3) DSM-IV drug dependence; and (4) emerging dependence problems (1 or 2 newly incident clinical features of DSM-IV drug dependence), among subjects with no prior clinical features of drug use disorders. RESULTS: Prior PTSD (but not trauma only) was associated with excess risk for drug abuse or dependence (adjusted relative risk, 4.9; 95% confidence interval, 1.6-15.2) and emerging dependence problems (adjusted relative risk, 4.9; 95% confidence interval, 1.2-20.1) compared with the no-trauma group controlling for childhood factors. Subjects with PTSD also had a greater adjusted relative risk for drug abuse or dependence compared with subjects exposed to trauma only (adjusted relative risk, 2.0; 95% confidence interval, 1.1-3.8) controlling for childhood factors. CONCLUSIONS: Association of PTSD with subsequent incident drug use disorders remained substantial after statistical adjustment for early life experiences and predispositions reported in previous studies as carrying elevated risk for both disorders. Posttraumatic stress disorder might be a causal determinant of drug use disorders, possibly representing complications such as attempts to self-medicate troubling trauma-associated memories, nightmares, or painful hyperarousal symptoms. [Abstract]

Galea S, Brewin CR, Gruber M, Jones RT, King DW, King LA, McNally RJ, Ursano RJ, Petukhova M, Kessler RC
Exposure to hurricane-related stressors and mental illness after Hurricane Katrina.
Arch Gen Psychiatry. 2007 Dec;64(12):1427-34.
CONTEXT: Uncertainty exists about the prevalence, severity, and correlates of mental disorders among people exposed to Hurricane Katrina. OBJECTIVE: To estimate the prevalence and associations between DSM-IV anxiety-mood disorders and hurricane-related stressors separately among prehurricane residents of the New Orleans metropolitan area and the remainder of the areas in Alabama, Louisiana, and Mississippi affected by Katrina. DESIGN: Community survey. SETTING AND PARTICIPANTS: A probability sample of 1043 English-speaking prehurricane residents of the areas affected by Hurricane Katrina was administered via telephone survey between January 19 and March 31, 2006. The survey assessed hurricane-related stressors and screened for 30-day DSM-IV anxiety-mood disorders. MAIN OUTCOME MEASURES: The K6 screening scale of anxiety-mood disorders and the Trauma Screening Questionnaire scale for posttraumatic stress disorder (PTSD), both calibrated against blinded structured clinical reappraisal interviews to approximate the 30-day prevalence of DSM-IV disorders. RESULTS: Prehurricane residents of the New Orleans metropolitan area were estimated to have a 49.1% 30-day prevalence of any DSM-IV anxiety-mood disorder (30.3% estimated prevalence of PTSD) compared with 26.4% (12.5% PTSD) in the remainder of the sample. The vast majority of respondents reported exposure to hurricane-related stressors. Extent of stressor exposure was more strongly related to the outcomes in the New Orleans metropolitan area subsample than the remainder of the sample. The stressors most strongly related to these outcomes were physical illness/injury and physical adversity in the New Orleans metropolitan area subsample and property loss in the remainder of the sample. Sociodemographic correlates were not explained either by differential exposure or reactivity to hurricane-related stressors. CONCLUSIONS: The high prevalence of DSM-IV anxiety-mood disorders, the strong associations of hurricane-related stressors with these outcomes, and the independence of sociodemographics from stressors argue that the practical problems associated with ongoing stressors are widespread and must be addressed to reduce the prevalence of mental disorders in this population. [Abstract]

Feusner JD, Townsend J, Bystritsky A, Bookheimer S
Visual information processing of faces in body dysmorphic disorder.
Arch Gen Psychiatry. 2007 Dec;64(12):1417-25.
CONTEXT: Body dysmorphic disorder (BDD) is a severe psychiatric condition in which individuals are preoccupied with perceived appearance defects. Clinical observation suggests that patients with BDD focus on details of their appearance at the expense of configural elements. This study examines abnormalities in visual information processing in BDD that may underlie clinical symptoms. OBJECTIVE: To determine whether patients with BDD have abnormal patterns of brain activation when visually processing others' faces with high, low, or normal spatial frequency information. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: Twelve right-handed, medication-free subjects with BDD and 13 control subjects matched by age, sex, and educational achievement. Intervention Functional magnetic resonance imaging while performing matching tasks of face stimuli. Stimuli were neutral-expression photographs of others' faces that were unaltered, altered to include only high spatial frequency visual information, or altered to include only low spatial frequency visual information. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes in the BDD and control groups during tasks with each stimulus type. RESULTS: Subjects with BDD showed greater left hemisphere activity relative to controls, particularly in lateral prefrontal cortex and lateral temporal lobe regions for all face tasks (and dorsal anterior cingulate activity for the low spatial frequency task). Controls recruited left-sided prefrontal and dorsal anterior cingulate activity only for the high spatial frequency task. CONCLUSIONS: Subjects with BDD demonstrate fundamental differences from controls in visually processing others' faces. The predominance of left-sided activity for low spatial frequency and normal faces suggests detail encoding and analysis rather than holistic processing, a pattern evident in controls only for high spatial frequency faces. These abnormalities may be associated with apparent perceptual distortions in patients with BDD. The fact that these findings occurred while subjects viewed others' faces suggests differences in visual processing beyond distortions of their own appearance. [Abstract]

Klump KL, Burt SA, McGue M, Iacono WG
Changes in genetic and environmental influences on disordered eating across adolescence: a longitudinal twin study.
Arch Gen Psychiatry. 2007 Dec;64(12):1409-15.
CONTEXT: Previous research suggests substantial increases in genetic effects on disordered eating across adolescence. Unfortunately, these studies were cross-sectional and focused primarily on early (age 11 years) vs late (age 17 years) adolescence. OBJECTIVE: To examine longitudinal changes in genetic and environmental influences on disordered eating across early, mid, and late adolescence. DESIGN AND SETTING: Population-based study of female same-sex twins. PARTICIPANTS: Seven hundred seventy-two female adolescent twins from the Minnesota Twin Family Study assessed at ages 11, 14, and 18 years. MAIN OUTCOME MEASURES: Disordered eating symptoms (ie, body dissatisfaction, weight preoccupation, binge eating, and the use of compensatory behaviors) were assessed with the total score from the Minnesota Eating Behavior Survey. RESULTS: Biometric model-fitting indicated significant changes in genetic and shared environmental effects across early to mid adolescence. Although genetic factors accounted for a negligible proportion (6%) of variance at age 11 years, genes increased in importance and accounted for roughly half of the variance (46%) in disordered eating at ages 14 and 18 years. Shared environmental influences decreased substantially across these same ages. CONCLUSIONS: Findings highlight the transition from early to mid adolescence as a critical time for the emergence of a genetic diathesis for disordered eating. The increase in genetic effects during this developmental stage corroborates previous research implicating puberty in the genetic etiology of eating disorders. [Abstract]

Procopio M, Marriott P
Intrauterine hormonal environment and risk of developing anorexia nervosa.
Arch Gen Psychiatry. 2007 Dec;64(12):1402-7.
CONTEXT: Anorexia nervosa (AN) is approximately 10 times more common in females than in males. The reasons for this difference are not yet understood. Several mechanisms have been hypothesized as possible causes. OBJECTIVE: To determine whether the different hormonal environments to which male and female fetuses are exposed in utero might contribute to the increased risk of developing AN in females. DESIGN, SETTING, AND PARTICIPANTS: The study is based on a large population-based cohort of Swedish twins. The strategy used is to compare the prevalence for AN between same-sex and opposite-sex twins. RESULTS: The study shows that the risk of developing AN in female twins is higher than in male twins, as expected. The only exception is male members of opposite-sex pairs, who have a higher risk of developing the illness when compared with other males (P = .62 for narrow diagnostic criteria and P = .60 for broad diagnostic criteria). In fact, their risk is at a level that is not statistically significantly different from that of females from such a pair. A plausible explanation for this phenomenon is that in pregnancies bearing a female fetus, a substance is produced, probably hormonal, that increases the risk of having AN in adulthood. Because the male half of an opposite-sex twin pair would also be exposed to this substance, it could account for the observed elevated risk in males with female twins. The most likely candidates are sex steroid hormones. CONCLUSIONS: The results of our study are compatible with the hypothesis that intrauterine exposure to sex hormones might influence neurodevelopment, affecting the risk of developing AN in adult life. This might be a factor contributing to the higher risk of developing AN in females. [Abstract]

Kubzansky LD, Thurston RC
Emotional vitality and incident coronary heart disease: benefits of healthy psychological functioning.
Arch Gen Psychiatry. 2007 Dec;64(12):1393-401.
CONTEXT: The potentially toxic effects of psychopathology and poorly regulated emotion on physical health have long been considered, but less work has addressed whether healthy psychological functioning may also benefit physical health. Emotional vitality--characterized by a sense of energy, positive well-being, and effective emotion regulation--has been hypothesized to reduce risk of heart disease, but no studies have examined this relationship. OBJECTIVES: To examine whether emotional vitality is associated with reduced risk of coronary heart disease (CHD). Secondary aims are to consider whether effects are independent of negative emotion and how they may occur. DESIGN: A prospective population-based cohort study. SETTING: National Health and Nutrition Examination Survey I and follow-up studies (a probability sample of US adults). PARTICIPANTS: Six thousand twenty-five men and women aged 25 to 74 years without CHD at baseline, followed up for a mean 15 years after the baseline interview. MAIN OUTCOME MEASURES: Measures of incident CHD were obtained from hospital records and death certificates. During the follow-up period, 1141 cases of incident CHD occurred. RESULTS: At the baseline interview (1971-1975), participants completed the General Well-being Schedule from which we derived a measure of emotional vitality. Compared with individuals with low levels, those reporting high levels of emotional vitality had multivariate-adjusted relative risks of 0.81 (95% confidence interval, 0.69-0.94) for CHD. A dose-response relationship was evident (P < .001). Significant associations were also found for each individual emotional vitality component with CHD, but findings with the overall emotional vitality measure were more reliable. Further analyses suggested that one way in which emotional vitality may influence coronary health is via health behaviors. However, the effect remained significant after controlling for health behaviors and other potential confounders, including depressive symptoms or other psychological problems. CONCLUSION: Emotional vitality may protect against risk of CHD in men and women. [Abstract]

Arabia G, Grossardt BR, Geda YE, Carlin JM, Bower JH, Ahlskog JE, Maraganore DM, Rocca WA
Increased risk of depressive and anxiety disorders in relatives of patients with Parkinson disease.
Arch Gen Psychiatry. 2007 Dec;64(12):1385-92.
CONTEXT: Relatives of patients with Parkinson disease (PD) have an increased risk of PD and other neurologic disorders; however, their risk of psychiatric disorders remains uncertain. OBJECTIVE: To study the risk of depressive disorders and anxiety disorders among first-degree relatives of patients with PD compared with first-degree relatives of controls. DESIGN, SETTING, AND PARTICIPANTS: In a population-based, historical cohort study, we included 1000 first-degree relatives of 162 patients with PD and 850 first-degree relatives of 147 controls. Both patients with PD and controls were representative of the population of Olmsted County, Minnesota. MAIN OUTCOME MEASURES: Documentation of psychiatric disorders was obtained for each relative separately through a combination of telephone interviews with the relatives (or their proxies) and review of their medical records from a records-linkage system (family study method). Psychiatric disorders were defined using clinical criteria from the DSM-IV or routine diagnoses. RESULTS: We found an increased risk of several psychiatric disorders in first-degree relatives of patients with PD compared with first-degree relatives of controls (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.21-1.95; P <.001). In particular, we found an increased risk of depressive disorders (HR, 1.45; 95% CI, 1.11-1.89; P = .006) and anxiety disorders (HR, 1.55; 95% CI, 1.05-2.28; P = .03). The results were consistent in analyses that adjusted for type of interview, excluded relatives who developed parkinsonism, or excluded relatives who developed both a depressive disorder and an anxiety disorder. CONCLUSION: These findings suggest that depressive disorders and anxiety disorders may share familial susceptibility factors with PD. [Abstract]

Agerbo E
High income, employment, postgraduate education, and marriage: a suicidal cocktail among psychiatric patients.
Arch Gen Psychiatry. 2007 Dec;64(12):1377-84.
CONTEXT: Studies dating back over 100 years have shown that the risk of suicide in the general population is associated with low income, unemployment, educational underachievement, and singleness. However, little is known about the association between suicide risk and these factors in psychiatric patients. OBJECTIVE: To estimate the association between suicide risk, socioeconomic position, and marital status in psychiatric patients. DESIGN, SETTING, AND PATIENTS: Population-based cohort study of all first-ever psychiatric patients aged 16 to 65 years admitted from 1981 to 1998, with administrative longitudinal data on income, labor market affiliation, educational attainment, and marital and cohabitational status (96,369 patients, 256,619 admissions, and 2727 suicides). MAIN OUTCOME MEASURES: Suicide risks after hospital discharge were depicted using Kaplan-Meier product-limit methods. Hazard ratios (HRs) for suicide from Cox proportional hazards regression and case-crossover/individually stratified analyses were calculated while adjusting for overall social drift. RESULTS: Using Cox proportional hazards regression, compared with patients in the highest income quartile, the suicide HR decreased from 0.90 (95% confidence interval [CI], 0.79-1.02) in the third lowest to 0.83 (95% CI, 0.73-0.93) in the second lowest and to 0.68 (95% CI, 0.61-0.76) in the lowest income group. Compared with the fully employed, the HR for unemployed patients was 0.85 (95% CI, 0.77-0.93); for social benefits' recipients, 0.58 (95% CI, 0.48-0.70); and for disability or age pensioners, 0.63 (95% CI, 0.55-0.71). Compared with postgraduate education, HRs (95% CIs) associated with a bachelor's degree, vocational school, or primary school education were 0.82 (0.67-1.02), 0.66 (0.55-0.80), and 0.54 (0.44-0.65), respectively. The HRs (95% CIs) for widowed, divorced, and never-married patients were 1.07 (0.89-1.30), 0.74 (0.66-0.84), and 0.88 (0.79-0.98), respectively. Using individually stratified analyses, HRs (95% CIs) for transition into the third lowest, the second lowest, and the lowest income quartile were 1.19 (0.76-1.86), 1.47 (0.92-2.34), and 1.84 (1.14-2.97), respectively. The HRs (95% CIs) for patients who became unemployed, social benefits' recipients, disability or age pensioners, widowed patients, and divorced patients were 1.41 (1.01-1.95), 1.73 (1.06-2.80), 1.45 (0.91-2.30), 2.59 (0.76-8.89), and 1.86 (1.07-3.21), respectively. CONCLUSIONS: Suicide risk is generally associated with low income, unemployment, educational underachievement, and singleness, but this study suggests that the opposite is true among psychiatric patients. However, loss of income, labor market status, and marriage increase the suicide risk. [Abstract]

Hippisley-Cox J, Vinogradova Y, Coupland C, Parker C
Risk of malignancy in patients with schizophrenia or bipolar disorder: nested case-control study.
Arch Gen Psychiatry. 2007 Dec;64(12):1368-76.
CONTEXT: There is conflicting evidence on whether people with schizophrenia have a different risk of cancer from that of the general population. OBJECTIVE: To determine the risk of 6 common cancers in patients with schizophrenia or bipolar disorder. DESIGN: Population-based, nested, case-control study. SETTING: A total of 454 practices contributing to the QRESEARCH general practice database. PARTICIPANTS: We analyzed 40,441 incident cases of 6 cancers (breast, colon, rectal, gastroesophageal, prostate, and respiratory) and up to 5 controls per case matched by single year of age, sex, general practice, and calendar time. MAIN OUTCOME MEASURES: Odds ratios (ORs) for cancer risk associated with schizophrenia and bipolar disorder, adjusting for smoking, body mass index, socioeconomic status, comorbidities, and prescribed medications, including antipsychotics. RESULTS: For breast cancer, we identified 10,535/50,074 cases/controls; colon cancer, 5108/24,458; rectal cancer, 3248/15,552; gastroesophageal cancer, 3854/18,477; prostate cancer, 10,190/48,748; and respiratory cancer, 7506/35,981. After adjustment, patients with schizophrenia had a 190% increased colon cancer risk (adjusted OR, 2.90; 95% confidence interval [CI], 1.85-4.57), a marginal increased breast cancer risk (adjusted OR, 1.52; 95% CI, 1.10-2.11), and a 47% decreased respiratory cancer risk (adjusted OR, 0.53, 95% CI, 0.34-0.85). Patients with schizophrenia taking antipsychotics had a 308% increased colon cancer risk (adjusted OR, 4.08; 95% CI, 2.43-6.84). Patients with bipolar disorder had cancer risks similar to patients with neither condition after adjustment. CONCLUSIONS: Patients with schizophrenia have a significantly higher risk of colon cancer and a lower risk of respiratory cancer compared with patients without schizophrenia after adjustment for confounders. In contrast, the risks of cancer in patients with and without bipolar disorder are similar, suggesting that residual confounding is unlikely to explain the findings. The increased risk of colon cancer is particularly marked in patients with schizophrenia who take antipsychotic medications. [Abstract]

Gur RE, Loughead J, Kohler CG, Elliott MA, Lesko K, Ruparel K, Wolf DH, Bilker WB, Gur RC
Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia.
Arch Gen Psychiatry. 2007 Dec;64(12):1356-66.
CONTEXT: Deficits in emotion processing are prominent in schizophrenia, and flat affect is resistant to treatment and portends poor outcome. Investigation of the underlying neural circuitry can elucidate affective dysfunction. OBJECTIVE: To examine the brain circuitry for facial emotion processing, dissecting response to task demands from effects of the appearance of facial expressions. DESIGN: A facial emotion identification task was presented during high-field (4-T) magnetic resonance imaging. Blood oxygenation level-dependent changes were contrasted for task compared with a scrambled face baseline (blocked analysis) and for the appearance of each of the following 4 target expressions compared with neutral faces (event related): happy, sad, anger, and fear. SETTING: Participants from the Schizophrenia Research Center underwent a functional magnetic resonance imaging study at the University of Pennsylvania Medical Center. PARTICIPANTS: Patients with DSM-IV-defined schizophrenia (n = 16) and healthy controls (n = 17) were recruited from the community. MAIN OUTCOME MEASURES: The percentage of signal change for each contrast and performance and clinical symptom severity ratings. RESULTS: Patients showed reduced limbic activation compared with controls for the emotion identification task. However, event-related analysis revealed that whereas in controls greater amygdala activation was associated with correct identifications of threat-related (anger and fear) expressions, patients showed the opposite effect of greater limbic activation, portending misidentifications. Furthermore, greater amygdala activation to the presentation of fearful faces was highly correlated with greater severity of flat affect. CONCLUSIONS: Abnormal amygdala activation in schizophrenia in response to presentation of fearful faces is paradoxically associated with failure to recognize the emotion and with more severe flat affect. This finding suggests that flat affect in schizophrenia relates to overstimulation of the limbic system. [Abstract]

Toulopoulou T, Picchioni M, Rijsdijk F, Hua-Hall M, Ettinger U, Sham P, Murray R
Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples.
Arch Gen Psychiatry. 2007 Dec;64(12):1348-55.
CONTEXT: The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder. OBJECTIVES: To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia. DESIGN: Genetic model fitting to monozygotic and dizygotic twin data. SETTING: United Kingdom psychiatric research institute. PARTICIPANTS: Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs. MAIN OUTCOME MEASURES: The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified. RESULTS: Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = -0.61; 95% confidence interval, -0.71 to -0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance. CONCLUSION: Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia. [Abstract]

Harris JC
The Water-lily pond--symphony in green.
Arch Gen Psychiatry. 2007 Dec;64(12):1347. [Abstract]

Manev H, Manev R
5-lipoxygenase as a possible biological link between depressive symptoms and atherosclerosis.
Arch Gen Psychiatry. 2007 Nov;64(11):1333. [Abstract]

Stewart JC, Janicki DL, Muldoon MF, Sutton-Tyrrell K, Kamarck TW
Negative emotions and 3-year progression of subclinical atherosclerosis.
Arch Gen Psychiatry. 2007 Feb;64(2):225-33.
CONTEXT: Although depression, anxiety, and hostility/anger have each been associated with an increased risk of coronary artery disease, these overlapping negative emotions have not been simultaneously examined as predictors of the progression of subclinical atherosclerosis. OBJECTIVE: To evaluate the relative importance of depressive symptoms, anxiety symptoms, and hostility/anger in predicting subclinical atherosclerotic progression over a 3-year period. Design/ SETTING: The Pittsburgh Healthy Heart Project, an ongoing prospective cohort study of healthy, older men and women from the general community. At baseline, questionnaires were administered to assess depressive symptoms, anxiety symptoms, hostility, anger experience, and anger expression. Mean carotid intima-media thickness was assessed by B-mode ultrasonography during the baseline and 3-year follow-up visits. PARTICIPANTS: Of the 464 adults enrolled in the project, 324 (69.8%) were included in this report because they had complete baseline and follow-up data. Main Outcome Measure Three-year change in mean carotid intima-media thickness. RESULTS: Regression analyses indicated that higher depressive symptoms at baseline were associated with greater 3-year change in carotid intima-media thickness (DeltaR(2) = 0.026, P = .002), even after taking into account demographic factors, cardiovascular risk factors, medication use, medical conditions, and other correlated negative emotions. Measures of anxiety symptoms, hostility, anger experience, and anger expression were each unrelated to intima-media thickness change. Post hoc analyses examining depressive symptom clusters showed that the somatic-vegetative symptoms of depression (DeltaR(2) = 0.027, P = .002), but not the cognitive-affective symptoms, were positively associated with intima-media thickness change. CONCLUSION: Our findings suggest that the somatic-vegetative features of depression, but perhaps not anxiety and hostility/anger, may play an important role in the earlier stages of the development of coronary artery disease. [Abstract]

King-Hele SA, Abel KM, Webb RT, Mortensen PB, Appleby L, Pickles AR
Risk of sudden infant death syndrome with parental mental illness.
Arch Gen Psychiatry. 2007 Nov;64(11):1323-30.
CONTEXT: Sudden infant death syndrome is the leading cause of postneonatal death in developed countries. Little is known about risks linked with parental mental illness per se or how such risks are modified by specific psychiatric conditions and by maternal vs paternal psychopathological abnormalities. OBJECTIVE: To investigate cause-specific postneonatal death, including sudden infant death syndrome, in infants whose parents had been admitted as psychiatric inpatients. DESIGN: National cohort study. SETTING: The entire Danish population. Patients All of the singleton live births registered from January 1, 1973, to December 31, 1998. Linkage to the national psychiatric register enabled identification of all of the parental admissions from April 1, 1969, onward. MAIN OUTCOME MEASURE: All of the cases of sudden infant death syndrome in the postneonatal period classified via national mortality registration between January 1, 1973, and December 31, 1998. RESULTS: Psychiatric admission history in either parent doubled the risk of sudden infant death syndrome, but there was no difference in risk whether infants were exposed to maternal or paternal admission. Risk was particularly high if both parents had been admitted for any psychiatric disorder (relative risk, 6.9; 95% confidence interval, 4.1-11.6). Among specific parental disorders, the greatest risk was associated with admission for alcohol- or drug-related disorders (mothers: relative risk, 5.0; 95% confidence interval, 3.4-7.5; fathers: relative risk, 2.5; 95% confidence interval, 1.7-3.8). Contrary to prior expectation, parental schizophrenia and related disorders did not confer higher risks than other parental disorders that resulted in admission. CONCLUSIONS: Infants whose parents have been admitted for psychiatric treatment are at greater risk for sudden infant death syndrome. However, risks may be lower than previously thought with maternal schizophrenia and related disorders. Clinicians should be aware of particularly high risks if both parents have received any psychiatric inpatient treatment or if either parent (but the mother especially) was admitted with an alcohol- or drug-related disorder. [Abstract]

Kendler KS, Myers J, Prescott CA
Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence.
Arch Gen Psychiatry. 2007 Nov;64(11):1313-20.
CONTEXT: Although genetic risk factors have been found to contribute to dependence on both licit and illicit psychoactive substances, we know little of how these risk factors interrelate. OBJECTIVE: To clarify the structure of genetic and environmental risk factors for symptoms of dependence on cannabis, cocaine, alcohol, caffeine, and nicotine in males and females. DESIGN: Lifetime history by structured clinical interview. SETTING: General community. PARTICIPANTS: Four thousand eight hundred sixty-five members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure Lifetime symptoms of abuse of and dependence on cannabis, cocaine, alcohol, caffeine, and nicotine. RESULTS: Controlling for greater symptom prevalence in males, genetic and environmental parameters could be equated across sexes. Two models explained the data well. The best-fit exploratory model contained 2 genetic factors and 1 individual environmental factor contributing to all substances. The first genetic factor loaded strongly on cocaine and cannabis dependence; the second, on alcohol and nicotine dependence. Nicotine and caffeine had high substance-specific genetic effects. A confirmatory model, which also fit well, contained 1 illicit drug genetic factor--loading only on cannabis and cocaine--and 1 licit drug genetic factor loading on alcohol, caffeine, and nicotine. However, these factors were highly intercorrelated (r = + 0.82). Large substance-specific genetic effects remained for nicotine and caffeine. CONCLUSIONS: The pattern of genetic and environmental risk factors for psychoactive substance dependence was similar in males and females. Genetic risk factors for dependence on common psychoactive substances cannot be explained by a single factor. Rather, 2 genetic factors-one predisposing largely to illicit drug dependence, the other primarily to licit drug dependence-are needed. Furthermore, a large proportion of the genetic influences on nicotine and particularly caffeine dependence appear to be specific to those substances. [Abstract]

Côté SM, Boivin M, Nagin DS, Japel C, Xu Q, Zoccolillo M, Junger M, Tremblay RE
The role of maternal education and nonmaternal care services in the prevention of children's physical aggression problems.
Arch Gen Psychiatry. 2007 Nov;64(11):1305-12.
CONTEXT: Physical violence is an important health problem, and low maternal education is a significant risk for the development of chronic physical aggression (PA). We hypothesized that nonmaternal care (NMC) services could prevent the development of childhood PA problems, depending on the age at which the services are initiated. Method Children who followed a trajectory of atypically frequent PA between 17 and 60 months of age among a population sample of 1691 Canadian families were identified. Maternal education and NMC were considered in predicting group membership while controlling for confounding family characteristics. RESULTS: Children of mothers with low education levels (ie, no high school diploma) were less likely to receive NMC. Those who did receive such care had significantly lower risk of a high PA trajectory. Results from logistic regressions indicated that NMC reduced the risk of high PA, especially when initiated before age 9 months (odds ratio, 0.20; 95% confidence interval, 0.05-0.90). Children of mothers who graduated from high school were less at risk of PA problems, and NMC had no additional protective effect. CONCLUSIONS: Nonmaternal care services to children of mothers with low levels of education could substantially reduce their risk of chronic PA, especially if provided soon after birth. Because children most likely to benefit from NMC services are less likely to receive them, special measures encouraging the use of NMC services among high-risk families are needed. [Abstract]

D'Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Rathouz PJ, Lahey BB
Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems.
Arch Gen Psychiatry. 2007 Nov;64(11):1296-304.
CONTEXT: Existing research on the neurobehavioral consequences of prenatal alcohol exposure (PAE) has not adequately accounted for genetic and environmental confounds. OBJECTIVE: To examine the association between PAE and offspring externalizing problems in a large representative sample of families in the United States using measured covariates and a quasi-experimental design to account for unmeasured genetic and environmental confounds. DESIGN: This study combines information from the National Longitudinal Survey of Youth and the Children of the National Longitudinal Survey of Youth. The analyses statistically controlled for measured characteristics of the mothers and families and exposure to other prenatal psychoactive substances. In the primary analyses, siblings differentially exposed to prenatal alcohol were compared. SETTING AND PARTICIPANTS: Women were recruited from the community using a stratified and clustered probability sample and were followed longitudinally. The sample included 8621 offspring of 4912 mothers. MAIN OUTCOME MEASURES: Maternal report of conduct problems (CPs) and attention/impulsivity problems (AIPs) during childhood (ages 4-11 years) using standardized assessments related to psychiatric diagnoses. RESULTS: There was an association between PAE and offspring CPs that was independent of confounded genetic and fixed environmental effects and the measured covariates. The CPs in children of mothers who drank daily during pregnancy were 0.35 SD greater than those in children whose mothers never drank during pregnancy. Although AIPs were associated with PAE when comparing unrelated offspring, children whose mothers drank more frequently during pregnancy did not have more AIPs than siblings who were less exposed to alcohol in utero. Additional subsample analyses suggested that maternal polysubstance use during pregnancy may account for the associations between PAE and AIPs. CONCLUSION: These results are consistent with PAE exerting an environmentally mediated causal effect on childhood CPs, but the relation between PAE and AIPs is more likely to be caused by other factors correlated with maternal drinking during pregnancy. [Abstract]

Peterson BS, Choi HA, Hao X, Amat JA, Zhu H, Whiteman R, Liu J, Xu D, Bansal R
Morphologic features of the amygdala and hippocampus in children and adults with Tourette syndrome.
Arch Gen Psychiatry. 2007 Nov;64(11):1281-91.
CONTEXT: Limbic portions of cortical-subcortical circuits are likely involved in the pathogenesis of Tourette syndrome (TS). They are anatomically, developmentally, neurochemically, and functionally related to the basal ganglia, and the basal ganglia are thought to produce the symptoms of tics, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder that commonly affect persons with TS. OBJECTIVE: To study the morphologic features of the hippocampus and amygdala in children and adults with TS. DESIGN: A cross-sectional, case-control study using anatomical magnetic resonance imaging. SETTING: University research center. PARTICIPANTS: A total of 282 individuals (154 patients with TS and 128 controls) aged 6 to 63 years. MAIN OUTCOME MEASURES: Volumes and measures of surface morphologic features of the hippocampus and amygdala. RESULTS: The overall volumes of the hippocampus and amygdala were significantly larger in the TS group. Surface analyses suggested that the increased volumes in the TS group derived primarily from the head and medial surface of the hippocampus (over the length of the dentate gyrus) and the dorsal and ventral surfaces of the amygdala (over its basolateral and central nuclei). Volumes of these subregions declined with age in the TS group but not in controls, so the subregions were significantly larger in children with TS but significantly smaller in adults with TS than in their control counterparts. In children and adults, volumes in these subregions correlated inversely with the severity of tic, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder symptoms, suggesting that enlargement of the subregions may have a compensatory and neuromodulatory effect on tic-related symptoms. CONCLUSION: These findings are consistent with the known plasticity of the dentate gyrus and with findings from previous imaging studies suggesting the presence of failed compensatory plasticity in adults with TS who have not experienced the usual decline in symptoms during adolescence. [Abstract]

Ashtari M, Cottone J, Ardekani BA, Cervellione K, Szeszko PR, Wu J, Chen S, Kumra S
Disruption of white matter integrity in the inferior longitudinal fasciculus in adolescents with schizophrenia as revealed by fiber tractography.
Arch Gen Psychiatry. 2007 Nov;64(11):1270-80.
CONTEXT: There is increasing evidence that schizophrenia is characterized by abnormalities in white matter. OBJECTIVE: To investigate the integrity of white matter tracts in adolescents with schizophrenia. DESIGN: Cross-sectional, case-control, whole-brain, voxel-based analysis and fiber tractography using diffusion tensor magnetic resonance imaging. SETTING: University research institute. PARTICIPANTS: Forty-four individuals (age range, 11-18 years), 23 with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and 21 demographically similar healthy controls. MAIN OUTCOME MEASURES: Fractional anisotropy, trace, and radial diffusivity of diffusion tensor and quantitative tractography. RESULTS: Voxelwise analysis revealed that adolescents with schizophrenia had reduced fractional anisotropy within the left inferior temporal (P < .001) and occipital (P < .001) regions. Tractography was performed to extract the left and the right inferior longitudinal fasciculi (ILF). Measuring the mean diffusion indices along the left ILF, patients had significantly reduced fractional anisotropy (P < .001) as well as significantly increased radial diffusivity (P < .001) and trace (P = .003) after adjusting for differences in a measure thought to reflect premorbid intelligence, Wide Range Achievement Test 3 reading scores. Exploratory analyses revealed that patients with a history of visual hallucinations had lower fractional anisotropy in the left ILF (P = .02) than patients without visual hallucinations. CONCLUSION: Our findings, which benefited from greater image resolution and methodological control than previous studies conducted in adolescents with schizophrenia, provide strong evidence for lower white matter integrity in the left ILF, particularly for patients with a history of visual hallucinations. [Abstract]

Rosenheck RA, Leslie DL, Sindelar JL, Miller EA, Tariot PN, Dagerman KS, Davis SM, Lebowitz BD, Rabins P, Hsiao JK, Lieberman JA, Schneider LS
Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer disease.
Arch Gen Psychiatry. 2007 Nov;64(11):1259-68.
CONTEXT: Second-generation antipsychotics (SGAs) are prescribed for psychosis, aggression, and agitation in Alzheimer disease (AD). OBJECTIVE: To conduct a cost-benefit analysis of SGAs and placebo (taken to represent a "watchful waiting" treatment strategy) for psychosis and aggression in outpatients with AD. DESIGN: Randomized placebo-controlled trial of alternative SGA initiation strategies. SETTING: Forty-two outpatient clinics. PARTICIPANTS: Outpatients with AD and psychosis, aggression, or agitation (N = 421). Intervention Participants were randomly assigned to treatment with olanzapine, quetiapine fumarate, risperidone, or placebo with the option of double-blind rerandomization to another antipsychotic or citalopram hydrobromide or open treatment over 9 months. MAIN OUTCOME MEASURES: Monthly interviews documented health service use and costs. The economic perspective addressed total health care and medication costs. Costs of study drugs were estimated from wholesale prices with adjustment for discounts and rebates. Quality-adjusted life-years (QALYs) were assessed with the Health Utilities Index Mark 3 and were supplemented with measures of functioning, activities of daily living, and quality of life. Primary analyses were conducted using all available data. Secondary analyses excluded observations after the first medication change (ie, phase 1 only). Cost-benefit analysis was conducted using the net health benefits approach in a sensitivity analysis in which QALYs were valued at $50,000 per year and $100,000 per year. RESULTS: Average total health costs, including medications, were significantly lower for placebo than for SGAs, by $50 to $100 per month. There were no differences between treatments in QALYs or other measures of function. Phase 1-only analyses were broadly similar. Net-benefit analysis showed greater net health benefits for placebo as compared with other treatments, with probabilities ranging from 50% to 90%. CONCLUSIONS: There were no differences in measures of effectiveness between initiation of active treatments or placebo (which represented watchful waiting) but the placebo group had significantly lower health care costs. TRIAL REGISTRATION: Identifier: NCT00015548. [Abstract]

Alden A, Brennan P, Hodgins S, Mednick S
Psychotic disorders and sex offending in a Danish birth cohort.
Arch Gen Psychiatry. 2007 Nov;64(11):1251-8.
CONTEXT: Psychotic disorders are associated with an increased risk of aggressive behavior and violent crime. Whether there is also an association with sex offending is unknown. OBJECTIVES: To estimate the lifetime prevalence of arrests for sexual offenses (with and without physical aggression) among men and women with psychotic disorders, the moderating effects of comorbid personality disorders and substance use disorders, and the prevalence rates for 4 specific psychotic disorders. DESIGN: We examined official records of arrests for sexual offenses with and without physical aggression to compare persons hospitalized with a psychotic disorder with those who had never been hospitalized. SETTING: Denmark. PARTICIPANTS: All 358,180 persons born from January 1, 1944, through December 31, 1947, in Denmark. Main Outcome Measure Official arrest records. RESULTS: Among the men, 2.2% were hospitalized with psychotic disorders. These men committed 8.4% of the physically aggressive sexual offenses and 9.0% of the non-physically aggressive sexual offenses of the men in the cohort. Compared with men who had never been hospitalized, men with psychotic disorders without a personality disorder or a substance use disorder were not at increased risk of arrest for physically aggressive sexual offenses but were 3 times more likely to have been arrested for non-physically aggressive sexual offenses. Psychotic disorders with comorbid personality disorders or substance use disorders were associated with a 6-fold increased risk of physically aggressive sex offending and a 3- to 5-fold increased risk of non-physically aggressive sex offending. CONCLUSIONS: Psychotic disorders comorbid with personality disorders and substance use disorders are associated with an increased risk of sex offending with and without physical aggression. Mental health policy and practice need to take account of these findings to improve functional outcome among persons with psychotic disorders. [Abstract]

Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ
Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia.
Arch Gen Psychiatry. 2007 Nov;64(11):1242-50.
CONTEXT: Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia. OBJECTIVE: To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia. DESIGN: Family-based heritability study. SETTING: Seven sites across the United States. PARTICIPANTS: At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes. MAIN OUTCOME MEASURES: Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article. RESULTS: All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable (P < or = .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures. CONCLUSION: This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia. [Abstract]

Haenschel C, Bittner RA, Haertling F, Rotarska-Jagiela A, Maurer K, Singer W, Linden DE
Contribution of impaired early-stage visual processing to working memory dysfunction in adolescents with schizophrenia: a study with event-related potentials and functional magnetic resonance imaging.
Arch Gen Psychiatry. 2007 Nov;64(11):1229-40.
CONTEXT: Working memory (WM) deficits in patients with schizophrenia have mainly been associated with prefrontal dysfunction. However, the contribution of perceptual deficits and abnormalities in sensory areas has not been explored. The present study closes this important gap in our understanding of WM dysfunction in schizophrenia by monitoring neural activity during WM encoding and retrieval with event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). OBJECTIVE: To investigate the neurophysiological changes that contribute to WM impairment in early-onset schizophrenia at perceptual and cognitive stages using the ERP components P1, P3a, P370, and P570 and fMRI data from extrastriate visual areas. DESIGN: We conducted the study between June 1, 2003, and December 20, 2006. Electroencephalographic and fMRI data were acquired separately during a visual delayed discrimination task. Participants encoded up to 3 abstract shapes that were presented sequentially for 600 milliseconds each and decided after a 12-second delay whether a probe matched 1 of the sample stimuli. SETTING: Between-group study at an inpatient psychiatric hospital and outpatient psychiatric facilities. PARTICIPANTS: Seventeen adolescents with early-onset schizophrenia according to DSM-IV criteria and 17 matched controls participated in the study. MAIN OUTCOME MEASURES: Amplitude of the ERP components P1, P3a, P370, and P570 and the fMRI signal from extrastriate visual areas. RESULTS: The P1 amplitude was reduced in patients during encoding and retrieval. The P1 amplitude increased with WM load during encoding only in controls. In this group, a stronger P1 amplitude increase predicted better WM performance. The P1 reduction was mirrored by reduced activation of visual areas in patients in fMRI. The P370 amplitude during encoding and retrieval was also reduced in patients. CONCLUSIONS: The P1 amplitude reduction indicates an early visual deficit in adolescents with schizophrenia. Our findings suggest that P1 is of particular relevance for successful WM encoding. Early visual deficits contribute to impaired WM in schizophrenia in addition to deficits in later memory-related processes. [Abstract]

Harris JC
Beata Beatrix.
Arch Gen Psychiatry. 2007 Nov;64(11):1228. [Abstract]

Wilson RS, Schneider JA, Arnold SE, Bienias JL, Bennett DA
Conscientiousness and the incidence of Alzheimer disease and mild cognitive impairment.
Arch Gen Psychiatry. 2007 Oct;64(10):1204-12.
CONTEXT: The personality trait of conscientiousness has been related to morbidity and mortality in old age, but its association with the development of Alzheimer disease is not known. OBJECTIVE: To test the hypothesis that a higher level of conscientiousness is associated with decreased risk of Alzheimer disease. DESIGN: Longitudinal clinicopathologic cohort study with up to 12 years of annual follow-up. SETTING: The Religious Orders Study. PARTICIPANTS: A total of 997 older Catholic nuns, priests, and brothers without dementia at enrollment, recruited from more than 40 groups across the United States. At baseline, they completed a standard 12-item measure of conscientiousness. Those who died underwent a uniform neuropathologic evaluation from which previously established measures of amyloid burden, tangle density, Lewy bodies, and chronic cerebral infarction were derived. MAIN OUTCOME MEASURES: Clinical diagnosis of Alzheimer disease and change in previously established measures of global cognition and specific cognitive functions. RESULTS: Conscientiousness scores ranged from 11 to 47 (mean, 34.0; SD, 5.0). During follow-up, 176 people developed Alzheimer disease. In a proportional hazards regression model adjusted for age, sex, and education, a high conscientiousness score (90th percentile) was associated with an 89% reduction in risk of Alzheimer disease compared with a low score (10th percentile). Results were not substantially changed by controlling for other personality traits, activity patterns, vascular conditions, or other risk factors. Conscientiousness was also associated with decreased incidence of mild cognitive impairment and reduced cognitive decline. In those who died and underwent brain autopsy, conscientiousness was unrelated to neuropathologic measures, but it modified the association of neurofibrillary pathologic changes and cerebral infarction with cognition proximate to death. CONCLUSION: Level of conscientiousness is a risk factor for Alzheimer disease. [Abstract]

Druss BG, Wang PS, Sampson NA, Olfson M, Pincus HA, Wells KB, Kessler RC
Understanding mental health treatment in persons without mental diagnoses: results from the National Comorbidity Survey Replication.
Arch Gen Psychiatry. 2007 Oct;64(10):1196-203.
CONTEXT: Epidemiologic surveys have consistently found that approximately half of respondents who obtained treatment for mental or substance use disorders in the year before interview did not meet the criteria for any of the disorders assessed in the survey. Concerns have been raised that this pattern might represent evidence of misallocation of treatment resources. OBJECTIVE: To examine patterns and correlates of 12-month treatment of mental health or substance use problems among people who do not have a 12-month DSM-IV disorder. DESIGN AND SETTING: Data are from the National Comorbidity Survey Replication, a nationally representative face-to-face US household survey performed between February 5, 2001, and April 7, 2003, that assessed DSM-IV disorders using a fully structured diagnostic interview, the World Health Organization Composite International Diagnostic Interview (CIDI). PARTICIPANTS: A total of 5692 English-speaking respondents 18 years and older. MAIN OUTCOME MEASURES: Patterns of 12-month service use among respondents without any 12-month DSM-IV CIDI disorders. RESULTS: Of respondents who used 12-month services, 61.2% had a 12-month DSM-IV CIDI diagnosis, 21.1% had a lifetime but not a 12-month diagnosis, and 9.7% had some other indicator of possible need for treatment (subthreshold 12-month disorder, serious 12-month stressor, or lifetime hospitalization). The remaining 8.0% of service users accounted for only 5.6% of all services and even lower proportions of specialty (1.9%-2.4%) and general medical (3.7%) visits compared with higher proportions of human services (18.9%) and complementary and alternative medicine (7.6%) visits. Only 26.5% of the services provided to the 8.0% of presumably low-need patients were delivered in the mental health specialty or general medical sectors. CONCLUSIONS: Most services provided for emotional or substance use problems in the United States go to people with a 12-month diagnosis or other indicators of need. Patients who lack these indicators of need receive care largely outside the formal health care system. [Abstract]

Dempster EL, Burcescu I, Wigg K, Kiss E, Baji I, Gadoros J, Tamás Z, Kennedy JL, Vetró A, Kovacs M, Barr CL
Evidence of an association between the vasopressin V1b receptor gene (AVPR1B) and childhood-onset mood disorders.
Arch Gen Psychiatry. 2007 Oct;64(10):1189-95.
CONTEXT: Disturbances in stress hormones have been implicated in mood disorders, in particular in the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Arginine vasopressin (AVP) plays a crucial role in modulating the HPA axis under stress and does so through a G protein-coupled receptor, vasopressin V1b receptor (AVPR1b). OBJECTIVE: To determine if genetic variation in AVPR1B could be contributing to vulnerability to mood disorders. DESIGN: We genotyped single nucleotide polymorphisms (SNPs) across the AVPR1B gene in a family-based sample with childhood-onset mood disorders. Six SNPs were genotyped; 2 were novel nonsynonymous polymorphisms, and the other 4 were constituents of a haplotype that was previously shown to be protective against depression. SETTING: Twenty-three mental health facilities in Hungary. PARTICIPANTS: The sample was composed of 382 Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorder. MAIN OUTCOME MEASURES: Association with childhood-onset mood disorders was tested using the transmission disequilibrium test, which measures the transmission frequency of alleles, or haplotypes, from parents to affected offspring. RESULTS: Two of the AVPR1B SNPs showed association individually (Lys65Asn: chi(2) = 7.81, P = .005; S4: chi(2) = 4.58, P = .03); of particular interest is Lys65Asn, which causes an amino acid change in an intracellular protein domain. Haplotype analysis demonstrated significant overtransmission of the most frequent haplotype (chi(2)(3) = 22.42, P <.001). Furthermore, stratifying the sample by sex established that the association was predominantly in affected females, which is consistent with previous observations. CONCLUSIONS: We have found evidence to implicate the AVPR1B gene in the etiology of mood disorders, particularly in females. Antagonists of AVPR1b exhibit antidepressant qualities; hence, genetic variation in AVPR1B may have implications in HPA axis dysregulation in mood disorders. [Abstract]

Merikangas KR, Ames M, Cui L, Stang PE, Ustun TB, Von Korff M, Kessler RC
The impact of comorbidity of mental and physical conditions on role disability in the US adult household population.
Arch Gen Psychiatry. 2007 Oct;64(10):1180-8.
CONTEXT: There is limited information that accounts for comorbidity on the impact of role disability associated with a wide range of mental and physical disorders in population-based samples. OBJECTIVE: To estimate the comparative effects of common mental and physical conditions on role disability in the general population using a novel method that accounts for comorbidity. DESIGN: Direct interviews about physical and mental conditions during the past year. SETTING: The National Comorbidity Survey Replication, a nationally representative series of face-to-face interviews. PATIENTS: A nationally representative sample of adults living in households (N = 5962 respondents, 18 years and older). MAIN OUTCOME MEASURE: Disability in major life roles was assessed with the World Health Organization Disability Assessment Schedule. Simulations that allow for complex interactions among conditions were used to estimate the conditions' effects on disability days, when respondents were completely unable to carry out their usual daily activities because of problems with mental or physical health, in the past 12 months. RESULTS: An estimated 53.4% of US adults have 1 or more of the mental or physical conditions assessed in the survey. These respondents report an average 32.1 more role-disability days in the past year than demographically matched controls, equivalent to nearly 3.6 billion days of role disability in the population. Musculoskeletal disorders and major depression had the greatest effects on disability days. Mental conditions accounted for more than half as many disability days as all physical conditions at the population level. Associations of specific conditions with disability decreased substantially after controlling for comorbidity, suggesting that prior studies, which generally did not control for comorbidity, overestimated disease-specific effects. CONCLUSION: The staggering amount of health-related disability associated with mental and physical conditions should be considered in establishing priorities for the allocation of health care and research resources. [Abstract]

Brotman LM, Gouley KK, Huang KY, Kamboukos D, Fratto C, Pine DS
Effects of a psychosocial family-based preventive intervention on cortisol response to a social challenge in preschoolers at high risk for antisocial behavior.
Arch Gen Psychiatry. 2007 Oct;64(10):1172-9.
CONTEXT: Salivary cortisol levels during social challenge relate to adaptive functioning in children and adults. Low cortisol levels have been related to conduct problems and antisocial behavior. Although studies in rodents implicate early-life social experience in cortisol regulation, no studies with humans have examined the effects of an experimentally manipulated early-life social experience on cortisol regulation. OBJECTIVE: To examine the effects of experimental manipulations of social experience on cortisol response to a social challenge in preschoolers at risk for antisocial behavior. DESIGN: Randomized controlled trial. SETTING: Department of Child and Adolescent Psychiatry, New York University School of Medicine. PARTICIPANTS: Ninety-two preschool-age siblings of youths adjudicated for delinquent acts. Intervention Family-based intervention included 22 weekly group sessions for parents and preschoolers and 10 biweekly home visits conducted during a 6- to 8-month period. MAIN OUTCOME MEASURES: Salivary cortisol levels before and after a social challenge (entry into an unfamiliar peer group). RESULTS: Relative to controls, children in the intervention condition had increased cortisol levels in anticipation of the peer social challenge. Increases were relative to both preintervention cortisol levels during the challenge and cortisol levels in the home, which were not altered by the intervention. CONCLUSIONS: A family-based preventive intervention for children at high risk for antisocial behavior alters stress response in anticipation of a peer social challenge. The experimentally induced change in cortisol levels parallels patterns found in normally developing, low-risk children. [Abstract]

Johnson SC, Ries ML, Hess TM, Carlsson CM, Gleason CE, Alexander AL, Rowley HA, Asthana S, Sager MA
Effect of Alzheimer disease risk on brain function during self-appraisal in healthy middle-aged adults.
Arch Gen Psychiatry. 2007 Oct;64(10):1163-71.
CONTEXT: Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks. OBJECTIVE: To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA. DESIGN: Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words. SETTING: An academic medical center with a research-dedicated 3.0-T MR imaging facility. PARTICIPANTS: Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH. MAIN OUTCOME MEASURE: Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging. RESULTS: Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype. CONCLUSIONS: Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors. [Abstract]

Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, Sheps D
Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study.
Arch Gen Psychiatry. 2007 Oct;64(10):1153-60.
CONTEXT: Previous studies have documented an association of depression and phobic anxiety with cardiovascular morbidity and mortality, but little is known about the cardiovascular sequelae of panic anxiety. OBJECTIVE: To determine whether panic attacks are associated with risk of cardiovascular morbidity and mortality in postmenopausal women. DESIGN: Prospective cohort survey. SETTING: Ten clinical centers of the 40-center Women's Health Initiative. PARTICIPANTS: A total of 3369 community-dwelling, generally healthy postmenopausal women (aged 51-83 years) enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study who completed a questionnaire about occurrence of panic attacks in the previous 6 months. MAIN OUTCOME MEASURES: Cardiovascular/cerebrovascular outcomes (fatal and nonfatal myocardial infarction and stroke) and all-cause mortality were ascertained after a mean of 5.3 years of follow-up. RESULTS: A 6-month history of full-blown panic attacks, endorsed by 10% of postmenopausal women in this cohort, was associated with both coronary heart disease (hazard ratio, 4.20; 95% confidence interval, 1.76-9.99) and the combined end point of coronary heart disease or stroke (hazard ratio, 3.08; 95% confidence interval, 1.60-5.94) after controlling for multiple potential confounders. The hazard ratio for all-cause mortality, excluding those with a history of cardiovascular/cerebrovascular events, was 1.75 (95% confidence interval, 1.04-2.94). CONCLUSION: Panic attacks are relatively common among postmenopausal women and appear to be an independent risk factor for cardiovascular morbidity and mortality in older women. [Abstract]

Elkins IJ, McGue M, Iacono WG
Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse.
Arch Gen Psychiatry. 2007 Oct;64(10):1145-52.
CONTEXT: Attention-deficit/hyperactivity disorder (ADHD), an early manifestation of externalizing behavior, may identify children at high risk for later substance abuse. However, the ADHD-substance abuse relationship often disappears when co-occurring conduct disorder (CD) is considered. OBJECTIVE: To determine whether there is a prospective relationship between ADHD and the initiation of substance use and disorders, and whether this relationship depends on the ADHD subtype (hyperactive/impulsive or inattentive), CD, or sex. DESIGN, SETTING, AND PARTICIPANTS: Dimensional and categorical measures of ADHD and CD were examined via logistic regression analyses in relation to subsequent initiation of tobacco, alcohol, and illicit drug use by 14 years of age and onset of substance use disorders by 18 years of age in a population-based sample of 11-year-old twins (760 female and 752 male twins) from the Minnesota Twin Family Study. MAIN OUTCOME MEASURES: Structured interviews were administered to adolescents and their mothers regarding substance use and to generate diagnoses. RESULTS: For boys and girls, hyperactivity/impulsivity predicted initiation of all types of substance use, nicotine dependence, and cannabis abuse/dependence (for all, P < .05), even when controlling for CD at 2 time points. By contrast, relationships between inattention and substance outcomes disappeared when hyperactivity/impulsivity and CD were controlled for, with the possible exception of nicotine dependence. A categorical diagnosis of ADHD significantly predicted tobacco and illicit drug use only (adjusted odds ratios, 2.01 and 2.82, respectively). A diagnosis of CD between 11 and 14 years of age was a powerful predictor of substance disorders by 18 years of age (all odds ratios, > 4.27). CONCLUSIONS: Hyperactivity/impulsivity predicts later substance problems, even after growth in later-emerging CD is considered, whereas inattention alone poses less risk. Even a single symptom of ADHD or CD is associated with increased risk. Failure in previous research to consistently observe relationships between ADHD and substance use and abuse outcomes could be due to reliance on less-sensitive categorical diagnoses. [Abstract]

March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J
The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes.
Arch Gen Psychiatry. 2007 Oct;64(10):1132-43.
CONTEXT: The Treatment for Adolescents With Depression Study evaluates the effectiveness of fluoxetine hydrochloride therapy, cognitive behavior therapy (CBT), and their combination in adolescents with major depressive disorder. OBJECTIVE: To report effectiveness outcomes across 36 weeks of randomized treatment. DESIGN AND SETTING: Randomized, controlled trial conducted in 13 academic and community sites in the United States. Cognitive behavior and combination therapies were not masked, whereas administration of placebo and fluoxetine was double-blind through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were treated openly after week 12, and the placebo group is not included in these analyses by design. PARTICIPANTS: Three hundred twenty-seven patients aged 12 to 17 years with a primary DSM-IV diagnosis of major depressive disorder. INTERVENTIONS: All treatments were administered per protocol. MAIN OUTCOME MEASURES: The primary dependent measures rated blind to treatment status by an independent evaluator were the Children's Depression Rating Scale-Revised total score and the response rate, defined as a Clinical Global Impressions-Improvement score of much or very much improved. RESULTS: Intention-to-treat analyses on the Children's Depression Rating Scale-Revised identified a significant time x treatment interaction (P < .001). Rates of response were 73% for combination therapy, 62% for fluoxetine therapy, and 48% for CBT at week 12; 85% for combination therapy, 69% for fluoxetine therapy, and 65% for CBT at week 18; and 86% for combination therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36. Suicidal ideation decreased with treatment, but less so with fluoxetine therapy than with combination therapy or CBT. Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%). CONCLUSIONS: In adolescents with moderate to severe depression, treatment with fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment appears superior to either monotherapy as a treatment for major depression in adolescents. [Abstract]

Saha S, Chant D, McGrath J
A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time?
Arch Gen Psychiatry. 2007 Oct;64(10):1123-31.
CONTEXT: Despite improvements in mental health services in recent decades, it is unclear whether the risk of mortality in schizophrenia has changed over time. OBJECTIVE: To explore the distribution of standardized mortality ratios (SMRs) for people with schizophrenia. DATA SOURCES: Broad search terms were used in MEDLINE, PsychINFO, Web of Science, and Google Scholar to identify all studies that investigated mortality in schizophrenia, published between January 1, 1980, and January 31, 2006. References were also identified from review articles, reference lists, and communication with authors. STUDY SELECTION: Population-based studies that reported primary data on deaths in people with schizophrenia. DATA EXTRACTION: Operationalized criteria were used to extract key study features and mortality data. DATA SYNTHESIS: We examined the distribution of SMRs and pooled selected estimates using random-effects meta-analysis. We identified 37 articles drawn from 25 different nations. The median SMR for all persons for all-cause mortality was 2.58 (10%-90% quantile, 1.18-5.76), with a corresponding random-effects pooled SMR of 2.50 (95% confidence interval, 2.18-2.43). No sex difference was detected. Suicide was associated with the highest SMR (12.86); however, most of the major causes-of-death categories were found to be elevated in people with schizophrenia. The SMRs for all-cause mortality have increased during recent decades (P = .03). CONCLUSIONS: With respect to mortality, a substantial gap exists between the health of people with schizophrenia and the general community. This differential mortality gap has worsened in recent decades. In light of the potential for second-generation antipsychotic medications to further adversely influence mortality rates in the decades to come, optimizing the general health of people with schizophrenia warrants urgent attention. [Abstract]

Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG
Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect?
Arch Gen Psychiatry. 2007 Oct;64(10):1115-22.
CONTEXT: Cognitive impairment in schizophrenia is frequent, involves multiple domains, and is enduring. Numerous recent clinical trials have suggested that second-generation antipsychotic medications significantly enhance cognition in schizophrenia. However, none of these studies included healthy controls undergoing repeated testing to assess the possibility that improvements might reflect simple practice effects. OBJECTIVE: To report the results on cognition of a randomized comparison of 2 widely prescribed second-generation antipsychotic medications, olanzapine and risperidone, in patients with first-episode schizophrenia and a healthy control group. DESIGN: Randomized clinical trial. SETTING: Hospital-based research units. Patients A total of 104 participants with first-episode schizophrenia and 84 healthy controls. MAIN OUTCOME MEASURES: Cognitive assessment of all study participants occurred at baseline, 6 weeks later, and 16 weeks later. Neurocognitive tests included measures of working memory and attention, speed, motor function, episodic memory, and executive function. RESULTS: No differential drug effects were observed. Of 16 cognitive measures, 9 demonstrated improvement over time and only 2 demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment. The composite effect size for cognitive change was 0.33 in the healthy control group (attributed to practice) and 0.36 in the patients with first-episode schizophrenia. Improvements in cognition in the first-episode schizophrenia group could not be accounted for by medication dose, demographic variables, or intellectual level. CONCLUSIONS: The cognitive improvements observed in the trial were consistent in magnitude with practice effects observed in healthy controls, suggesting that some of the improvements in cognition in the first-episode schizophrenia group may have been due to practice effects (ie, exposure, familiarity, and/or procedural learning). Our results also indicated that differential medication effects on cognition were small. We believe that these findings have important implications for drug discovery and the design of registration trials that attempt to demonstrate cognitive enhancement. [Abstract]

Saxon AJ
Dopamine and depression.
Arch Gen Psychiatry. 2007 Sep;64(9):1101. [Abstract]

Recent Articles in The American Journal of Psychiatry

[In Process Citation]
Am J Psychiatry. 2007 Dec;164(12): . [Abstract]

Bortolato M, Muroni A, Marrosu F
Treatment of Tourette's Syndrome With Finasteride.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Modjtahedi B, Xiong GL
Hyperammonemia and valproic Acid-induced encephalopathy.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Carpenter WT, Conley RR
Challenge to atypical antipsychotic drug effect on cognition.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Wohlfarth T, Boer F, van den Brink W
Withdrawal of attention rather than pharmacological treatment affects suicide rates in depressed children and adolescents.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Jureidini J
The black box warning: decreased prescriptions and increased youth suicide?
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Olfson M, Shaffer D
SSRI Prescriptions and the Rate of Suicide.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Martin LF, Hall MH, Ross RG, Zerbe G, Freedman R, Olincy A
Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups. [Abstract]

Ho BC, Andreasen NC, Dawson JD, Wassink TH
Association Between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and Progressive Brain Volume Changes in Schizophrenia.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: Factors underlying progressive brain volume changes in schizophrenia remain poorly understood. The authors investigated whether a gene polymorphism influencing neuroplasticity may contribute to longitudinal brain volume alterations. METHOD: High-resolution magnetic resonance (MR) images of the whole brain were obtained for 119 patients with recent-onset schizophrenia spectrum disorders. Changes in brain volumes over an average of 3 years were compared between brain-derived neurotrophic factor (BDNF) val66met genotype groupings. Exploratory analyses were conducted to examine relationships between antipsychotic treatment and brain volume changes as well as the effects of BDNF genotype on changes in cognition and symptoms. RESULTS: Significant genotype effects were observed on within-subject changes in volumes of frontal lobe gray matter, lateral ventricles, and sulcal CSF. Met allele carriers had significantly greater reductions in frontal gray matter volume, with reciprocal volume increases in the lateral ventricles and sulcal (especially frontal and temporal) CSF than Val homozygous patients. Independent of BDNF genotype, more antipsychotic exposure between MRI scans correlated with greater volume reductions in frontal gray matter, particularly among patients who were initially treatment naive. There were no statistically significant genotype effects on within-subject changes in cognition or symptoms. CONCLUSIONS: BDNF(Met) variant may be one of several factors affecting progressive brain volume changes in schizophrenia. [Abstract]

Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O
Lateralized Caudate Metabolic Abnormalities in Adolescent Major Depressive Disorder: A Proton MR Spectroscopy Study.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: Proton magnetic resonance spectroscopy ((1)H-MRS) has been increasingly used to examine striatal neurochemistry in adult major depressive disorder. This study extends the use of this modality to pediatric major depression to test the hypothesis that adolescents with major depression have elevated concentrations of striatal choline and creatine and lower concentrations of N-acetylaspartate. METHOD: Fourteen adolescents (ages 12-19 years, eight female) who had major depressive disorder for at least 8 weeks and a severity score of 40 or higher on the Children's Depression Rating Scale-Revised and 10 healthy comparison adolescents (six female) group-matched for gender, age, and handedness were enrolled. All underwent three-dimensional 3-T (1)H-MRS at high spatial resolution (0.75-cm(3) voxels). Relative levels of choline, creatine, and N-acetylaspartate in the left and right caudate, putamen, and thalamus were scaled into concentrations using phantom replacement, and levels were compared for the two cohorts. RESULTS: Relative to comparison subjects, adolescents with major depressive disorder had significantly elevated concentrations of choline (2.11 mM versus 1.56 mM) and creatine (6.65 mM versus 5.26 mM) in the left caudate. No other neurochemical differences were observed between the groups. CONCLUSIONS: These findings most likely reflect accelerated membrane turnover and impaired metabolism in the left caudate. The results are consistent with prior imaging reports of focal and lateralized abnormalities in the caudate in adult major depression. [Abstract]

Silk JS, Dahl RE, Ryan ND, Forbes EE, Axelson DA, Birmaher B, Siegle GJ
Pupillary Reactivity to Emotional Information in Child and Adolescent Depression: Links to Clinical and Ecological Measures.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: Pupil dilation provides a quantitative index of the temporal pattern of brain reactivity to emotional stimuli. Previous reports indicate that depressed adults show sustained pupil dilation to emotional words, but this phenomenon has not been investigated in children. This study investigated pupil dilation in children with depression and examined how differences in pupillary responses to emotional stimuli correlate with self-rated emotional experiences in participants' natural environments in everyday life. METHOD: Participants were 20 children with major depressive disorder and 22 comparison children ages 8-17. Pupil dilation was measured during a valence identification task. Participants also rated positive and negative affect in their natural environments as part of an ecological momentary assessment protocol. RESULTS: Children showed greater pupil dilation to negative words than to neutral or positive words. Children with major depression had diminished late pupil dilation relative to comparison children 9-12 sec after a negative word was presented. Diminished late pupil dilation to negative words was associated with greater severity of depression and with higher levels of negative affect and lower levels of positive affect in the natural environment. CONCLUSIONS: Depressed children exhibit a dynamic change in cognitive-affective resources devoted to processing negative emotional words, with more dramatic decreases than in comparison children after a negative word is initially processed, a pattern that differs markedly from that observed in depressed adults. Diminished late pupil dilation in children with major depression could be a marker for problems in emotional reactivity and/or regulation associated with pediatric depression. [Abstract]

Orstavik RE, Kendler KS, Czajkowski N, Tambs K, Reichborn-Kjennerud T
The relationship between depressive personality disorder and major depressive disorder: a population-based twin study.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: One of the most important controversies regarding depressive personality disorder is the overlap with mood disorders. The aim of this study was to estimate the genetic and environmental sources of covariance between depressive personality disorder and major depressive disorder and to what extent genetic, shared, and unique environmental factors are specific to each disorder. METHOD: A total of 2,801 young adult twins from the Norwegian Institute of Public Health Twin Panel were assessed at personal interview for depressive personality disorder and major depressive disorder with the Structured Interview for DSM-IV Personality and the Composite International Diagnostic Interview. Bivariate Cholesky models were fitted to the data by using the Mx statistical program. RESULTS: In the best-fitting model, the covariation between depressive personality disorder and major depressive disorder were accounted for by genetic and unique environmental factors only. A model that did not include genetic factors specific to major depressive disorder was rejected. The authors found no clear evidence for gender differences in sources of comorbidity of depressive personality disorder and major depressive disorder. CONCLUSIONS: Although depressive personality disorder and major depressive disorder share a substantial proportion of genetic and environmental risk factors, the results from this study support the hypothesis that the two disorders are distinct entities with overlapping, but not identical, etiologies. [Abstract]

Bhagwagar Z, Murthy N, Selvaraj S, Hinz R, Taylor M, Fancy S, Grasby P, Cowen P
5-HTT Binding in Recovered Depressed Patients and Healthy Volunteers: A Positron Emission Tomography Study With [11C]DASB.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: The serotonin transporter (5-HTT) is a key target for selective serotonin reuptake inhibitors and may be involved in the pathophysiology of major depression. It is now possible to image 5-HTT directly in the human brain, but results from studies of acutely depressed patients have been inconsistent. The purpose of this study was to determine whether abnormalities in 5-HTT might be present in recovered depressed patients. METHOD: The authors measured the binding potential of 5-HTT using [ (11)C]DASB in conjunction with positron emission tomography (PET) in 24 medication-free, recovered depressed male patients and 20 healthy male comparison subjects. The regional estimates of binding potential were obtained using a metabolite-corrected plasma input function method followed by Logan analysis, with the cerebellum as a reference region. RESULTS: The authors found no significant difference in the binding potential of [ (11)C]DASB between the recovered depressed patients and healthy comparison subjects in any of the brain regions (amygdala, anterior cingulate cortex, caudate nucleus, frontal cortex, hippocampus, insula, thalamus, and dorsal raphe) studied. CONCLUSIONS: Men who recover from depression have normal availability of 5-HTT in brain regions thought to be involved in the pathophysiology of depression. The findings therefore do not support the proposal that recurrent depression is associated with long-standing deficits in 5-HTT. [Abstract]

Mühlau M, Gaser C, Ilg R, Conrad B, Leibl C, Cebulla MH, Backmund H, Gerlinghoff M, Lommer P, Schnebel A, Wohlschläger AM, Zimmer C, Nunnemann S
Gray matter decrease of the anterior cingulate cortex in anorexia nervosa.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: The brain regions that are critically involved in the pathophysiology of anorexia nervosa have not been clearly elucidated. Moreover, decrease in cerebral tissue during extreme malnutrition has been demonstrated repeatedly in anorexia nervosa, but data regarding the reversibility of this cerebral tissue decrease are conflicting. The authors examined region-specific gray matter changes and global cerebral volumes in recovered patients with anorexia nervosa. METHOD: High-resolution, T1-weighted magnetic resonance imaging (MRI) and voxel-based morphometry were performed in 22 recovered women with anorexia nervosa and in 37 healthy comparison women. Recovery was defined as a body mass index above 17.0 kg/m(2) and regular menses for at least 6 months. RESULTS: The global volumes of gray matter (but not white matter) were decreased in patients with anorexia nervosa by approximately 1%. Analyses of region-specific gray matter changes revealed a gray matter decrease bilaterally in the anterior cingulate cortex of approximately 5%, which remained significant after correction for global effects. This gray matter decrease correlated significantly with the lowest body mass index of lifetime but not with other clinical variables. CONCLUSIONS: In anorexia nervosa, part of the global gray matter loss persists over the long run. Region-specific gray matter loss in the anterior cingulate cortex is directly related to the severity of anorexia nervosa, indicating an important role of this area in the pathophysiology of the disorder. Further research is warranted to determine the cause, specificity, and functional consequences of this structural brain change in anorexia nervosa. [Abstract]

Wagner A, Aizenstein H, Venkatraman VK, Fudge J, May JC, Mazurkewicz L, Frank GK, Bailer UF, Fischer L, Nguyen V, Carter C, Putnam K, Kaye WH
Altered Reward Processing in Women Recovered From Anorexia Nervosa.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: Individuals with anorexia nervosa are known to be ascetic and able to sustain self-denial of food as well as most comforts and pleasures in life. Building on previous findings of altered striatal dopamine binding in anorexia nervosa, the authors sought to assess the response of the anterior ventral striatum to reward and loss in this disorder. METHOD: Striatal responses to a simple monetary reward task were investigated using event-related functional magnetic resonance imaging. To avoid the confounding effects of malnutrition, the authors compared 13 healthy comparison women and 13 women who had recovered from restricting-type anorexia nervosa and had 1 year of normal weight and regular menstrual cycles, without binge eating or purging. RESULTS: Recovered women showed greater hemodynamic activation in the caudate than comparison women. Only the recovered women showed a significant positive relationship between trait anxiety and the percentage change in hemodynamic signal in the caudate during either wins or losses. In contrast, in the anterior ventral striatum, comparison women distinguished positive and negative feedback, whereas recovered women had similar responses to both conditions. CONCLUSIONS: Individuals who have recovered from anorexia nervosa may have difficulties in differentiating positive and negative feedback. The exaggerated activation of the caudate, a region involved in linking action to outcome, may constitute an attempt at "strategic" (as opposed to hedonic) means of responding to reward stimuli. The authors hypothesize that individuals with anorexia nervosa have an imbalance in information processing, with impaired ability to identify the emotional significance of a stimulus but increased traffic in neurocircuits concerned with planning and consequences. [Abstract]

Silbersweig D, Clarkin JF, Goldstein M, Kernberg OF, Tuescher O, Levy KN, Brendel G, Pan H, Beutel M, Pavony MT, Epstein J, Lenzenweger MF, Thomas KM, Posner MI, Stern E
Failure of frontolimbic inhibitory function in the context of negative emotion in borderline personality disorder.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: The authors sought to test the hypothesis that in patients with borderline personality disorder, the ventromedial prefrontal cortex and associated regions would not be activated during a task requiring motor inhibition in the setting of negative emotion. Such a finding would provide a plausible neural basis for the difficulty borderline patients have in modulating their behavior during negative emotional states and a potential marker for treatment interventions. METHOD: A specifically designed functional magnetic resonance imaging (fMRI) activation probe was used, with statistical parametric mapping analyses, to test hypotheses concerning decreased prefrontal inhibitory function in the context of negative emotion in patients with borderline personality disorder (N=16) and healthy comparison subjects (N=14). 3-T fMRI scanning was used to study brain activity while participants performed an emotional linguistic go/no-go task. RESULTS: Analyses confirmed that under conditions associated with the interaction of behavioral inhibition and negative emotion, borderline patients showed relatively decreased ventromedial prefrontal activity (including medial orbitofrontal and subgenual anterior cingulate) compared with healthy subjects. In borderline patients, under conditions of behavioral inhibition in the context of negative emotion, decreasing ventromedial prefrontal and increasing extended amygdalar-ventral striatal activity correlated highly with measures of decreased constraint and increased negative emotion, respectively. CONCLUSIONS: These findings suggest specific frontolimbic neural substrates associated with core clinical features of emotional and behavioral dyscontrol in borderline personality disorder. [Abstract]

Curlin FA, Lawrence RE, Odell S, Chin MH, Lantos JD, Koenig HG, Meador KG
Religion, spirituality, and medicine: psychiatrists' and other physicians' differing observations, interpretations, and clinical approaches.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: This study compared the ways in which psychiatrists and nonpsychiatrists interpret the relationship between religion/spirituality and health and address religion/spirituality issues in the clinical encounter. METHOD: The authors mailed a survey to a stratified random sample of 2,000 practicing U.S. physicians, with an oversampling of psychiatrists. The authors asked the physicians about their beliefs and observations regarding the relationship between religion/spirituality and patient health and about the ways in which they address religion/spirituality in the clinical setting. RESULTS: A total of 1,144 physicians completed the survey. Psychiatrists generally endorse positive influences of religion/spirituality on health, but they are more likely than other physicians to note that religion/spirituality sometimes causes negative emotions that lead to increased patient suffering (82% versus 44%). Compared to other physicians, psychiatrists are more likely to encounter religion/spirituality issues in clinical settings (92% versus 74% report their patients sometimes or often mention religion/spirituality issues), and they are more open to addressing religion/spirituality issues with patients (93% versus 53% say that it is usually or always appropriate to inquire about religion/spirituality). CONCLUSIONS: This study suggests that the vast majority of psychiatrists appreciate the importance of religion and/or spirituality at least at a functional level. Compared to other physicians, psychiatrists also appear to be more comfortable, and have more experience, addressing religion/spirituality concerns in the clinical setting. [Abstract]

Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A, Zurick A, Cohen LS
Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: This study estimated the risk of recurrence of mood episodes among women with a history of bipolar disorder who continued or discontinued treatment with mood stabilizers during pregnancy. METHOD: In a prospective observational clinical cohort study, the authors determined recurrence risk and survival-analysis-based time to recurrence of a new episode in 89 pregnant women with DSM-IV bipolar disorder. Eligible subjects were euthymic at conception and continued mood stabilizer treatment or discontinued treatment proximate to conception. RESULTS: The overall risk of at least one recurrence in pregnancy was 71%. Among women who discontinued versus continued mood stabilizer treatment, recurrence risk was twofold greater, median time to first recurrence was more than fourfold shorter, and the proportion of weeks ill during pregnancy was five times greater. Median recurrence latency was 11 times shorter after abrupt/rapid versus gradual discontinuation of mood stabilizer. Most recurrences were depressive or mixed (74%), and 47% occurred during the first trimester. Predictors of recurrence included bipolar II disorder diagnosis, earlier onset, more recurrences/year, recent illness, use of antidepressants, and use of anticonvulsants versus lithium. CONCLUSIONS: Discontinuation of mood stabilizer, particularly abruptly, during pregnancy carries a high risk for new morbidity in women with bipolar disorder, especially for early depressive and dysphoric states. However, this risk is reduced markedly by continued mood stabilizer treatment. Treatment planning for pregnant women with bipolar disorder should consider not only the relative risks of fetal exposure to mood stabilizers but also the high risk of recurrence and morbidity associated with stopping maintenance mood stabilizer treatment. [Abstract]

Woolley JD, Wilson MR, Hung E, Gorno-Tempini ML, Miller BL, Shim J
Frontotemporal dementia and mania.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Attia E, Walsh BT
Anorexia nervosa.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

McGurk SR, Twamley EW, Sitzer DI, McHugo GJ, Mueser KT
A meta-analysis of cognitive remediation in schizophrenia.
Am J Psychiatry. 2007 Dec;164(12):
OBJECTIVE: This study evaluated the effects of cognitive remediation for improving cognitive performance, symptoms, and psychosocial functioning in schizophrenia. METHOD: A meta-analysis was conducted of 26 randomized, controlled trials of cognitive remediation in schizophrenia including 1,151 patients. RESULTS: Cognitive remediation was associated with significant improvements across all three outcomes, with a medium effect size for cognitive performance (0.41), a slightly lower effect size for psychosocial functioning (0.36), and a small effect size for symptoms (0.28). The effects of cognitive remediation on psychosocial functioning were significantly stronger in studies that provided adjunctive psychiatric rehabilitation than in those that provided cognitive remediation alone. CONCLUSIONS: Cognitive remediation produces moderate improvements in cognitive performance and, when combined with psychiatric rehabilitation, also improves functional outcomes. [Abstract]

Monteggia LM
Elucidating the role of brain-derived neurotrophic factor in the brain.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Leon AC
The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Andrews G, Slade T, Sunderland M, Anderson T
Issues for DSM-V: Simplifying DSM-IV to Enhance Utility: The Case of Major Depressive Disorder.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

2007 in review.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Siegle GJ
Brain Mechanisms of Borderline Personality Disorder at the Intersection of Cognition, Emotion, and the Clinic.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Eichelman B
Religion, spirituality, and medicine.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Freeman MP
Bipolar disorder and pregnancy: risks revealed.
Am J Psychiatry. 2007 Dec;164(12): [Abstract]

Wilfley DE, Crow SJ, Hudson JI, Mitchell JE, Berkowitz RI, Blakesley V, Walsh BT
Efficacy of Sibutramine for the Treatment of Binge Eating Disorder: A Randomized Multicenter Placebo-Controlled Double-Blind Study.
Am J Psychiatry. 2007 Dec 3;
Objective Preliminary evidence suggests that the antiobesity agent sibutramine is effective in the treatment of binge eating disorder, impacting both binge eating and weight. This study is the first large-scale, multisite, placebo-controlled trial to test the efficacy of sibutramine in binge eating disorder. Method Participants (N=304) who met DSM-IV criteria for binge eating disorder were randomly assigned to 24 weeks of double-blind sibutramine (15 mg) or placebo treatment. The outcome measures included the frequency of eating binges (primary outcome), binge day frequency, body mass index, body weight, global improvement, response categories, associated eating pathology, and quality of life. The primary analysis for continuous measures was the difference between groups in the change from baseline to endpoint using analysis of variance (ANOVA) with the last observation carried forward. Results Compared with subjects receiving placebo, participants who received sibutramine had a significantly greater reduction in weekly binge frequency (sibutramine group mean=2.7 [SD=1.7], placebo group mean=2.0 [SD=2.3]); weight loss (sibutramine group mean=4.3 kg [SD=4.8], placebo group mean=0.8 kg [SD=3.5]); reduction in frequency of binge days; reduction in body mass index; global improvement; level of response, including the percentage of abstinence from binge eating (sibutramine group: 58.7%; placebo group: 42.8%); and reduction in eating pathology (cognitive restraint, disinhibition, and hunger). The change in quality of life scores was not significant. Sibutramine was associated with significantly higher incidence of headache, dry mouth, constipation, insomnia, and dizziness. Conclusions This trial demonstrated the efficacy of sibutramine in reducing binge eating, weight, and associated psychopathology. [Abstract]

Langleben DD, Ruparel K, Elman I, Busch-Winokur S, Pratiwadi R, Loughead J, O'Brien CP, Childress AR
Acute Effect of Methadone Maintenance Dose on Brain fMRI Response to Heroin-Related Cues.
Am J Psychiatry. 2007 Dec 3;
Objective Environmental drug-related cues have been implicated as a cause of illicit heroin use during methadone maintenance treatment of heroin dependence. The authors sought to identify the functional neuroanatomy of the brain response to visual heroin-related stimuli in methadone maintenance patients. Method Event-related functional magnetic resonance imaging was used to compare brain responses to heroin-related stimuli and matched neutral stimuli in 25 patients in methadone maintenance treatment. Patients were studied before and after administration of their regular daily methadone dose. Results The heightened responses to heroin-related stimuli in the insula, amygdala, and hippocampal complex, but not the orbitofrontal and ventral anterior cingulate cortices, were acutely reduced after administration of the daily methadone dose. Conclusions The medial prefrontal cortex and the extended limbic system in methadone maintenance patients with a history of heroin dependence remains responsive to salient drug cues, which suggests a continued vulnerability to relapse. Vulnerability may be highest at the end of the 24-hour interdose interval. [Abstract]

Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G, Lofving S, Rasmussen F, Wicks S, Karlsson H
Infections in the CNS During Childhood and the Risk of Subsequent Psychotic Illness: A Cohort Study of More Than One Million Swedish Subjects.
Am J Psychiatry. 2007 Dec 3;
Objective Infections during early life have been suggested to play a role in the etiology of schizophrenia. Most studies have focused on fetal life; few have explored risk associated with infection during childhood. The results of these have been inconsistent. The present study aims to investigate whether there is an increased risk of schizophrenia and other nonaffective psychoses associated with viral or bacterial CNS infections during childhood and, if so, which specific agents are involved. Method A national cohort consisting of 1.2 million children born between 1973 and 1985 was followed up by using Swedish national registers to retrieve data on hospital admissions for CNS infections at 0-12 years of age (bacterial: N=2,435, viral: N=6,550) as well as admissions for nonaffective psychotic illnesses from the 14th birthday (N=2,269). Results There was a slightly increased risk of nonaffective psychotic illness associated with viral CNS infections, as well as schizophrenia. There was no evidence of increased risk in relation to bacterial infections. When divided into specific agents, exposures to mumps virus or cytomegalovirus were associated with subsequent psychoses. Conclusions Serious viral CNS infections during childhood appear to be associated with the later development of schizophrenia and nonaffective psychoses. The association with specific viruses suggests that the risk is related to infectious agents with a propensity to invade the brain parenchyma. [Abstract]

Kiang M, Kutas M, Light GA, Braff DL
An Event-Related Brain Potential Study of Direct and Indirect Semantic Priming in Schizophrenia.
Am J Psychiatry. 2007 Dec 3;
Objective Following a meaningful prime stimulus, schizophrenia patients have been hypothesized to exhibit impaired neurophysiological activation of related concepts in general, and/or supranormal activation of weakly related concepts in particular, within semantic memory. The former abnormality may occur at longer intervals, and the latter at shorter intervals, after the prime. The authors tested these hypotheses using the N400 event-related brain potential as a probe of activation of concepts in semantic memory. Method Event-related potentials were recorded in 16 schizophrenia patients and 16 normal comparison subjects who viewed prime words, each followed by a target that was a directly (strongly) related word, indirectly (weakly) related word, unrelated word, or nonword, in a lexical-decision task. Equal numbers of each target type were presented 300 and 750 msec after the prime. Results In the comparison subjects, N400 amplitude was largest (most negative) following unrelated targets, intermediate after indirectly related targets, and smallest after directly related targets. In contrast, patients' N400 amplitudes did not differ between these target types, reflecting larger amplitudes following both directly and indirectly related targets in patients than in comparison subjects; these findings held regardless of prime-to-target stimulus-onset asynchrony. Within patients, at the longer asynchrony, larger N400 amplitudes after directly and indirectly related targets correlated with positive psychotic symptoms. Conclusions The results suggest hypoactivation of strongly and weakly related concepts following a meaningful stimulus, regardless of interval, in schizophrenia. An N400 index of this hypoactivation correlated with severity of delusions, suggesting a role for abnormal semantic processing in their pathogenesis. [Abstract]

Lissek S, Levenson J, Biggs AL, Johnson LL, Ameli R, Pine DS, Grillon C
Elevated Fear Conditioning to Socially Relevant Unconditioned Stimuli in Social Anxiety Disorder.
Am J Psychiatry. 2007 Nov 15;
Objective Though conditioned fear has long been acknowledged as an important etiologic mechanism in social anxiety disorder, past psychophysiological experiments have found no differences in general conditionability among social anxiety patients using generally aversive but socially nonspecific unconditioned stimuli (e.g., unpleasant odors and painful pressure). The authors applied a novel fear conditioning paradigm consisting of socially relevant unconditioned stimuli of critical facial expressions and verbal feedback. This study represents the first effort to assess the conditioning correlates of social anxiety disorder within an ecologically enhanced paradigm. Method Subjects with social anxiety disorder and age- and gender-matched healthy comparison subjects underwent differential classical conditioning. Conditioned stimuli included images of three neutral facial expressions, each of which was paired with one of three audiovisual unconditioned stimuli: negative insults with critical faces (US(neg)), positive compliments with happy faces (US(pos)), or neutral comments with neutral faces (US(neu)). The conditioned response was measured as the fear-potentiation of the startle-blink reflex elicited during presentation of the conditioned stimuli. Results Only social anxiety subjects demonstrated fear conditioning in response to facial expressions, as the startle-blink reflex was potentiated by the CS(neg) versus both CS(neu) and CS(pos) among those with the disorder, while healthy comparison subjects displayed no evidence of conditioned startle-potentiation. Such group differences in conditioning were independent of levels of anxiety to the unconditioned stimulus, implicating associative processes rather than increased unconditioned stimulus reactivity as the active mechanism underlying enhanced conditioned startle-potentiation among social anxiety subjects. Conclusions Results support a conditioning contribution to social anxiety disorder and underscore the importance of disorder-relevant unconditioned stimuli when studying the conditioning correlates of pathologic anxiety. [Abstract]

Matsunaga H, Maebayashi K, Hayashida K, Okino K, Matsui T, Iketani T, Kiriike N, Stein DJ
Symptom Structure in Japanese Patients With Obsessive-Compulsive Disorder.
Am J Psychiatry. 2007 Nov 15;
Objective Obsessive-compulsive disorder (OCD) comprises a number of specific symptom dimensions. The authors factor analyzed data on the Yale-Brown Obsessive Compulsive Scale symptom checklist in a large group of Japanese OCD patients to examine whether symptom dimensions were stable across cultures. Method A principal components analysis of Yale-Brown Obsessive Compulsive Scale major symptom categories was performed on Japanese OCD patients (N=343). The association between symptom dimensions and clinical variables, including 1-year outcome after combination treatment, was also examined using Pearson correlations. Results Four factors explaining 57.7% of the variance were identified: 1) contamination/washing, 2) hoarding, 3) symmetry/repeating and ordering, and 4) aggressive/checking symptoms. The symmetry dimension was associated with early age at onset, and both the symmetry and hoarding dimensions were associated with decreased functioning and treatment resistance. Conclusions The findings in this study support transcultural stability in the symptom structure of OCD, which is consistent with the hypothesis that OCD is mediated by universal psychobiological mechanisms. [Abstract]

Biederman J, Petty CR, Wilens TE, Fraire MG, Purcell CA, Mick E, Monuteaux MC, Faraone SV
Familial Risk Analyses of Attention Deficit Hyperactivity Disorder and Substance Use Disorders.
Am J Psychiatry. 2007 Nov 15;
Objective A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. In addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. Conclusions Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence. [Abstract]

Monk CS, Klein RG, Telzer EH, Schroth EA, Mannuzza S, Moulton JL, Guardino M, Masten CL, McClure-Tone EB, Fromm S, Blair RJ, Pine DS, Ernst M
Amygdala and Nucleus Accumbens Activation to Emotional Facial Expressions in Children and Adolescents at Risk for Major Depression.
Am J Psychiatry. 2007 Nov 6;
Objective Offspring of parents with major depressive disorder face a threefold higher risk for major depression than offspring without such family histories. Although major depression is a significant cause of morbidity and mortality, neural correlates of risk for major depression remain poorly understood. This study compares amygdala and nucleus accumbens activation in children and adolescents at high and low risk for major depression under varying attentional and emotional conditions. Method Thirty-nine juveniles, 17 offspring of parents with major depression (high-risk group) and 22 offspring of parents without histories of major depression, anxiety, or psychotic disorders (low-risk group) completed a functional magnetic resonance imaging study. During imaging, subjects viewed faces that varied in intensity of emotional expressions across blocks of trials while attention was unconstrained (passive viewing) and constrained (rate nose width on face, rate subjective fear while viewing face). Results When attention was unconstrained, high-risk subjects showed greater amygdala and nucleus accumbens activation to fearful faces and lower nucleus accumbens activation to happy faces (small volume corrected for the amygdala and nucleus accumbens). No group differences emerged in amygdala or nucleus accumbens activation during constrained attention. Exploratory analysis showed that constraining attention was associated with greater medial prefrontal cortex activation in the high-risk than in the low-risk group. Conclusions Amygdala and nucleus accumbens responses to affective stimuli may reflect vulnerability for major depression. Constraining attention may normalize emotion-related neural function possibly by engagement of the medial prefrontal cortex; face-viewing with unconstrained attention may engage aberrant processes associated with risk for major depression. [Abstract]

Hajcak G, Franklin ME, Foa EB, Simons RF
Increased Error-Related Brain Activity in Pediatric Obsessive-Compulsive Disorder Before and After Treatment.
Am J Psychiatry. 2007 Nov 7;
Objective The error-related negativity is a negative deflection in the event-related potential maximal approximately 50 msec after the commission of errors. The error-related negativity is generated in the anterior cingulate cortex, and both anterior cingulate cortex hyperactivity and increased error-related brain activity have been reported in adults with obsessive-compulsive disorder (OCD). However, no study to date, to the authors' knowledge, has examined error-related brain activity in pediatric patients with OCD, and no study has examined error-related brain activity in OCD both before and after treatment. Method The error-related negativity was measured in 18 treatment-seeking pediatric patients with OCD and 18 age-matched comparison subjects. Of these patients, 10 returned for a second testing session after cognitive behavior therapy; 13 comparison children participated a second time after a comparable interval. Results In the pretreatment group, the error-related negativity was reliably larger in pediatric patients with OCD in relation to comparison subjects. This difference was also evident after treatment. There was no relationship between error-related negativity and symptom severity or changes in symptom severity. Conclusions Consistent with studies in adult patients, increased error-related brain activity is evident in pediatric patients with OCD. Furthermore, increased error-related brain activity does not appear to change as a function of symptom reduction after therapy. These results suggest that an increased error-related negativity may be a trait-like marker for psychopathology and might be a useful endophenotype. [Abstract]

Morrato EH, Libby AM, Orton HD, Degruy FV, Brent DA, Allen R, Valuck RJ
Frequency of Provider Contact After FDA Advisory on Risk of Pediatric Suicidality With SSRIs.
Am J Psychiatry. 2007 Nov 6;
Objective The Food and Drug Administration (FDA) issued a public health advisory in October 2003 on the risk of suicide in pediatric patients taking antidepressants and advised maintaining "close supervision" of such patients. In this study, the authors compared trends in the frequency of provider contacts for patients with depression before and after the advisory was issued. Method Retrospective cohorts of children (N=27,370) and adults (N=193,151) with new episodes of depression treated with antidepressants were created from a national claims database of managed care plans (1998-2005). Two standards were used in measuring patient monitoring: the Health Plan Employer Data and Information Set (HEDIS) quality-of-care criterion calling for three contacts in 3 months and the FDA-recommended contact schedule totaling seven visits in 3 months. Time-series models compared postadvisory trends to the expected trend based on preadvisory measures. Results Less than 5% of all patients met FDA contact recommendations before the advisory, and the rate did not change after the advisory. A greater proportion of patients met the HEDIS contact criterion before the advisory (60% for children and 40% for adults), and the rate did not change after the advisory. A greater proportion of pediatric patients seen by a psychiatrist (80%) met the HEDIS criterion than those seen by a pediatrician (60%) or a non-pediatrician primary care physician (54%), and than adults seen by a psychiatrist (65%) or a primary care physician (37%). The proportions of pediatric patients who met the FDA recommendations did not differ by specialty Conclusions Contrary to expectations, the frequency of visits by patients with new episodes of depression treated with antidepressants did not increase after the October 2003 FDA advisory was issued. [Abstract]

Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, Haroon E, Pham D, Heinz A, Kumar A
Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression.
Am J Psychiatry. 2007 Nov 6;
Objective Despite evidence for hippocampal abnormalities in elderly depression, it is unknown whether these changes are regionally specific. This study used three-dimensional mapping techniques to identify regional hippocampal abnormalities in early- and late-onset depression. Neuropsychological correlates of hippocampal morphology were also investigated. Method With high-resolution magnetic resonance imaging, hippocampal morphology was compared among elderly patients with early- (N=24) and late-onset (N=22) depression and comparison subjects (N=34). Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups. Results Hippocampal volumes differed between depressed patients and comparison subjects but not between patients with early- and late-onset depression. However, statistical mapping results showed that regional surface contractions were significantly pronounced in late- compared to early-onset depression in the anterior of the subiculum and lateral posterior of the CA1 subfield in the left hemisphere. Significant shape differences were observed bilaterally in anterior CA1-CA3 subfields and the subiculum in patients in relation to comparison subjects. These results were similar when each disease group was separately compared to comparison subjects. Hippocampal surface contractions significantly correlated with memory measures among late- but not early-onset depressed patients or comparison subjects. Conclusions More pronounced regional volume deficits and their associations with memory in late-onset depression may suggest that these patients are more likely to develop cognitive impairment over time than individuals with early-onset depression. Mapping regional hippocampal abnormalities and their cognitive correlates may help guide research in defining risk profiles and treatment strategies. [Abstract]

Buchanan RW, Conley RR, Dickinson D, Ball MP, Feldman S, Gold JM, McMahon RP
Galantamine for the Treatment of Cognitive Impairments in People With Schizophrenia.
Am J Psychiatry. 2007 Nov 6;
Objective People with schizophrenia are characterized by a broad range of cognitive impairments. Despite appropriate treatment with conventional or second-generation antipsychotics, they continue to exhibit pronounced impairments. The current study was designed to examine the efficacy and safety of galantamine, an acetylcholinesterase inhibitor that also acts as an allosteric modulator at the alpha(4)beta(2) and alpha(7) nicotinic receptors, for the treatment of these impairments. Method Eighty-six people with schizophrenia were entered into a 12-week double-blind, placebo-controlled, randomized clinical trial. Forty-two subjects were assigned to galantamine and 44 were assigned to placebo. The efficacy of galantamine for cognitive impairments was evaluated with neuropsychological measures of attention, motor speed, processing speed, verbal and visual memory, and working memory. Results The treatment effect for the overall composite score was not significant, but the heterogeneity of treatment effect analysis was significant. Follow-up analyses revealed that the subjects taking galantamine exhibited significant improvements on the WAIS-III digit symbol and verbal memory measures. In contrast, the subjects taking placebo showed a significant improvement on the GDS distractibility test. The group differences on the WAIS-III digit symbol and GDS distractibility test remained significant after correction for multiple comparisons. There were no significant between-group differences in motor speed or working memory. In general, safety analyses revealed that galantamine was well tolerated. Conclusions Study results suggest that galantamine may have selective benefits for aspects of processing speed and verbal memory but interferes with practice effects during the performance of an attention task. [Abstract]

Recent Articles in Biological Psychiatry

Sand PG, Langguth B, Prikryl R, Kucerova H, Ceskova E
A Putative DRD3 Schizophrenia Risk Haplotype Deconstructed.
Biol Psychiatry. 2007 Dec 7; . [Abstract]

Spring B, Hitsman B, Baruah S, Price LH
Biol Psychiatry. 2007 Dec 5; [Abstract]

Cameron HA, Dayer AG
New Interneurons in the Adult Neocortex: Small, Sparse, but Significant?
Biol Psychiatry. 2007 Dec 5;
During the last decade, the intense study of adult hippocampal neurogenesis has led to several new lines of inquiry in the field of psychiatry. Although it is generally believed that adult mammalian neurogenesis is restricted to the hippocampus and olfactory bulb, a growing number of studies have described new neurons in the adult neocortex in both rodents and nonhuman primates. Interestingly, all of the new neurons observed in these studies have features of interneurons rather than pyramidal cells, the largest neuronal population of the neocortex. In this review, we discuss features of these interneurons that may explain why cortical neurogenesis has been so difficult to detect. In addition, these features suggest ways that production of even a small numbers of new neurons in the adult cortex could make a significant impact on neocortical function. [Abstract]

Bruder GE, Sedoruk JP, Stewart JW, McGrath PJ, Quitkin FM, Tenke CE
Electroencephalographic Alpha Measures Predict Therapeutic Response to a Selective Serotonin Reuptake Inhibitor Antidepressant: Pre- and Post-Treatment Findings.
Biol Psychiatry. 2007 Nov 29;
BACKGROUND: There is growing evidence that individual differences among depressed patients on electrophysiologic (EEG), neuroimaging, and neurocognitive measures are predictive of therapeutic response to antidepressant drugs. This study replicates prior findings of pretreatment differences between selective serotonin reuptake inhibitor (SSRI) responders and nonresponders in EEG alpha power or asymmetry and examines whether these differences normalize or are stable after treatment. METHODS: Resting EEG (eyes open and closed) was recorded from 28 electrodes (nose reference) in 18 depressed patients when off medication and at the end of 12 weeks of fluoxetine treatment. Clinical response was assessed by an independent rater with the Clinical Global Impression Improvement scale. The EEG data were also obtained for 18 healthy adults matched to patients in gender and age. RESULTS: Treatment responders had greater alpha power compared with nonresponders and healthy control subjects, with largest differences at occipital sites where alpha was largest. There were also differences in alpha asymmetry between responders and nonresponders at occipital sites. Responders showed greater alpha (less activity) over right than left hemisphere, whereas nonresponders tended to show the opposite asymmetry. Neither alpha power nor asymmetry changed after treatment, and test-retest correlations were high, particularly for alpha power. Alpha power and asymmetry showed reasonable positive predictive value but less negative predictive value. CONCLUSIONS: The findings confirm reports of alpha differences between antidepressant responders and nonresponders and raise hopes for developing EEG tests for selecting effective treatments for patients. The stability of alpha power and asymmetry differences between SSRI responders and nonresponders after treatment suggests that they represent state-independent characteristics. [Abstract]

Batra NA, Seres-Mailo J, Hanstock C, Seres P, Khudabux J, Bellavance F, Baker G, Allen P, Tibbo P, Hui E, Le Melledo JM
Proton Magnetic Resonance Spectroscopy Measurement of Brain Glutamate Levels in Premenstrual Dysphoric Disorder.
Biol Psychiatry. 2007 Nov 29;
BACKGROUND: Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS: Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS: A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS: The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders. [Abstract]

Meloni EG, Reedy CL, Cohen BM, Carlezon WA
Activation of Raphe Efferents to the Medial Prefrontal Cortex by Corticotropin-Releasing Factor: Correlation with Anxiety-Like Behavior.
Biol Psychiatry. 2007 Nov 29;
BACKGROUND: Parallel lines of research suggest that dysfunction affecting both corticotropin-releasing factor (CRF) and serotonin (5-HT) systems is involved in the pathophysiology of psychiatric illnesses such as anxiety and depression. The effect of CRF on behavior and on the accompanying change in activity of 5-HT neurons in the dorsal and median raphe nuclei (DR and MR) that project to the ventral medial prefrontal cortex (mPFC), a brain area implicated in mood and anxiety disorders, was studied. METHODS: Male Sprague-Dawley rats with intra-mPFC deposits of fluorescent microspheres received injections of CRF (1 mug, intracerebroventricular [ICV]) and were tested for CRF-enhanced startle, a behavioral assay believed to reflect stress- or anxiety-like states. C-Fos immunohistochemistry was used to measure CRF-induced activity in retrogradely labeled neurons in the DR and MR and correlate this level of activity with the level of CRF-enhanced startle. RESULTS: The CRF-enhanced startle was accompanied by an increased c-Fos expression in retrogradely labeled cells in the raphe. In the DR and MR, there was a clear topography of activation, with a higher-percent activation in retrogradely labeled neurons in caudal sections. In the caudal DR, this effect was positively correlated with the level of CRF-enhanced startle. Co-expression of retrogradely labeled cells with tryptophan hydroxylase showed that the majority (> 90%) of raphe efferents to the mPFC were from serotonergic neurons. CONCLUSIONS: These data indicate that CRF activates a subpopulation of cortical-projecting 5-HT raphe neurons and suggest that increased 5-HT release in the mPFC might be an important component driving some types of anxiety-like behaviors. [Abstract]

Gusella JF, Macdonald ME
Expanding the Notion of Disease in Huntington's Disease.
Biol Psychiatry. 2007 Dec 15;62(12): [Abstract]

Insel TR
From animal models to model animals.
Biol Psychiatry. 2007 Dec 15;62(12): [Abstract]

Centonze D, Rossi S, Mercaldo V, Napoli I, Ciotti MT, Chiara VD, Musella A, Prosperetti C, Calabresi P, Bernardi G, Bagni C
Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome.
Biol Psychiatry. 2007 Oct 27;
BACKGROUND: Structural and functional neuroimaging studies suggest abnormal activity in the striatum of patients with the fragile X syndrome (FXS), the most common form of inherited mental retardation. METHODS: Neurophysiological and immunofluorescence experiments in striatal brain slices. We studied the synaptic transmission in a mouse model for FXS, as well as the subcellular localization of fragile X mental retardation protein (FMRP) and brain cytoplasmic (BC1) RNA in striatal axons. RESULTS: Our results show that absence of FMRP is associated with apparently normal striatal glutamate-mediated transmission, but abnormal gamma-aminobutyric acid (GABA) transmission. This effect is likely secondary to increased transmitter release from GABAergic nerve terminals. We detected the presence of FMRP in axons of striatal neurons and observed a selective increase in the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs, mIPSCs) in fmr1-knockout mice. We also observed reduced paired-pulse ratio of evoked IPSCs, a finding that is consistent with the idea that transmitter release probability from striatal GABAergic nerve terminals is higher than normal in these mutants. Finally, we have identified the small noncoding BC1 RNA as a critical coplayer of FMRP in the regulation of striatal synaptic transmission. CONCLUSIONS: Understanding the physiologic action of FMRP and the synaptic defects associated with GABA transmission might be useful to design appropriate pharmacologic interventions for FXS. [Abstract]

Mathew SJ, Price RB, Mao X, Smith EL, Coplan JD, Charney DS, Shungu DC
Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder.
Biol Psychiatry. 2007 Oct 27;
BACKGROUND: Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging ((1)H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. METHODS: Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by (1)H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures. RESULTS: A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety. CONCLUSIONS: These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted. [Abstract]

Pinault D
N-Methyl d-Aspartate Receptor Antagonists Ketamine and MK-801 Induce Wake-Related Aberrant gamma Oscillations in the Rat Neocortex.
Biol Psychiatry. 2007 Nov 16;
BACKGROUND: Single subanesthetic doses of ketamine, a non-competitive NMDA receptor (NMDAr) antagonist, induce cognitive impairment, schizophreniform psychosis, hallucinations, and exacerbate schizophrenia symptoms. The neuronal mechanisms underlying transient disruption in NMDAr function are unknown. Disorders of cognition-related coherences of gamma frequency (30-80 Hz) oscillations between cortical areas are a major functional abnormality in schizophrenic patients. Does a single subanesthetic dose of ketamine or MK-801 alter properties of cortical gamma oscillations? METHODS: Properties of spontaneously occurring gamma oscillations in the electrocorticogram of the neocortex of freely moving rats (n = 16) were measured before and after subcutaneous administration of a single dose of ketamine (</= 10 mg/kg), MK-801 (</= .16 mg/kg), d-amphetamine (</= 1 mg/kg), apomorphine (</= 1.6 mg/kg), or vehicle (sodium chloride, .9%). RESULTS: The present study gives the first evidence that ketamine and MK-801, both of which induce NMDAr-dependent functional disconnections, dose-dependently increase the power (200%-400%) of wake-related gamma oscillations in the neocortex. Substances that modulate dopaminergic neurotransmission could also increase the gamma power but to a lesser degree. CONCLUSIONS: The present findings suggest that abnormal increased synchronization in ongoing gamma oscillations in cortical-related networks might cause dysfunctions of conscious integration, as seen in patients with schizophrenia. [Abstract]

Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E
Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review.
Biol Psychiatry. 2007 Nov 13;
BACKGROUND: Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence. METHODS: Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers. RESULTS: Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines. CONCLUSIONS: These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia. [Abstract]

Gotlib IH, Joormann J, Minor KL, Hallmayer J
HPA Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression.
Biol Psychiatry. 2007 Nov 13;
BACKGROUND: Recent evidence indicates that individuals who are homozygous for the short (s) allele in the promoter region of the serotonin transporter gene have higher rates of depression and other psychiatric disorders as a function of exposure to increasing levels of stressful life events than do individuals who have one or two copies of the long (l) allele. Despite the reliability of this association, the mechanism by which this polymorphism confers risk for psychopathology in the presence of stress is not understood. This study was designed to examine the formulation that individuals who are homozygous for the s allele are characterized by a greater biological reactivity to stress than are their counterparts who have one or two copies of the l allele. METHODS: Girls at high (n = 25) and low (n = 42) risk for depression by virtue of the presence or absence of a family history of this disorder were genotyped and exposed to a standardized laboratory stress task. Cortisol levels were assessed before the stressor, after the stressor, and during an extended recovery period. RESULTS: Girls who were homozygous for the s allele produced higher and more prolonged levels of cortisol in response to the stressor than did girls with an l allele. CONCLUSIONS: These findings indicate that the 5-HTTLPR polymorphism is associated with biological stress reactivity, which may increase susceptibility to depression in the face of stressful life events. [Abstract]

Salomon RM
Interpreting Tryptophan Depletion in Tobacco Smokers.
Biol Psychiatry. 2007 Nov 13; [Abstract]

Krystal JH
Biological psychiatry: increasing impact.
Biol Psychiatry. 2007 Dec 1;62(11): [Abstract]

Smith KM, Fagel DM, Stevens HE, Rabenstein RL, Maragnoli ME, Ohkubo Y, Picciotto MR, Schwartz ML, Vaccarino FM
Deficiency in Inhibitory Cortical Interneurons Associates with Hyperactivity in Fibroblast Growth Factor Receptor 1 Mutant Mice.
Biol Psychiatry. 2007 Nov 5;
BACKGROUND: Motor hyperactivity due to hyper-dopaminergic neurotransmission in the basal ganglia is well characterized; much less is known about the role of the neocortex in controlling motor behavior. METHODS: Locomotor behavior and motor, associative, and spatial learning were examined in mice with conditional null mutations of fibroblast growth factor receptor 1 (Fgfr1) restricted to telencephalic neural precursors (Fgfr1(f/f;hGfapCre)). Locomotor responses to a dopamine agonist (Amphetamine 2 mg/kg and Methylphenidate 10 mg/kg) and antagonists (SCH233390 .025 mg/kg and Haloperidol .2 mg/kg) were assessed. Stereological and morphological characterization of various monoaminergic, excitatory, and inhibitory neuronal subtypes was performed. RESULTS: Fgfr1(f/f;hGfapCre) mice have spontaneous locomotor hyperactivity characterized by longer bouts of locomotion and fewer resting points that is significantly reduced by the D1 and D2 receptor antagonists. No differences in dopamine transporter, tyrosine hydroxylase, or serotonin immunostaining were observed in Fgfr1(f/f;hGfapCre) mice. There was no change in cortical pyramidal neurons, but parvalbumin+, somatostatin+, and calbindin+ inhibitory interneurons were reduced in number in the cerebral cortex. The decrease in parvalbumin+ interneurons in cortex correlated with the extent of hyperactivity. CONCLUSIONS: Dysfunction in specific inhibitory cortical circuits might account for deficits in behavioral control, providing insights into the neurobiology of psychiatric disorders. [Abstract]

Mayes LC
The enduring impact of perceptual memories.
Biol Psychiatry. 2007 Nov 15;62(10): [Abstract]

Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM
Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy.
Biol Psychiatry. 2007 Nov 2;
BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in neural plasticity in the adult nervous system and has been suggested as a target gene for antidepressant treatment. The neurotrophic hypothesis of depression suggests that loss of BDNF from the hippocampus contributes to an increased vulnerability for depression, whereas upregulation of BDNF in the hippocampus is suggested to mediate antidepressant efficacy. METHODS: We have used a viral-mediated gene transfer approach to assess the role of BDNF in subregions of the hippocampus in a broad array of behavioral paradigms, including depression-like behavior and antidepressant responses. We have combined the adeno-associated virus (AAV) with the Cre/loxP site-specific recombination system to induce the knockout of BDNF selectively in either the CA1 or dentate gyrus (DG) subregions of the hippocampus. RESULTS: We show that the loss of BDNF in either the CA1 or the DG of the hippocampus does not alter locomotor activity, anxiety-like behavior, fear conditioning, or depression-related behaviors. However, the selective loss of BDNF in the DG but not the CA1 region attenuates the actions of desipramine and citalopram in the forced swim test. CONCLUSIONS: These data suggest that the loss of hippocampal BDNF per se is not sufficient to mediate depression-like behavior. However, these results support the view that BDNF in the DG might be essential in mediating the therapeutic effect of antidepressants. [Abstract]

Brown ES, Woolston DJ, Frol AB
Amygdala Volume in Patients Receiving Chronic Corticosteroid Therapy.
Biol Psychiatry. 2007 Nov 2;
BACKGROUND: Hippocampal volume reduction and declarative memory deficits are reported in humans and animals exposed to exogenous corticosteroids. The amygdala is another brain structure involved in the stress response that has important interactions with the hypothalamic-pituitary-adrenal axis. To our knowledge, no studies in animals or humans have examined the impact of exogenous corticosteroid administration on the amygdala. We assessed amygdala volume in patients receiving chronic prescription corticosteroid therapy and control subjects with similar medical histories not receiving corticosteroids. METHODS: Fifteen patients on long-term prednisone therapy and 13 control subjects of similar age, gender, ethnicity, education, height, and medical history were assessed with magnetic resonance imaging. Amygdala volume was manually traced and compared between groups using a two-way analysis of variance (ANOVA). Correlations between amygdala volume, age, and corticosteroid dose/duration were assessed using Pearson's correlation coefficient. RESULTS: Compared with control subjects, corticosteroid-treated patients had significantly smaller amygdala volumes. Right amygdala volume correlated significantly with age in control subjects and with duration of corticosteroid therapy in patients. CONCLUSIONS: Patients receiving chronic corticosteroid therapy had smaller amygdala volumes than control subjects that correlated with duration of corticosteroid therapy. These findings suggest that corticosteroid exposure may be associated with changes in the amygdala as well as hippocampus. [Abstract]

Ford JM, Roach BJ, Faustman WO, Mathalon DH
Out-of-Synch and Out-of-Sorts: Dysfunction of Motor-Sensory Communication in Schizophrenia.
Biol Psychiatry. 2007 Nov 2;
BACKGROUND: Phase synchronization of neural activity preceding a motor act may reflect an efference copy of the motor plan and its expected sensory consequences (corollary discharge), which is sent to sensory cortex to herald the arrival of self-generated sensations and dampen the resulting sensory experience. We performed time-frequency decomposition of response-locked electroencephalogram (EEG) to examine phase synchronization of oscillations across trials (phase-locking factor [PLF]) to self-paced button presses. If prepress PLF reflects the activity in motor cortex, it should be contralateralized. If it reflects the action of the efference copy, it should be related to subsequent sensory suppression. If efference copy/corollary discharge mechanisms are abnormal in schizophrenia, it should be reduced in patients with schizophrenia. METHODS: Electroencephalogram was collected while 23 patients (20 schizophrenia; 3 schizoaffective) and 25 age-matched control subjects pressed a button, at will, every 1 to 2 sec. Phase-locking factor preceding and following button presses was calculated from single-trial EEG; averaging single trials yielded response-locked event-related potentials (ERPs) to the tactile response associated with button pressing. RESULTS: Consistent with its hypothesized reflection of efference copy/corollary discharge signals, prepress gamma band neural synchrony was 1) maximal over the contralateral sensory-motor cortex in healthy subjects, 2) correlated with the ipsilateralized somatosensory ERP amplitude evoked by the press, and 3) reduced in patients. Prepress neural synchrony in the beta band was also reduced in patients, especially those with avolition/apathy. CONCLUSIONS: These data are consistent with dysfunction of forward model circuitry in schizophrenia and suggest that the specific motor-sensory system affected is selectively linked to symptoms involving that system. [Abstract]

Buka SL, Cannon TD, Torrey EF, Yolken RH
Maternal Exposure to Herpes Simplex Virus and Risk of Psychosis Among Adult Offspring.
Biol Psychiatry. 2007 Nov 2;
BACKGROUND: Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection. METHODS: We conducted a nested case-control study of 200 adults with psychoses and 554 matched control subjects (matched for city and date of birth, race/ethnicity, gender, and parent history of treatment for mental disorder) from three cohorts of the Collaborative Perinatal Project (Boston, Providence, and Philadelphia). We analyzed stored serum samples that had been obtained from these mothers at the end of pregnancy for antibodies directed at HSV-2, using type-specific solid-phase enzyme immunoassay techniques. RESULTS: Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1-2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4-4.6). CONCLUSIONS: Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy. [Abstract]

Godin O, Dufouil C, Maillard P, Delcroix N, Mazoyer B, Crivello F, Alpérovitch A, Tzourio C
White Matter Lesions as a Predictor of Depression in the Elderly: The 3C-Dijon Study.
Biol Psychiatry. 2007 Oct 29;
BACKGROUND: There is increasing evidence for a link between cerebrovascular disease and depression in the elderly but the mechanisms are still unknown. This study examines the longitudinal relationship between depression and white matter lesions (WML) in a sample of elderly aged 65 years and older. METHODS: Three City (3C)-Dijon is a 4-year follow-up population-based prospective study of 1658 subjects. At baseline, lifetime major depressive episode diagnosis was established using the Mini International Neuropsychiatric Interview. At each study wave, severity of depressive symptoms was assessed using Center for Epidemiological Studies-Depression (CES-D), and antidepressants intake was recorded. At baseline, lifetime major depression (LMD) was defined as lifetime major depressive episode or antidepressant medication intake. At follow-up, subjects were classified "incident depression" if scoring high at CES-D or antidepressant users. At baseline, cerebral magnetic resonance imaging (MRI) was performed to quantify WML volumes using an automated method of detection. At 4-year follow-up, 1214 subjects had a second MRI. RESULTS: Cross-sectional analysis showed a significantly higher WML volume in subjects with LMD compared with other subjects. Adjusted longitudinal analysis showed that increase in WML load was significantly higher in subjects with baseline LMD (2.1 cm(3) vs. 1.5 cm(3), p = .004). Among subjects free of depression up to baseline (n = 956), the higher the baseline WML volume, the higher the risk of developing depression during follow-up (odds ratio one quartile increase: 1.3; 95% confidence interval: = 1.1-1.7). CONCLUSIONS: Our data show that depression and WML volumes are strongly related. These results are consistent with the hypothesis of a vascular depression in the elderly. [Abstract]

Groom MJ, Bates AT, Jackson GM, Calton TG, Liddle PF, Hollis C
Event-Related Potentials in Adolescents with Schizophrenia and Their Siblings: A Comparison with Attention-Deficit/Hyperactivity Disorder.
Biol Psychiatry. 2007 Oct 29;
BACKGROUND: Identifying trait markers specific to schizophrenia might uncover mechanisms underlying illness susceptibility. Previous research shows the N2 and P3 event-related potentials are abnormal in schizophrenia; specificity of these potential trait markers has not been well established. METHODS: Electroencephalogram data were recorded from four adolescent groups: early-onset schizophrenia patients (SZ; n = 30); non-psychotic siblings of schizophrenia patients (SZ-SIB; n = 36); healthy control subjects (HC; n = 36); a neurodevelopmental attention-deficit/hyperactivity disorder (ADHD) comparison group (n = 27), during auditory oddball and visual go/no-go tasks. The P3 was measured to targets in the oddball task. The N2 and P3 were measured to go and no-go stimuli in the go/no-go task. RESULTS: Compared with the HC group, the SZ and SZ-SIB groups showed significantly reduced auditory oddball P3 amplitude. Visual P3 amplitude was significantly reduced in the SZ group for no-go stimuli and the SZ-SIB group for go and no-go stimuli. The P3 amplitude in the ADHD group was not significantly reduced for either paradigm. The SZ and ADHD groups showed significantly reduced N2 amplitude in the go/no-go task; the SZ-SIB group was not significantly different from the HC group. CONCLUSIONS: Results revealed reduced P3 amplitude in schizophrenia patients and adolescent non-psychotic siblings in an auditory oddball and a visual go/no-go task. The SZ-SIB and ADHD groups showed a different ERP profile when each was compared with the HC group: siblings showed reduced P3 amplitude in both tasks and normal N2 in the go/no-go task; the opposite pattern was observed in the ADHD group. [Abstract]

Barr RS, Pizzagalli DA, Culhane MA, Goff DC, Evins AE
A Single Dose of Nicotine Enhances Reward Responsiveness in Nonsmokers: Implications for Development of Dependence.
Biol Psychiatry. 2007 Oct 30;
BACKGROUND: Tobacco smoking, driven by the addictive properties of nicotine, is the most prevalent preventable cause of death in the Western world. Accumulated evidence suggests that nicotine may increase appetitive responding for nondrug incentives in the environment. METHODS: To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled, crossover study of the effect of a single dose of transdermal nicotine on reward responsiveness in 30 psychiatrically healthy nonsmokers. A novel signal detection task in which correct responses were differentially rewarded in a 3:1 ratio was used to assess the extent to which participants modulated their behavior as a function of reward. RESULTS: Despite expected adverse effects such as nausea, nicotine significantly increased response bias toward the more frequently rewarded condition, at the expense of accuracy, independent of effects on attention or overall vigilance. Additionally, response bias on placebo was greater in participants who received nicotine in the first session, indicating that an effect of nicotine on reward responsiveness or reward-based learning persisted for at least 1 week. CONCLUSIONS: These findings suggest that a single dose of nicotine enhances response to non-drug-related rewards in the environment, with lasting effects. This effect may contribute to reinforcement of early smoking behavior and development of nicotine dependence. [Abstract]

Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL, Davidson RJ, Kalin NH
A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder.
Biol Psychiatry. 2007 Oct 25;
BACKGROUND: Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD). METHODS: Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment. RESULTS: The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group. CONCLUSIONS: These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD. [Abstract]

López de Munain A, Alzualde A, Gorostidi A, Otaegui D, Ruiz-Martínez J, Indakoetxea B, Ferrer I, Pérez-Tur J, Sáenz A, Bergareche A, Barandiarán M, Poza JJ, Zabalza R, Ruiz I, Urtasun M, Fernández-Manchola I, Olasagasti B, Espinal JB, Olaskoaga J, Ruibal M, Moreno F, Carrera N, Massó JF
Mutations in Progranulin Gene: Clinical, Pathological, and Ribonucleic Acid Expression Findings.
Biol Psychiatry. 2007 Oct 19;
BACKGROUND: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. METHODS: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. RESULTS: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. CONCLUSIONS: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder. [Abstract]

Touriño C, Ledent C, Maldonado R, Valverde O
CB(1)Cannabinoid Receptor Modulates 3,4-Methylenedioxymethamphetamine Acute Responses and Reinforcement.
Biol Psychiatry. 2007 Oct 19;
BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug widely abused by young people. The endocannabinoid system is involved in the addictive processes induced by different drugs of abuse. However, the role of this system in the pharmacological effects of MDMA has not yet been clarified. METHODS: Locomotion, body temperature, and anxiogenic-like responses were evaluated after acute MDMA administration in CB(1) cannabinoid receptor 1 knockout mice. Additionally, MDMA rewarding properties were investigated in the place conditioning and the intravenous self-administration paradigms. Extracellular levels of dopamine (DA) in the nucleus accumbens were also analyzed after a single administration of MDMA by in vivo microdialysis. RESULTS: Acute MDMA administration increased locomotor activity, body temperature, and anxiogenic-like responses in wild-type mice, but these responses were lower or abolished in knockout animals. 3,4-Methylenedioxymethamphetamine produced similar conditioned place preference and increased dopamine extracellular levels in the nucleus accumbens in both genotypes. Nevertheless, CB(1) knockout mice failed to self-administer MDMA at any of the doses used. CONCLUSIONS: These results indicate that CB(1) cannabinoid receptors play an important role in the acute prototypical effects of MDMA and are essential in the acquisition of an operant behavior to self-administer this drug. [Abstract]

Blasey C, Debattista C
Biol Psychiatry. 2007 Oct 19; [Abstract]

Kollins SH, March JS
Advances in the pharmacotherapy of attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2007 Nov 1;62(9): [Abstract]

Geschwind D
Autism: searching for coherence.
Biol Psychiatry. 2007 Nov 1;62(9): [Abstract]

Wright MJ, Luciano M, Hansell NK, Montgomery GW, Geffen GM, Martin NG
QTLs Identified for P3 Amplitude in a Non-Clinical Sample: Importance of Neurodevelopmental and Neurotransmitter Genes.
Biol Psychiatry. 2007 Oct 17;
BACKGROUND: The P3(00) event-related potential is an index of processing capacity (P3 amplitude) and stimulus evaluation (P3 latency) as well as a phenotypic marker of various forms of psychopathology where P3 abnormalities have been reported. METHODS: A genome-wide linkage scan of 400-761 autosomal markers, at an average spacing of 5-10 centimorgans (cM), was completed in 647 twins/siblings (306 families mostly comprising dizygotic twins), mean age 16.3, range 15.4-20.1 years, for whom P3 amplitude and latency data were available. RESULTS: Significant linkage for P3 amplitude was observed on chromosome 7q for the central recording site (logarithm-of-odds [LOD] = 3.88, p = .00002) and in the same region for both frontal (LOD = 2.19, p = .0015) and parietal (LOD = 1.67, p = .0053) sites, with multivariate analysis also identifying linkage in this region (LOD = 2.14, p = .0017). Suggestive linkage was also identified on 6p (LOD(max) = 2.49) and 12q (LOD(max) = 2.24), with other promising regions identified on 9q (LOD(max) = 2.14) and 10p (LOD(max) = 2.18). Less striking were the results for P3 latency; LOD > 1.5 were found on chromosomes 1q, 9q, 10q, 12q, and 19p. CONCLUSIONS: This is a first step in the identification of genes for normal variation in the P3. Loci identified here for P3 amplitude suggest the possible importance of neurodevelopmental genes in addition to those influencing neurotransmitters, fitting with the evidence that P3 amplitude is sensitive to diverse types of brain abnormalities. [Abstract]

Munafò MR, Brown SM, Hariri AR
Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis.
Biol Psychiatry. 2007 Oct 17;
BACKGROUND: We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship. METHODS: We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry. RESULTS: Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes. CONCLUSIONS: Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality. [Abstract]

Laje G, McMahon FJ
The pharmacogenetics of major depression: past, present, and future.
Biol Psychiatry. 2007 Dec 1;62(11): [Abstract]

Paulus MP, Lovero KL, Wittmann M, Leland DS
Reduced Behavioral and Neural Activation in Stimulant Users to Different Error Rates during Decision Making.
Biol Psychiatry. 2007 Oct 17;
BACKGROUND: Behavioral processes and neural systems dysfunctions that put individuals at risk for drug use in general, and stimulant use in particular, are poorly understood. Here, the hypothesis is examined that stimulant-using subjects adjust their decision making less as a function of errors as evidenced by attenuated behavioral and neural substrate activation patterns. METHODS: Twelve young adults who had used stimulants were compared with 12 education-matched, stimulant-naïve comparison subjects. Subjects completed the two-choice prediction task with three fixed error-rate conditions (20%, 50%, or 80% errors) during functional magnetic resonance imaging. RESULTS: Stimulant users relative to comparison subjects showed less strategy adjustment to different error rates, for example, they were less likely to stay with winning responses (win-stay) and to shift away from losing responses (lose-shift). These subjects also showed different activation patterns as a function of error rate in left insular and bilateral dorsolateral prefrontal cortex but not anterior cingulate. The degree to which individuals adjusted switching rate, or win-stay/lose-shift consistent responses, as a function of errors was correlated with the difference in insular cortex activation differences between high and low error rates. CONCLUSIONS: The behavior of stimulant users is less adaptive to the frequency of errors made and fewer brain processing resources are deployed during decision making to anticipate erroneous performance. These findings could be markers for the predisposition of drug taking; however, their relevance for development of drug dependence requires further study. [Abstract]

Carola V, Frazzetto G, Pascucci T, Audero E, Puglisi-Allegra S, Cabib S, Lesch KP, Gross C
Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter x Environment Risk Factor for Anxiety and Depression.
Biol Psychiatry. 2007 Oct 17;
BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT x environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse. METHODS: We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene x environment effects. RESULTS: Mice experiencing low maternal care showed deficient gamma-aminobutyric acid-A receptor binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT x environment risk factor. CONCLUSIONS: These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF as a molecular substrate of this risk factor. [Abstract]

Fu CH, Mourao-Miranda J, Costafreda SG, Khanna A, Marquand AF, Williams SC, Brammer MJ
Pattern Classification of Sad Facial Processing: Toward the Development of Neurobiological Markers in Depression.
Biol Psychiatry. 2007 Oct 17;
BACKGROUND: Methods of analysis that examine the pattern of cerebral activity over the whole brain have been used to identify and predict neurocognitive states in healthy individuals. Such methods may be applied to functional neuroimaging data in patient groups to aid in the diagnosis of psychiatric disorders and the prediction of treatment response. We sought to examine the sensitivity and specificity of whole brain pattern classification of implicit processing of sad facial expressions in depression. METHODS: Nineteen medication-free patients with depression and 19 healthy volunteers had been recruited for a functional magnetic resonance imaging (fMRI) study involving serial scans. The fMRI paradigm entailed incidental affective processing of sad facial stimuli with modulation of the intensity of the emotional expression (low, medium, and high intensity). The fMRI data were analyzed at each level of affective intensity with a support vector machine pattern classification method. RESULTS: The pattern of brain activity during sad facial processing correctly classified up to 84% of patients (sensitivity) and 89% of control subjects (specificity), corresponding to an accuracy of 86% (p < .0001). Classification of patients' clinical response at baseline, prior to the initiation of treatment, showed a trend toward significance. CONCLUSIONS: Significant classification of patients in an acute depressive episode was achieved with whole brain pattern analysis of fMRI data. The prediction of treatment response showed a trend toward significance due to the reduced power of the subsample. Such methods may provide the first steps toward developing neurobiological markers in psychiatry. [Abstract]

Donohoe G, Morris DW, De Sanctis P, Magno E, Montesi JL, Garavan HP, Robertson IH, Javitt DC, Gill M, Corvin AP, Foxe JJ
Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia.
Biol Psychiatry. 2007 Oct 16;
BACKGROUND: Variation at the dysbindin gene (DTNBP1) has been associated with increased risk for schizophrenia in numerous independent samples and recently with deficits in general and domain-specific cognitive processing. The relationship between dysbindin risk variants and sensory-level deficits in schizophrenia remains to be explored. We investigated P1 performance, a component of early visual processing on which both patients and their relatives show deficits, in carriers and noncarriers of a known dysbindin risk haplotype. METHODS: Event-related potential responses to simple visual isolated-check stimuli were measured using high-density electrical scalp recordings in 26 individuals meeting DSM-IV criteria for schizophrenia, comprising 14 patients who were carriers of the dysbindin risk haplotype and 12 patients who were nonrisk haplotype carriers. RESULTS: Carriers of the dysbindin risk haplotype demonstrated significantly reduced P1 amplitudes compared with noncarriers. A large effect size of d = .89 was calculated for the difference in P1 amplitude over scalp sites where the deficit was maximal. CONCLUSIONS: The P1 deficits associated with a dysbindin risk haplotype previously identified in our sample presents functional confirmation of its deleterious effect on brain activity. Building on evidence of dysbindin's role in higher cognitive function, these early visual processing deficits suggest a generalized role for dysbindin in brain function and is likely to be part of the mechanism by which illness susceptibility is mediated. [Abstract]

Low NC, Cui L, Merikangas KR
Community versus Clinic Sampling: Effect on the Familial Aggregation of Anxiety Disorders.
Biol Psychiatry. 2007 Oct 16;
BACKGROUND: Most research on the familial aggregation of mental disorders has been based on probands selected from clinics. Sparse research examines the clustering of psychiatric illnesses among families ascertained from the community. Such ascertainment bias limits the generalizability and may compromise the validity of study findings. The objective of this study was to illustrate differences between familial aggregation on the basis of the source of proband ascertainment in a family study of anxiety disorders. METHODS: Forty anxiety probands were recruited from clinics; 36 anxiety probands and 60 control subjects were recruited from the community. All probands and their relatives were assessed using standardized psychiatric assessments. RESULTS: Selection of probands with panic and generalized anxiety disorders from clinical settings compared with the same local community settings was associated with greater risk to relatives. In contrast, the familial aggregation of social anxiety was greater in the community sample, and there were no differences in the risk of specific phobia to relatives between probands from clinics versus community. CONCLUSIONS: Clinic versus community sampling affects familial clustering of anxiety disorders. In general, the effect of clinic sampling is likely attributable to the greater severity of clinic cases, which may also be associated with increased familial morbidity. Differences observed between the anxiety disorders may be artifactual because of the diagnostic criteria of the anxiety disorders or low power. This study illustrates the importance of establishing standards for case-control selection, especially as complex disorder genetics moves increasingly toward population-based sampling. [Abstract]

Evans DL, Lynch KG, Benton T, Dubé B, Gettes DR, Tustin NB, Lai JP, Metzger D, Douglas SD
Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome.
Biol Psychiatry. 2007 Oct 16;
BACKGROUND: Natural killer (NK) cells play an important role in innate immunity and are involved in the host defense against human immunodeficiency virus (HIV) infection. This study examines the potential role of three underlying regulatory systems that have been under investigation in central nervous system research as well as immune and viral research: serotonin, neurokinin, and glucocorticoid systems. METHODS: Fifty-one HIV-seropositive subjects were recruited to achieve a representative sample of depressed and nondepressed women. The effects of a selective serotonin reuptake inhibitor (SSRI), a substance P (SP) antagonist, and a glucocorticoid antagonist on NK cell function were assessed in a series of ex vivo experiments of peripheral blood mononuclear cells from each HIV-seropositive subject. RESULTS: Natural killer cell cytolytic activity was significantly increased by the SSRI citalopram and by the substance P antagonist CP-96345 relative to control conditions; the glucocorticoid antagonist, RU486, showed no effect on NK cytotoxicity. Our results suggest that the effects of the three agents did not differ as a function of depression. CONCLUSIONS: Our findings provide evidence that NK cell function in HIV infection may be enhanced by serotonin reuptake inhibition and by substance P antagonism. It remains to be determined if HIV-related impairment in not only NK cytolytic activity but also NK noncytolytic activity can be improved by an SSRI or an SP antagonist. Clinical studies are warranted to address these questions and the potential roles of serotonergic agents and SP antagonists in improving NK cell immunity, delaying HIV disease progression, and extending survival with HIV infection. [Abstract]

Guehl D, Benazzouz A, Aouizerate B, Cuny E, Rotgé JY, Rougier A, Tignol J, Bioulac B, Burbaud P
Neuronal Correlates of Obsessions in the Caudate Nucleus.
Biol Psychiatry. 2007 Oct 16;
BACKGROUND: Metabolic overactivity of corticosubcortical loops including the caudate nucleus (CN) has been reported in obsessive-compulsive disorder (OCD) using functional imaging techniques. However, direct proof of a modification of neuronal activity within the CN of OCD patients is still lacking. We tested the hypothesis that obsessions or compulsions might be associated with particular features of neuronal activity in the CN of OCD patients. METHODS: Single unit recordings were performed peroperatively in the CN of three patients with severe forms of obsessive-compulsive disorder (OCD) who were candidates for deep brain stimulation of the CN. Severity of obsessions was assessed preoperatively with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and peroperatively with a subjective obsession score based on a visual analog scale (VAS). RESULTS: Frequency of CN discharge and variability of interspike intervals were found to be abnormally high in two patients with a high VAS score during surgery but not in one with a low VAS score. Lateralization and depth of recording influenced neuronal activity variably among patients. CONCLUSIONS: Because the three patients had high Y-BOCS scores before surgery, these findings suggest that caudate hyperactivity in OCD is concomitant with the occurrence of the obsession process. [Abstract]

Recent Articles in Molecular Psychiatry

Dempster EL, Kiss E, Kapornai K, Daróczy G, Mayer L, Baji I, Tamas Z, Gadoros J, Kennedy JL, Vetró A, Kovacs M, Barr CL
No evidence of association between a functional polymorphism in the MTHFR gene and childhood-onset mood disorders.
Mol Psychiatry. 2007 Dec;12(12): . [Abstract]

Teranishi KS, Slager SL, Garriock H, Kraft JB, Peters EJ, Reinalda MS, Jenkins GD, McGrath PJ, Hamilton SP
Variants in PDE11A and PDE1A are not associated with citalopram response.
Mol Psychiatry. 2007 Dec;12(12): [Abstract]

Reyes S, Kane GC, Miki T, Seino S, Terzic A
K(ATP) channels confer survival advantage in cocaine overdose.
Mol Psychiatry. 2007 Dec;12(12): [Abstract]

Renou J, De Luca V, Zai CC, Bulgin N, Remington G, Meltzer HY, Lieberman JA, Le Foll B, Kennedy JL
Multiple variants of the DRD3, but not BDNF gene, influence age-at-onset of schizophrenia.
Mol Psychiatry. 2007 Dec;12(12): [Abstract]

Francks C, Maegawa S, Laurén J, Abrahams BS, Velayos-Baeza A, Medland SE, Colella S, Groszer M, McAuley EZ, Caffrey TM, Timmusk T, Pruunsild P, Koppel I, Lind PA, Matsumoto-Itaba N, Nicod J, Xiong L, Joober R, Enard W, Krinsky B, Nanba E, Richardson AJ, Riley BP, Martin NG, Strittmatter SM, Möller HJ, Rujescu D, St Clair D, Muglia P, Roos JL, Fisher SE, Wade-Martins R, Rouleau GA, Stein JF, Karayiorgou M, Geschwind DH, Ragoussis J, Kendler KS, Airaksinen MS, Oshimura M, Delisi LE, Monaco AP
LRRTM1 protein is located in the endoplasmic reticulum (ER) in mammalian cells.
Mol Psychiatry. 2007 Dec;12(12): [Abstract]

Wexler EM, Geschwind DH, Palmer TD
Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation.
Mol Psychiatry. 2007 Oct 30;
Neural stem cells give rise to new hippocampal neurons throughout adulthood, and defects in neurogenesis may predispose an individual to mood disorders, such as major depression. Our understanding of the signals controlling this process is limited, so we explored potential pathways regulating adult hippocampal progenitor (AHP) proliferation and neuronal differentiation. We demonstrate that the mood stabilizer lithium directly expands pools of AHPs in vitro, and induces them to become neurons at therapeutically relevant concentrations. We show that these effects are independent of inositol monophosphatase, but dependent on Wnt pathway components. Both downregulation of glycogen synthase kinase-3beta, a lithium-sensitive component of the canonical Wnt signaling pathway, and elevated beta-catenin, a downstream component of the same pathway produce effects similar to lithium. In contrast, RNAi-mediated inhibition of beta-catenin abolishes the proliferative effects of lithium, suggesting that Wnt signal transduction may underlie lithium's therapeutic effect. Together, these data strengthen the connection between psychopharmacologic treatment and the process of adult neurogenesis, while also suggesting the pursuit of modulators of Wnt signaling as a new class of more effective mood stabilizers/antidepressants.Molecular Psychiatry advance online publication, 30 October 2007; doi:10.1038/ [Abstract]

Kesner Y, Zohar J, Merenlender A, Gispan I, Shalit F, Yadid G
WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model.
Mol Psychiatry. 2007 Oct 30;
Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop after the experiencing or witnessing of a life-threatening event. PTSD is defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyperarousal, which persist for at least 1 month in survivors of the event (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Using an established model of PTSD, we addressed the well-accepted clinical finding that only a minority (about 20%) of the individuals exposed to a traumatic event develop PTSD. Moreover, we followed individual rat behavior for up to a month, and then treated the PTSD-like animals with citalopram. Our data demonstrate high face (20% of rats exposed to a reminder of the stressor develop symptoms characteristic of PTSD) and predictive (response to citalopram) validities. Based on these validities we identified alterations in the Wolframin gene in the CA1 and amygdala regions, specifically in exposed PTSD-like rats, which were normalized after treatment with citalopram. We suggest the Wolframin gene as a putative biomarker for PTSD. Since Wolframin gene undergoes alternative splicing and has polymorphism in the population, it may serve a future marker for identification of the vulnerable population exposed to a traumatic event.Molecular Psychiatry advance online publication, 30 October 2007; doi:10.1038/ [Abstract]

Vastenhouw B, van der Have F, van der Linden AJ, von Oerthel L, Booij J, Burbach JP, Smidt MP, Beekman FJ
Movies of dopamine transporter occupancy with ultra-high resolution focusing pinhole SPECT.
Mol Psychiatry. 2007 Nov;12(11):
A pivotal question in neuropharmacology is how the function of neurotransmitter systems relates to psychiatric diseases. In experimental neuropharmacology, we have dreamt about a looking glass that would allow us to see neurotransmitter systems in action, and about animals that would faithfully serve us as models for human psychiatric disease. Analysis of animal models has been limited by the availability of methods to study in vivo neurotransmitter dynamics. Now, a single photon emission computed tomography system called U-SPECT can localize dopamine transporters in sub-compartments of the mouse brain during a range of points in time. Applied to the midbrain dopamine system of different models of disease, this will aid the understanding of dynamic processes of this neurotransmitter that underlie brain functions and human brain pathology. [Abstract]

Dawood T, Anderson J, Barton D, Lambert E, Esler M, Hotchkin E, Haikerwal D, Kaye D, Lambert G
Reduced overflow of BDNF from the brain is linked with suicide risk in depressive illness.
Mol Psychiatry. 2007 Nov;12(11): [Abstract]

Liu C, Shi J, Badner JA, Zou H, Qian Y, Gershon ES
No association of trace amine receptor genes with bipolar disorder.
Mol Psychiatry. 2007 Nov;12(11): [Abstract]

Toma C, Rossi M, Sousa I, Blasi F, Bacchelli E, Alen R, Vanhala R, Monaco AP, Järvelä I, Maestrini E
Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations.
Mol Psychiatry. 2007 Nov;12(11): [Abstract]

Yasuhara D, Hashiguchi T, Kawahara K, Nakahara T, Harada T, Taguchi H, Yamada S, Maruyama I, Inui A
High mobility group box 1 and refeeding-resistance in anorexia nervosa.
Mol Psychiatry. 2007 Nov;12(11): [Abstract]

Sibille E, Su J, Leman S, Le Guisquet AM, Ibarguen-Vargas Y, Joeyen-Waldorf J, Glorioso C, Tseng GC, Pezzone M, Hen R, Belzung C
Upregulated sirtuin 5 gene expression in frontal cortex of serotonin 1b receptor knock out mice.
Mol Psychiatry. 2007 Nov;12(11): [Abstract]

Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ
The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study.
Mol Psychiatry. 2007 Oct 23;
Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information. However, the neural substrates underpinning these changes have not been fully elucidated. The current study, therefore, used functional magnetic resonance imaging (fMRI) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term (7 days) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine. Twenty-four healthy volunteers were randomly assigned to 7-day double-blind intervention with reboxetine or placebo. On day 7, neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI. Questionnaires monitoring mood, hostility and anxiety were given before and during this intervention. During categorization, reboxetine was associated with greater activation to positive words, relative to negative words, in left precuneus and right inferior frontal gyrus. By contrast, at subsequent recognition reboxetine was associated with reduced response to positive words, relative to negative words, in left precuneus, anterior cingulate and medial frontal gyrus. These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety. Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression.Molecular Psychiatry advance online publication, 23 October 2007; doi:10.1038/ [Abstract]

López-León S, Janssens AC, González-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, van Duijn CM
Meta-analyses of genetic studies on major depressive disorder.
Mol Psychiatry. 2007 Oct 16;
The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case-control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE varepsilon2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44 bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40 bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4).Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Pennington K, Beasley CL, Dicker P, Fagan A, English J, Pariante CM, Wait R, Dunn MJ, Cotter DR
Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder.
Mol Psychiatry. 2007 Oct 16;
There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Ribasés M, Ramos-Quiroga JA, Hervás A, Bosch R, Bielsa A, Gastaminza X, Artigas J, Rodriguez-Ben S, Estivill X, Casas M, Cormand B, Bayés M
Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.
Mol Psychiatry. 2007 Oct 16;
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Berman SM, Voytek B, Mandelkern MA, Hassid BD, Isaacson A, Monterosso J, Miotto K, Ling W, London ED
Changes in cerebral glucose metabolism during early abstinence from chronic methamphetamine abuse.
Mol Psychiatry. 2007 Oct 16;
Changes in brain function during the initial weeks of abstinence from chronic methamphetamine abuse may substantially affect clinical outcome, but are not well understood. We used positron emission tomography with [F-18]fluorodeoxyglucose (FDG) to quantify regional cerebral glucose metabolism, an index of brain function, during performance of a vigilance task. A total of 10 methamphetamine-dependent subjects were tested after 5-9 days of abstinence, and after 4 additional weeks of supervised abstinence. A total of 12 healthy control subjects were tested at corresponding times. Global glucose metabolism increased between tests (P=0.01), more in methamphetamine-dependent (10.9%, P=0.02) than control subjects (1.9%, NS). Glucose metabolism did not change in subcortical regions of methamphetamine-dependent subjects, but increased in neocortex, with maximal increase (>20%) in parietal regions. Changes in reaction time and self-reports of negative affect varied more in methamphetamine-dependent than in control subjects, and correlated both with the increase in parietal glucose metabolism, and decrease in relative activity (after scaling to the global mean) in some regions. A robust relationship between change in self-reports of depressive symptoms and relative activity in the ventral striatum may have great relevance to treatment success because of the role of this region in drug abuse-related behaviors. Shifts in cortical-subcortical metabolic balance either reflect new processes that occur during early abstinence, or the unmasking of effects of chronic methamphetamine abuse that are obscured by suppression of cortical glucose metabolism that continues for at least 5-9 days after cessation of methamphetamine self-administration.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D, Gerth CW, Gross S, Schreiber D, Lilley K, Wayland M, Oxley D, Leweke FM, Bahn S
Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues.
Mol Psychiatry. 2007 Oct 16;
Although some insights into the etiology of schizophrenia have been gained, an understanding of the illness at the molecular level remains elusive. Recent advances in proteomic profiling offer great promise for the discovery of markers underlying pathophysiology of diseases. In the present study, we employed two high-throughput proteomic techniques together with traditional methods to investigate cerebrospinal fluid (CSF), brain and peripheral tissues (liver, red blood cells and serum) of schizophrenia patients in an attempt to identify peripheral/surrogate disease markers. The cohorts used to investigate each tissue were largely independent, although some CSF and serum samples were collected from the same patient. To address the major confounding factor of antipsychotic drug treatment, we also included a large cohort of first-onset drug-naive patients. Apolipoprotein A1 (apoA1) showed a significant decrease in expression in schizophrenia patients compared to controls in all five tissues examined. Specifically, using SELDI-TOF mass spectrometry, apoA1 was found decreased in CSF from schizophrenia patients (-35%, P=0.00001) and, using 2D-DIGE, apoA1 was also found downregulated in liver (-30%, P=0.02) and RBCs (-60%, P=0.003). Furthermore, we found a significant reduction of apoA1 in sera of first-onset drug-naive schizophrenia patients using enzyme-linked immunosorbent assay (-18%, P=0.00008) and in two investigations of post-mortem brain tissue using western blot analysis (-35%, P=0.05; -51%, P=0.05). These results show that apoA1 is consistently downregulated in the central nervous system as well as peripheral tissues of schizophrenia patients and may be linked to the underlying disease mechanism.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, Ffrench-Mullen J, Turecki G
Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression.
Mol Psychiatry. 2007 Oct 16;
The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Abou Jamra R, Becker T, Georgi A, Feulner T, Schumacher J, Stromaier J, Schirmbeck F, Schulze TG, Propping P, Rietschel M, Nöthen MM, Cichon S
Genetic variation of the FAT gene at 4q35 is associated with bipolar affective disorder.
Mol Psychiatry. 2007 Oct 16;
A recent study suggested that the cadherin gene FAT exerts an influence on susceptibility to bipolar affective disorder (BPAD). We aimed to replicate this finding in a German sample (425 BPAD I and 419 controls). In addition, we performed a comprehensive linkage disequilibrium mapping of the whole genomic region of FAT and the neighboring circadian gene MTNR1A (48 single nucleotide polymorphisms (SNPs) covering 191 kb). No significant association was observed for SNPs located in the MTNR1A gene. In FAT, however, nine SNPs showed association, eight of them being located in the same haplotype block found to be associated with BPAD by Blair et al. The smallest P-value of 0.00028 (OR 1.71) was seen for non-synonymous SNP rs2637777. A combination of five markers including this marker showed a haplotype distribution with a nominal P-value of 1.8 x 10(-5) that withstands correction for multiple testing. While the control allele frequencies between our sample and the samples of the original study are comparable, tendencies of risk allele frequencies are opposite. Possible explanations for this include potential differences in linkage disequilibrium structure between the German, Australian, UK, and Bulgarian populations sampling variation, multilocus effects and/or the occurrence of independent mutational events. We conclude that our results support an involvement of variation at the FAT gene in the etiology of BPAD, but that further work is needed both to clarify possible reasons for the observed risk allele differences and to ultimately identify the functionally relevant variant(s).Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Talati A, Fyer AJ, Weissman MM
A comparison between screened NIMH and clinically interviewed control samples on neuroticism and extraversion.
Mol Psychiatry. 2007 Oct 16;
The National Institute of Mental Health (NIMH) has supported the collection of DNA samples on over 4000 subjects for use primarily as controls in psychiatric genetic studies. These subjects, though screened online, were not directly interviewed or assessed on family history. We compared this sample to one that was directly interviewed using structured diagnostic assessments on comparable measures of neuroticism and extraversion. The screened sample completed an online self-report based on the Composite International Diagnostic Instrument Short-Form (CIDI-SF). The interviewed sample was assessed by clinically trained personnel using the Schedule for Affective Disorders and Schizophrenia (SADS-LA-IV) and Family History Screen; final diagnoses were made blind to trait scores by a clinician using the best-estimate procedure. Neuroticism and extraversion were assessed on the NEO five-factor inventory (NEO-FFI) and the revised Eysenck Personality Questionnaire short form (EPQ-R). We found that subjects in the NIMH-screened sample who did not report any psychiatric symptoms on the self-report were indistinguishable from interviewed diagnosis free and family history negative controls on neuroticism and extraversion. Subjects in the screened sample who screened positive for anxiety disorders, however, deviated significantly on these measures both from the screened subjects with no self-reported symptoms, as well as from subjects in the interviewed sample diagnosed with comparable disorders. These findings suggest that control groups generated from the NIMH sample should ideally be restricted to subjects free of any self-reported symptoms, regardless of the disorder being addressed, in order to maximize their reflection of diagnosis-free populations.Molecular Psychiatry advance online publication, 16 October 2007; doi:10.1038/ [Abstract]

Karoutzou G, Emrich HM, Dietrich DE
The myelin-pathogenesis puzzle in schizophrenia: a literature review.
Mol Psychiatry. 2007 Oct 9;
Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.Molecular Psychiatry advance online publication, 9 October 2007; doi:10.1038/ [Abstract]

Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM
The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons.
Mol Psychiatry. 2007 Oct 9;
Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium- or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium- or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3alpha or GSK-3beta isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.Molecular Psychiatry advance online publication, 9 October 2007; doi:10.1038/ [Abstract]

McIntosh AM, Moorhead TW, Job D, Lymer GK, Muñoz Maniega S, McKirdy J, Sussmann JE, Baig BJ, Bastin ME, Porteous D, Evans KL, Johnstone EC, Lawrie SM, Hall J
The effects of a neuregulin 1 variant on white matter density and integrity.
Mol Psychiatry. 2007 Oct 9;
Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.Molecular Psychiatry advance online publication, 9 October 2007; doi:10.1038/ [Abstract]

Catania C, Sotiropoulos I, Silva R, Onofri C, Breen KC, Sousa N, Almeida OF
The amyloidogenic potential and behavioral correlates of stress.
Mol Psychiatry. 2007 Oct 2;
Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-beta (Abeta). We also show that exogenous Abeta can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Abeta and GC. Previous work has indicated a role for Abeta in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Abeta administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Abeta, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Abeta include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.Molecular Psychiatry advance online publication, 2 October 2007; doi:10.1038/ [Abstract]

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK
The DISC locus in psychiatric illness.
Mol Psychiatry. 2007 Oct 2;
The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention.Molecular Psychiatry advance online publication, 2 October 2007; doi:10.1038/ [Abstract]

McIntosh AM, Moorhead TW, McKirdy J, Sussmann JE, Hall J, Johnstone EC, Lawrie SM
Temporal grey matter reductions in bipolar disorder are associated with the BDNF Val66Met polymorphism.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Reiners J, Schmidt M, Packer J, Unger L, Wernet W
A polymorphism linked to bipolar affective disorder does not alter the CRE activity of constitutively activated trace amine receptor 4.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Light KJ, Miller AL, Doughty CJ, Joyce PR, Olds RJ, Kennedy MA
FAT and bipolar affective disorder.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A
Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Sanchez MM, Alagbe O, Felger JC, Zhang J, Graff AE, Grand AP, Maestripieri D, Miller AH
Activated p38 MAPK is associated with decreased CSF 5-HIAA and increased maternal rejection during infancy in rhesus monkeys.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Buckholtz JW, Sust S, Tan HY, Mattay VS, Straub RE, Meyer-Lindenberg A, Weinberger DR, Callicott JH
fMRI evidence for functional epistasis between COMT and RGS4.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Horiuchi Y, Ishiguro H, Koga M, Inada T, Iwata N, Ozaki N, Ujike H, Muratake T, Someya T, Arinami T
Support for association of the PPP3CC gene with schizophrenia.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Walters JT, Owen MJ
Endophenotypes in psychiatric genetics.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Buckholtz JW, Prust M, Sust S, Tan HY, Mattay VS, Straub RE, Meyer-Lindenberg A, Weinberger DR, Callicott JH
Imaging epistasis in vivo: COMT and RGS4.
Mol Psychiatry. 2007 Oct;12(10): [Abstract]

Jungerius BJ, Hoogendoorn ML, Bakker SC, Van't Slot R, Bardoel AF, Ophoff RA, Wijmenga C, Kahn RS, Sinke RJ
An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia.
Mol Psychiatry. 2007 Sep 25;
Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P=6.1 x 10(-6)). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed P</=0.01). Our approach-of screening genes involved in a particular pathway for association-resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.Molecular Psychiatry advance online publication, 25 September 2007; doi:10.1038/ [Abstract]

Forbes EE, Brown SM, Kimak M, Ferrell RE, Manuck SB, Hariri AR
Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity.
Mol Psychiatry. 2007 Sep 25;
Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.Molecular Psychiatry advance online publication, 25 September 2007; doi:10.1038/ [Abstract]

Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP
Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition.
Mol Psychiatry. 2007 Sep 25;
Evidence both from animal and human studies suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are likely candidates to confer risk for autism spectrum disorders (ASD). In lower mammals, oxytocin is important in a wide range of social behaviors, and recent human studies have shown that administration of oxytocin modulates behavior in both clinical and non-clinical groups. Additionally, two linkage studies and two recent association investigations also underscore a possible role for the OXTR gene in predisposing to ASD. We undertook a comprehensive study of all 18 tagged SNPs across the entire OXTR gene region identified using HapMap data and the Haploview algorithm. Altogether 152 subjects diagnosed with ASDs (that is, DSM IV autistic disorder or pervasive developmental disorder-NOS) from 133 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED set of programs. Significant association with single SNPs and haplotypes (global P-values <0.05, following permutation test adjustment) were observed with ASD. Association was also observed with IQ and the Vineland Adaptive Behavior Scales (VABS). In particular, a five-locus haplotype block (rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated with ASD (nominal global P=0.000019; adjusted global P=0.009) and a single haplotype (carried by 7% of the population) within that block showed highly significant association (P=0.00005). This is the third association study, in a third ethnic group, showing that SNPs and haplotypes in the OXTR gene confer risk for ASD. The current investigation also shows association with IQ and total VABS scores (as well as the communication, daily living skills and socialization subdomains), suggesting that this gene shapes both cognition and daily living skills that may cross diagnostic boundaries.Molecular Psychiatry advance online publication, 25 September 2007; doi:10.1038/ [Abstract]

Bensemain F, Hot D, Ferreira S, Dumont J, Bombois S, Maurage CA, Huot L, Hermant X, Levillain E, Hubans C, Hansmannel F, Chapuis J, Hauw JJ, Schraen S, Lemoine Y, Buée L, Berr C, Mann D, Pasquier F, Amouyel P, Lambert JC
Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease.
Mol Psychiatry. 2007 Sep 25;
To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n=2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC -389 G/A and -241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.Molecular Psychiatry advance online publication, 25 September 2007; doi:10.1038/ [Abstract]

Recent Articles in Neuropsychopharmacology

Ricaurte GA
Dr lewis s seiden, 1934-2007.
Neuropsychopharmacology. 2008 Feb;33(2): . [Abstract]

Mello NK
Jack harold mendelson, 1929-2007.
Neuropsychopharmacology. 2008 Feb;33(2): [Abstract]

Galloway MP
Francis j white.
Neuropsychopharmacology. 2008 Feb;33(2): [Abstract]

Kuntzman R, Conney A
Dr john j burns, 1920-2007.
Neuropsychopharmacology. 2008 Feb;33(2): [Abstract]

Yuwiler A
Dr samuel eiduson, 1918-2007.
Neuropsychopharmacology. 2008 Feb;33(2): [Abstract]

Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A
Neural Pathways Underlying Lactate-Induced Panic.
Neuropsychopharmacology. 2007 Dec 5;
Panic disorder is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as 0.5 M sodium lactate infusions. Although studied for four decades, the mechanism of lactate sensitivity in panic disorder has not been understood. The dorsomedial hypothalamus/perifornical region (DMH/PeF) coordinates rapid mobilization of behavioral, autonomic, respiratory and endocrine responses to stress, and rats with disrupted GABA inhibition in the DMH/PeF exhibit panic-like responses to lactate, similar to panic disorder patients. Utilizing a variety of anatomical and pharmacological methods, we provide evidence that lactate, via osmosensitive periventricular pathways, activates neurons in the compromised DMH/PeF, which relays this signal to forebrain limbic structures such as the bed nucleus of the stria terminalis to mediate anxiety responses, and specific brainstem sympathetic and parasympathetic pathways to mediate the respiratory and cardiovascular components of the panic-like response. Acutely restoring local GABAergic tone in the DMH/PeF blocked lactate-induced panic-like responses. Autonomic panic-like responses appear to be a result of DMH/PeF-mediated mobilization of sympathetic responses (verified with atenolol) and resetting of the parasympathetically mediated baroreflex. Based on our findings, DMH/PeF efferent targets such as the C1 adrenergic neurons, paraventricular hypothalamus, and the central amygdala are implicated in sympathetic mobilization; the nucleus of the solitary tract is implicated in baroreflex resetting; and the parabrachial nucleus is implicated in respiratory responses. These results elucidate neural circuits underlying lactate-induced panic-like responses and the involvement of both sympathetic and parasympathetic systems.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301621. [Abstract]

Alvarez-Jaimes L, Polis I, Parsons LH
Attenuation of Cue-Induced Heroin-Seeking Behavior by Cannabinoid CB(1) Antagonist Infusions into the Nucleus Accumbens Core and Prefrontal Cortex, but Not Basolateral Amygdala.
Neuropsychopharmacology. 2007 Dec 5;
As with other drugs of abuse, heroin use is characterized by a high incidence of relapse following detoxification that can be triggered by exposure to conditioned stimuli previously associated with drug availability. Recent findings suggest that cannabinoid CB(1) receptors modulate the motivational properties of heroin-conditioned stimuli that induce relapse behavior. However, the neural substrates through which CB(1) receptors modulate cue-induced heroin seeking have not been elucidated. In this study, we evaluated alterations in cue-induced reinstatement of heroin-seeking behavior produced by infusions of the CB(1) receptor antagonist SR 141716A (0, 0.3 and 3 mug per side) delivered into the prefrontal cortex (PFC), nucleus accumbens (NAC), and basolateral amygdala (BLA) of rats. Results show that following extinction of operant behavior the presentation of a discriminative stimulus conditioned to heroin availability reinstated nonreinforced lever pressing to levels comparable to preextinction levels. Intra-PFC SR 141716A dose-dependently reduced cue-induced reinstatement of heroin seeking, with a significant reduction following the 3 mug per side dose. In the NAC, both SR 141716A doses induced a significant reduction in cue-induced reinstatement, with the highest dose completely blocking the effect of the cue. In contrast, intra-BLA SR 141716A did not alter cue-induced reinstatement of responding while systemic administration of this antagonist (3 mg/kg, i.p.) significantly blocked cue-induced reinstatement in all three-placement groups (BLA, PFC, and NAC). These findings provide new insights into the neural mechanisms through which CB(1) receptors modulate the motivational properties of heroin-associated cues inducing relapse.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301630. [Abstract]

Lang N, Hasan A, Sueske E, Paulus W, Nitsche MA
Cortical Hypoexcitability in Chronic Smokers? A Transcranial Magnetic Stimulation Study.
Neuropsychopharmacology. 2007 Dec 5;
Studies in animal models and humans indicate that chronic nicotine intake influences neuronal excitability, resulting in functional and structural CNS changes. The aim of the present study was to explore human primary motor cortex (M1) excitability with transcranial magnetic stimulation (TMS) in chronic smokers. A total of 44 right-handed volunteers, aged 20-30 years, participated in the study. Chronic smokers were compared with age- and sex-matched healthy nonsmokers. We tested cortical excitability with single- and paired-pulse TMS to the left M1 and short-latency afferent inhibition (SAI) by combining median nerve stimulation and motor cortex TMS. Compared with nonsmoking controls, chronic smokers showed a significantly larger amount of SAI, which is thought to depend upon the activity of cholinergic inhibitory circuits produced by somatosensory inputs. Moreover, TMS-evoked inhibitory cortical silent periods were prolonged, whereas paired-pulse intracortical facilitation and motor-evoked potentials during moderate contraction were reduced. The results suggest that chronic nicotine intake may not only strengthen cholinergic inhibitory circuits, but could also be associated with enhanced inhibitory and reduced facilitatory mechanism of specific neuronal circuits in motor cortex. These changes may form a physiological basis for neurobiological and behavioral variations associated with chronic smoking.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301645. [Abstract]

Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL
N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT(1A) Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity.
Neuropsychopharmacology. 2007 Dec 5;
Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H(1) receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT(1A), 5-HT(1E), 5-HT(2A), 5-HT(2B), 5-HT(7) receptors, the alpha(1B)-adrenergic receptor, and the M(1), M(3), and M(5) muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT(1D), 5-HT(2C), 5-HT(3), 5-HT(5), 5-HT(6), alpha(1A), alpha(2A), alpha(2B), alpha(2C), H(2), M(2), M(4), and dopamine D(1), D(2), D(3), and D(4) receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K(i) of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT(1A) receptor. N-Desalkylquetiapine was an antagonist at 5-HT(2A), 5-HT(2B), 5-HT(2C), alpha(1A), alpha(1D), alpha(2A), alpha(2C), H(1), M(1), M(3), and M(5) receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT(1A) agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301646. [Abstract]

Wang CZ, Yang SF, Xia Y, Johnson KM
Postnatal Phencyclidine Administration Selectively Reduces Adult Cortical Parvalbumin-Containing Interneurons.
Neuropsychopharmacology. 2007 Dec 5;
Transient postnatal NMDA receptor blockade by phencyclidine (PCP), ketamine, or MK-801 induces developmental neuroapoptosis and adult behavioral deficits, which resemble abnormal human behaviors typically present in schizophrenia. This study tested the hypothesis that PCP-induced developmental apoptosis causes a specific deficit of GABAergic interneurons containing parvalbumin (PV), calretinin (CR), or calbindin (CB). Young adult (PND56) rats that were given a single dose of PCP (10 mg/kg) on PND7 exhibited no densitometric change of either CR or CB neurons in any brain region studied, but demonstrated a selective deficit of PV-containing neurons in the superficial layers (II-IV) of the primary somatosensory (S1), motor (M), and retrosplenial cortices, but not in the striatum (CPu) or hippocampus. Further, CR and CB neurons, which were expressed at the time of PCP administration, showed no colocalization with cellular markers of apoptosis (terminal dUTP nick-end labeling (TUNEL) of broken DNA or cleaved caspase-3), indicating that CR- and CB-containing neurons were protected from the toxic effect of PCP and survived into adulthood. This suggests that the deletion of PV neurons occurred during development, but cleaved caspase-3 showed no colocalization with BrdU, a specific marker of S-phase proliferation. These data suggest that the loss of PV-containing neurons was not due to an effect of PCP on proliferating neurons, but rather an effect on post-mitotic neurons. The developmental dependence and neuronal specificity of this effect of PCP provides further evidence that this model may be valuable in exploring the pathophysiology of schizophrenia.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301647. [Abstract]

Gerdeman GL, Schechter JB, French ED
Context-Specific Reversal of Cocaine Sensitization by the CB(1) Cannabinoid Receptor Antagonist Rimonabant.
Neuropsychopharmacology. 2007 Dec 5;
The CB(1) cannabinoid receptor is implicated in the rewarding properties of many drugs of abuse, including cocaine. While CB(1) receptor involvement in the acute rewarding properties of cocaine is controversial, CB(1) antagonists such as SR141716 (rimonabant) have clearly been found to prevent cue- and cocaine-elicited reinstatement of cocaine self-administration in rodents. Here we demonstrate the novel involvement of CB(1) receptors in the maintenance of behavioral sensitization to cocaine in C57BL/6 mice. Consistent with previous reports, the induction of locomotor sensitization following repeated daily cocaine was not prevented by systemic pretreatment of either rimonabant, Delta(9)-tetrahydrocannabinol (THC), or a 1:1 mixture of THC and cannabidiol (CBD). In contrast, established cocaine sensitization was markedly disrupted following subchronic treatment with rimonabant alone. This effect was notably context-dependent, in that rimonabant did not diminish established cocaine sensitization if delivered in the home cage, but only if the rimonabant-injected mice were exposed to activity chambers previously paired with cocaine. These findings are consistent with CB(1) receptor involvement in conditioned cocaine-seeking behaviors, and further suggest that endocannabinoid (eCB)-mediated synaptic plasticity may act specifically within drug-paired environments to maintain cocaine-directed behavioral responses.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301648. [Abstract]

Uslaner JM, Dell'orco JM, Pevzner A, Robinson TE
The Influence of Subthalamic Nucleus Lesions on Sign-Tracking to Stimuli Paired with Food and Drug Rewards: Facilitation of Incentive Salience Attribution?
Neuropsychopharmacology. 2007 Dec 5;
It is well known that the subthalamic nucleus (STN) plays an important role in regulating motor function, but recent studies suggest the STN is also involved in regulating motivated behavior. For example, bilateral lesions of the STN increase motivation for both food and cocaine as assessed by 'breakpoint' on a progressive ratio schedule. However, the psychological mechanism(s) by which STN lesions increase motivation for rewards is unknown. We hypothesized that STN lesions might influence one specific component of motivation, the attribution of incentive value (incentive salience) to reward-related cues. We tested this hypothesis by quantifying the ability of a discrete cue that had been paired with the non-contingent delivery of either food or cocaine to elicit approach towards it (ie, to produce a 'sign-tracking' conditioned response, CR). STN lesions made prior to training increased asymptotic levels of sign-tracking behavior directed towards a cue paired with either food or cocaine. In addition, when STN lesions were made after animals had already undergone Pavlovian training, and animals were tested under extinction conditions, the STN lesion still facilitated a sign-tracking CR. Finally, reintroduction of the US (food) following extinction immediately restored robust sign-tracking behavior in animals with STN lesions. We speculate, therefore, that the STN is part of a neural system that moderates the amount of incentive salience attributed to reward-related stimuli. Activity in this neural system may help mitigate the development of compulsive behavioral disorders, such as addiction, which are characterized by pathological control over behavior by reward-associated cues.Neuropsychopharmacology advance online publication, 5 December 2007; doi:10.1038/sj.npp.1301653. [Abstract]

Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF
Metabotropic Glutamate 5 Receptor (mGluR5) Antagonists Decrease Nicotine Seeking, But Do Not Affect the Reinforcement Enhancing Effects of Nicotine.
Neuropsychopharmacology. 2007 Nov 28;
Nicotine self-administration models typically evaluate the effects of smoking cessation aides on 'primary reinforcement' engendered by nicotine. However, the more recently described reinforcement enhancing effects of the drug are not always included in experimental analyses of potential therapeutics. We evaluated the effects of pretreatment with noncompetitive antagonists of the metabotropic glutamate 5 receptor (mGluR5) on each reinforcement-related effect of nicotine using a model in which a reinforcing visual stimulus (VS) and nicotine infusions were concurrently available. Five groups (2-lever, VS-only, NIC+VS, NIC-only, or SAL-only) were instrumented for self-administration. The 2-lever group could earn a nicotine infusion (0.06 mg/kg per infusion free base) for meeting the schedule on one lever (eg right), or VS for meeting the schedule on the other lever (eg left). The VS-only group could earn VS or saline under similar contingencies. Remaining rats could press one lever to earn both reinforcers (NIC+VS), nicotine infusions (NIC-only), or saline infusions (SAL-only); the other lever was 'inactive'. Responding on the VS lever in the 2-lever group was greater than that of the VS-only group, reflecting the reinforcement-enhancing effect of nicotine. Pretreatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) decreased nicotine intake as well as the enhanced responding for the concurrently available VS. In follow-up studies, replacing nicotine via experimenter-administered infusions sustained the drugs reinforcement enhancing effect; neither MPEP nor MTEP decreased the enhancing effects of nicotine. These findings are consistent with other studies suggesting that mGlu5 receptors mediate nicotine seeking, but do not alter the reinforcement enhancing effects of nicotine.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301623. [Abstract]

Gibbs ME, Hutchinson DS, Summers RJ
Role of beta-Adrenoceptors in Memory Consolidation: beta(3)-Adrenoceptors Act on Glucose Uptake and beta(2)-Adrenoceptors on Glycogenolysis.
Neuropsychopharmacology. 2007 Nov 28;
Noradrenaline, acting via beta(2)- and beta(3)-adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated beta(3)- rather than beta(2)-ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na(+)/energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with beta(3)-AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with beta(2)-AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) beta(2)- and beta(3)-ARs consolidate memory by different mechanisms; beta(3)-ARs stimulate central glucose transport, whereas beta(2)-ARs stimulate central glycogenolysis.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301629. [Abstract]

Schubert M, Albrecht D
Activation of Kainate GLU(K5) Transmission Rescues Kindling-Induced Impairment of LTP in the Rat Lateral Amygdala.
Neuropsychopharmacology. 2007 Nov 28;
The amygdala is a component of the limbic system that plays a central role in emotional behavior and certain psychiatric diseases. Pathophysiological alterations of neuronal excitability in the amygdala are characteristic features of temporal lobe epilepsy and certain (epilepsy accompanying) psychiatric illnesses such as anxiety and depressive disorders. The role of kainate receptors in the activity of synaptic networks, in brain function, and diseases is still poorly understood. Various kainate receptor subtypes have been shown to contribute to synaptic transmission and modulate presynaptic release of glutamate and gamma-aminobutyric acid (GABA). Several lines of evidence point to the importance of GLU(K5) kainate receptors in epilepsy. In this study we investigated the role of specific GLU(K5) kainate receptor in the lateral nucleus of the amygdala (LA). The cellular mechanisms for emotional learning in the amygdala are believed to be the result of changes in synaptic transmission efficacy, similar to long-term potentiation (LTP). Here, we used both field potential and intracellular recordings in horizontal rat amygdala slices, and showed that LTP in the LA, induced by high-frequency stimulation of afferents running within LA, is impaired 48 h after the last induced seizure. This kindling-induced impairment was reversed by the specific kainate GLU(K5) agonist ATPA. Partial blockade of GABAergic transmission with the specific GABA(A) receptor antagonist SR95531 also significantly facilitated the induction of early LA-LTP, but only partially abolished the kindling-induced impairment of LA-LTP. This study shows that the stimulation of the GLU(K5) kainate receptor subtype rescues the kindling-induced impairment of LA-LTP at least within 48 h after the last seizure. Therefore, GLU(K5) kainate receptor subunits are involved in kindling-induced plasticity changes in the amygdala.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301633. [Abstract]

Ingram SL, Macey TA, Fossum EN, Morgan MM
Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists.
Neuropsychopharmacology. 2007 Nov 28;
Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of mu-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize mu-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC(50)=281 nM) compared to saline (EC(50)=8.8 muM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) suggesting that repeated morphine administration enhances agonist stimulation of mu-opioid receptor coupling to G-proteins. Although supersensitivity of mu-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of mu-opioid receptors.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301634. [Abstract]

McElligott ZA, Winder DG
alpha(1)-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders.
Neuropsychopharmacology. 2007 Nov 28;
The glutamatergic synapse in specific brain regions has been shown to be a site for convergence of stress and addictive substances. The bed nucleus of the stria terminalis (BNST), a nucleus that relays between higher order processing centers and classical reward and stress pathways, receives dense noradrenergic inputs that are known to influence behavioral paradigms of both anxiety and stress-induced relapse to drug seeking. alpha(1)-Adrenergic receptors (alpha(1)-ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an alpha(1)-AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20 min, but not a 10 min, application of 100 muM norepinephrine (NE) in a prazosin-sensitive manner. This alpha(1)-AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described alpha(1)-AR LTD in the hippocampus and visual cortex; however, it was dependent on the activation of L-type voltage gated calcium channels (VGCCs). In addition, alpha(1)-AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, alpha(1)-AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in alpha(2a)-AR and NE transporter (NET) knockout (KO) mice. Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301635. [Abstract]

Robinson ES, Dalley JW, Theobald DE, Glennon JC, Pezze MA, Murphy ER, Robbins TW
Opposing Roles for 5-HT(2A) and 5-HT(2C) Receptors in the Nucleus Accumbens on Inhibitory Response Control in the 5-Choice Serial Reaction Time Task.
Neuropsychopharmacology. 2007 Nov 28;
Serotonin (5-HT) is thought to play an important role in the regulation of behavioral inhibition. Studies manipulating 5-HT function in the rodent brain indicate that 5-HT receptors regulate distinct forms of impulsive behavior, including impulsive responding in the 5-choice serial reaction time task (5CSRTT). The present study investigates the loci of effects mediated by 5-HT(2A) and 5-HT(2C) receptors in attention and inhibitory response control using microinfusions targeted at the nucleus accumbens (NAc), prelimbic cortex (PL) and infralimbic cortex (IL). Rats were implanted with bilateral guide cannulas and received infusions of the selective 5-HT(2A) receptor antagonist M100907 (0.1 and 0.3 mug) or selective 5-HT(2C) receptor antagonist SB242084 (0.1 and 0.5 mug) immediately prior to testing. The results show that intra-NAc infusions of M100907 significantly decrease impulsive responding on the 5CSRTT and at the highest dose increased omissions as well. By contrast, infusions of SB242084 into the NAc selectively and dose-dependently increased impulsivity. Neither M100907 nor SB242084 significantly altered impulsive responding following either intra-PL or intra-IL administration. However, SB242084 significantly decreased omissions following intra-PL administration (0.5 mug only). These data reveal opposing effects on impulsivity following 5-HT(2A) and 5-HT(2C) blockade in the NAc. Our results suggest that the NAc, but not the PL or IL, is implicated in the mediation of the effects of M100907 and SB242084 on inhibitory response control during baseline 5CSRTT performance.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301636. [Abstract]

Bellgrove MA, Barry E, Johnson KA, Cox M, Dáibhis A, Daly M, Hawi Z, Lambert D, Fitzgerald M, McNicholas F, Robertson IH, Gill M, Kirley A
Spatial Attentional Bias as a Marker of Genetic Risk, Symptom Severity, and Stimulant Response in ADHD.
Neuropsychopharmacology. 2007 Nov 28;
Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (3' untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 3'-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301637. [Abstract]

Carpenter WT, Koenig JI
The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities.
Neuropsychopharmacology. 2007 Nov 28;
Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301639. [Abstract]

Böer U, Cierny I, Krause D, Heinrich A, Lin H, Mayr G, Hiemke C, Knepel W
Chronic Lithium Salt Treatment Reduces CRE/CREB-Directed Gene Transcription and Reverses Its Upregulation by Chronic Psychosocial Stress in Transgenic Reporter Gene Mice.
Neuropsychopharmacology. 2007 Nov 28;
The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced beta-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301640. [Abstract]

Dalton GL, Wang YT, Floresco SB, Phillips AG
Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear.
Neuropsychopharmacology. 2007 Nov 28;
Synaptic plasticity in the form of long-term potentiation (LTP) plays a critical role in the formation of a Pavlovian fear association. However, the role that synaptic plasticity plays in the suppression of a learned fear response remains to be clarified. Here, we assessed the role that long-term depression (LTD) plays in the acquisition, expression, and extinction of a conditioned fear response. We report that blockade of LTD with a GluR2-derived peptide (Tat-GluR2(3Y); 1.5 mumol/kg, i.v.) that blocks regulated alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis during an initial extinction training session disrupted both the expression and recall of extinction learning. A similar impairment of extinction during training, but not recall, was observed when NMDA receptor-dependent LTD was inhibited through the selective blockade of NMDA NR2B receptors with Ro 25-6981. In contrast, blockade of LTD with Tat-GluR2(3Y) during fear conditioning or during a fear recall test did not effect the expression or recall of either contextual or cue-induced conditioned fear. Similarly, administration of Tat-GluR2(3Y) prior to an extinction recall test did not affect spontaneous recovery or rate of re-extinction in previously extinguished rats. These data demonstrate that AMPA receptor endocytosis does not mediate acquisition or expression of conditioned fear, but may play a role in the extinction of fear memories. Furthermore, these findings suggest that LTD may be a molecular mechanism that facilitates the selective modification of a learned association while leaving intact the ability to form a new memory.Neuropsychopharmacology advance online publication, 28 November 2007; doi:10.1038/sj.npp.1301642. [Abstract]

Hot topics.
Neuropsychopharmacology. 2008 Jan;33(1): [Abstract]

Kalivas P, Manji HK
Neuroplasticity: a new window on therapeutics in neuropsychiatric disease.
Neuropsychopharmacology. 2008 Jan;33(1): [Abstract]

Enna SJ
Neuropsychopharmacology reviews: the next generation of progress.
Neuropsychopharmacology. 2008 Jan;33(1): [Abstract]

Beneyto M, Meador-Woodruff JH
Lamina-Specific Abnormalities of NMDA Receptor-Associated Postsynaptic Protein Transcripts in the Prefrontal Cortex in Schizophrenia and Bipolar Disorder.
Neuropsychopharmacology. 2007 Nov 21;
The hypothesis of N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia was initially based on observations that blockade of the NMDA subtype of glutamate receptor by noncompetitive antagonists, such as phencyclidine and ketamine, can lead to clinical symptoms similar to those present in schizophrenia. Recently, glutamate has also been implicated in the pathophysiology of the mood disorders. As impaired NMDA receptor activity may be the result of a primary defect in the NMDA receptors themselves, or secondary to dysfunction in the protein complexes that mediate their signaling, we measured expression of both NMDA subunits and associated postsynaptic density (PSD) proteins (PSD95, neurofilament-light (NF-L), and SAP102) transcripts in the dorsolateral prefrontal cortex in subjects with schizophrenia, bipolar disorder, major depression, and a comparison group using tissue from the Stanley Foundation Neuropathology Consortium. We found decreased NR1 expression in all three illnesses, decreased NR2A in schizophrenia and major depression, and decreased NR2C in schizophrenia. We found no changes of NR2B or NR2D. Receptor autoradiography revealed no alterations in receptor binding in any of the illnesses, indicating no change in total receptor number, but taken with the subunit data suggests abnormal receptor stoichiometry. In the same subjects, PSD95 was unchanged in all three illnesses, while reduced NF-L expression was found in schizophrenia, especially in large cells of layer V. SAP102 expression was reduced in bipolar disorder restricted to small cells of layer II and large cells of layer III in bipolar disorder. These alterations likely reflect altered signaling cascades associated with glutamate-mediated neurotransmission within specific cortical circuits in these psychiatric illnesses.Neuropsychopharmacology advance online publication, 21 November 2007; doi:10.1038/sj.npp.1301604. [Abstract]

Jonkman S, Risbrough VB, Geyer MA, Markou A
Spontaneous Nicotine Withdrawal Potentiates the Effects of Stress in Rats.
Neuropsychopharmacology. 2007 Nov 21;
Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-beta-erythroidine hydrobromide (DHbetaE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.Neuropsychopharmacology advance online publication, 21 November 2007; doi:10.1038/sj.npp.1301607. [Abstract]

Carroll BJ
'Effects of Risperidone Augmentation in Patients with Treatment-Resistant Depression: Results of Open-Label Treatment Followed by Double-Blind Continuation.'
Neuropsychopharmacology. 2007 Nov 21; [Abstract]

Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ
alpha6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens.
Neuropsychopharmacology. 2007 Nov 21;
Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing beta2 subunit-containing (beta2(*)) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of beta2(*)-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of alpha6beta2(*)-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The alpha6-specific antagonist alpha-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the beta2(*)-selective antagonist dihydro-beta-erythroidine (DHbetaE) in NAc, but less so in CPu. The greater role for alpha6(*)-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that alpha6beta2(*)-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other beta2(*)-nAChRs (eg alpha4(*)), These data offer new insights to suggest striatal alpha6(*)-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.Neuropsychopharmacology advance online publication, 21 November 2007; doi:10.1038/sj.npp.1301617. [Abstract]

George O, Mandyam CD, Wee S, Koob GF
Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments.
Neuropsychopharmacology. 2007 Nov 21;
Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3-17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.Neuropsychopharmacology advance online publication, 21 November 2007; doi:10.1038/sj.npp.1301626. [Abstract]

Rapaport MH
Response to Dr Bernard Carroll.
Neuropsychopharmacology. 2007 Nov 14; [Abstract]

Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, Bovet P, Bush AI, Conus P, Copolov D, Fornari E, Meuli R, Solida A, Vianin P, Cuénod M, Buclin T, Do KQ
Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients.
Neuropsychopharmacology. 2007 Nov 14;
In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.Neuropsychopharmacology advance online publication, 14 November 2007; doi:10.1038/sj.npp.1301624. [Abstract]

Clipperton AE, Spinato JM, Chernets C, Pfaff DW, Choleris E
Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice.
Neuropsychopharmacology. 2007 Nov 14;
There is an evolutionary advantage to learning food preferences from conspecifics, as social learning allows an individual to bypass the risks associated with trial and error individual learning. The social transmission of food preferences (STFP) paradigm examines this advantage. Females in the proestrus and diestrus phases of the estrous cycle show a prolonged preference for the demonstrated food relative to estrus and ovariectomized females. Additionally, both estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) knockout mice show impaired social recognition, which suggests that both receptors may be involved in other types of socially dependent learning, including the STFP. The present study investigated the effect of the ERalpha selective agonist PPT (1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole) and the ERbeta selective agonist WAY-200070 (7-Bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol) on the STFP. Results showed that ovariectomized (ovx) mice treated with PPT failed to learn the socially acquired preference, while WAY-200070-treated ovx mice showed a two-fold prolonged preference for the food eaten by their demonstrator. The effects of PPT on the socially acquired food preference cannot be explained by effects on the total food intake of the groups or on the type of interaction with the demonstrator mouse. The effects of WAY-200070 may be partially due to effects on Submissive Behavior. The higher WAY-200070 doses produced prolonged preferences similar to those seen previously in intact female mice during the proestrus and diestrus phases. This suggests that the estrous cycle's effects on social learning may be due to the action of ERbeta on Submissive Behavior, or to ERbeta countering that of ERalpha.Neuropsychopharmacology advance online publication, 14 November 2007; doi:10.1038/sj.npp.1301625. [Abstract]

Brown ES, Wolfshohl J, Shad MU, Vazquez M, Osuji IJ
Attenuation of the Effects of Corticosteroids on Declarative Memory with Lamotrigine.
Neuropsychopharmacology. 2007 Nov 14;
An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.Neuropsychopharmacology advance online publication, 14 November 2007; doi:10.1038/sj.npp.1301627. [Abstract]

Wong DF, Bra?i? JR, Singer HS, Schretlen DJ, Kuwabara H, Zhou Y, Nandi A, Maris MA, Alexander M, Ye W, Rousset O, Kumar A, Szabo Z, Gjedde A, Grace AA
Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET.
Neuropsychopharmacology. 2007 Nov 7;
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D(2) receptors (D(2)-R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA(rel)) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT(2A) receptors (5-HT(2A)R), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA(rel) was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D(2)-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D(2)-R, 5-HT(2A)R, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA(rel) and 5-HT(2A) BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA(rel) is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT(2A)R in individuals with TS who had increased DA(rel), suggest a condition of increased phasic DA(rel) modulated by low 5-HT in concomitant OCD.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301528. [Abstract]

Chen CH, Suckling J, Ooi C, Fu CH, Williams SC, Walsh ND, Mitterschiffthaler MT, Pich EM, Bullmore E
Functional Coupling of the Amygdala in Depressed Patients Treated with Antidepressant Medication.
Neuropsychopharmacology. 2007 Nov 7;
The amygdala plays a central role in various aspects of affect processing and mood regulation by its rich anatomical connections to other limbic and cortical regions. It is plausible that depressive disorders, and response to antidepressant drugs, may reflect changes in the physiological coupling between the amygdala and other components of affect-related large-scale brain systems. We explored this hypothesis by mapping the functional coupling of right and left amygdalae in functional magnetic resonance imaging data acquired from 19 patients with major depressive disorder and 19 healthy volunteers, each scanned twice (at baseline and 8 weeks later) during performance of an implicit facial affect processing task. Between scanning sessions, the patients received treatment with an antidepressant drug, fluoxetine 20 mg/day. We found that the amygdala was positively coupled bilaterally with medial temporal and ventral occipital regions, and negatively coupled with the anterior cingulate cortex. Antidepressant treatment was associated with significantly increased coupling between the amygdala and right frontal and cingulate cortex, striatum, and thalamus. Treatment-related increases in functional coupling to frontal and other regions were greater for the left amygdala than for the right amygdala. These results indicate that antidepressant drug effects can be measured in terms of altered coupling between components of cortico-limbic systems and that these effects were most clearly demonstrated by enhanced functional coupling of the left amygdala.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301593. [Abstract]

Ben Menachem-Zidon O, Goshen I, Kreisel T, Ben Menahem Y, Reinhartz E, Ben Hur T, Yirmiya R
Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis.
Neuropsychopharmacology. 2007 Nov 7;
The proinflammatory cytokine interleukin-1 (IL-1) within the brain is critically involved in mediating the memory impairment induced by acute inflammatory challenges and psychological stress. However, the role of IL-1 in memory impairment and suppressed neurogenesis induced by chronic stress exposure has not been investigated before now. We report here that mice that were isolated for 4 weeks displayed a significant elevation in hippocampal IL-1beta levels concomitantly with body weight loss, specific impairment in hippocampal-dependent memory, and decreased hippocampal neurogenesis. To examine the causal role of IL-1 in these effects, we developed a novel approach for long-term delivery of IL-1 receptor antagonist (IL-1ra) into the brain, using transplantation of neural precursor cells (NPCs), obtained from neonatal mice with transgenic overexpression of IL-1ra (IL-1raTG) under the glial fibrillary acidic protein promoter. Four weeks following intrahippocampal transplantation of IL-1raTG NPCs labeled with PKH-26, the transplanted cells were incorporated within the dentate gyrus and expressed mainly astrocytic markers. IL-1ra levels were markedly elevated in the hippocampus, but not in other brain regions, by 10 days and for at least 4 weeks post-transplantation. Transplantation of IL-1raTG NPCs completely rescued the chronic isolation-induced body weight loss, memory impairment, and suppressed hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham operated. The transplantation had no effect in group-housed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic isolation and suggest that transplantation of IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in chronic inflammatory and neurological conditions.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301606. [Abstract]

Biber K, Pinto-Duarte A, Wittendorp MC, Dolga AM, Fernandes CC, Von Frijtag Drabbe Künzel J, Keijser JN, de Vries R, Ijzerman AP, Ribeiro JA, Eisel U, Sebastião AM, Boddeke HW
Interleukin-6 Upregulates Neuronal Adenosine A(1) Receptors: Implications for Neuromodulation and Neuroprotection.
Neuropsychopharmacology. 2007 Nov 7;
The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A(1) receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A(1) receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301612. [Abstract]

Bechtholt AJ, Valentino RJ, Lucki I
Overlapping and Distinct Brain Regions Associated with the Anxiolytic Effects of Chlordiazepoxide and Chronic Fluoxetine.
Neuropsychopharmacology. 2007 Nov 7;
Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test. In the first experiment, rats were treated acutely with the anxiolytic, chlordiazepoxide (2.5 or 5 mg/kg, i.p.). In separate experiments, animals were implanted with osmotic minipumps delivering vehicle or fluoxetine (5 or 20 mg/kg per day s.c.) for 3 or 28 days. NIH was assessed by giving animals access to a familiar palatable food in a novel environment. Associated brain areas were identified using c-fos immunohistochemistry. NIH was mitigated by acute chlordiazepoxide and chronic fluoxetine. Both drugs reversed novelty-induced changes in c-fos expression in the lateral division of the posterolateral part of the bed nucleus of the stria terminalis (STLP), cingulate cortex (Cg), and dorsal field CA2 of the hippocampus (dCA2). Chronic fluoxetine additionally increased c-fos expression in the anterior nucleus accumbens (aAcb) and the piriform cortex (Pir). The effects of the drugs on c-fos expression in many regions correlated with anxiolytic efficacy. These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301616. [Abstract]

McClernon FJ, Kozink RV, Rose JE
Individual Differences in Nicotine Dependence, Withdrawal Symptoms, and Sex Predict Transient fMRI-BOLD Responses to Smoking Cues.
Neuropsychopharmacology. 2007 Nov 7;
Exposure to smoking cues increases craving for cigarettes and can precipitate relapse. Whereas brain imaging studies have identified a distinct network of brain regions subserving the processing of smoking cues, little is known about the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related blood oxygen level-dependent responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerström test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others. Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC) whereas negative associations were observed between prescan craving and reactivity in ventral striatum. Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC. Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus. Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables.Neuropsychopharmacology advance online publication, 7 November 2007; doi:10.1038/sj.npp.1301618. [Abstract]

Recent Articles in The Journal of Clinical Psychiatry

Nickel MK
Aripiprazole treatment of patients with borderline personality disorder.
J Clin Psychiatry. 2007 Nov;68(11):1815-6. [Abstract]

Hettema JM, Ross DE
A case of aripiprazole-related tardive akathisia and its treatment with ropinirole.
J Clin Psychiatry. 2007 Nov;68(11):1814-5. [Abstract]

Kane JM, Meltzer HY, Carson WH, McQuade RD, Marcus RN, Sanchez R
Dr. Kane and Colleagues Reply.
J Clin Psychiatry. 2007 Nov;68(11):1813-1814.
Abstract not available. [Abstract]

Rosenheck RA
Aripiprazole and perphenazine: no difference.
J Clin Psychiatry. 2007 Nov;68(11):1812-3; author reply 1813-4. [Abstract]

Plener PL, Kokaliari E
Response to self-injurious behaviors in a community sample of young women.
J Clin Psychiatry. 2007 Nov;68(11):1811; author reply 1811-2. [Abstract]

Favaro A, Ferrara S, Santonastaso P
Dr. Favaro and Colleagues Reply.
J Clin Psychiatry. 2007 Nov;68(11):1811-1812.
Abstract not available. [Abstract]

Bhat SK
Are you analyzing me?
J Clin Psychiatry. 2007 Nov;68(11):1809-10. [Abstract]

Kane JM
Teaching and practicing psychopharmacology.
J Clin Psychiatry. 2007 Nov;68(11):1807-8. [Abstract]

The roadmap for antipsychotic psychopharmacology: an overview.
J Clin Psychiatry. 2007 Nov;68(11):1799-806. [Abstract]

Saddichha S, Manjunatha N, Ameen S, Akhtar S
Effect of olanzapine, risperidone, and haloperidol treatment on weight and body mass index in first-episode schizophrenia patients in India: a randomized, double-blind, controlled, prospective study.
J Clin Psychiatry. 2007 Nov;68(11):1793-8.
OBJECTIVE: The presence of obesity and increases in body mass are important risk factors for cardiovascular disease and diabetes. This study examined the effects of olanzapine, risperidone, and haloperidol on weight, body mass index (BMI), and development of obesity in a drug-naive population compared with a matched healthy control group. METHOD: Consecutive patients during the period from June through October 2006 with DSM-IV schizophrenia at our referral psychiatric hospital were recruited for an extensive prospective study that included anthropometric measures of weight, waist circumference, waist-hip ratio, and BMI. Subjects were randomly assigned to receive haloperidol, olanzapine, or risperidone and compared with a matched healthy control group. The prevalence of obesity, which was the main outcome measure, was assessed on the basis of 2 criteria: revised World Health Organization (WHO) definition for Asians and criteria of the International Diabetes Federation (IDF). Inclusions started in June 2006, and patients were followed for a period of 6 weeks. RESULTS: The analysis of 66 patients showed a prevalence of overweight (WHO criteria) at 22.7% and obesity at 31.8% (IDF criteria). The prevalence of obesity (IDF criteria) in our patients is over 30 times as high as that of the matched healthy control group (p < .001). Subjects in the olanzapine group had the greatest weight gain at 5.1 kg, followed by risperidone at 4.1 kg and haloperidol at 2.8 kg. CONCLUSIONS: Obesity is highly prevalent among patients treated with atypical antipsychotics for schizophrenia. Assessment and monitoring of obesity along with preventive and curative measures should be part of the clinical management of patients treated with antipsychotics. TRIAL REGISTRATION:, NCT00534183, [Abstract]

Schaffer A, Cairney J, Veldhuizen S, Cheung A, Levitt A
Comparison of antidepressant use between subjects with bipolar disorder and major depressive disorder with or without comorbid anxiety.
J Clin Psychiatry. 2007 Nov;68(11):1785-92.
OBJECTIVE: Antidepressants are recommended for the treatment of depressive and anxiety symptoms in patients with major depressive disorder, but caution is urged when used for the treatment of these symptoms in bipolar disorder. It is not known whether these differing recommendations are reflected in clinical practice, as comparative analyses of rates of antidepressant use between bipolar disorder and major depressive disorder subjects with or without comorbid anxiety have not been reported. METHOD: Data source was the Canadian Community Health Survey on Mental Health and Well-Being, a large, representative mental health survey conducted from May to December 2002. Rates of antidepressant use were compared for subjects with bipolar disorder according to the World Mental Health-Composite International Diagnostic Interview or major depressive disorder according to DSM-IV criteria, with or without comorbid anxiety (DSM-IV). The independent effects of the diagnostic group and of a comorbid anxiety disorder were determined by controlling for sociodemographic and clinical variables using logistic regression. RESULTS: Rate of antidepressant use was significantly higher among all subjects with bipolar disorder (N = 756) compared with all subjects with major depressive disorder (N = 3863) (27.2% vs. 23.1%, p = .02), but this difference was no longer significant when other factors were controlled for in the regression analysis. With the major depressive disorder without anxiety group as the reference, the likelihood of antidepressant use was significantly higher in both the bipolar disorder with anxiety group (OR = 1.83, 95% CI = 1.02 to 3.27, p = .04) and the major depressive disorder with anxiety group (OR = 1.45, 95% CI = 1.00 to 2.09, p = .05). CONCLUSION: After sociodemographic and clinical variables were controlled for, similar rates of antidepressant use were identified among bipolar disorder and major depressive disorder subjects. Further efforts are needed to enhance screening for bipolar disorder among depressed patients and to re-examine the risk/benefit analysis of antidepressants for bipolar disorder patients in light of emerging alternatives. Significantly increased rates of antidepressant use in subjects with a comorbid anxiety disorder suggest that anxiety symptoms may be a key reason why physicians are choosing to prescribe antidepressants for patients with bipolar disorder and major depressive disorder. [Abstract]

Wingo AP, Ghaemi SN
A systematic review of rates and diagnostic validity of comorbid adult attention-deficit/hyperactivity disorder and bipolar disorder.
J Clin Psychiatry. 2007 Nov;68(11):1776-84.
OBJECTIVE: Adult attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized and reported to frequently coexist with bipolar disorder. Concurrent diagnosis of adult ADHD and bipolar disorder remains controversial. In this study, we conducted a systematic review to examine the rates and diagnostic validity of the concept of comorbid adult ADHD and bipolar disorder. DATA SOURCES: MEDLINE, Embase, PsycInfo, and Cochrane databases were searched for articles published before March 30, 2007, using the keywords manic, bipolar, attention deficit hyperactivity, and adult. The computer search was supplemented with bibliographic cross-referencing. STUDY SELECTION: Exclusion criteria were studies with only pediatric subjects, childhood ADHD only but not adult ADHD, and either bipolar disorder or ADHD only, but not both; review articles, case reports; letters to the editor; and book chapters. Of the 262 citations found, 12 studies met our inclusion criteria. DATA EXTRACTION: Specific diagnostic validating criteria examined were phenomenology, course of illness, heredity, biological markers, and treatment response. There were 6 studies on comorbid rates, 4 on phenomenology, 3 on course of illness, 2 on heredity, none on biological markers, and 1 on treatment response. DATA SYNTHESIS: The proposed comorbid syndrome is fairly common (present in up to 47% of adult ADHD and 21% of bipolar disorder populations), with a more severe course of illness compared with that of bipolar disorder alone, and high rates of comorbidity with other psychiatric disorders. Its treatment appears to require initial mood stabilization. CONCLUSIONS: Comorbid adult ADHD and bipolar disorder has been insufficiently studied, with more emphasis on comorbidity rates and few data on course, neurobiology, heredity, and treatment. The diagnostic validity of adult ADHD/ bipolar disorder as a true comorbidity is not well-established on the basis of this equivocal and insufficient literature. More studies are greatly needed to further clarify its diagnostic validity and treatment approach. [Abstract]

Freeman MP
Early Careers and New Data.
J Clin Psychiatry. 2007 Nov;68(11):1775.
Abstract not available. [Abstract]

Gaebel W, Riesbeck M, Wölwer W, Klimke A, Eickhoff M, von Wilmsdorff M, Jockers-Scherübl MC, Kühn KU, Lemke M, Bechdolf A, Bender S, Degner D, Schlösser R, Schmidt LG, Schmitt A, Jäger M, Buchkremer G, Falkai P, Klingberg S, Köpcke W, Maier W, Häfner H, Ohmann C, Salize HJ, Schneider F, Möller HJ
Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German research network on schizophrenia.
J Clin Psychiatry. 2007 Nov;68(11):1763-74.
OBJECTIVE: Second-generation antipsychotics (SGAs) have proven superior to first-generation antipsychotics regarding relapse prevention, mainly in multiple-episode patients. Practice guidelines recommend SGAs as first-line treatment particularly in first-episode patients, although evidence for this group is still limited. Accordingly, the hypothesis of whether 1-year relapse rate in first-episode schizophrenia under maintenance treatment with risperidone is lower compared to haloperidol in low dose was tested. METHOD: Between November 2000 and May 2004, 1372 patients had been screened for eligibility in the inpatient facilities of 13 German psychiatric university hospitals. 159 remitted patients were enrolled after treatment of an acute first episode of schizophrenia according to ICD-10 F20 criteria. In the randomized controlled trial, double-blind antipsychotic treatment with risperidone or haloperidol was maintained in a targeted dose of 2 to 4 mg/day for 1 year. 151 patients were eligible for analysis. For 127 patients, this was a continuation trial after 8 weeks of randomized, double-blind, acute treatment with the same drugs; 24 patients were additionally randomly assigned after open acute treatment. RESULTS: With both antipsychotics (risperidone, N = 77; haloperidol, N = 74), no relapse evolved. Additionally, according to 2 post hoc defined measures of "marked clinical deterioration," significant differences occurred neither in the 2 respective deterioration rates (risperidone = 9%/23%; haloperidol = 8%/22%) nor in time until deterioration. Both antipsychotics were equally effective regarding significant symptom reduction and improvement in quality of life. Extrapyramidal symptoms were slightly higher with haloperidol. The overall dropout rate of 68%, however, was not significantly different between the 2 drug groups. CONCLUSION: Against the background of an overall favorable outcome, the hypothesized difference between risperidone and low-dose haloperidol regarding relapse prevention could not be supported for this sample of patients with first-episode schizophrenia. Possible design-related reasons for this finding are discussed. With regard to the high dropout rate, special programs are needed to keep schizophrenia patients who are in their early acute and postacute illness course in effective and safe treatment. CLINICAL TRIALS REGISTRATION: identifier: NCT00159081. [Abstract]

Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, Essock SM, Finnerty M, Marder SR, Miller del D, McEvoy JP, Robinson DG, Schooler NR, Shon SP, Stroup TS, Miller AL
The Texas medication algorithm project antipsychotic algorithm for schizophrenia: 2006 update.
J Clin Psychiatry. 2007 Nov;68(11):1751-62.
BACKGROUND: A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness. METHOD: Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference. RESULTS: The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus). CONCLUSIONS: These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available. [Abstract]

Kamath P, Reddy YC, Kandavel T
Suicidal behavior in obsessive-compulsive disorder.
J Clin Psychiatry. 2007 Nov;68(11):1741-50.
OBJECTIVE: There are limited data on suicidal behavior in obsessive-compulsive disorder (OCD). This study examines suicidal behavior and its clinical correlates in OCD subjects. METHOD: One hundred consecutive DSM-IV OCD subjects attending the specialty OCD clinic and the inpatient services of a major psychiatric hospital in India from November 1, 2003, to October 31, 2004, formed the sample of this study. Subjects were assessed systematically by using structured interviews and various rating scales. The Scale for Suicide Ideation-worst ever (lifetime) and -current measured suicidal ideation. The 24-item Hamilton Rating Scale for Depression (HAM-D) measured severity of depression, and the Beck Hopelessness Scale (BHS) measured hopelessness. We performed assessments at study entry. We employed binary logistic regression (Wald) forward stepwise analysis for prediction of suicidal ideation and suicide attempt, and we used structural equation modeling for identifying the potential factors contributing to suicidal ideation. RESULTS: The rates of suicidal ideation, worst ever and current, were 59% and 28%, respectively. History of suicide attempt was reported in 27% of the subjects. For past suicide attempt, worst ever suicidal ideation (p < .001) was the only significant predictor, with an overall prediction of 89%, and accounted for 60% of the variance. For worst ever suicidal ideation, major depression (p = .043), HAM-D score (p = .013), BHS score (p = .011), and history of attempt (p = .009) were significant predictors, with an overall prediction of 82% and variance of 56%. Somewhat similar predictors emerged as significant for current suicidal ideators, with an overall prediction of 85% and variance of 50%. In the structural equation model, too, presence of depression and high BHS score contributed to suicidal ideation. CONCLUSIONS: OCD is associated with a high risk for suicidal behavior. Depression and hopelessness are the major correlates of suicidal behavior. It is vital that patients with OCD undergo detailed assessment for suicide risk and associated depression. Aggressive treatment of depression may be warranted to modify the risk for suicide. Future studies should examine suicidal behavior in a prospective design in larger samples to examine if severity of OCD and treatment nonresponse contribute to suicide risk. [Abstract]

Perez-Iglesias R, Crespo-Facorro B, Amado JA, Garcia-Unzueta MT, Ramirez-Bonilla ML, Gonzalez-Blanch C, Martinez-Garcia O, Vazquez-Barquero JL
A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive, first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone.
J Clin Psychiatry. 2007 Nov;68(11):1733-40.
OBJECTIVE: This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first-episode drug-naive subjects. METHOD: A randomized, open-label, prospective clinical trial was conducted. Participants were 145 consecutive subjects included in a first-episode psychosis program (PAFIP) from February 2002 to February 2005, experiencing their first episode of psychosis (DSM-IV codes 295, 297, and 298), and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine, or risperidone treatment during 12 weeks. The main outcome measures were changes at 12 weeks in body weight; body mass index; and 12-hours-fasting morning levels of total cholesterol, tri-glycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, glucose, homeostasis model assessment (HOMA) index, and insulin. RESULTS: At the endpoint, 128 patients were evaluated (88.3%). The mean doses were haloperidol = 4.2 mg/day, olanzapine = 12.7 mg/day, and risperidone = 3.6 mg/day. A significant weight gain was observed with the 3 antipsychotics: haloperidol = 3.8 (SD = 4.9) kg, olanzapine = 7.5 (SD = 5.1) kg, and risperidone = 5.6 (SD = 4.5) kg. Metabolic parameters showed a worsening lipid profile with the 3 treatments (statistically significant increase in total cholesterol and LDL cholesterol levels). Only the olanzapine group showed significant increases in triglyceride levels. After the 12-week study period, there were no significant changes in parameters involving glucose metabolism for any group. CONCLUSIONS: Drug-naive patients experienced an extraordinary weight gain with first- and second-generation antipsychotics after the first 12 weeks of treatment. Significant increases in total cholesterol and LDL cholesterol levels are associated with the 3 treatments. Weight gain and metabolic disturbances induced by antipsychotics may increase the risk of developing cardiovascular disease. [Abstract]

Lemoine P, Guilleminault C, Alvarez E
Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine.
J Clin Psychiatry. 2007 Nov;68(11):1723-32.
OBJECTIVE: Patients with major depressive disorder (MDD) experience sleep disturbances that may be worsened by some antidepressant drugs early in treatment. The aim of this study was to assess the subjective quality of sleep of patients receiving agomelatine, a new antidepressant with melatonergic MT(1) and MT(2) receptor agonist and 5-HT(2C) antagonist properties, compared with that of patients receiving venlafaxine, a serotonin-norepinephrine reuptake inhibitor. METHOD: This double-blind, randomized study involved 332 patients with MDD (DSM-IV criteria), lasted 6 weeks, and compared the effects of agomelatine 25-50 mg/day and venlafaxine 75-150 mg/day, with a possible dose adjustment at 2 weeks. Subjective sleep was assessed with the Leeds Sleep Evaluation Questionnaire (LSEQ), and the main efficacy criterion was the "getting to sleep" score. Antidepressant efficacy was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions (CGI) global improvement scale. The study was performed between November 2002 and June 2004. RESULTS: After 6 weeks, the antidepressant efficacy of agomelatine was similar to that of venlafaxine. The LSEQ "getting to sleep" score was significantly better with agomelatine (70.5 +/- 16.8 mm) than with venlafaxine (64.1 +/- 18.2 mm); the between-treatment difference at the last visit was 6.36 mm (p = .001), and the difference was already significant at week 1. Secondary sleep items, including LSEQ quality of sleep (p = .021), sleep awakenings (p = .040), integrity of behavior (p = .024), and sum of HAM-D items 4, 5, and 6 (insomnia score) (p = .044), were also significantly improved compared to venlafaxine, as was the CGI global improvement score (p = .016). Incidence of adverse events was 52.1% with agomelatine and 57.1% with venlafaxine, and withdrawals due to adverse events were more common with venlafaxine than with agomelatine (13.2% vs. 4.2%). CONCLUSION: Agomelatine showed similar antidepressant efficacy with earlier and greater efficacy in improving subjective sleep than venlafaxine in MDD patients. [Abstract]

Grant JE, Won Kim S
Clinical characteristics and psychiatric comorbidity of pyromania.
J Clin Psychiatry. 2007 Nov;68(11):1717-22.
BACKGROUND: There have been few systematic studies of individuals with pyromania, and this paucity of research has hindered our understanding and treatment of this disorder. This study details the demographic and phenomenological features of individuals with DSM-IV lifetime pyromania. METHOD: Twenty-one adult and adolescent subjects (recruited from inpatient and outpatient studies of impulse-control disorders) with lifetime DSM-IV pyromania were administered a semi-structured interview to elicit demographic data and information on the phenomenology, age at onset, and associated features of the disorder. Data were collected from October 2003 to September 2006. RESULTS: Twenty-one subjects (10 female [47.6%]) with lifetime pyromania (mean +/- SD age = 26.1 +/- 11.8 years; range, 15-49 years) were studied. The mean +/- SD age at onset for pyromania was 18.1 +/- 5.8 years. Eighteen subjects (85.7%) reported urges to set fires. Subjects reported a mean +/- SD frequency of setting 1 fire every 5.9 +/- 3.8 weeks. Much of the fire setting did not meet the legal definition of arson. Thirteen (61.9%) had a current comorbid Axis I mood disorder, and 10 (47.6%) met criteria for a current impulse-control disorder. CONCLUSION: Pyromania appears to be associated with high rates of psychiatric comorbidity. Research is needed to optimize patient care for individuals with this disorder. [Abstract]

Brecht S, Courtecuisse C, Debieuvre C, Croenlein J, Desaiah D, Raskin J, Petit C, Demyttenaere K
Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial.
J Clin Psychiatry. 2007 Nov;68(11):1707-16.
OBJECTIVE: Experience of pain in major depressive disorder (MDD) can complicate diagnosis and impair treatment outcomes. This study evaluated the efficacy and safety of duloxetine in the treatment of patients with moderate pain associated with depression. METHOD: In this double-blind, placebo-controlled, 8-week study, conducted from May 2005 to May 2006, outpatients 18 years of age or older, presenting with major depressive disorder (DSM-IV criteria; Montgomery-Asberg Depression Rating Scale [MADRS] score >or= 20), moderate pain (Brief Pain Inventory-Short Form [BPI-SF] average pain score >or= 3), and Clinical Global Impressions-Severity of Illness scale (CGI-S) score >or= 4 were randomly assigned to either placebo (N = 165) or duloxetine 60 mg (N = 162) once daily. Primary outcome was change in item 5 score (average pain in the last 24 hours) of the BPI-SF from baseline. Secondary measures were MADRS total score, other BPI-SF items, CGI-S, CGI-Improvement scale, Patient Global Impressions-Improvement scale, Symptom Checklist-90-Revised, response and remission rates, safety, and tolerability. RESULTS: Duloxetine, compared with placebo, significantly reduced pain and improved depression with significant mean changes at endpoint in both BPI-SF average pain scores (-2.57 vs. -1.64, p < .001) and in MADRS total scores (-16.69 vs. -11.31, p < .001). Remission of MDD and response rates in pain and MDD were significantly (p <or= .001) higher in duloxetine-treated patients. Duloxetine separated from placebo on most secondary outcome measures including the BPI-SF interference with daily life due to pain. Treatment-emergent adverse events (>or= 10%) in duloxetine-treated patients were nausea, hyperhidrosis, and dry mouth. CONCLUSION: These results support duloxetine's efficacy and tolerability in the treatment of pain and depression in patients with at least moderate pain associated with depression. TRIAL REGISTRATION: identifier NCT00191919 ( [Abstract]

Rasmussen KG, Mueller M, Knapp RG, Husain MM, Rummans TA, Sampson SM, O'Connor MK, Petrides G, Fink M, Kellner CH
Antidepressant medication treatment failure does not predict lower remission with ECT for major depressive disorder: a report from the consortium for research in electroconvulsive therapy.
J Clin Psychiatry. 2007 Nov;68(11):1701-6.
OBJECTIVE: To test whether antidepressant medication treatment failure predicts differential remission with electroconvulsive therapy (ECT) in nonpsychotic unipolar depression. METHOD: Depressed patients diagnosed with the Structured Clinical Interview for DSM-IV receiving ECT were assessed for medication use with the Antidepressant Treatment History Form (ATHF) (N = 345). Response to ECT was assessed with the 24-item Hamilton Rating Scale for Depression. Baseline medication treatment failure was analyzed as a possible predictor of remission status. Dates of study enrollment were from May 1997 to July 2004. RESULTS: Resistance to antidepressant medication as assessed by the ATHF, either taken as a whole or for any individual class of medication, was not predictive of acute remission status with ECT. CONCLUSION: Treatment failure with anti-depressant medication does not predict acute remission status with ECT for nonpsychotically depressed patients. [Abstract]

Furieri FA, Nakamura-Palacios EM
Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2007 Nov;68(11):1691-700.
OBJECTIVE: This study examined the efficacy of a 28-day gabapentin treatment in reducing alcohol consumption and craving. METHOD: A randomized, double-blind, placebo-controlled trial was performed in a Brazilian public outpatient drug treatment center, with 60 male alcohol-dependent subjects with a mean age of 44 years and an average of 27 years of alcohol use, who consumed 17 drinks per day (165-170 g/day) over the past 90 days before baseline and had no other significant medical or psychiatric condition. Subjects were recruited between July 8, 2004, and February 24, 2005. Following screening, 60 subjects were selected and received diazepam and vitamins as treatment for acute withdrawal for at least 7 days. After the detoxification treatment, 30 subjects were randomly assigned to receive gabapentin (300 mg twice daily) for 4 weeks, and 30 subjects, with similar baseline characteristics, were randomly assigned to receive matching placebo tablets for the same period. RESULTS: After 28 days of treatment, the gabapentin group showed a significant reduction in both number of drinks per day and mean percentage of heavy drinking days (p = .02 for both), and an increase in the percentage of days of abstinence (p = .008), compared to the placebo group. Additionally, some improvement in obsessive-compulsive symptoms was noted in both groups after the treatment, but it resulted in a more pronounced decrease in automaticity of drinking and aspects of craving in the gabapentin group than in the placebo group. CONCLUSION: Gabapentin reduces alcohol consumption and craving, which may help patients to maintain abstinence. These results, together with the virtual absence of side effects and a favorable safety profile, support gabapentin as a potential drug for the treatment of alcohol withdrawal and dependence. [Abstract]

Bushe CJ, Leonard BE
Blood glucose and schizophrenia: a systematic review of prospective randomized clinical trials.
J Clin Psychiatry. 2007 Nov;68(11):1682-90.
OBJECTIVE: Most of the data evaluating the potential relationship between diabetes, schizophrenia, and anti-psychotics currently derive from retrospective analysis. Relevant confounders of such data include screening and selection bias. Prospective data collected from randomized controlled trials may reduce such biases. As no single trial has glucose comparisons as a primary endpoint, we undertook a systematic review of available data. DATA SOURCES: Embase, HealthStar, MEDLINE, Pre-MEDLINE, and PsycINFO databases were searched online for relevant articles. Abstracts from major congresses held between January 2000 and April 2006 were included. Search terms included all currently available antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone, aripiprazole, haloperidol, chlorpromazine, and zotepine. STUDY SELECTION: Prospective clinical trials involving schizophrenia patients with no stated previous glucose abnormalities randomly assigned to cohorts receiving active or placebo comparator antipsychotic medications were included with no restrictions on study length. 16 studies were from peer-reviewed publications, 4 were from posters at major congresses, and 2 were available only on Internet-based sites. DATA EXTRACTION: Glucose parameters reported included fasting and random glucose and glycosylated hemoglobin. Data reported included mean changes and categorical reports of abnormal levels. DATA SYNTHESIS: Data were available in 6329 patients from 22 trials. The most common comparator agents were aripiprazole and olanzapine in 4 studies including 1432 patients. 14 studies reported fasting and 9 studies reported nonfasting data. 15 studies were a minimum of 5 months, with 8 studies of at least 1 year's duration. No consistent significant glucose differences were found between any comparator antipsychotics or placebo in any trial. CONCLUSIONS: In contrast to some of the retrospective data, an analysis of prospective data from randomized clinical trials showed no consistent significant differences in the incidence of treatment-emergent glucose abnormalities in patients treated with antipsychotics. The reduction in both screening and selection biases may be relevant. Although one third of the studies had at least 1 year's duration, the data are not sufficient to reach conclusions regarding patients receiving longer-term treatment with atypical antipsychotics. [Abstract]

Munk Laursen T, Munk-Olsen T, Nordentoft M, Bo Mortensen P
A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a danish population-based cohort.
J Clin Psychiatry. 2007 Nov;68(11):1673-81.
OBJECTIVE: Growing evidence of an etiologic overlap between schizophrenia and bipolar disorder has become increasingly difficult to disregard. In this study, we examined paternal age, urbanicity of place of birth, being born "small for gestational age," and parental loss as risk factors for primarily schizophrenia and bipolar disorder, but also unipolar depressive disorder and schizo-affective disorder. Furthermore, we examined the incidence of the disorders in a population-based cohort and evaluated our results in the context of the Kraepelinian dichotomization. METHOD: We established a register-based cohort study of more than 2 million persons born in Denmark between January 1, 1955, and July 1, 1987. Overall follow-up began on January 1, 1973 and ended on June 30, 2005. Relative risks for schizophrenia, bipolar disorder, unipolar depressive disorder, and schizoaffective disorder (ICD-8 or ICD-10) were estimated by survival analysis, using Poisson regression. RESULTS: Differences were found in age-specific incidences. Loss of a parent (especially by suicide) was a risk factor for all 4 disorders. High paternal age and urbanization at birth were risk factors for schizophrenia. Children born pre-term had an excess risk of all disorders except schizophrenia if they were born "small for gestational age." CONCLUSIONS: An overlap in the risk factors examined in this study was found, and the differences between the phenotypes were quantitative rather than qualitative, which suggests a genetic and environmental overlap between the disorders. However, large gender differences and differences in the age-specific incidences in the 4 disorders were present, favoring the Kraepelinian dichotomization. [Abstract]

Liebowitz MR, Yeung PP, Entsuah R
A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder.
J Clin Psychiatry. 2007 Nov;68(11):1663-72.
OBJECTIVE: This study evaluated the efficacy and tolerability of desvenlafaxine succinate (desvenlafaxine) in the treatment of major depressive disorder (MDD). METHOD: In this 8-week, multicenter, randomized, double-blind, placebo-controlled trial, adult outpatients (aged 18-75 years) with a primary diagnosis of MDD (DSM-IV criteria) were randomly assigned to treatment with desvenlafaxine (100-200 mg/day) or placebo. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score at final on-therapy evaluation. The Clinical Global Impressions-Improvement scale (CGI-I) was the key secondary measure. Other secondary measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness scale, Visual Analog Scale-Pain Intensity (VAS-PI) overall and subcomponent scores, and HAM-D(17) response and remission rates. The study was conducted from June 2003 to May 2004. RESULTS: Of the 247 patients randomly assigned to treatment, 234 comprised the intent-to-treat population. Following titration, mean daily desvenlafaxine doses ranged from 179 to 195 mg/day. At endpoint, there were no significant differences in scores between the desvenlafaxine (N = 120) and placebo (N = 114) groups on the HAM-D(17) or CGI-I. However, the desvenlafaxine group had significantly greater improvement in MADRS scores (p = .047) and in VAS-PI overall pain (p = .008), back pain (p = .006), and arm, leg, or joint pain (p < .001) scores than the placebo group. The most common treatment-emergent adverse events (at least 10% and twice the rate of placebo) were nausea, dry mouth, constipation, anorexia, somnolence, and nervousness. CONCLUSION: Desvenlafaxine was generally safe and well tolerated. In this study, it did not show significantly greater efficacy than placebo on the primary or key secondary efficacy endpoints, but it did demonstrate efficacy on an alternate depression scale and pain measure associated with MDD. CLINICAL TRIALS REGISTRATION: identifier NCT00063206. [Abstract]

Torres LR, Zayas LH, Cabassa LJ, Pérez MC
Diagnosing co-occurring substance-related disorders: agreement between SCID, Hispanic clinicians, and Non-Hispanic clinicians.
J Clin Psychiatry. 2007 Nov;68(11):1655-62.
OBJECTIVE: Given the composition of the mental health and substance abuse workforce in the United States, Hispanic immigrants are often assigned to non-Hispanic, English-speaking clinicians. This produces challenges in communication and in understanding linguistic and cultural nuances and greatly impacts the accuracy of diagnoses and the delivery of appropriate services. With the inclusion of objective criteria in diagnostic categories, clinician-to-clinician agreement ought not to be impacted by the ethnicity of the client or the clinician. Both practice and research, however, suggest that this is not the case, particularly when diagnosing co-occurring mental health and substance abuse disorders. We explored the degree to which Hispanic and non-Hispanic clinicians agreed with each other and with the Structured Clinical Interview for DSM-IV-TR, Research Version (SCID) when diagnosing co-occurring substance-related disorders. METHOD: Using a naturalistic design, 88 adult clients were videotaped in diagnostic intake interviews (utilizing the DSM-IV-TR) with Hispanic or non-Hispanic clinicians. Videotapes were then viewed and rated by clinicians who were ethnically cross-matched to those on tape. Clients were also administered the SCID. Data were collected from September 15, 2003, through February 7, 2005. RESULTS: Non-Hispanic clinicians diagnosed significantly more substance-related disorders than Hispanic clinicians, and both Hispanic and non-Hispanic clinicians significantly under-diagnosed substance-related diagnoses compared to the SCID. Clinicians had very low diagnostic reliability with each other and with the SCID. Implications for the assessment, diagnosis, and treatment of co-occurring substance-related disorders are discussed. CONCLUSION: Findings seem to concur with past research suggesting that clinicians may be influenced by factors other than the diagnostic criteria (e.g., cultural and social biases) when diagnosing, and that they may make erroneous attributions of pathology when diagnosing across cultures. [Abstract]

Lerner V, Miodownik C, Kaptsan A, Bersudsky Y, Libov I, Sela BA, Witztum E
Vitamin B6 treatment for tardive dyskinesia: a randomized, double-blind, placebo-controlled, crossover study.
J Clin Psychiatry. 2007 Nov;68(11):1648-54.
BACKGROUND: Tardive dyskinesia (TD) is a significant clinical problem. Vitamin B(6) is a potent antioxidant and takes part in almost all of the possible mechanisms that are suggested as being associated with appearance of TD. The aims of this study were (1) to reexamine the efficacy and safety of higher doses of vitamin B(6) versus placebo in a greater sample of patients for a longer time and (2) to evaluate the carryover effect of vitamin B(6). METHOD: A 26-week, double-blind, placebo-controlled trial was conducted in a university-based research clinic from August 2002 to January 2005 on 50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD. In a double-blind crossover paradigm, all study subjects were randomly assigned to start treatment with either vitamin B(6) (daily dose of 1200 mg) or placebo. After 12 weeks of treatment and then a 2-week washout, subjects were crossed over to receive the other treatment for 12 weeks. The primary outcome measure was the change from baseline in Extra-pyramidal Symptom Rating Scale (ESRS) scores. RESULTS: The mean decrease in ESRS clinical global impression scores from baseline to endpoint was 2.4 points in patients treated with vitamin B(6) and 0.2 points in patients treated with placebo (p < .0001). The mean decrease in the parkinsonism subscale score was 18.5 points and 1.4 points, respectively (p < .00001), and the mean decrease in the dyskinesia subscale score was 5.2 points and -0.8 points, respectively (p < .0001). CONCLUSION: Vitamin B(6) appears to be effective in reducing symptoms of TD. The specific mechanisms by which vitamin B(6) attenuates symptoms of TD are not clear. [Abstract]

Difede J, Cukor J, Jayasinghe N, Patt I, Jedel S, Spielman L, Giosan C, Hoffman HG
Virtual reality exposure therapy for the treatment of posttraumatic stress disorder following September 11, 2001.
J Clin Psychiatry. 2007 Nov;68(11):1639-47.
OBJECTIVE: This preliminary study endeavored to evaluate the use of virtual reality (VR) enhanced exposure therapy for the treatment of posttraumatic stress disorder (PTSD) consequent to the World Trade Center attacks of September 11, 2001. METHOD: Participants were assigned to a VR treatment (N = 13) or a waitlist control (N = 8) group and were mostly middle-aged, male disaster workers. All participants were diagnosed with PTSD according to DSM-IV-TR criteria using the Clinician-Administered PTSD Scale (CAPS). The study was conducted between February 2002 and August 2005 in offices located in outpatient buildings of a hospital campus. RESULTS: Analysis of variance showed a significant interaction of time by group (p < .01) on CAPS scores, with a between-groups posttreatment effect size of 1.54. The VR group showed a significant decline in CAPS scores compared with the waitlist group (p < .01). CONCLUSIONS: Our preliminary data suggest that VR is an effective treatment tool for enhancing exposure therapy for both civilians and disaster workers with PTSD and may be especially useful for those patients who cannot engage in imaginal exposure therapy. [Abstract]

Freeman MP
Early Career Psychiatrists Section.
J Clin Psychiatry. 2007 Nov;68(11):1638.
Abstract not available. [Abstract]

Faraone SV, Upadhyaya HP
The effect of stimulant treatment for ADHD on later substance abuse and the potential for medication misuse, abuse, and diversion.
J Clin Psychiatry. 2007 Nov;68(11):e28.
Attention-deficit/hyperactivity disorder (ADHD) is known to be a strong risk factor for substance use disorders (SUD) in adolescence and in adulthood. Research shows that stimulant treatment does not increase the risk of SUD in adolescents or adults with ADHD but rather that stimulant treatments may have a protective effect. However, 2 in 10 youths with ADHD misuse their medication. Recent evidence suggests that slow uptake of medication in the brain allows for effective treatment without patients experiencing the euphoric qualities of immediate-release agents that lead to abuse or diversion. As a result, extended-release products and different formulations, such as lisdexamfetamine dimesylate (LDX), are less likely to be misused and diverted and may have lower abuse potential. [Abstract]

Gardner NC
A clinician's view of the data on bipolar disorder.
J Clin Psychiatry. 2007 Nov;68(11):e27.
Limited data on patients with bipolar disorder in the maintenance phase makes implementing evidence-based treatments for maintenance therapy difficult. But, clinicians can practice evidence-based treatment by applying the data to individual patient's needs. The clinician provides the knowledge base, which should then by aligned with individual patient factors that may have an effect on treatment. Implementing this dynamic clinician-patient alliance and individualizing treatment gives patients their best possible outcome. [Abstract]

Lydiard RB
Recognition and treatment of panic disorder.
J Clin Psychiatry. 2007 Nov;68(11):e26.
Panic disorder is a common, disabling condition that affects 3% to 5% of the world's population. Although it is treatable, panic disorder goes unrecognized and untreated in many patients. Patients with panic disorder have an increased risk for other psychiatric disorders, especially other anxiety disorders, and panic disorder is associated with other medical conditions such as migraines, fibromyalgia, and irritable bowel syndrome. Clinicians treating panic disorder must be able to recognize the disorder, differentiate it from other disorders in which panic attacks are part of the symptomatology, and map out an individualized treatment plan for each patient. This presentation discusses the importance of collaboration between doctor and patient and details available treatment options, including antidepressants, benzodiazepines, and cognitive-behavioral therapy. [Abstract]

Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB
Family and Partner Psychopathology and the Risk of Postpartum Mental Disorders.
J Clin Psychiatry. 2007 Oct 19;e1-e7.
OBJECTIVE: Family and partner psychopathology characterizes 2 different types of potential risk factors for mental disorders linked to both biological and psychosocial processes, and no studies have included both variables in a study of risk of postpartum mental disorders (PPMD). The aim was to assess how a history of mental disorders in either a first-degree family member or partner affects the risk of admission or outpatient contact with PPMD. METHOD: A population-based cohort study using Danish registers was conducted, and survival analyses were performed. A total of 1,188,822 men and women became first-time parents during the study period from 1973 to 2005. The main outcome measure was incident admission or outpatient contact for any mental disorder (according to ICD-8 or ICD-10 criteria) 0 to 12 months after the birth of a first live-born child. RESULTS: A total of 2174 mothers and 1175 fathers experienced an incident admission or outpatient contact during the 12 months after the birth of the child. Mothers with no family or partner psychopathology had an increased risk of admission/outpatient contact 0 to 30 days postpartum; relative risk (RR) = 3.49 (95% CI = 3.01 to 4.04) compared to the reference group. During the same period, motherws with observed psychopathology in relatives and/or partners were at higher risk of PPMD: for family psychopathology, RR = 6.47 (95% CI = 5.25 to 7.97); for partner psychopathology, RR = 6.86 (95% CI = 3.95 to 11.90); and for both family and partner psychopathology, RR = 10.94 (95% CI = 5.18 to 23.09). Additionally, a 24-fold increased risk of PPMD 0 to 30 days postpartum was found in women with a first-degree relative with bipolar affective disorder compared to the reference group. CONCLUSIONS: Results indicated that family psychopathology represents a particular risk in the immediate postpartum period, especially if a family member suffers from bipolar affective disorder compared to other diagnostic groups. However, additional studies are needed to establish if partner psychopathology is a risk factor for PPMD specifically or has a more general influence on risk of mental disorders throughout pregnancy and postpartum. [Abstract]

Henderson DC
Weight gain with atypical antipsychotics: evidence and insights.
J Clin Psychiatry. 2007;68 Suppl 1218-26.
Weight gain associated with antipsychotic medication can be a barrier to the overall improvement of mental health patients due to a discontinuation of treatment. The goal of this article is to establish a better understanding regarding the mechanisms of antipsychotic medications and their associated risk of weight gain, obesity, and subsequent mortality and morbidity. Additionally, the need to closely monitor patients' lifestyles and homeostatic components in order to prevent weight gain or facilitate weight loss is emphasized. [Abstract]

Citrome L
The effectiveness criterion: balancing efficacy against the risks of weight gain.
J Clin Psychiatry. 2007;68 Suppl 1212-7.
The decision to stay with a treatment or switch to a different one depends on the balance between overall effectiveness, efficacy, and tolerability. One of the challenges with antipsychotic medication treatment of serious mental illness is the risk of weight gain, which can be considerable for some patients. This article reviews the issue of weight gain associated with antipsychotics and places it within the context of metabolic issues in general. The concept of "number needed to treat" is introduced to interpret the results of the Clinical Antipsychotic Trials of Intervention Effectiveness for schizophrenia, particularly to examine the balance between overall effectiveness, efficacy, and tolerability of the different antipsychotic treatments tested. Predictors of weight gain for olanzapine are reviewed for schizophrenia and bipolar disorder, as is a monitoring plan applicable for all patients receiving antipsychotic therapy. [Abstract]

Vreeland B
Treatment decisions in major mental illness: weighing the outcomes.
J Clin Psychiatry. 2007;68 Suppl 125-11.
Increased morbidity and mortality in persons with severe mental illness (SMI) are due in large part to preventable medical conditions. An array of factors contributes to the development of obesity and other medical problems, such as diabetes and cardiovascular disease. A holistic approach that integrates both mental and physical health is critical in treating individuals with SMI. The most common causes of disability and death are influenced by behaviors such as smoking, poor nutrition, and lack of exercise. Nonpharmacologic interventions focusing on lifestyle changes can help to prevent and manage psychotropic-associated weight gain. Furthermore, monitoring and treatment guidelines are underutilized in people with SMI; increased use of these guidelines could help to detect and possibly prevent some cardiometabolic problems. [Abstract]

Citrome L
Introduction: weighing the evidence: weight management insights for treating major mental illness.
J Clin Psychiatry. 2007;68 Suppl 124. [Abstract]

Preda A
Sponsored clinical trials and bias.
J Clin Psychiatry. 2007 Oct;68(10):1621-2; author reply 1622. [Abstract]

Gelenberg AJ, Freeman MP
The art (and blood sport) of psychopharmacology research: who has a dog in the fight?
J Clin Psychiatry. 2007 Feb;68(2):185. [Abstract]

Gharabawi GM, Bossie CA, Pandina GJ, Kujawa MJ, Greenspan AJ, Zhu Y
A discussion of 2 double-blind studies comparing risperidone and quetiapine in patients with schizophrenia.
J Clin Psychiatry. 2007 Feb;68(2):333; author reply 334. [Abstract]

Recent Articles in Journal of Clinical Psychopharmacology

Subject index.
J Clin Psychopharmacol. 2007 Dec;27(6):739-62. [Abstract]

Author index.
J Clin Psychopharmacol. 2007 Dec;27(6):734-8. [Abstract]

Segraves RT, Balon R
Patient and provider attitudes toward free drug samples in psychiatric practice.
J Clin Psychopharmacol. 2007 Dec;27(6):732-3. [Abstract]

Lutz UC, Wiatr G, Gaertner HJ, Bartels M
Oxcarbazepine treatment during breast-feeding: a case report.
J Clin Psychopharmacol. 2007 Dec;27(6):730-2. [Abstract]

de Haas S, Dingemanse J, Hoever P, Cohen A, van Gerven J
Pseudohallucinations after zolpidem intake: a case report.
J Clin Psychopharmacol. 2007 Dec;27(6):728-30. [Abstract]

Baba H, Kubota Y, Suzuki T, Arai H
Seven cases of late-life depression treated with cilostazol-augmented therapy.
J Clin Psychopharmacol. 2007 Dec;27(6):727-8. [Abstract]

Litvan L, Alcoverro-Fortuny O
Sibutramine and psychosis.
J Clin Psychopharmacol. 2007 Dec;27(6):726-7. [Abstract]

Praharaj SK, Arora M
Sertraline-induced facial paresthesia.
J Clin Psychopharmacol. 2007 Dec;27(6):725. [Abstract]

Petersson A, Garle M, Granath F, Thiblin I
Convulsions in users of anabolic androgenic steroids: possible explanations.
J Clin Psychopharmacol. 2007 Dec;27(6):723-5. [Abstract]

Gálvez-Andres A, Blasco-Fontecilla H, González-Parra S, Molina Jde D, Padín JM, Rodriguez RH
Secondary bipolar disorder and Diogenes syndrome in frontotemporal dementia: behavioral improvement with quetiapine and sodium valproate.
J Clin Psychopharmacol. 2007 Dec;27(6):722-3. [Abstract]

Klier CM, Mossaheb N, Saria A, Schloegelhofer M, Zernig G
Pharmacokinetics and elimination of quetiapine, venlafaxine, and trazodone during pregnancy and postpartum.
J Clin Psychopharmacol. 2007 Dec;27(6):720-2. [Abstract]

Bergemann N, Abu-Tair F, Strowitzki T
Estrogen in the treatment of late-onset schizophrenia.
J Clin Psychopharmacol. 2007 Dec;27(6):717-20. [Abstract]

Quante A, Zeugmann S, Bajbouj M, Anghelescu I
Clozapine in medication- and electroconvulsive therapy-resistant, depressed inpatients: a case series.
J Clin Psychopharmacol. 2007 Dec;27(6):715-7. [Abstract]

Mathewson KA, Lindenmayer JP
Clozapine and granulocyte colony-stimulating factor: potential for long-term combination treatment for clozapine-induced neutropenia.
J Clin Psychopharmacol. 2007 Dec;27(6):714-5. [Abstract]

Lim M, Park DY, Kwon JS, Joo YH, Hong KS
Prevalence and clinical characteristics of obsessive-compulsive symptoms associated with atypical antipsychotics.
J Clin Psychopharmacol. 2007 Dec;27(6):712-3. [Abstract]

Bachmann CJ, Nicksch B, de Lange D, Theisen FM, Remschmidt H
Repeated creatine kinase elevation under treatment with quetiapine, clozapine, and aripiprazole in an adolescent.
J Clin Psychopharmacol. 2007 Dec;27(6):710-1. [Abstract]

Wang PS, Schneeweiss S, Setoguchi S, Patrick A, Avorn J, Mogun H, Choudhry NK, Brookhart MA
Ventricular arrhythmias and cerebrovascular events in the elderly using conventional and atypical antipsychotic medications.
J Clin Psychopharmacol. 2007 Dec;27(6):707-10. [Abstract]

Urbano M, Spiegel D, Rai A
Atypical antipsychotic withdrawal dyskinesia in 4 patients with mood disorders.
J Clin Psychopharmacol. 2007 Dec;27(6):705-7. [Abstract]

Keshavan MS, Prasad KM, Montrose DM, Miewald JM, Kupfer DJ
Sleep quality and architecture in quetiapine, risperidone, or never-treated schizophrenia patients.
J Clin Psychopharmacol. 2007 Dec;27(6):703-5. [Abstract]

Kohno T, Shiga T, Toyomaki A, Kusumi I, Matsuyama T, Inoue T, Katoh C, Koyama T, Tamaki N
Effects of lithium on brain glucose metabolism in healthy men.
J Clin Psychopharmacol. 2007 Dec;27(6):698-702.
Lithium is clinically available for the treatment of mood disorders. However, it has remained unclear how lithium acts on the brain to produce its effects. The aim of this study was to evaluate the effects of chronic lithium on human brain activity using positron emission tomography and clarify the correlation between brain activity changes and cognitive functional changes as induced by chronic lithium administration. A total of 20 healthy male subjects (mean age, 32 +/- 6 years) underwent positron emission tomographic scans with F-fluorodeoxyglucose and a battery of neuropsychological tests at baseline condition and after 4 weeks of lithium administration. Brain metabolic data were analyzed using statistical parametric mapping. Lithium increased relative regional cerebral glucose metabolism (rCMRglc) in the bilateral dorsomedial frontal cortices including the anterior cingulate gyrus and decreased rCMRglc in the right cerebellum and left lingual gyrus/cuneus. There was no difference in any of the variables of cognitive functions between the baseline condition and after chronic lithium administration. There was no correlation between rCMRglc changes in any of the brain regions and individual variable changes in any of the neuropsychological tests. The results suggest that the effects of chronic lithium are associated with increased activity in the bilateral dorsomedial frontal cortices including the anterior cingulate gyrus and decreased activity in the right cerebellum and left lingual gyrus/cuneus. [Abstract]

Delaveau P, Salgado-Pineda P, Micallef-Roll J, Blin O
Amygdala activation modulated by levodopa during emotional recognition processing in healthy volunteers: a double-blind, placebo-controlled study.
J Clin Psychopharmacol. 2007 Dec;27(6):692-7.
A critical role of dopaminergic systems in emotional processing has been revealed by several animal and clinical studies in Parkinson disease and schizophrenia.We conducted a study with functional magnetic resonance imaging (fMRI) in 13 healthy volunteers to test the dopaminergic modulation on amygdala response to emotional processing and to evaluate if it was the result of a direct action on amygdalar nuclei or indirect modulation via medial prefrontal cortex projecting on amygdala.A placebo-controlled crossover experimental design was used. Subjects received either levodopa (100 mg) or placebo in 2 fMRI sessions. Amygdala activation was evaluated during a facial emotion recognition test.The statistical comparison between placebo versus levodopa situations revealed a significant reduction in activation of right amygdala during the levodopa fMRI session. The functional connectivity analysis revealed only a change of correlated activations between right and left amygdala, and not medial prefrontal cortex, after levodopa administration.Our results suggest that administration of levodopa to healthy volunteers impairs the amygdalar activation. It supports the hypothesis that amygdala activation follows an inverted U-shaped curve in relation to dopamine (DA) concentration. The results of the functional connectivity seem to suggest a dopaminergic action on amygdalar nuclei rather than a modulation of medial prefrontal cortex on amygdala. [Abstract]

Siepmann T, Ziemssen T, Mueck-Weymann M, Kirch W, Siepmann M
The effects of venlafaxine on autonomic functions in healthy volunteers.
J Clin Psychopharmacol. 2007 Dec;27(6):687-91.
Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition. [Abstract]

Beasley CM, Ball SG, Nilsson ME, Polzer J, Tauscher-Wisniewski S, Plewes J, Acharya N
Fluoxetine and adult suicidality revisited: an updated meta-analysis using expanded data sources from placebo-controlled trials.
J Clin Psychopharmacol. 2007 Dec;27(6):682-6.
Selective serotonin reuptake inhibitor treatments have been suggested by some to induce emergence of suicidality (ideation and behaviors). The objective of this study was to assess suicidality emergence by adverse event and rating scale data in the largest available, adult, major depression, double-blind, placebo-controlled, fluoxetine trial database (18 trials). Adverse event reports and comments for patients (fluoxetine, n = 2200; placebo, n = 1551) were searched for suicide-related events that were then classified into Food and Drug Administration categories. For 16 trials, suicidality was also examined by Hamilton Depression Scale item 3 (suicide) scores, and these data were analyzed along with the combination of event-based data and scale-based data. Comparisons between treatments were made for various estimates of worsening (risk) and improvement (benefit) of suicidality. Fluoxetine treatment did not result in greater worsening but was associated with greater improvement and faster resolution of ideation (P < or = 0.05 vs placebo). Data sources were differentially sensitive in detecting changes in suicidal ideation and behaviors. Fluoxetine treatment led to greater benefit rather than risk for suicidality. [Abstract]

Lindley SE, Carlson EB, Hill K
A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder.
J Clin Psychopharmacol. 2007 Dec;27(6):677-81.
BACKGROUND: Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. METHODS: Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. RESULTS: Baseline Clinician-Administered PTSD Scale scores were 62.1 +/- 13.9 for placebo and 61.0 +/- 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. CONCLUSIONS: Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population. [Abstract]

Thase ME, Pritchett YL, Ossanna MJ, Swindle RW, Xu J, Detke MJ
Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by remission rates in patients with major depressive disorder.
J Clin Psychopharmacol. 2007 Dec;27(6):672-6.
It has been proposed that serotonin and norepinephrine reuptake inhibitors (SNRIs) may result in higher remission rates of major depressive disorder than therapy with selective serotonin reuptake inhibitors (SSRIs). To test this hypothesis, a meta-analysis of individual patient data (N = 1833) was performed for the complete set of 6 phase II/III studies that compared duloxetine (fixed doses; range, 40-120 mg/d) with 2 SSRIs (paroxetine or fluoxetine; 20 mg/d) in outpatients with major depressive disorder. Remission was defined as an end point score of less than or equal to 7 on the 17-item Hamilton Rating Scale for Depression (HAMD17); alternate outcome criteria were also examined, as were remission rates among the 1044 patients with moderate-to-severe depression (HAMD17 total score greater than or equal to 19). The HAMD17 remission rates were 40.3% (351/871), 38.3% (162/423), and 28.4% (144/507) for duloxetine, the 2 SSRIs, and placebo, respectively. Both active treatments were superior to placebo; the difference between duloxetine and SSRIs was not statistically significant. Similar findings were observed for alternate outcomes. Duloxetine therapy was significantly more effective than therapy with the 2 SSRIs for patients with more severe depression, with remission rates of 35.9% (183/510) versus 28.6% (70/245) (P = 0.046). A secondary analysis of dose-response relationships indicated that this advantage was not attributable to the studies using higher doses of duloxetine. Thus, whereas duloxetine and the 2 SSRIs were comparably efficacious overall, therapy with the serotonin and norepinephrine reuptake inhibitor resulted in a significantly higher remission rate among patients with moderate-to-severe depression. [Abstract]

He JL, Xiang YT, Li WB, Cai ZJ, Ungvari GS
Hemoperfusion in the treatment of acute clozapine intoxication in China.
J Clin Psychopharmacol. 2007 Dec;27(6):667-71.
BACKGROUND AND AIMS: No systematic study has focused on the characteristics and outcome of acute clozapine intoxication, although clozapine is the most widely used antipsychotic agent in China. The study reported herein examined the features of clozapine intoxication and the therapeutic effect of hemoperfusion (HP). METHODS: In a retrospective chart review, the notes of 47 patients who attempted suicide by ingesting large amounts of clozapine and were treated at the only psychiatric emergency service in Beijing were analyzed. Of the 20 unconscious patients with plasma clozapine concentrations of more than 2000 ng/mL, 14 received a combination of HP and symptomatic treatment, whereas the other 6 and the remaining 27 patients received only symptomatic treatment. Patients' psychiatric conditions and both plasma clozapine and norclozapine concentrations were closely monitored and registered. RESULTS: One patient died of pulmonary edema and subsequent heart failure, but the rest of the patients recovered without any sequelae. Patients who received HP regained consciousness significantly faster than their counterparts with the same level of clozapine plasma concentration (>2000 ng/mL) who did not receive HP. CONCLUSIONS: A combination of HP and symptomatic treatment is the best therapeutic option when plasma clozapine concentration is high. [Abstract]

Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, Hinze-Selch D, Kraus T, Dittmann RW, Pollmächer T
Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study.
J Clin Psychopharmacol. 2007 Dec;27(6):662-6.
The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale 0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale 0-6: clozapine, 36.6 +/- 8.8 to 15.9 +/- 13.7; olanzapine, 36.7 +/- 9.9 to 19.1 +/- 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 +/- 0.6 to 2.5 +/- 1.5; olanzapine, 4.5 +/- 0.6 to 2.3 +/- 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports. [Abstract]

Byerly M, Suppes T, Tran QV, Baker RA
Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives.
J Clin Psychopharmacol. 2007 Dec;27(6):639-61.
Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia. [Abstract]

Abanades S, Farré M, Barral D, Torrens M, Closas N, Langohr K, Pastor A, de la Torre R
Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users.
J Clin Psychopharmacol. 2007 Dec;27(6):625-38.
OBJECTIVES: Despite the increasing concern about gamma-hydroxybutyric acid (GHB) toxicity, there are few studies examining the clinical pharmacology of GHB and its abuse potential. To evaluate GHB-induced subjective and physiological effects, its relative abuse liability and its impact on psychomotor performance in club drug users. MATERIALS AND METHODS: Twelve healthy male recreational users of GHB participated in 5 experimental sessions in the framework of a clinical trial. The study was randomized, double-blind, double-dummy, and crossover. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Study variables included vital signs (blood pressure, heart rate, oral temperature, pupil diameter), psychomotor performance (digit symbol substitution test, balance, Maddox-Wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory-49 items, and Evaluation of the Subjective Effects of Substances with Potential of Abuse questionnaires), and pharmacokinetics. RESULTS: All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. Gamma-hydroxybutyric acid induced a biphasic time profile with an initial stimulant-like effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. Gamma-hydroxybutyric acid increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. Gamma-hydroxybutyric acid and flunitrazepam impaired psychomotor performance, digit symbol substitution test, and balance task, whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task. CONCLUSIONS: Our results suggest a high abuse liability of GHB and flunitrazepam in club drug users. [Abstract]

Dannon PN, Lowengrub K, Musin E, Gonopolsky Y, Kotler M
12-month follow-up study of drug treatment in pathological gamblers: a primary outcome study.
J Clin Psychopharmacol. 2007 Dec;27(6):620-4.
BACKGROUND: Pathological gambling (PG) is a relatively common and highly disabling impulse control disorder. A range of psychotherapeutic agents including selective serotonin reuptake inhibitors, antiepileptic drugs, and opioid antagonists are shown to be effective in the short-term treatment of PG. The use of a wide range of pharmacological treatments for PG is consistent with the observation that PG shares features of obsessive-compulsive spectrum disorders, impulse control disorders, and addictive disorders. The aim of the study is to assess the rate of relapse in treatment-responder pathological gamblers after discontinuation of the active treatment. METHODS: Our study sample was composed of 43 male pathological gamblers who had been full responders to 1 of 4 drug treatment regimens (fluvoxamine, topiramate, bupropion SR, or naltrexone) from several previous acute open-label (12-week) comparison studies. Full response was defined as the absence of gambling for a 1-month duration together with improvement on the Clinical Global Improvement scale. The 43 full responders were then followed prospectively for an additional 9 months, which included a 3-month open-label continuation phase and a 6-month medication-free follow-up phase. Follow-up visits were performed on a monthly basis throughout the duration of study. At every follow-up visit, a comprehensive psychiatric diagnostic evaluation was performed on all patients, and patients were assessed for symptoms of gambling using a self-report instrument and collateral family reports. The Clinical Global Impression Improvement scale was also administered at every follow-up visit. Raters were blind to the previous drug treatment. RESULTS: Most patients did not relapse during the 6-month medication-free follow-up phase. Three of 6 patients with fluvoxamine, 3 of 9 with topiramate, 7 of 18 with bupropion SR, and 4 of 10 with naltrexone relapsed. Relapse was strictly defined as gambling behavior at any time during the 6-month medication-free follow-up period. Most of the patients did not gamble during the follow-up period, and the patients that did gamble reported a decrease in gambling losses. CONCLUSIONS: This naturalistic long-term follow-up outcome study demonstrates that among pathological gamblers who respond to a 6-month trial of medication, most patients seem to maintain full-response during a 6-month medication-free follow-up phase. Further studies are needed to confirm our findings. [Abstract]

Dunlop BW, Crits-Christoph P, Evans DL, Hirschowitz J, Solvason HB, Rickels K, Garlow SJ, Gallop RJ, Ninan PT
Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study.
J Clin Psychopharmacol. 2007 Dec;27(6):614-9.
BACKGROUND: Previous studies suggest that adjunctive modafinil treatment provides benefit for patients with depression with significant sleepiness and fatigue. METHODS: We conducted a multisite, double-blind, placebo-controlled study of the treatment of major depression characterized by excessive sleepiness and fatigue, adding adjunctive modafinil or placebo to a selective serotonin reuptake inhibitor from the beginning of treatment. Seventy-three of 90 consenting patients met all screening criteria to begin treatment with open-label selective serotonin reuptake inhibitor therapy and double-blind addition of either modafinil (100 mg/d for 1 week then 200 mg/d) or matching placebo for 6 weeks. RESULTS: Mixed-model analysis of the change in the Epworth Sleepiness Scale, the primary outcome measure, showed no difference between modafinil- and placebo-treated patients. However, the hypersomnia items on the 31-item Hamilton Depression Scale were significantly more improved with modafinil than placebo. The total 31-item Hamilton Depression Scale score was significantly better with modafinil than placebo at Weeks 4 and 5, but not at the final study visit. There was no difference in dropout rates caused by adverse events, but 2 patients in the modafinil-treated group developed new onset or worsening of suicidal ideation, leading to the trial being discontinued prematurely. CONCLUSIONS: Power to detect differences between modafinil and placebo was limited because of the premature discontinuation of the trial. Although modafinil did not show evidence of benefit over placebo on the Epworth Sleepiness Scale, secondary measures suggested modafinil may have provided benefit for symptoms of excessive sleepiness in patients with depression. [Abstract]

Lennestål R, Källén B
Delivery outcome in relation to maternal use of some recently introduced antidepressants.
J Clin Psychopharmacol. 2007 Dec;27(6):607-13.
Little is known concerning possible hazards of maternal use of the recently introduced antidepressant drugs with noradrenergic and varying serotonergic activity (serotonin-noradrenaline reuptake inhibitor [SNRI]/noradrenergic reuptake inhibitor [NRI] drugs).Using the Swedish Medical Birth Registry, we identified 732 women who had used SNRI/NRI drugs in early pregnancy. Maternal characteristics were studied as well as delivery outcome: pregnancy duration, birth weight, neonatal diagnoses, infant deaths, and congenital malformations. Comparisons were made with all deliveries in the population (n = 860,215) after adjustment for identified confounders, and risks were expressed as odds ratios or (when numbers were low) as risk ratios.Women using SNRI/NRI deviated from other women by being older, more often having their first infant, being more extensive smokers, having a higher body mass index, and more often being born within Sweden.These characteristics, like the pattern of concomitant drug use, resembled much those of women using selective serotonin reuptake inhibitor (SSRI) drugs. The rate of preterm births was significantly increased (odds ratio, 1.6; 95% confidence interval, 1.19-2.15), and neonatal symptoms such as respiratory problems, low Apgar score, hypoglycemia, and neonatal convulsions showed a similar pattern as seen after maternal SSRI treatment.We found no increased risk for stillbirths or congenital malformations. Delivery outcome after exposure to SNRI/NRI drugs resembles much what has been described after use of SSRI drugs. No signs of teratogenicity were found. [Abstract]

Ahrens T, Frankhauser P, Lederbogen F, Deuschle M
Effect of single-dose sertraline on the hypothalamus-pituitary-adrenal system, autonomic nervous system, and platelet function.
J Clin Psychopharmacol. 2007 Dec;27(6):602-6.
OBJECTIVE: Pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) is thought to decrease coronary risk in patients with depressive disorder. Selective serotonin reuptake inhibitor intake may (1) attenuate the hypothalamus-pituitary-adrenal (HPA) system, (2) improve disturbances of the autonomous nervous system, and (3) dampen the aggregability of platelets. There is only limited information about the influence of acute treatment with SSRIs on these systems, which is especially important for the initiation of therapy in high-risk cardiac patients. We compared the reaction of these systems to physical stress with single-dose SSRI treatment (100 mg) with that of placebo treatment. METHODS: Using a double-blind, crossover, placebo-controlled design, we assessed HPA system activity via serum cortisol and corticotropin as well as sympathetic nervous system by determining serum norepinephrine and epinephrine levels at baseline and as a response to stress. Analysis of heart rate variability (HRV) provided information on sympathetic/parasympathetic balance. Platelet activity was measured via flow-cytometric determination of platelet surface activation markers along with the serotonin (5-HT) uptake of platelets. RESULTS: We studied 12 healthy young men under placebo and verum conditions. We found higher HPA system activity at baseline and after physical activity under sertraline when compared with placebo, no difference in sympathetic nervous system activity after physical exertion and only slightly heightened baseline epinephrine values after sertraline intake. No difference was seen between sertraline and placebo intake regarding platelet activity and 5-HT uptake, HRV, blood pressure, and HR. CONCLUSIONS: Initiating sertraline treatment increases HPA system activity and epinephrine concentrations. We found no clinically relevant effect of single-dose sertraline treatment on autonomous nervous function, platelet activity, or platelet 5-HT uptake. These findings may not be extrapolated to patients with affective or cardiac disorders or to other SSRIs. [Abstract]

Barnett MJ, Wehring H, Perry PJ
Comparison of risk of cerebrovascular events in an elderly VA population with dementia between antipsychotic and nonantipsychotic users.
J Clin Psychopharmacol. 2007 Dec;27(6):595-601.
INTRODUCTION: The credibility of an increased risk of cerebrovascular events (CVEs) in elderly patients with dementia being treated with second-generation antipsychotics (SGAs) is debatable. Although early published and unpublished data indicated a risk, much of the subsequent literature has not supported this initial finding. Previously published studies were flawed in part because they lacked a control group and did not stratify by dementia subtype. This study examined the risk of a CVE in patients diagnosed with Alzheimer or vascular dementia while being treated with SGA, first-generation antipsychotics, or no antipsychotic medication. METHODS: Data from 14,029 patients aged 65 years and older were evaluated using patient information from Veterans Administration and Medicare databases. Patients who received care for dementia were categorized according to dementia subtype (vascular or Alzheimer) and antipsychotic use during an 18-month period. Patients were observed until they were admitted to a hospital for a CVE, stopped taking or switched antipsychotics, died, or until the 18-month observation period ended. RESULTS: Overall, CVE risk did not differ whether patients were receiving a first-generation antipsychotic, SGA, or no antipsychotic therapy. However, patients with vascular dementia had an increased risk in hospitalization for a CVE. There was no increase in risk of a CVE for patients treated with quetiapine, olanzapine, or risperidone relative to haloperidol, or for patients receiving olanzapine or risperidone relative to quetiapine. Stratified subgroup analyses demonstrated no difference in risk for CVE-related admission patients with Alzheimer dementia among individual agents. However, patients with vascular dementia receiving risperidone, but not olanzapine or quetiapine, were found to be at decreased risk for CVE admission relative to haloperidol. CONCLUSIONS: This study found no increase in overall risk for CVE-related hospital admission in patients treated with antipsychotic medications. [Abstract]

Winsberg B, Usubiaga H, Cooper T
Ghrelin and leptin response to oral glucose challenge among antipsychotic drug-treated children.
J Clin Psychopharmacol. 2007 Dec;27(6):590-4.
We investigated ghrelin, leptin, glucose, and insulin response to an oral glucose tolerance test among children receiving antipsychotics. Hormone concentrations were assayed at fasting, 30, 60, and 120 minutes. The sample was composed of 9 obese (defined as at or above the 95th percentile for age) and 10 overweight/normal children (defined as less than the 95th percentile in weight) based on National Institutes of Health criteria. Ages of the obese (10.7 +/- 3.4 years) and the overweight/normal (13.1 +/- 1.6 years) did not differ. Leptin was significantly higher among the obese group and did not change consequent to glucose. Ghrelin did not differ between the groups, and when the values were combined, ghrelin decreased at 30 minutes and approached fasting concentrations at 120 minutes. To further explore our data, we constituted separate groups based upon z score changes. When weight gain defined as an increase in z score (X = 0.4), the nongainers showed leptin concentrations to decrease over time. Findings encourage further oral glucose tolerance test studies to explain the leptin response to weight gain seen among children receiving antipsychotic medication. [Abstract]

Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Thompson TR, Volavka J, Webster EL
Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials.
J Clin Psychopharmacol. 2007 Dec;27(6):582-9.
OBJECTIVE:: Lamotrigine previously was found to attenuate ketamine-induced behavioral changes and, in 2 placebo-controlled trials, to improve psychosis when added to antipsychotic medication. We sought to evaluate the potential role of lamotrigine augmentation in schizophrenia patients resistant to atypical antipsychotic medication. METHODS:: Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100-400 mg/d) with placebo as add-on treatment in schizophrenia patients with stable, residual psychotic symptoms. The primary end point was changed in Positive and Negative Syndrome Scale total score at week 12. RESULTS:: Two hundred seventeen patients were enrolled in study 1 and 212 in study 2; completion rates in the intent-to-treat samples were 71% and 74%, respectively, and did not differ between treatment groups. Overall, mean Positive and Negative Syndrome Scale total scores improved in both studies and did not differ between treatment groups. In study 1, the Scale for Assessment of Negative Symptoms total score and Clinical Global Impression improved more with placebo than with lamotrigine; in study 2, the cognitive composite score improved more with lamotrigine than with placebo. CONCLUSIONS:: Results from these 2 studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study. [Abstract]

Chaudhry IB, Husain N, Khan S, Badshah S, Deakin B, Kapur S
Amoxapine as an antipsychotic: comparative study versus haloperidol.
J Clin Psychopharmacol. 2007 Dec;27(6):575-81.
It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics.The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups.The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low. [Abstract]

Pelizza L, Melegari M
Clozapine-induced microscopic colitis: a case report and review of the literature.
J Clin Psychopharmacol. 2007 Dec;27(6):571-4.
Both diarrhea and colitis associated with clozapine have been reported. In this article, the authors present a case of clozapine-induced microscopic colitis (MC)-the first reported in the literature. The definitive diagnosis was suggested on colon biopsy, which showed an intraepithelial lymphocytosis (with >20 lymphocytes for every 100 epithelial cells) more striking in the surface epithelium than in the crypts. In addition, there were a mixed inflammatory infiltrate in the lamina propria (with lymphocytes predominating over eosinophils and neutrophils), an architecturally preserved colonic mucosa (particularly in the crypts), and a subepithelial collagen band normally thickened (<10 microm). Clozapine was thought to be the culprit and discontinued. After some days, the patient gradually improved. Diarrhea and spiking fever disappeared within 72 hours. Multiple colon biopsies taken after 7 days from the discontinuation of the clozapine revealed no abnormal histological findings. It is important to clarify the issue of clozapine-induced MC because MC may require the use of expensive or potentially toxic treatments and can occasionally be life-threatening (eg, hypokalemia). Thus, any case of MC that can be cured by withdrawal of the clozapine must be investigated and identified. [Abstract]

Surguladze SA, Chu EM, Evans A, Anilkumar AP, Patel MX, Timehin C, David AS
The effect of long-acting risperidone on working memory in schizophrenia: a functional magnetic resonance imaging study.
J Clin Psychopharmacol. 2007 Dec;27(6):560-70.
ABSTRACT: Cognitive abnormalities represent an important therapeutic target in the treatment of schizophrenia. Working memory deficits are among the core abnormalities and affect social functioning.We used functional magnetic resonance imaging to examine cortical systems supporting working memory in patients with schizophrenia treated with risperidone long-acting injections (RLAIs) versus those on conventional depot medication (CONV). Sixteen patients on RLAI, 16 patients on CONV matched for clinical symptoms and other illness variables, and 8 HCs performed an n-back task (1-, 2-, 3-back) in the scanner.The level of performance decreased with increasing memory load, which was particularly evident in the CONV group. Patients on RLAI and controls demonstrated task-dependent decreases in activation in medial PFC, whereas the CONV group overactivated that region. The CONV group also showed underactivation of VLPFC compared with controls under conditions of increasing memory load, with the RLAI group showing an activation pattern not significantly different from either group.We conclude that RLAI may contribute to normalization of brain activation in regions involved in working memory functioning in people with chronic schizophrenia. [Abstract]

López-Muñoz F, Alamo C, Juckel G, Assion HJ
Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors.
J Clin Psychopharmacol. 2007 Dec;27(6):555-9. [Abstract]

Recent Articles in The British Journal of Psychiatry

Leavey G, King M
Authors' reply.
Br J Psychiatry. 2007 Dec;191565. [Abstract]

Mackin P, Gallagher P
Authors' reply.
Br J Psychiatry. 2007 Dec;191564. [Abstract]

Dein S
Psychiatry and faith-based organisations.
Br J Psychiatry. 2007 Dec;191564. [Abstract]

Masil S
Psychiatry and faith-based organisations.
Br J Psychiatry. 2007 Dec;191564-5. [Abstract]

Kapusta ND, Etzersdorfer E, Sonneck G
Authors' reply.
Br J Psychiatry. 2007 Dec;191563. [Abstract]

Banerjee A, Basu D
Cardiovascular risk with antipsychotics: case-control study or survey?
Br J Psychiatry. 2007 Dec;191563-4. [Abstract]

McPhedran S, McPhedran S, Baker J
Austrian firearms: data require cautious approach.
Br J Psychiatry. 2007 Dec;191562. [Abstract]

De Leo D, Klieve HH, Barnes M
Austrian firearms: data require cautious approach.
Br J Psychiatry. 2007 Dec;191562-3. [Abstract]

Mossman D, Sellke T
Avoiding errors about ;margins of error'.
Br J Psychiatry. 2007 Dec;191561. [Abstract]

Hart SD, Michie C, Cooke DJ
Authors' reply.
Br J Psychiatry. 2007 Dec;191561-2. [Abstract]

Salib E, Cortina-Borja M, Anderson D
Hot weather and suicide: a real risk or statistical illusion?
Br J Psychiatry. 2007 Dec;191560. [Abstract]

Page LA, Hajat S, Kovats RS
Authors' reply.
Br J Psychiatry. 2007 Dec;191560-1. [Abstract]

Charman T, Baird G, Simonoff E, Loucas T, Chandler S, Meldrum D, Pickles A
Efficacy of three screening instruments in the identification of autistic-spectrum disorders.
Br J Psychiatry. 2007 Dec;191554-9.
BACKGROUND: Screening instruments for autistic-spectrum disorders have not been compared in the same sample. AIMS: To compare the Social Communication Questionnaire (SCQ), the Social Responsiveness Scale (SRS) and the Children's Communication Checklist (CCC). METHOD: Screen and diagnostic assessments on 119 children between 9 and 13 years of age with special educational needs with and without autistic-spectrum disorders were weighted to estimate screen characteristics for a realistic target population. RESULTS: The SCQ performed best (area under receiver operating characteristic curve (AUC)=0.90; sensitivity 0.86; specificity 0.78). The SRS had a lower AUC (0.77) with high sensitivity (0.78) and moderate specificity (0.67). The CCC had a high sensitivity but lower specificity (AUC=0.79; sensitivity 0.93; specificity 0.46). The AUC of the SRS and CCC was lower for children with IQ < 70. Behaviour problems reduced specificity for all three instruments. CONCLUSIONS: The SCQ, SRS and CCC showed strong to moderate ability to identify autistic-spectrum disorder in this at-risk sample of school-age children with special educational needs. [Abstract]

Carter GL, Clover K, Whyte IM, Dawson AH, D'Este C
Postcards from the EDge: 24-month outcomes of a randomised controlled trial for hospital-treated self-poisoning.
Br J Psychiatry. 2007 Dec;191548-53.
BACKGROUND: Repetition of self-poisoning is common. AIMS: To report the 24-month outcomes of a non-obligatory postcard intervention (plus treatment as usual) compared with treatment as usual. METHOD: In a randomised-controlled trial (Zelen design) conducted in Newcastle, Australia, eight postcards were sent to participants over a 12-month period. The principal outcomes were the proportion of participants with one or more repeat episodes of self-poisoning and the number of repeat episodes per person. RESULTS: No significant reduction was observed in the proportion of people repeating self-poisoning in the intervention group (21.2%, 95% CI 17.0-25.3) compared with the control group (22.8%, 95% CI 18.7-27.0; chi(2)=0.32, d.f.=1, P=0.57); the difference between groups was -1.7% (95% CI -7.5 to 4.2). There was a significant reduction in the rate of repetition, with an incidence risk ratio of 0.49 (95% CI 0.33-0.73). CONCLUSIONS: A postcard intervention maintained the halving of the rate of repetition of hospital-treated self-poisoning events over a 2-year period, although it did not significantly reduce the proportion of individuals who repeated self-poisoning. [Abstract]

Junghan UM, Leese M, Priebe S, Slade M
Staff and patient perspectives on unmet need and therapeutic alliance in community mental health services.
Br J Psychiatry. 2007 Dec;191543-7.
BACKGROUND: Therapeutic alliance between clinicians and their patients is important in community mental healthcare. It is unclear whether providing effective interventions influences therapeutic alliance. AIMS: To assess the impact of meeting previously unmet mental health needs on the therapeutic alliance between patients and clinicians. METHOD: Secondary analysis of data from a longitudinal study assessing 101 patients and paired staff. RESULTS: Patient-rated unmet need was negatively associated with patient-rated and staff-rated therapeutic alliance. Staff-rated unmet need was positively associated with patient-rated therapeutic alliance only. Reducing patient-rated unmet need increased patient-rated but not staff-rated therapeutic alliance, even when controlling for other variables. Reducing staff-rated unmet need increased staff-rated but not patient-rated therapeutic alliance, but the effect became insignificant when controlling for other variables. CONCLUSIONS: Patient-rated therapeutic alliance will be maximised by focusing assessment and interventions on patient-rated rather than staff-rated unmet need. [Abstract]

Morriss R, Dowrick C, Salmon P, Peters S, Dunn G, Rogers A, Lewis B, Charles-Jones H, Hogg J, Clifford R, Rigby C, Gask L
Cluster randomised controlled trial of training practices in reattribution for medically unexplained symptoms.
Br J Psychiatry. 2007 Dec;191536-42.
BACKGROUND: Reattribution is frequently taught to general practitioners (GPs) as a structured consultation that provides a psychological explanation for medically unexplained symptoms. AIMS: To determine if practice-based training of GPs in reattribution changes doctor-patient communication, thereby improving outcomes in patients with medically unexplained symptoms of 3 months' duration. METHOD: Cluster randomised controlled trial in 16 practices, 74 GPs and 141 patients with medically unexplained symptoms of 6 hours of reattribution training v. treatment as usual. RESULTS: With training, the proportion of consultations mostly consistent with reattribution increased (31 v. 2%, P=0.002). Training was associated with decreased quality of life (health thermometer difference -0.9, 95% CI -1.6 to -0.1; P=0.027) with no other effects on patient outcome or health contacts. CONCLUSIONS: Practice-based training in reattribution changed doctor-patient communication without improving outcome of patients with medically unexplained symptoms. [Abstract]

Chisholm D, Lund C, Saxena S
Cost of scaling up mental healthcare in low- and middle-income countries.
Br J Psychiatry. 2007 Dec;191528-35.
BACKGROUND: No systematic attempt has been made to calculate the costs of scaling up mental health services in low- and middle-income countries. AIMS: To estimate the expenditures needed to scale up the delivery of an essential mental healthcare package over a 10-year period (2006-2015). METHOD: A core package was defined, comprising pharmacological and/or psychosocial treatment of schizophrenia, bipolar disorder, depression and hazardous alcohol use. Current service levels in 12 selected low- and middle-income countries were established using the WHO-AIMS assessment tool. Target-level resource needs were derived from published need assessments and economic evaluations. RESULTS: The cost per capita of providing the core package at target coverage levels (in US dollars) ranged from $1.85 to $2.60 $2.60 per year in low-income countries and $3.20 to $6.25 per year in lower-middle-income countries, an additional annual investment of $0.18-0.55 per capita. CONCLUSIONS: Although significant new resources need to be invested, the absolute amount is not large when considered at the population level and against other health investment strategies. [Abstract]

Byford S, Barrett B, Roberts C, Wilkinson P, Dubicka B, Kelvin RG, White L, Ford C, Breen S, Goodyer I
Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behavioural therapy in adolescents with major depression.
Br J Psychiatry. 2007 Dec;191521-7.
BACKGROUND: Major depression is an important and costly problem among adolescents, yet evidence to support the provision of cost-effective treatments is lacking. AIMS: To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression. METHOD: Pragmatic randomised controlled trial in the UK. Outcomes and costs were assessed at baseline, 12 and 28 weeks. RESULTS: The trial comprised 208 adolescents, aged 11-17 years, with major or probable major depression who had not responded to a brief initial psychosocial intervention. There were no significant differences in outcome between the groups with and without CBT. Costs were higher in the group with CBT, although not significantly so (P=0.057). Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 30% probability that CBT plus SSRIs is more cost-effective than SSRIs alone. CONCLUSIONS: A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care. [Abstract]

Perrin MA, Chen H, Sandberg DE, Malaspina D, Brown AS
Growth trajectory during early life and risk of adult schizophrenia.
Br J Psychiatry. 2007 Dec;191512-20.
BACKGROUND: Growth abnormalities have been suggested as a precursor to schizophrenia, but previous studies have not assessed growth patterns using repeated measures. AIMS: To assess the association between early life/later childhood growth patterns and risk of schizophrenia. METHODS: Using prospectively collected data from a birth cohort (born 1959-1967), measurements of height, weight and body mass index (BMI) were analysed to compare growth patterns during early life and later childhood between 70 individuals with schizophrenia-spectrum disorder (SSD) and 7710 without. RESULTS: For women, growth in the SSD group was approximately 1 cm/year slower during early life (P < 0.01); no association was observed for men. Later childhood growth was not associated with SSD. Weight patterns were not associated with SSD, whereas slower change in BMI was observed among the SSD group during later childhood. CONCLUSIONS: The association between slower growth in early life and schizophrenia in women suggests that factors responsible for regulating growth might be important in the pathogenesis of the disorder. [Abstract]

Iversen AC, Fear NT, Simonoff E, Hull L, Horn O, Greenberg N, Hotopf M, Rona R, Wessely S
Influence of childhood adversity on health among male UK military personnel.
Br J Psychiatry. 2007 Dec;191506-11.
BACKGROUND: Exposure to childhood adversity may explain why only a minority of combatants exposed to trauma develop psychological problems. AIMS: To examine the association between self-reported childhood vulnerability and later health outcomes in a large randomly selected male military cohort. METHOD: Data are derived from the first stage of a cohort study comparing Iraq veterans and non-deployed UK military personnel. We describe data collected by questionnaire from males in the regular UK armed forces (n=7937). RESULTS: Pre-enlistment vulnerability is associated with being single, of lower rank, having low educational attainment and serving in the Army. Pre-enlistment vulnerability is associated with a variety of negative health outcomes. Two main factors emerge as important predictors of ill health: a ;family relationships' factor reflecting the home environment and an ;externalising behaviour' factor reflecting behavioural disturbance. CONCLUSIONS: Pre-enlistment vulnerability is an important individual risk factor for ill health in military men. Awareness of such factors is important in understanding post-combat psychiatric disorder. [Abstract]

Thomas H, Weaver N, Patterson J, Jones P, Bell T, Playle R, Dunstan F, Palmer S, Lewis G, Araya R
Mental health and quality of residential environment.
Br J Psychiatry. 2007 Dec;191500-5.
BACKGROUND: There is increasing interest in the proposition that residential environment can affect mental health. AIMS: To study the degree to which common mental disorder clusters according to postcode units and households. To investigate whether contextual measures of residential environment quality and geographical accessibility are associated with symptoms of common mental disorder. METHOD: A total of 1058 individuals aged 16-75 years (response rate 66%) participated in a cross-sectional survey. The 12-item General Health Questionnaire measured symptoms of common mental disorder. RESULTS: Only 2% (95% CI 0-6) of the unexplained variation in symptoms existed at postcode unit level, whereas 37% (95% CI 27-49) existed at household-level, but the postcode unit variation was reduced to zero after adjustments. There was little evidence to suggest that residential quality or accessibility were associated with symptoms. CONCLUSIONS: There was substantial unexplained variation at the household level but we could find no evidence of postcode unit variation and no association with residential environmental quality or geographical accessibility. It is likely that the psychosocial environment is more important than the physical environment in relation to common mental disorder. [Abstract]

Emerson E, Hatton C
Mental health of children and adolescents with intellectual disabilities in Britain.
Br J Psychiatry. 2007 Dec;191493-9.
BACKGROUND: Few studies have employed formal diagnostic criteria to determine the prevalence of psychiatric disorders in contemporaneous samples of children with and without intellectual disabilities. AIMS: To establish the prevalence of psychiatric disorders against ICD-10 criteria among children with and without intellectual disabilities, the association with social/environmental risk factors, and risk attributable to intellectual disability. METHOD: Secondary analysis of the 1999 and 2004 Office for National Statistics surveys of the mental health of British children and adolescents with (n=641) and without (n=17 774) intellectual disability. RESULTS: Prevalence of psychiatric disorders was 36% among children with intellectual disability and 8% among children without (OR=6.5). Children with intellectual disabilities accounted for 14% of all British children with a diagnosable psychiatric disorder. Increased prevalence was particularly marked for autistic-spectrum disorder (OR=33.4), hyperkinesis (OR=8.4) and conduct disorders (OR=5.7). Cumulative risk of exposure to social disadvantage was associated with increased prevalence. CONCLUSIONS: A significant proportion of the elevated risk for psychopathology among children with intellectual disability may be due to their increased rate of exposure to psychosocial disadvantage. [Abstract]

Johnstone EC, Owens DG, Hoare P, Gaur S, Spencer MD, Harris J, Stanfield AW, Moffat V, Brearley N, Miller P, Lawrie SM, Muir WJ
Schizotypal cognitions as a predictor of psychopathology in adolescents with mild intellectual impairment.
Br J Psychiatry. 2007 Dec;191484-92.
BACKGROUND: There is evidence to suggest that among young people with mild intellectual disability there are those whose cognitive difficulties may predict the subsequent manifestation of a schizophrenic phenotype. It is suggested that they may be detectable by simple means. AIMS: To gain adequate cooperation from educational services, parents and students so as to recruit a sufficiently large sample to test the above hypothesis, and to examine the hypothesis in the light of the findings. METHOD: The sample was screened with appropriate instruments, and groups hypothesised as being likely or not likely to have the phenotype were compared in terms of psychopathology and neuropsychology. RESULTS: Simple screening methods detect a sample whose psychopathological and neuropsychological profile is consistent with an extended phenotype of schizophrenia. CONCLUSIONS: Difficulties experienced by some young people with mild and borderline intellectual disability are associated with enhanced liability to schizophrenia. Clinical methods can both identify those with this extended phenotype and predict those in whom psychosis will occur. [Abstract]

Morgan C, Burns T, Fitzpatrick R, Pinfold V, Priebe S
Social exclusion and mental health: Conceptual and methodological review.
Br J Psychiatry. 2007 Dec;191477-83.
BACKGROUND: The concept of social exclusion is now widely used in discussions about the nature of disadvantage, and there are ongoing initiatives to promote social inclusion among those with mental health problems. AIMS: To conduct a conceptual and methodological review of social exclusion, focusing initially on the origins and definitions of the concept and then on approaches to its measurement, both in general and in relation to mental health. METHOD: We used two main strategies. First, we utilised expertise within the study team to identify major texts and reviews on social exclusion and related topics. Second, we searched major bibliographic databases for literature on social exclusion and mental health. We adopted a non-quantitative approach to synthesising the findings. RESULTS: There is no single accepted definition of social exclusion. However, most emphasise lack of participation in social activities as the core characteristic. There are a number of approaches to measuring social exclusion, including use of indicator lists and dimensions. In the mental health literature, social exclusion is poorly defined and measured. CONCLUSIONS: If social exclusion is a useful concept for understanding the social experiences of those with mental health problems, there is an urgent need for more conceptual and methodological work. [Abstract]

Young AH, Hammond JM
Lithium in mood disorders: increasing evidence base, declining use?
Br J Psychiatry. 2007 Dec;191474-6.
Use of lithium for the treatment of bipolar disorder may be declining even as knowledge of the efficacy and side-effects of lithium has increased. Recent meta-analyses confirm the benefits of maintenance lithium treatment and show that it reduces suicide and suicidality. Psychiatrists should continue to utilise this efficacious treatment for bipolar disorder. [Abstract]

Marks IM, Cavanagh K, Gega L
Computer-aided psychotherapy: revolution or bubble?
Br J Psychiatry. 2007 Dec;191471-3.
Research into computer-aided psychotherapy is thriving around the world. Most of it concerns computer-aided cognitive-behavioural therapy (CCBT). A recent narrative review found 97 computer-aided psychotherapy systems from nine countries reported in 175 studies, of which 103 were randomised controlled trials. The rapid spread of the mass delivery of psychotherapy through CCBT, catalysed in the UK by the National Institute for Health and Clinical Excellence's recommendation of two CCBT programmes and the Department of Health's CCBT implementation guidance, seems unprecedented. This editorial is a synopsis of the current status of CCBT and its future directions. [Abstract]

Psychiatry in pictures.
Br J Psychiatry. 2007 Dec;191A22. [Abstract]

Minnis H, Reekie J, Young D, Gray A, O'Connor T, Ronald A, Plomin R
Attachment disorders: an evolutionary perspective.
Br J Psychiatry. 2007 Nov;191460. [Abstract]

O'Connell HP
Attachment disorders: an evolutionary perspective.
Br J Psychiatry. 2007 Nov;191459; author reply 459-60. [Abstract]

Al-Adwani A, Nahata R
Heroin-assisted treatment: no difference in treatment retention.
Br J Psychiatry. 2007 Nov;191458; author reply 458. [Abstract]

Haasen C
Author's reply.
Br J Psychiatry. 2007 Nov;191458. [Abstract]

Kripalani M, Badanapuram R, Gash A, Morris S
Factors in those who repeatedly self-harm.
Br J Psychiatry. 2007 Nov;191458; author reply 458-9. [Abstract]

Young R
Authors' reply:.
Br J Psychiatry. 2007 Nov;191458-9. [Abstract]

Berg JE
Substance misuse disguised as ADHD?
Br J Psychiatry. 2007 Nov;191457; author reply 457-8. [Abstract]

Kessler RC, Fayyad J, Karam EG, Alonso J, Demyttenaere K, Haro JM, Lara C, Lépine JP, Zaslavsky AM
Authors' reply.
Br J Psychiatry. 2007 Nov;191457-8. [Abstract]

Kho KH
Depression post-myocardial infarction.
Br J Psychiatry. 2007 Nov;191456; author reply 456-7. [Abstract]

de Jonge P, van Melle JP, Ormel J
Authors' reply:.
Br J Psychiatry. 2007 Nov;191456-7. [Abstract]

Korszun A, Stansfeld S, Frenneaux M
Depression post-myocardial infarction.
Br J Psychiatry. 2007 Nov;191455; author reply 456-7. [Abstract]

Shetty A
Depression post-myocardial infarction.
Br J Psychiatry. 2007 Nov;191455-6; author reply 456-7. [Abstract]

Owen GS, Cutting J, David AS
Are people with schizophrenia more logical than healthy volunteers?
Br J Psychiatry. 2007 Nov;191453-4.
We tested a phenomenological hypothesis about theoretical and practical rationality in people with schizophrenia. This hypothesis states that in schizophrenia there is an enhancement of theoretical rationality. Our case-control experiment supported this hypothesis. Philosophical models of rationality that prioritise theoretical over practical rationality may thereby apply more in schizophrenic than in healthy states. The study is an example of how experimental psychopathology can illuminate areas of philosophical dispute that are difficult to settle by thought alone. [Abstract]

Recent Articles in Schizophrenia Research

Kerns JG, Becker TM
Communication disturbances, working memory, and emotion in people with elevated disorganized schizotypy.
Schizophr Res. 2007 Dec 7; .
This study examined whether people with elevated disorganized schizotypy would differ from control participants on characteristics associated with disorganization symptoms in schizophrenia and also whether disorganized schizotypy was associated with problems processing emotion. People with disorganized schizotypy (n=32) exhibited greater communication disturbances (CD) than control participants (n=34) for emotionally negative topics but not for positive topics. In addition, the disorganized group exhibited poorer performance on a working memory task but not on a psychometrically matched verbal intelligence task. In addition, poor working memory was associated with increased CD for negative topics and, after controlling for group differences in working memory, group differences in CD were not significant. Moreover, the disorganized group exhibited greater emotional ambivalence and ambivalence was associated with increased CD in the disorganized group. These results suggest that people with disorganized schizotypy exhibit some similar characteristics to people with schizophrenia who have disorganization symptoms and that disorganized schizotypy is also associated with poor emotion processing. [Abstract]

Shen Q, Li ZQ, Sun Y, Wang T, Wan CL, Li XW, Zhao XZ, Feng GY, Li S, St Clair D, He L, Yu L
The role of pro-inflammatory factors in mediating the effects on the fetus of prenatal undernutrition: Implications for schizophrenia.
Schizophr Res. 2007 Dec 5;
Exposure to prenatal undernutrition or malnutrition increases the risk of schizophrenia, although little is known about the mechanism. Pro-inflammatory factors are critical in brain development, and are believed to play an important role in neurodevelopmental disorders associated with prenatal exposure to infection, including schizophrenia. However it is not known whether pro-inflammatory factors also mediate the effects on the fetus of prenatal malnutrition or undernutrition. In this study, we established a new prenatal undernourished rat model induced by maternal exposure to a diet restricted to 50% of the low (6%) protein diet (RLP50). We observed the disappearance of maternal nest-building behavior in the RLP50 dams, increased levels of TNFA and IL6 in the placentas (P<0.001; P=0.879, respectively) and fetal livers (P<0.001; P<0.05, respectively), and a decrease in the fetal brains (P<0.05; P<0.01, respectively). Our results are similar to previous studies of maternal infection, which implies that a common pathway mediated by pro-inflammatory factors may contribute to the brain development, consequently increasing the risk of schizophrenia and other psychiatric diseases programmed by varied maternal adversities. We also provide a new prenatal undernourished model for researching prenatal problems, which differs from previous malnourished model in terms of the maternal behavior of dams and of observed pro-inflammatory factor levels in fetal tissues. [Abstract]

Takeshita M, Yamada K, Hattori E, Iwayama Y, Toyota T, Iwata Y, Tsuchiya KJ, Sugihara G, Hashimoto K, Watanabe H, Iyo M, Kikuchi M, Okazaki Y, Yoshikawa T
Genetic examination of the PLXNA2 gene in Japanese and Chinese schizophrenics.
Schizophr Res. 2007 Dec 5;
Aberrant neuronal development is one of the integrative theories for the etiology of schizophrenia. The plexin A2 (PLXNA2) gene is one of the receptor genes for axonal guidance factors. Recently, four single nucleotide polymorphisms (SNPs), rs841865, rs752016, rs1327175 and rs2498028, from the PLXNA2 genomic interval have been reported to be associated with schizophrenia in samples from European Americans, Latin Americans and Asian Americans. We tested these four SNPs for association with disease in two Asian populations: 1140 case-control Japanese samples and 293 Chinese pedigrees (1163 samples). In the Japanese samples, significant differences in the allelic frequency and genotypic distribution of rs841865 (p=0.019 and 0.020, respectively) were observed between cases and controls. Haplotype analysis also revealed a significant association of the gene with the disease (global p=0.028). In contrast, there was no genetic contribution of PLXNA2 to Chinese schizophrenia, either by linkage analysis or association tests (allelic and haplotypic transmission disequilibrium tests). These findings suggest that PLXNA2 confers a varying genetic risk for schizophrenia among different populations. [Abstract]

Takizawa R, Kasai K, Kawakubo Y, Marumo K, Kawasaki S, Yamasue H, Fukuda M
Reduced frontopolar activation during verbal fluency task in schizophrenia: A multi-channel near-infrared spectroscopy study.
Schizophr Res. 2007 Dec 4;
Functional neuroimaging studies to date have shown prefrontal dysfunction during executive tasks in schizophrenia. However, relationships between hemodynamic response in prefrontal sub-regions and clinical characteristics have been unclear. The objective of this study is to evaluate prefrontal hemodynamic response related to an executive task in schizophrenia and to assess the relationship between activation in the prefrontal sub-regions and clinical status. Fifty-five subjects with schizophrenia and age- and gender-matched 70 healthy subjects were recruited for this case-control study in a medical school affiliated hospital in the Tokyo metropolitan area, Japan. We measured hemoglobin concentration changes in the prefrontal (dorsolateral, ventrolateral, and frontopolar regions) and superior temporal cortical surface area during verbal fluency test using 52-channel near-infrared spectroscopy, which enables real-time monitoring of cerebral blood volumes in the cortical surface area under a more restraint-free environment than positron emission tomography or functional magnetic resonance imaging. The two groups showed distinct spatiotemporal pattern of oxy-hemoglobin concentration change during verbal fluency test. Schizophrenia patients were associated with slower and reduced increase in prefrontal activation than healthy controls. In particular, reduced activations of the frontopolar region, rather than lateral prefrontal or superior temporal regions, showed significant positive correlations with lower global assessment of functioning scores in the patient group, although task performance was not significantly associated with the scores. These results suggest that reduced frontopolar cortical activation is associated with functional impairment in patients with schizophrenia and that near-infrared spectroscopy may be an efficient clinical tool for monitoring these characteristics. [Abstract]

Rejas J, Bobes J, Arango C, Aranda P, Carmena R, Garcia-Garcia M
Concordance of standard and modified NCEP ATP III criteria for identification of metabolic syndrome in outpatients with schizophrenia treated with antipsychotics: A corollary from the CLAMORS study.
Schizophr Res. 2007 Dec 4;
OBJECTIVE: To analyze the concordance between standard and modified NCEP-ATP-III criteria for identification of metabolic syndrome (MS) in outpatients with schizophrenia. METHOD: We used the sample from a cross-sectional study carried out to ascertain the prevalence of MS in schizophrenia. Kappa agreement and the symmetry Kendall's tau-b coefficients were calculated in a post-hoc analysis, a long with McNemar test and logistic regression models. RESULTS: The study enrolled 1,452 consecutive outpatients. MS was found in 24.6% (95%CI: 22.4%-26.8%) using the standard criteria and in 25.5% (23.2%-27.7%) using the modified criteria. Agreement was high; kappa 0.81 (p<0.0001) and tau-b 0.81 (p<0.0001), with a McNemar value of 0.2325. Kappa coefficients varied between 1.0 and 0.76 in subgroups according to sex, age-group, severity of disease, and duration of therapy. CONCLUSIONS: MS in outpatients with schizophrenia may be assessed by either the standard or the modified NCEP ATP III criteria without losing reliability. [Abstract]

Ellett L, Freeman D, Garety PA
The psychological effect of an urban environment on individuals with persecutory delusions: The Camberwell walk study.
Schizophr Res. 2007 Nov 29;
BACKGROUND: Epidemiological studies have found that individuals who live in urban areas are at increased risk of developing psychosis. However it is unknown whether exposure to urban environments exacerbates psychotic symptoms in people who have a diagnosed psychotic disorder. The aim of the study was to examine the psychological and clinical effects of exposure to one specific deprived urban environment on individuals with persecutory delusions. It was predicted that the urban environment would affect emotional and reasoning processes highlighted in a cognitive model of persecutory delusions and would increase paranoia. METHOD: Thirty patients with persecutory delusions were randomised to exposure to a deprived urban environment or to a brief mindfulness relaxation task. After exposure, assessments of symptoms, reasoning, and affective processes were taken. Thirty matched non-clinical participants also completed the study measures to enable interpretation of the test scores. RESULTS: In individuals with persecutory delusions, exposure to the urban environment, rather than participation in a mindfulness task, increased levels of anxiety, negative beliefs about others and jumping to conclusions. It also increased paranoia. The individuals with persecutory delusions scored significantly differently from the non-clinical group on all measures. CONCLUSIONS: For individuals with psychosis, spending time in an urban environment makes them think more negatively about other people and increases anxiety and the jumping to conclusions reasoning bias. Their paranoia is also increased. A number of processes hypothesised in cognitive models to lead to paranoid thoughts are exacerbated by a deprived urban environment. Further research is needed to clarify which aspects of urban environments cause the negative effects. Methodological challenges in the research area are raised. [Abstract]

Lai IC, Yang CC, Kuo TB, Wang YC, Shieh KR
Immediate impact of electroconvulsive therapy on cardiac autonomic function in schizophrenia: A preliminary study.
Schizophr Res. 2007 Nov 28; [Abstract]

Yoshimi A, Takahashi N, Saito S, Ito Y, Aleksic B, Usui H, Kawamura Y, Waki Y, Yoshikawa T, Kato T, Iwata N, Inada T, Noda Y, Ozaki N
Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder.
Schizophr Res. 2007 Dec 4;
Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population. [Abstract]

Modestin J, Wehrli MV, Stephan PL, Agarwalla P
Evolution of neuroleptic-induced extrapyramidal syndromes under long-term neuroleptic treatment.
Schizophr Res. 2007 Dec 4;
BACKGROUND: The long-term evolution of neuroleptic-induced extrapyramidal syndromes (EPS) of Parkinsonism, akathisia and tardive dyskinesia (TD) is still a controversial issue worth exploring. METHOD: A total of 200 inpatients on regular typical neuroleptics (NL) and/or clozapine were assessed in 1995 with regard to the prevalence of EPS. Altogether, 83 patients could be reassessed in 2003/04 (63 had died) using the same methods. Strict definitions of EPS were used. The complete account of NL therapy the patients were prescribed between 1995 and 2003/04 (including atypical NL other than clozapine) was considered. RESULTS: The prevalences found in 1995 and 2003/04 were 17% and 29% for Parkinsonism, 14% and 14% for akathisia, and 24% and 13% for TD. There were considerable intra-individual fluctuations in EPS occurrence even when the overall prevalence rate remained the same. In intra-individual comparisons of EPS ratings on both assessments, there was a tendency for worsening of Parkinsonism to be associated with a current (2003/04) therapy with typical NL; worsening of akathisia was associated with a current therapy with atypical NL other than clozapine, amelioration of akathisia with a current therapy with clozapne; and, basically, there were no significant associations found between the changes in TD ratings and the long-term therapy with typical NL, clozapine, and other atypical NL, considering cumulative doses of all these drugs. In a multivariate analysis, there was a tendency for the long-term evolution of TD to depend on illness duration as the only variable. CONCLUSIONS: There are intra-individual fluctuations in all EPS over longer time periods. The choice of current NL therapy has an impact on Parkinsonism and akathisia. The long-term evolution of TD appears independent of NL prescriptions. [Abstract]

Sprong M, Becker HE, Schothorst PF, Swaab H, Ziermans TB, Dingemans PM, Linszen D, van Engeland H
Pathways to psychosis: A comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State"
Schizophr Res. 2007 Dec 3;
BACKGROUND: The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways. AIM: To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder. METHOD: 80 ARMS- and 32 MCDD-adolescents (12-18 years) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits (Schizotypal Personality Questionnaire-Revised). RESULTS: Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met criteria for ARMS. CONCLUSION: These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups. [Abstract]

Twamley EW, Woods SP, Zurhellen CH, Vertinski M, Narvaez JM, Mausbach BT, Patterson TL, Jeste DV
Neuropsychological substrates and everyday functioning implications of prospective memory impairment in schizophrenia.
Schizophr Res. 2007 Dec 3;
Individuals with schizophrenia demonstrate impairment in prospective memory (ProM), which describes the multifaceted ability to execute a future intention. Despite its clear implications for everyday functioning, the neuropsychological substrates and functional correlates of ProM impairment in schizophrenia remain poorly understood. In this study, the Memory for Intentions Screening Test (MIST), a standardized measure of ProM, was administered to 72 outpatients with schizophrenia or schizoaffective disorder as part of a comprehensive neuropsychological and psychiatric research evaluation. Results showed that ProM was positively correlated with standard clinical tests of attention, working memory, processing speed, learning, and executive functioning, but not delayed recall. In the context of multiple neuropsychological predictors, learning ability was the only domain that independently contributed to ProM. Importantly, better ProM was predictive of higher functional capacity (as measured by the UCSD Performance-Based Skills Assessment-Brief Version), above and beyond the variability explained by demographic and disease factors. Analysis of component processes revealed that event-based ProM, as well as no response (i.e., omission) and task substitution errors were the strongest predictors of everyday functioning. Overall, these findings suggest that ProM impairment in schizophrenia is associated with multiple cognitive substrates, particularly episodic learning deficits, and plays an important role in everyday living skills. Studies regarding the potential effectiveness of ProM-based remediation strategies to improve functional outcomes in schizophrenia are indicated. [Abstract]

Mauri MC, Moliterno D, Rossattini M, Colasanti A
Depression in schizophrenia: Comparison of first- and second-generation antipsychotic drugs.
Schizophr Res. 2007 Dec 3;
The aim of this study was to compare the effects of different antipsychotics on depressive symptoms in schizophrenic patients. The data were drawn from a retrospective, naturalistic, observational study in which 222 subjects diagnosed as being affected by schizophrenia during a re-exacerbation phase received 6 weeks of monotherapy with fluphenazine decanoate, haloperidol decanoate, haloperidol, clozapine, olanzapine, quetiapine, risperidone or l-sulpiride. The Brief Psychiatric Rating Scale (BPRS), Extrapyramidal Side Effects Rating Scale (EPSE) and Anticholinergic Rating Scale (ACS) were administered at baseline and six weeks after the beginning of the study; depressive symptoms were evaluated using the BPRS items "depressive mood" and "guilt feelings". All of the antipsychotic drugs led to improvements in the depressive dimension, but this was statistically significant only in the case of fluphenazine decanoate, haloperidol, olanzapine, risperidone and l-sulpiride. A clinical improvement in the depressive dimension significantly correlated with the severity of the psychotic picture and its amelioration. Female patients were significantly more likely to show an improvement in depressive symptoms. In conclusion, our findings suggest that atypical antipsychotics as a class do not seem to be more effective on the depressive dimension during the course of schizophrenia than typical ones, at least as far as the collected BPRS data are concerned. The only factor that seemed to influence the improvement in depressive symptoms during our study was gender, as females were significantly more likely to improve although there were no between-gender differences in the baseline severity of the clinical picture. [Abstract]

Leppänen JM, Niehaus DJ, Koen L, Du Toit E, Schoeman R, Emsley R
Deficits in facial affect recognition in unaffected siblings of Xhosa schizophrenia patients: Evidence for a neurocognitive endophenotype.
Schizophr Res. 2007 Dec 3;
The present study in an African Xhosa sample examined whether familial vulnerability to schizophrenia is associated with deficits in facial affect recognition. Healthy comparison subjects, unaffected siblings of schizophrenia patients, and schizophrenia patients were tested with a task requiring rapid recognition of matched positive (happy), negative (angry), and neutral facial expressions. Siblings and patients demonstrated impaired recognition of negative relative to positive facial expressions whereas comparison subjects recognized negative and positive expressions at an equal level of accuracy. These results suggest that deficits in the processing negative affect from social cues are transmitted in families and may represent a heritable endophenotype of schizophrenia. [Abstract]

Tolosa A, Sanjuán J, Leal C, Costas J, Moltó MD, de Frutos R
Rapid evolving RNA gene HAR1A and schizophrenia.
Schizophr Res. 2007 Nov 26; [Abstract]

Dean B, Karl T, Pavey G, Boer S, Duffy L, Scarr E
Increased levels of serotonin(2A) receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice.
Schizophr Res. 2007 Nov 26;
Changes in neuregulin 1 expression have been reported in the CNS from subjects with schizophrenia. As neuregulin 1 is important in cortical development we postulated that changes in neuregulin 1 expression may contribute towards changes in cholinergic, glutamatergic and serotonergic markers that are well documented in the CNS of subjects with that disorder. To begin to test this hypothesis, we used in situ radioligand binding to measure levels of muscarinic M1/M4 receptors, the kainate receptor, the NMDA receptor, the serotonin 2A receptor, the serotonin 1A receptor and the serotonin transporter in the CNS from heterozygous transmembrane domain neuregulin 1 mutant mice. The major outcomes from these studies was the demonstration of an overall increase in levels of the serotonin 2A receptor (F=11.3, d.f.=3,1,72, p=0.0012) and serotonin transporter (F=5.00, d.f.=1,3,72, p<0.05) in the mutant mice. Levels of the other receptors did not vary in the mutant mice compared to their wild type-like litter mates. These data are the first evidence to suggest that NRG1 gene expression may be involved in regulating the development of the serotonergic system in the mammalian CNS. [Abstract]

Perez-Iglesias R, Crespo-Facorro B, Martinez-Garcia O, Ramirez-Bonilla ML, Alvarez-Jimenez M, Pelayo-Teran JM, Garcia-Unzueta MT, Amado JA, Vazquez-Barquero JL
Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a randomized clinical trial in a drug-naïve population.
Schizophr Res. 2007 Nov 28;
BACKGROUND: There is little information about weight gain induced by antipsychotics at long-term. OBJECTIVE: To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-naïve subjects after 1 year of treatment. METHODS: This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted. RESULTS: A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445). CONCLUSIONS: Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain. [Abstract]

Williams LM, Whitford TJ, Flynn G, Wong W, Liddell BJ, Silverstein S, Galletly C, Harris AW, Gordon E
General and social cognition in first episode schizophrenia: Identification of separable factors and prediction of functional outcome using the IntegNeuro test battery.
Schizophr Res. 2007 Nov 27;
OBJECTIVE: It is increasingly recognized that cognitive assessments, unlike symptom ratings, provide a reliable predictor of functional outcome in schizophrenia. This study evaluated the utility of the 'IntegNeuro' computerized test battery for assessing cognition in first episode schizophrenia. We determined the presence of separable factors of general and social cognition, their equivalence to the consensus domains identified by the NIMH MATRICS project, and their effectiveness in predicting real world functional outcomes. METHOD: Fifty six first episode schizophrenia (FES) patients and 112 matched healthy controls were assessed on the touchscreen-based 'IntegNeuro' cognitive test battery and FES patients for social functioning (SOFAS) and quality of life (WHOQOL-BREF). RESULTS: Principal components analysis identified i) six factors corresponding to MATRICS domains of general cognition ('Information Processing Speed', 'Verbal Recall', 'Working Memory Capacity', 'Sustained Attention/Vigilance', 'Verbal Processing', 'Executive Function'), ii) an 'Emotional Intelligence' factor corresponding to the MATRICS social cognition domain, and iii) an additional 'Sensori-Motor Function' factor of general cognition and 'Negativity' factor of social cognition. Patients showed impairments relative to controls across all factors, but especially for Working Memory Capacity, followed by Verbal Memory, Sustained Attention/Vigilance and Negativity. These factors strongly predicted poorer social functioning in FES, along with poorer quality of life in psychological, social, and health satisfaction facets. CONCLUSION: The IntegNeuro battery has utility for assessing separable domains of general and social cognition in FES, which are predictive of real world outcomes. Thus, it may be appropriate for clinical application, including in multi-center trials targeting new treatments for cognition in schizophrenia. [Abstract]

Bowie CR, Reichenberg A, McClure MM, Leung WL, Harvey PD
Age-associated differences in cognitive performance in older community dwelling schizophrenia patients: Differential sensitivity of clinical neuropsychological and experimental information processing tests.
Schizophr Res. 2007 Nov 27;
Cognitive dysfunction is a common feature of schizophrenia and deficits are present before the onset of psychosis, and are moderate to severe by the time of the first episode. Controversy exists over the course of cognitive dysfunction after the first episode. This study examined age-associated differences in performance on clinical neuropsychological (NP) and information processing tasks in a sample of geriatric community living schizophrenia patients (n=172). Compared to healthy control subjects (n=70), people with schizophrenia did not differ on NP tests across age groups but showed evidence for age-associated cognitive worsening on the more complex components of an information-processing test. Age-related changes in cognitive function in schizophrenia may be a function of both the course of illness and the processing demands of the cognitive measure of interest. Tests with fixed difficulty, such as clinical NP tests, may differ in their sensitivity from tests for which parametric difficulty manipulations can be performed. [Abstract]

Pinkham AE, Hopfinger JB, Pelphrey KA, Piven J, Penn DL
Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders.
Schizophr Res. 2007 Nov 27;
Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits remain unknown. Recent research suggests that social cognitive deficits in both disorders may arise from dysfunctions in the neural systems that underlie social cognition. We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum disorders during complex social judgments of faces. Twelve individuals with autism spectrum disorders (ASD), 12 paranoid individuals with schizophrenia (P-SCZ), 12 non-paranoid individuals with schizophrenia (NP-SCZ), and 12 non-clinical healthy controls participated in this cross sectional study. Neural activation, as indexed by blood oxygenation level dependent (BOLD) contrast, was measured in a priori regions of interest while individuals rated faces for trustworthiness. All groups showed significant activation of a social cognitive network including the amygdala, fusiform face area (FFA), superior temporal sulcus (STS), and ventrolateral prefrontal cortex (VLPFC) while completing a task of complex social cognition (i.e. trustworthiness judgments). ASD and P-SCZ individuals showed significantly reduced neural activation in the right amygdala, FFA, and left VLPFC as compared to controls and in the left VLPFC as compared to NP-SCZ individuals during this task. These findings lend support to models hypothesizing well-defined neural substrates of social cognition and suggest a specific neural mechanism that may underlie social cognitive impairments in both autism and paranoid schizophrenia. [Abstract]

Kamath V, Bedwell JS
Olfactory identification performance in individuals with psychometrically-defined schizotypy.
Schizophr Res. 2007 Nov 23;
While deficits in olfaction have been well documented in individuals with schizophrenia, less research has focused on olfactory identification performance in psychometrically-defined schizotypy. The Abbreviated Schizotypal Personality Questionnaire was used to define two groups of 26 individuals (62% female) reporting high and average levels of schizotypy. Overall group differences on the Brief Smell Identification Test did not approach statistical significance, and this finding did not differ within either sex. The findings may reflect either the abbreviated nature of the measures used, or a lack of reliable olfactory performance differences in schizotypy. [Abstract]

Friedman JI, Chang L, Ernst T, Tsopelas ND, Zhong K, Davis KL
Relationships between white matter metabolite abnormalities, cognitive and social functioning in elderly schizophrenic subjects.
Schizophr Res. 2007 Nov 23; [Abstract]

Cheng JY, Ko JS, Chen RY, Ng EM
Meta-regression analysis using latitude as moderator of paternal age related schizophrenia risk: High ambient temperature induced de novo mutations or is it related to the cold?
Schizophr Res. 2007 Nov 23;
While the season of birth, latitude and first admission effects suggest higher risk of schizophrenia with cold climate, the high ambient temperature induced de novo mutation hypothesis suggests the opposite. We conducted a systematic review and meta-analysis (4 case-control studies and 5 cohort studies). We used annual mean daily temperature and latitude of study sites as direct and indirect measures of ambient temperature respectively. Using case-control studies conducted in the Northern hemisphere for meta-regression, high latitude and low ambient temperature were found to increase paternal age related schizophrenia risk significantly. More research is needed to support the de novo mutation hypothesis. [Abstract]

Fu CH, Brammer MJ, Yágüez L, Allen P, Matsumoto K, van Haren N, Johns L, Weinstein S, Borgwardt S, Broome M, McGuire PK
Increased superior temporal activation associated with external misattributions of self-generated speech in schizophrenia.
Schizophr Res. 2007 Nov 23; [Abstract]

Asai Y, Takano A, Ito H, Okubo Y, Matsuura M, Otsuka A, Takahashi H, Ando T, Ito S, Arakawa R, Asai K, Suhara T
GABA(A)/Benzodiazepine receptor binding in patients with schizophrenia using [(11)C]Ro15-4513, a radioligand with relatively high affinity for alpha5 subunit.
Schizophr Res. 2007 Nov 23;
Dysfunction of the GABA system is considered to play a role in the pathology of schizophrenia. Individual subunits of GABA(A)/Benzodiazepine (BZ) receptor complex have been revealed to have different functional properties. alpha5 subunit was reported to be related to learning and memory. Changes of alpha5 subunit in schizophrenia were reported in postmortem studies, but the results were inconsistent. In this study, we examined GABA(A)/BZ receptor using [(11)C]Ro15-4513, which has relatively high affinity for alpha5 subunit, and its relation to clinical symptoms in patients with schizophrenia. [(11)C]Ro15-4513 bindings of 11 patients with schizophrenia (6 drug-naïve and 5 drug-free) were compared with those of 12 age-matched healthy control subjects using positron emission tomography. Symptoms were assessed using the Positive and Negative Syndrome Scale. [(11)C]Ro15-4513 binding was quantified by binding potential (BP) obtained by the reference tissue model. [(11)C]Ro15-4513 binding in the prefrontal cortex and hippocampus was negatively correlated with negative symptom scores in patients with schizophrenia, although there was no significant difference in BP between patients and controls. GABA(A)/BZ receptor including alpha5 subunit in the prefrontal cortex and hippocampus might be involved in the pathophysiology of negative symptoms of schizophrenia. [Abstract]

Capasso RM, Lineberry TW, Bostwick JM, Decker PA, St Sauver J
Mortality in schizophrenia and schizoaffective disorder: An Olmsted County, Minnesota cohort: 1950-2005.
Schizophr Res. 2007 Nov 19;
INTRODUCTION: Increased mortality in people with schizophrenia, compared to the general population, has been consistently reported worldwide. This mortality has been attributed predominantly to "unnatural" deaths-suicide, accidents, and homicide. Recent studies have shown an increase in natural causes of death. Our objective is to compare the mortality of schizophrenic and schizoaffective subjects to the general US population. METHODS: 319 Olmsted County residents meeting DSM-IV-TR criteria for schizophrenia or schizoaffective disorder seen at the Mayo Clinic between 1950 and 1980 were followed until February 2005 for a median of 23.5 years. RESULTS: At the end of follow-up, 44% of patients were deceased. Mortality was significantly (p<0.001) increased compared to the Caucasian population in the US for persons of like age, gender, and calendar year of birth. The median survival following diagnosis was 36.2 years. Death certificate cited cause of death was cardiac (29%), cancer - including lung (19%), and pulmonary disease (17%). Concerningly, there was no association with the year of diagnosis to survival. CONCLUSIONS: Tsuang and colleagues showed in 1975 that mortality in schizophrenics and later, those with schizoaffective disorder was significantly increased compared to the US general population. Thirty years later, with a demographically similar population, we have found the same pattern of increased mortality. In light of continued improvements in the general population's lifespan, the survival gap in schizophrenia/schizoaffective disorder appears to be increasing. [Abstract]

Fernandez-Egea E, Miller B, Bernardo M, Donner T, Kirkpatrick B
Parental history of Type 2 diabetes in patients with nonaffective psychosis.
Schizophr Res. 2007 Nov 19;
INTRODUCTION: We attempted to replicate two previous studies which found an increased risk of diabetes in the relatives of schizophrenia probands. METHODS: N=34 patients with newly-diagnosed nonaffective psychosis and N=52 non-psychiatric controls were interviewed for parental history of Type 2 diabetes. RESULTS: In a logistic regression model that included multiple potential confounders, psychosis was a significant predictor of Type 2 diabetes in either parent (p<0.04). DISCUSSION: We found an increased prevalence of Type 2 diabetes in the parents of nonaffective psychosis subjects. This association may be due to shared environmental or genetic risk factors, or both. [Abstract]

Skelly LR, Calhoun V, Meda SA, Kim J, Mathalon DH, Pearlson GD
Diffusion tensor imaging in schizophrenia: Relationship to symptoms.
Schizophr Res. 2007 Nov 19;
In this diffusion tensor imaging (DTI) study, the authors investigated white matter integrity in schizophrenia and the relationships between white matter alterations and specific symptoms of the disorder. We compared DTI images of 25 schizophrenia patients and 25 matched healthy controls and performed voxel-wise correlational analyses using the patient's DTI data and their severity scores of positive and negative symptoms. We found diffuse deficits in multiple types of white matter tracts in schizophrenia, and an inverse relationship of DTI fractional anisotropy (FA) values with positive symptom scores in association fibers, supporting a "disconnection" hypothesis of positive symptoms in schizophrenia. [Abstract]

de Leon J, Correa JC, Ruaño G, Windemuth A, Arranz MJ, Diaz FJ
Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels.
Schizophr Res. 2007 Nov 19;
The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase alpha SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCbeta, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia. [Abstract]

Heinrichs RW, Ammari N, McDermid Vaz S, Miles AA
Are schizophrenia and schizoaffective disorder neuropsychologically distinguishable?
Schizophr Res. 2007 Nov 19;
This study sought to objectify the distinction between schizophrenia and schizoaffective disorder in terms of standard tasks measuring verbal and non-verbal cognitive ability, auditory working memory, verbal declarative memory and visual processing speed. Research participants included 103 outpatients with a diagnosis of schizophrenia, 48 with schizoaffective disorder, and 72 non-patients from the community. Schizophrenia patients were impaired on all cognitive measures relative to schizoaffective patients and non-psychiatric participants. Regression-based prediction models revealed that cognitive measures classified schizophrenia patients accurately (91%), but not patients with schizoaffective disorder (35%). In addition, there was no statistical evidence for the unique predictive validity of any specific cognitive task. Patients with schizophrenia were significantly more symptomatic and had greater community support requirements than those with schizoaffective disorder. However, group differences in cognitive performance are insufficient to separate these syndromes of psychotic illness. [Abstract]

Byne W, Dracheva S, Chin B, Schmeidler JM, Davis KL, Haroutunian V
Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei.
Schizophr Res. 2007 Oct 26;
Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. [Abstract]

Lysaker PH, Tsai J, Yanos P, Roe D
Associations of multiple domains of self-esteem with four dimensions of stigma in schizophrenia.
Schizophr Res. 2007 Oct 26;
Research suggests global self-esteem among persons with schizophrenia may be negatively affected by stigma or stereotyped beliefs about persons with severe mental illness. Less clear however, is whether particular dimensions of self-esteem are linked to particular domains of stigma. To examine this we surveyed a range of self-esteem dimensions including lovability, personal power, competence and moral self-approval and four domains of stigma: Stereotype endorsement, Discrimination experience, Social withdrawal and Stigma rejection. Participants were 133 adults with diagnoses of schizophrenia or schizoaffective disorder. Stepwise multiple regressions controlling for a possible defensive response bias suggested that aspects of self-esteem related to lovability by others were more closely linked with lesser feelings of being alienated from others due to mental illness. Aspects of self-esteem related to the ability to manage one's own affairs were more closely associated with the rejection of stereotypes of mental illness. A sense of being able to influence others was linked to both the absence of discrimination experiences and the ability to ward off stigma. Implications for treatment are discussed. [Abstract]

Addington J, Penn D, Woods SW, Addington D, Perkins DO
Social functioning in individuals at clinical high risk for psychosis.
Schizophr Res. 2007 Nov 13;
Poor social functioning is a hallmark of schizophrenia. The purpose of this study was to examine social functioning in individuals at clinical high risk for psychosis. Social functioning was assessed in a sample of 86 clinical high risk (CHR) individuals and compared to that of 50 first-episode of psychosis (FE) subjects, 53 multi-episode schizophrenia subjects (ME) and 55 non-psychiatric controls (NPC). Subjects were assessed on the Social Functioning Scale (SFS), the Role Functioning subscale of the Quality of Life Scale (QLS-role), and the premorbid functioning scale. On the SFS, the CHR group did not differ significantly from the FE and ME groups and all were impaired relative to the NPCs. On QLS-role, the CHR group performed significantly better than the ME patients and significantly worse than NPCs. CHR subjects did not differ from patients in terms of premorbid functioning. This study demonstrates that even at the pre-psychotic phase of the illness, these young people are demonstrating significant deficits in social functioning, supporting that social deficits are present long before the onset of psychotic symptoms. [Abstract]

Shi J, Badner JA, Gershon ES, Liu C
Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis.
Schizophr Res. 2007 Nov 16;
The G72/G30 gene complex (G72 also known as D-amino acid oxidase activator, DAOA) and its chromosomal region 13q32-34 have been linked and associated with both schizophrenia (SCZ) and bipolar disorder (BP) in multiple studies, including our initial association report on BP. However, the inconsistency of associated variants across studies is obvious. Previous meta-analyses had small data sets. The present meta-analysis combined 18 association articles published before April of 2007. There were 19 independent studies of SCZ, with 4304 cases, 5423 controls, and 1384 families, and four independent studies of BP with 1145 cases, 1829 controls, and 174 families. Of 15 single nucleotide polymorphisms (SNPs) analyzed in the 95-kb G72/G30 gene region, M18/rs947267 and M22/rs778293 showed association with SCZ in Asians, and M24/rs1421292 with SCZ in Europeans. The associations of C allele at M18 and A allele at M22 with SCZ in Asians survived conservative Bonferroni correction for multiple testing for 15 markers and subgroup analysis (adjusted P=0.0000253 for M18; adjusted P=0.009 for M22). No single maker showed evidence of overall association with BP. These results suggest that G72/G30 may influence susceptibility to schizophrenia with weak effects. [Abstract]

Sumich A, Kumari V, Dodd P, Ettinger U, Hughes C, Zachariah E, Sharma T
N100 and P300 amplitude to Go and No-Go variants of the auditory oddball in siblings discordant for schizophrenia.
Schizophr Res. 2007 Nov 15;
BACKGROUND: P300 amplitude reduction is reliably seen in schizophrenia. Inconsistent reports of isolated frontal and/or parietal deficits in unaffected family members may be clarified using a task that places greater load on frontal function. METHOD: Go and No-Go versions of the auditory oddball task were performed by eighteen schizophrenia patients, age-matched unaffected siblings and healthy controls matched closely to unaffected siblings on age, sex, education, socioeconomic-status, handedness and ethnicity. Groups were compared on P300 and N100 amplitude and latency. Spearman correlations were used to test the relationship between ERP amplitudes and neuropsychological measures of executive function and memory. The relationship between schizotypy - as measured using the structured interview - and ERPs was explored in a combined group of siblings and controls. RESULTS: Independent of task, patients had lower P300 than controls and reduced parietal amplitude compared to siblings. Siblings had enhanced frontocentral N100 compared to controls. No-Go P300 amplitude and N100 latency was associated with executive function measures. There were significant intraclass correlations between patients and siblings for No-Go P300 amplitude, particularly at the central midline electrode. Frontocentral N100 and P300 amplitude were positively correlated with anxiety-related aspects of schizotypy. CONCLUSION: Enhanced N100 is present in unaffected siblings. Parietal P300 is intact in unaffected siblings, but reduced in patients. The No-Go-oddball is more sensitive than the Go-oddball to executive function deficits in patients and as an index of heritability. [Abstract]

Kale A, Joshi S, Naphade N, Sapkale S, Raju MS, Pillai A, Nasrallah H, Mahadik SP
Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients.
Schizophr Res. 2007 Nov 6;
Variable levels of essential polyunsaturated fatty acids (EPUFAs) reported in schizophrenia are likely due to differences in age, sex, ethnicity, diet, life style and treatments. The present study examined the EPUFAs levels in plasma, RBC and CSF in never-medicated first-episode psychotic patients and normal controls matched for ethnicity, diet and life style. The plasma EPUFAs levels were similar in both groups. Among the EPUFAs enriched in the brain, predominantly docosahexaenoic acid (DHA) levels were lower in RBC (p=<0.01) whereas higher in CSF (p=<0.01) in male>female patients. This altered DHA metabolism may provide clues for neuropathology and treatment of schizophrenia. [Abstract]

Fatemi SH, Folsom TD, Reutiman TJ, Sidwell RW
Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin.
Schizophr Res. 2007 Nov 8;
The current study investigated whether human influenza viral infection in midpregnancy leads to alterations in proteins involved in brain development. Human influenza viral infection was administered to E9 pregnant Balb/c mice. Brains of control and virally-exposed littermates were subjected to microarray analysis, SDS-PAGE and western blotting at three postnatal stages. Microarray analysis of virally-exposed mouse brains showed significant, two-fold change in expression of multiple genes in both neocortex and cerebellum when compared to sham-infected controls. Levels of mRNA and protein levels of four selected genes were examined in brains of exposed mice. Nucleolin mRNA was significantly decreased in day 0 and day 35 neocortex and significantly increased in day 35 cerebellum. Protein levels were significantly upregulated at days 35 and 56 in neocortex and at day 56 in cerebellum. Connexin 43 protein levels were significantly decreased at day 56 in neocortex. Aquaporin 4 mRNA was significantly decreased in day 0 neocortex. Aquaporin 4 protein levels decreased in neocortex significantly at day 35. Finally, microcephalin mRNA was significantly decreased in day 56 neocortex and protein levels were significantly decreased at 56 cerebellum. These data suggest that influenza viral infection in midpregnancy in mice leads to long-term changes in brain markers for enhanced ribosome genesis (nucleolin), increased production of immature neurons (microcephalin), and abnormal glial-neuronal communication and neuron migration (connexin 43 and aquaporin 4). [Abstract]

Lalor EC, Yeap S, Reilly RB, Pearlmutter BA, Foxe JJ
Dissecting the cellular contributions to early visual sensory processing deficits in schizophrenia using the VESPA evoked response.
Schizophr Res. 2007 Nov 7;
Electrophysiological research has shown clear dysfunction of early visual processing mechanisms in patients with schizophrenia. In particular, the P1 component of the visual evoked potential (VEP) is substantially reduced in amplitude in patients. A novel visual evoked response known as the VESPA (Visual Evoked Spread Spectrum Analysis) was recently described. This response has a notably different scalp topography from that of the traditional VEP, suggesting preferential activation of a distinct subpopulation of cells. As such, this method constitutes a potentially useful candidate for investigating cellular contributions to early visual processing deficits. In this paper we compare the VEP and VESPA responses between a group of healthy control subjects and a group of schizophrenia patients. We also introduce an extension of the VESPA method to incorporate nonlinear processing in the visual system. A significantly reduced P1 component was found in patients using the VEP (with a large effect size; Cohen's d=1.6), while there was no difference whatsoever in amplitude between groups for either the linear or nonlinear VESPA. This pattern of results points to a highly specific cellular substrate of early visual processing deficits in schizophrenia, suggesting that these deficits are based on dysfunction of magnocellular pathways with parvocellular processing remaining largely intact. [Abstract]

Ellingrod VL, Miller DD, Taylor SF, Moline J, Holman T, Kerr J
Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants.
Schizophr Res. 2007 Oct 30;
INTRODUCTION: The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two-to-four-fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications. PURPOSE: To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for >/=12 months. METHODS: Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298A/C genotype. RESULTS: Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR=3.7, (95% CI=1.24-12.66, p=0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F=8.35, df=5, 51, p<0.0001), with these two terms interacting (F=8.6, df=2, p=0.0006) suggesting that TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis. CONCLUSION: Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications. [Abstract]

McClure RK, Carew K, Greeter S, Maushauer E, Steen G, Weinberger DR
Absence of regional brain volume change in schizophrenia associated with short-term atypical antipsychotic treatment.
Schizophr Res. 2007 Oct 30;
The first aim of this pilot study was to determine if longitudinal change in caudate volume could be detected in chronic schizophrenic patients after 12 weeks of atypical antipsychotic treatment. A sub-aim of the first aim was to determine if similar results could be obtained from an operator-assisted segmentation tool for volumetric imaging (ITK-SNAP) and voxel-based morphometry (VBM) methods in the caudate. The second aim was to determine if frontal and temporal lobe grey matter, white matter, ventricular and sulcal cerebrospinal fluid volume change could be detected after 12 weeks of atypical antipsychotic treatment with VBM. Ten chronic schizophrenic inpatients, with illness duration averaging 10.6 years, underwent two MRI scans. The first scan was obtained after a mean of 39.4 days of antipsychotic withdrawal. The second MRI was obtained following twelve weeks of atypical antipsychotic treatment. Caudate volume change was first measured with ITK-SNAP. Then the location of grey matter volume change in the caudate was identified with VBM. Finally, the location of frontal and temporal lobe grey matter, white matter, ventricular and sulcal cerebrospinal fluid volume changes were identified with VBM. No longitudinal change in caudate volume or grey matter volume was observed after brief periods of atypical antipsychotic treatment. ITK-SNAP and VBM methods showed very similar results in the caudate. No statistically significant change was identified in the volume of frontal or temporal lobe grey matter, white matter, and lateral, third, or fourth ventricular cerebrospinal fluid. Although the results do not directly show that brief periods of atypical antipsychotic treatment are associated with basal ganglia and cortical volume change, there is much evidence to suggest that such an association exists. [Abstract]

Hoogendoorn ML, Vorstman JA, Jalali GR, Selten JP, Sinke RJ, Emanuel BS, Kahn RS
Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia.
Schizophr Res. 2007 Oct 25;
The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the overall prevalence of 22q11DS among schizophrenia patients by combining all available studies. Our sample, enriched for patients with the Deficit syndrome, had 88% power to detect an estimated prevalence of 5% of 22q11.2 deletions. No 22q11.2 deletions were detected in 311 schizophrenia patients, 146 of whom met criteria for the Deficit syndrome. Our literature research revealed that in eight studies sixteen deletions were identified in 2133 patients with schizophrenia. This corresponds to a prevalence of 0.75% (95%CI: 0.5%-1.2%). In conclusion: The prevalence of 22q11.2DS in schizophrenia patients with the Deficit syndrome is not higher than in the population of schizophrenia patients as a whole. The prevalence of 22q11.2DS in schizophrenia patients is lower than the frequently reported prevalence of 2% or more. [Abstract]

Recent Articles in The International Journal of Neuropsychopharmacology

Lichtenberg P, Even-Or E, Bar G, Levin R, Brin A, Heresco-Levy U
Reduced prepulse inhibition is associated with increased hypnotizability.
Int J Neuropsychopharmacol. 2007 Nov 30;1-5.
Hypnosis involves the manipulation of conscious attentional discrimination. The prepulse inhibition (PPI) paradigm assesses primary unconscious information processing. We investigated the correlation between hypnotizability and PPI of the startle reflex. Forty-eight healthy subjects were evaluated with the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) and acoustic PPI. Subjects were divided into low, medium, and high hypnotizable groups. The low-hypnotizable group showed a significantly higher inhibition of the startle response, at lead intervals 60 ms and 120 ms, than did the medium- and high-hypnotizable groups. We conclude that hypnotizability and PPI may be negatively correlated. These findings lend further support for the role of dopaminergic neurotransmission mechanisms in the determination of hypnotizability levels. [Abstract]

Degoulet M, Rouillon C, Rostain JC, David HN, Abraini JH
Modulation by the dorsal, but not the ventral, hippocampus of the expression of behavioural sensitization to amphetamine.
Int J Neuropsychopharmacol. 2007 Nov 30;1-12.
Although the dorsal hippocampus (DH) and the ventral hippocampus (VH) densely innervate the nucleus accumbens, which mediates the expression of behavioural sensitization, the respective and specific contribution of DH and VH in the expression of behavioural sensitization to amphetamine has not been investigated. In the present study, we investigated how lidocaine infused in DH or VH modulated behavioural locomotor sensitization induced by repeated administration of systemic amphetamine. Rats, well habituated to their environmental conditions and experimental protocol, were given repeated administration of systemic amphetamine. Once behavioural sensitization was developed, rats were challenged with amphetamine and infused with saline (controls) or lidocaine into DH or VH. We found that reversible inhibition by lidocaine of DH, but not VH, blocks the expression of behavioural sensitization to amphetamine. Control animals injected with saline solution do express behavioural sensitization. Our results bring new insights on the role of the hippocampus complex in the expression of behavioural sensitization, indicating that, in individuals well habituated to the drug-associated context, DH but not VH would play a key role. The results provide experimental evidence for clinical studies in human addicts that have demonstrated that exposure to environmental stimuli associated with drug-taking behaviour elicits craving and can promote relapse, and further suggest that in drug abusers, once addiction has occurred, the contextual and spatial conditions that are associated with drug consumption may play a critical role in the maintenance of drug abuse. [Abstract]

Drago A, Ronchi DD, Serretti A
5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies.
Int J Neuropsychopharmacol. 2007 Nov 30;1-21.
5-HT1A receptors are key components of the serotonin system, acting both pre- and post- synaptically in different brain areas. There is a growing amount of evidence showing the importance of 5-HT1A in different psychiatric disorders, from mood to anxiety disorders, moving through suicidal behaviour and psychotic disorders. Findings in the literature are not consistent with any definite 5-HT1A influence in psychiatric disorders. 5-HT1A gene variants have been reported to play some role in mood disorders, anxiety disorders and psychotic disorders. Again, the literature findings are not unequivocal. Concerning response to treatment, the C(-1019)G variant seems to be of primary interest in antidepressant response: C allele carriers generally show a better response to treatment, especially in Caucasian samples. Together with the C(-1019)G (rs6295) variant, the Ile28Val (rs1799921), Arg219Leu (rs1800044) and Gly22Ser (rs1799920) variants have been investigated in possible associations with psychiatric disorders, also with no definitive results. This lack of consistency can be also due to an incomplete gene investigation. To make progress on this point, a list of validated single nucleotide polymorphisms (SNPs) covering the whole gene is proposed for further investigations. [Abstract]

Cooper-Kazaz R, Lerer B
Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors.
Int J Neuropsychopharmacol. 2007 Nov 30;1-15.
The thyroid hormone, triiodothyronine (T3), is used as a supplement to antidepressant treatment of major depression, to accelerate and enhance response and as an augmenter in patients who have not responded. While there is support from controlled trials and meta-analyses for the use of T3 in conjunction with tricyclic antidepressants, the evidence base for supplementation of specific serotonin reuptake inhibitors (SSRIs) with T3 is more limited. We reviewed the available literature on T3 supplementation of SSRIs including open-label studies and randomized controlled trials (RCTs). Five RCTs were identified. Three were enhancement studies in which T3 was administered concurrently with the antidepressant from the start of treatment and two were augmentation studies in which T3 was added to the antidepressant treatment of patients who had not responded. Three open augmentation studies were identified. The RCTs were too disparate in methodology to allow a meta-analysis to be performed. The enhancement studies are inconclusive in that one showed strongly positive effects of T3, one showed no effect and one showed a trend. The open augmentation studies supported an effect of T3 in SSRI non-responsive patients with some support from a large RCT; a smaller, underpowered RCT did not show efficacy. T3 was well tolerated in most of the studies and adverse effects do not seem to be an impediment to clinical use. Some of the studies identified clinical and thyroid function correlates of response that require further investigation. Further research is needed before it can be definitively established whether T3 is an effective supplement to SSRIs in patients with MDD. The appropriate timing of T3 supplementation needs to be explored and also the dose and length of treatment. [Abstract]

Holmes AD, Chenery HJ, Copland DA
Transdermal nicotine modulates strategy-based attentional semantic processing in non-smokers.
Int J Neuropsychopharmacol. 2007 Nov 30;1-11.
Nicotine has been shown to improve various aspects of cognitive processing such as attention and memory, however, its effects on lexical-semantic processing are relatively uncharted. Recent investigations of mnemonic processing in minimally deprived smokers suggest that nicotine might selectively modulate processes concerned with associative memory. This study investigated the effects of nicotine on lexical-semantic processing in non-smokers using a strategy-based lexical-decision priming paradigm. Transdermal nicotine patches (7 mg/24 h) were administered within a double-blind, placebo-controlled, cross-over design. Participants were trained to expect target words to come from a specified semantic category based on the prime word, although in some instances trained expectations were not met. Participants were presented with the stimuli at either a short or long stimulus onset asynchrony (SOA) to target automatic and attentional processing, respectively (n=12 and 17 for the short and long SOAs, respectively). Nicotine was found to selectively affect priming condition reaction times at the long SOA, indicating a nicotinic modulation of attentional mechanisms. Specifically, facilitation effects were dominant under placebo compared to a dominance of inhibition effects under nicotine. These results suggest that nicotine supports inhibitory attentional mechanisms in cognitively demanding semantic processing paradigms. [Abstract]

Marchant NL, Trawley S, Rusted JM
Prospective memory or prospective attention: physiological and pharmacological support for an attentional model.
Int J Neuropsychopharmacol. 2007 Nov 27;1-11.
Previous studies have reported that nicotine, a cholinergic agonist, could improve prospective memory (PM) - memory for a delayed intention - in healthy young adults. In the present study, we asked whether nicotine effects on PM performance were attributable to a drug-induced non-specific increase in arousal. Therefore, a double-blind, placebo-controlled study compared the effect of nicotine to the effect of an arousal manipulation on PM performance. All participants were non-smokers; half received 1 mg nicotine via a nasal spray and half received a matched placebo. Within these groups, half of the volunteers were exposed to hard anagrams and exhibited heightened tense arousal, while half of the volunteers were given easy anagrams and showed no change in arousal. These manipulations resulted in four conditions, placebo/low-arousal (n=12), placebo/high-arousal (n=10), nicotine/low-arousal (n=12), nicotine/high-arousal (n=13). All participants completed an ongoing lexical decision task while maintaining a PM intention (to make a separate, non-focal, response to certain items embedded within the ongoing task). When introduced separately, both nicotine and high tense arousal improved PM performance, but when combined, this improvement was eliminated. It is argued that both nicotine and high tense arousal increase attentional resources, specifically improving monitoring of the PM targets, but when combined they no longer produce beneficial effects. Additionally, given that nicotine exerted no effect on physiological or subjective measures of arousal, we conclude that the observed effects of nicotine and of arousal on PM performance are driven by different pharmacological mechanisms. [Abstract]

Li C, Tao R, Qin W, Zheng Y, He G, Shi Y, Li X, Guo Z, Chen H, Feng G, He L
Positive association between PDLIM5 and schizophrenia in the Chinese Han population.
Int J Neuropsychopharmacol. 2007 Nov 19;1-8.
The PDZ and LIM domain 5 protein (PDLIM5) contains one PDZ (post-synaptic density-95/discs large/zone occludens-1) domain and three LIM (Lin-11, Isl-1, and Mec-3) domains, and is also known as Enigma homologue LIM domain (ENH) protein or LIM protein. DNA microarray analysis of post-mortem brains of schizophrenics has indicated up-regulation of the mRNA level of PDLIM5, and Horiuchi and colleagues reported two single nucleotide polymorphisms (SNPs) (rs2433320 and rs2433322) in the 5' region of the PDZ and LIM domain 5 gene (PDLIM5) to be significantly associated with schizophrenia in the Japanese population. On the other hand, no association with schizophrenia was observed by Kato and colleagues in a different sample of the Japanese population. In this study, we genotyped six SNPs (including rs2433320 and rs2433322) covering PDLIM5 in 507 schizophrenia patients and 530 normal controls recruited from Jiangxi Province, China. Although rs2433320 was negative in our samples, rs2433322 showed significantly different frequencies between cases and controls (P=0.000010). In addition, high linkage disequilibrium was observed between rs2433320 and rs2433322 (D'=0.880), and haplotypes constructed from the two SNPs were significantly associated with schizophrenia (global P=0.00019, even after strict Bonferroni correction). Our results provide further evidence to support PDLIM5 as a potential susceptible gene for schizophrenia. [Abstract]

Rybakowski JK
Two generations of mood stabilizers.
Int J Neuropsychopharmacol. 2007 Oct;10(5):709-11. [Abstract]

Tahiroglu AY, Avci A
Imipramine, methylphenidate and valproic acid-related EPS in a child: a case report.
Int J Neuropsychopharmacol. 2007 Oct;10(5):705-7. [Abstract]

Shalev AY, Videlock EJ, Peleg T, Segman R, Pitman RK, Yehuda R
Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses.
Int J Neuropsychopharmacol. 2007 Oct 31;1-8.
The aim of the study was to evaluate the association between post-traumatic disorder (PTSD) and hypothalamic-pituitary-adrenal (HPA) axis responses to the triggering trauma. A companion paper evaluates the adrenergic response and interactions between the two. We measured plasma and saliva cortisol, hourly urinary excretion of cortisol, plasma levels of adrenocorticotropin (ACTH), and the leukocyte glucocorticoid receptor (GR) density of 155 non-injured survivors of traumatic events (91 males and 64 females; 125 road traffic accidents, 19 terrorist attacks, 11 others). Measurements were taken during survivors' admissions to an emergency room (ER) of a general hospital, and in the mornings, 10 d, 1 month, and 5 months later. Symptoms of peri-traumatic dissociation, PTSD, and depression were assessed on each follow-up session. The clinician-administered PTSD scale (CAPS) conferred a diagnosis of PTSD at 5 months. Survivors with (n=31) and without (n=124) PTSD at 5 months had similar levels of hormones at all times. Plasma cortisol levels decreased with time in both groups. Female subjects had lower ACTH levels than males. PTSD in females was associated with higher levels of ACTH. In unselected cohorts of trauma survivors, PTSD is not preceded by a detectable abnormality of peripheral HPA axis hormones. [Abstract]

Oranje B, Jensen K, Wienberg M, Glenthøj BY
Divergent effects of increased serotonergic activity on psychophysiological parameters of human attention.
Int J Neuropsychopharmacol. 2007 Oct 31;1-11.
Selective serotonin reuptake inhibitors (SSRIs) are frequently combined to the antipsychotic medication of schizophrenia patients, to treat their depressed, cognitive or negative symptoms. No convincing neurochemical theory exists for this combination. The role of serotonin in those psychophysiological parameters of attention that are already found to be disturbed in schizophrenia, e.g. processing negativity (PN), mismatch negativity (MMN) and P300 amplitude, is poorly understood. In the present study the effects of increased serotonergic activity on these psychophysiological parameters is investigated. In a balanced, double-blind, placebo-controlled, cross-over experiment 18 healthy male volunteers received an oral dose of either placebo or of 10 mg escitalopram (a highly specific SSRI) on two separate test days, after which they were tested in an auditory selective attention paradigm and a MMN paradigm. Escitalopram significantly increased PN and MMN compared to placebo, without affecting the P300 amplitude. Furthermore, administration of escitalopram resulted in a small, yet significant, reduction of task performance in the selective attention paradigm compared to placebo, while it did not affect reaction time. Contrary to what was expected, escitalopram enhanced PN and MMN, without affecting the P300 amplitude. The results are discussed in the light of dosage issues and subtypes of serotonergic receptors. [Abstract]

Hirvonen J, Karlsson H, Kajander J, Lepola A, Markkula J, Rasi-Hakala H, Någren K, Salminen JK, Hietala J
Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-C]WAY-100635.
Int J Neuropsychopharmacol. 2007 Oct 31;1-12.
Serotonin (5-HT) is involved in the pathophysiology of major depressive disorder (MDD). Among the numerous serotonergic receptors, the 5-HT1A receptor subtype is of interest because of its involvement in cognition, hippocampal neurogenesis, and mechanism of action of antidepressant drugs. Previous imaging studies have suggested altered availability of 5-HT1A receptors in MDD but prior antidepressant medication and chronicity of the illness may confound the interpretation. We examined 21 drug-naive primary-care patients with MDD using positron emission tomography (PET) imaging with [carbonyl-11C]WAY-100635, a radioligand for 5-HT1A receptors, along with 15 healthy control subjects. Binding to receptors was assessed both regionally and at voxel level with the binding potential (BP) that was estimated using arterial blood input. Compared with healthy controls, the BP of [carbonyl-11C]WAY-100635 was reduced in patients with MDD in most brain regions, ranging from -9% to -25%. Voxel-level analysis confirmed this finding by showing a widespread reduction of [carbonyl-11C]WAY-100635 BP. No statistically significant associations were observed between BP and total HAMD scores in the patients, but lower BP was associated with higher likelihood of insomnia. This study demonstrated a widespread reduction in the availability of serotonin 5-HT1A receptors in a relatively large sample of drug-naive primary-care patients with MDD, suggesting the involvement of this receptor subtype in the pathophysiology of the illness. Lack of correlation with overall severity of the illness may relate to a largely trait-like nature of this abnormality in depressive disorders. [Abstract]

Videlock EJ, Peleg T, Segman R, Yehuda R, Pitman RK, Shalev AY
Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part II: The adrenergic response.
Int J Neuropsychopharmacol. 2007 Oct 31;1-8.
The aim of the study was to prospectively evaluate the association between the occurrence of post-traumatic stress disorder (PTSD) and the adrenergic response to the traumatic event, and additionally, to explore the link between PTSD and the initial norepinephrine:cortisol ratio. Plasma levels and urinary excretion of norepinephrine (NE) were measured in 155 survivors of traumatic events during their admission to a general hospital emergency room (ER) and at 10 d, 1 month and 5 months later. Symptoms of peri-traumatic dissociation, PTSD and depression were assessed in each follow-up session. The Clinician-Administered PTSD Scale (CAPS) conferred a diagnosis of PTSD at 5 months. Trauma survivors with (n=31) and without (n=124) PTSD had similar levels of plasma NE, urinary NE excretion, and NE:cortisol ratio in the ER. Plasma NE levels were lower in subjects with PTSD at 10 d, 1 month, and 5 months. There was a weak but significant positive correlation between plasma levels of NE in the ER and concurrent heart rate, and a negative correlation between NE in the ER and dissociation symptoms. Peripheral levels of NE, shortly after traumatic events, are poor risk indicators of subsequent PTSD among civilian trauma victims. Simplified biological models may not properly capture the complex aetiology of PTSD. [Abstract]

Takahashi H, Fujimura Y, Hayashi M, Takano H, Kato M, Okubo Y, Kanno I, Ito H, Suhara T
Enhanced dopamine release by nicotine in cigarette smokers: a double-blind, randomized, placebo-controlled pilot study.
Int J Neuropsychopharmacol. 2007 Oct 22;1-5.
Previous studies of smoking on dopamine release in humans were investigated only in smokers. Using nicotine gum, we examined the effect of nicotine on dopamine release in smokers and non-smokers and its relation to the degree of nicotine dependence. Smokers and non-smokers participated in a double-blind, randomized, placebo-controlled cross-over study. They participated in two PET measurements with [11C]raclopride, in which they received either nicotine or placebo. Changes in [11C]raclopride non-displaceable binding potential (BPND) following nicotine administration were quantified. Smokers showed significant decrease in BP in the striatum following nicotine administration, but non-smokers did not show such a decrease. The BPND difference between the two scanning sessions was correlated with the degree of nicotine dependence. The BPND difference might reflect enhanced dopamine release in smokers and the reinforced effect of nicotine. These data suggest the feasibility of our gum method as well as the importance of the degree of dependence in future studies of the nicotine effect on the dopamine system. [Abstract]

Michaelovsky E, Gothelf D, Korostishevsky M, Frisch A, Burg M, Carmel M, Steinberg T, Inbar D, Apter A, Weizman A
Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS.
Int J Neuropsychopharmacol. 2007 Oct 22;1-13.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs [rs2097603; rs4680 (158Val/Met); rs165599] representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, chi2=4.38, p=0.036) and OCD (OR 4.00, chi2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population. [Abstract]

Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, Blecha L, Lowenstein W, Martinot JL, Reynaud M, Lépine JP
New treatments for cocaine dependence: a focused review.
Int J Neuropsychopharmacol. 2007 Oct 10;1-14.
Cocaine, already a significant drug problem in North and South America, has become a more prominent part of the European drug scene. Cocaine dependence has major somatic, psychological, psychiatric, socio-economic, and legal implications. No specific effective pharmacological treatment exists for cocaine dependence. Recent advances in neurobiology have identified various neuronal mechanisms implicated in cocaine addiction and suggested several promising pharmacological approaches. Data were obtained from Medline, EMBASE, and PsycINFO searches of English-language articles published between 1985 and June 2007 using the key words: cocaine, addiction, cocaine dependence, clinical trials, pharmacotherapy(ies) singly and in combination. Large well-controlled studies with appropriate statistical methods were preferred. Pharmacological agents such as GABA agents (topiramate, tiagabine, baclofen and vigabatrin) and agonist replacement agents (modafinil, disulfiram, methylphenidate) seem to be the most promising in treatment of cocaine dependence. The results from trials of first- and second-generation neuroleptics are largely negative. Aripiprazole, a partial dopaminergic agonist that may modulate the serotonergic system, shows some promise. Preliminary results of human studies with anti-cocaine vaccine, N-acetylcysteine, and ondansetron, are promising, as are several compounds in preclinical development. While no medication has received regulatory approval for the treatment of cocaine dependence, several medications marketed for other indications have shown efficacy in clinical trials. An anti-cocaine vaccine and several compounds in preclinical development have also shown promise. Findings from early clinical trials must be confirmed in larger, less selective patient populations. [Abstract]

Stasi MA, Di Serio S, Vertechy M, Schiavone A, Ghirardi O, Minetti P, Campiani G, Borsini F, Carminati P
ST2472: a new potential antipsychotic with very low liability to induce side-effects.
Int J Neuropsychopharmacol. 2007 Oct 10;1-11.
ST2472 was shown to bind to multiple receptors, thus resembling the affinity spectrum of atypical antipsychotics. The present study investigates its in-vivo potential antipsychotic effects. ST2472 is effective in the conditioned avoidance response (CAR) test in rats (ED50=1.5 mg/kg p.o.), a model sensitive to antipsychotics. It antagonizes amphetamine-induced hypermotility at dosages (minimal effective dose=0.7 mg/kg p.o.) that are lower than those necessary to antagonize amphetamine-induced stereotypy (minimal effective dose=30 mg/kg p.o.), in rats. This finding, together with the fact that ST2472 does not induce catalepsy in rodents at up to 100 mg/kg p.o., indicates that ST2472 has very low liability to induce extrapyramidal side-effects. ST2472 does not increase prolactinaemia after chronic treatment. In mice, ST2472 does not appear to alter blood pressure and heart rate in a significant fashion. In conclusion, ST2472 seems to be an antipsychotic with lower liability to produce side-effects than other antipsychotics, such as haloperidol, risperidone, olanzapine and clozapine, which were evaluated as reference drugs. [Abstract]

Cohen BM, Murphy B
The effects of pentazocine, a kappa agonist, in patients with mania.
Int J Neuropsychopharmacol. 2007 Sep 26;1-5.
Past evidence suggests that activation of kappa opiate receptors may lower mood. However, kappa agonists may also induce psychotomimetic symptoms. We tested the effects of the kappa agonist pentazocine in patients in the manic phase of bipolar disorder to determine if pentazocine might reduce symptoms of mania without worsening psychosis. In an open-label, add-on, single-day acute-dose study, ten in-patients with bipolar disorder, type 1, hospitalized for mania received two 50 mg doses of pentazocine 2 h apart. Symptoms of mania were reduced 1 h after each dose, 44% after the first dose and 41% 1 h after the second dose (F=3.69, p=0.01). No adverse effects, including psychotomimetic effects were observed or reported. Sedation was minimal. Further study of pentazocine and other kappa agonists in mania seems warranted. [Abstract]

Newman-Tancredi A, Heusler P, Martel JC, Ormière AM, Leduc N, Cussac D
Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K channel modulation in transfected cells.
Int J Neuropsychopharmacol. 2007 Sep 26;1-15.
Interaction at dopamine D4 receptors may improve cognitive function, which is highly impaired in individuals with schizophrenia, but comparative studies of recent antipsychotics in cellular models of D4 receptor activation are lacking. Here, we report the in-vitro profile of over 30 ligands at recombinant hD4.4 receptors. In [35S]GTPgammaS binding experiments using membranes of CHO-hD4.4 cells, apomorphine, preclamol and the selective D4 agonists, ABT724, CP226269, Ro-10-5824 and PD168077, behaved as partial agonists (Emax 20-60% vs. dopamine), whereas L745870 and RBI257, displayed antagonist properties. The 'conventional' antipsychotic, haloperidol and the 'atypicals', clozapine and risperidone, exhibited antagonist properties, while 'third generation' compounds bifeprunox, SLV313 and F15063, acted as partial agonists (10-30%). Aripiprazole and SSR181507 slightly stimulated [35S]GTPgammaS binding at micromolar concentrations. In Xenopus laevis oocytes co-expressing hD4.4 receptors with G-protein-coupled inwardly rectifying potassium (GIRK) channels, apomorphine, preclamol, ABT724, CP226269, and PD168077 stimulated GIRK currents (Emax 70-80%). The 5-HT1A receptor ligands, WAY100635 and flibanserin, also exhibited partial agonist activity (30% and 15%, respectively). Haloperidol, clozapine, olanzapine and nemonapride did not stimulate GIRK currents, whereas aripiprazole, bifeprunox, SLV313 and F15063, but not SSR181507, exhibited partial agonism (Emax 20-35%). In-vitro responses depended on experimental conditions: increasing NaCl concentration (30 mm to 100 mm) reduced agonist efficacy in [35S]GTPgammaS binding, whereas decreasing the amount of hD4.4 cRNA injected into oocytes (from 2.0 to 0.5 ng/oocyte) reduced agonist efficacy of several compounds. These data indicate that, unlike conventional or 'atypical' antipsychotics, several 'third generation' agents display D4 receptor partial agonism that may be sufficient to influence physiological D4 receptor activity in vivo. [Abstract]

Papazisis G, Kallaras K, Kaiki-Astara A, Pourzitaki C, Tzachanis D, Dagklis T, Kouvelas D
Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy.
Int J Neuropsychopharmacol. 2007 Sep 26;1-9.
Hypoxic-ischaemic (HI) encephalopathy is a severe complication of perinatal asphyxia and remains a frequent cause of a variety of brain disorders with long-term effects on the patients' life. The associated brain damage is strongly related to the toxic action of excitatory amino acids, especially glutamate and aspartate. Lamotrigine is an anti-epileptic drug that blocks the voltage-gated sodium channels of the presynaptic neuron and inhibits the release of glutamate. In the present study a well-established model of perinatal asphyxia in 7-d-old rats was used to investigate the effect of lamotrigine on HI-induced damage to different hippocampal brain structures, since disruption of this brain area is thought to play a key role in schizophrenia and epilepsy. Therefore, a combination of ischaemia, induced by unilateral occlusion of the left common carotid artery, followed by exposure to a 1-h period of hypoxia, was carried out in neonatal 7-d-old rats. Immediately after the insult, lamotrigine was given i.p. The histological outcome in the hippocampus was conducted and the tissue levels of glutamate, aspartate, GABA, and glutamine in the same area were determined. A remarkable reduction of HI-evoked damaged neurons in most of the investigated hippocampal regions was noted after lamotrigine administration. Furthermore, lamotrigine decreased the asphyxia-induced hippocampal tissue levels of glutamate and aspartate. Immediately after perinatal asphyxia GABA levels were enhanced, while levels of glutamine were decreased. Lamotrigine administration did not affect either GABA or glutamine levels. These results suggest a neuroprotective effect of lamotrigine in this particular animal model of neonatal HI encephalopathy. [Abstract]

Loo CK, McFarquhar TF, Mitchell PB
A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression.
Int J Neuropsychopharmacol. 2007 Sep 20;1-28.
There is growing interest worldwide in rTMS as a clinical treatment for depression. Apart from efficacy, its safety as a clinical treatment must be considered before its widespread use can be advocated. All published, sham-controlled rTMS depression trials were reviewed for reported side-effects and outcomes of formal neuropsychological testing. In addition, all reports of seizures occurring with rTMS were reviewed. Other safety concerns (effects on hearing; headache, pain, induced currents in electrical circuits, histotoxicity, electromagnetic field exposure, psychiatric complications, safety in pregnancy) are discussed. Common side-effects were of a minor nature, e.g. headache. There was a low incidence of accidental seizures and induced hypomania, both of which were associated with identified risk factors for which subjects should be screened. Long-term effects of repeated rTMS sessions are as yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment. [Abstract]

Cheng MC, Liao DL, Hsiung CA, Chen CY, Liao YC, Chen CH
Chronic treatment with aripiprazole induces differential gene expression in the rat frontal cortex.
Int J Neuropsychopharmacol. 2007 Sep 17;1-10.
Chronic treatment of antipsychotic drugs can modulate gene expression in the brain, which may underscore their clinical efficacy. Aripiprazole is the first approved antipsychotic drug of the class of dopamine D2 receptor partial agonist, which has been shown to have similar efficacy and favourable side-effects profile compared to other antipsychotic drugs. This study aimed to identify differential gene expression induced by chronic treatment of aripiprazole. We used microarray-based gene expression profiling technology, real-time quantitative PCR and Western blot analysis to identify differentially expressed genes in the frontal cortex of rats under 4 wk treatment of aripiprazole (10 mg/kg). We were able to detect ten up-regulated genes, including early growth response gene 1, 2, 4 (Egr1, Egr2, Egr4), chromobox homolog 7 (Cbx7), cannabinoid receptor (Cnr1), catechol-O-methyltransferase (Comt), protein phosphatase 2c, magnesium dependent (Ppm2c), tachykinin receptor 3 (Tacr3), Wiscott-Aldrich syndrome-like gene (Wasl) and DNA methyltransferase 3a (Dnmt3a). Our data indicate that chronic administration of aripiprazole can induce differential expression of genes involved in transcriptional regulation and chromatin remodelling and genes implicated in the pathogenesis of psychosis. [Abstract]

Cardoso EF, Fregni F, Martins Maia F, Boggio PS, Luis Myczkowski M, Coracini K, Lopes Vieira A, Melo LM, Sato JR, Antonio Marcolin M, Rigonatti SP, Cruz AC, Reis Barbosa E, Amaro E
rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex.
Int J Neuropsychopharmacol. 2007 Aug 21;1-11.
The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson's disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network. [Abstract]

Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, Vanover KE, Hacksell U, Brann MR, Davis RE, Weiner DM
PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain.
Int J Neuropsychopharmacol. 2007 Aug 21;1-9.
The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated, in part, by interactions with the 5-HT2A receptor. Recently, it has been recognized that clinically effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists. In the present study, which is part of the clinical development of the novel, selective 5-HT2A receptor inverse agonist ACP-103, we applied positron emission tomography (PET) with the radioligand [11C]N-methylspiperone ([11C]NMSP) to study the relationship between oral dose, plasma level, and uptake of ACP-103 in living human brain. The safety of drug administration was also assessed. Four healthy volunteers were examined by PET at baseline, and after the oral administration of various single doses of ACP-103. Two subjects each received 1, 5, and 20 mg doses, and two subjects each received 2, 10, and 100 mg doses, respectively. ACP-103 was well tolerated. Detectable receptor binding was observed at very low ACP-103 serum levels. Cortical [11C]NMSP binding was found to be dose-dependent and fitted well to the law of mass action. A reduction in binding was detectable after an oral dose of ACP-103 as low as 1 mg, and reached near maximal displacement following the 10-20 mg dose. In conclusion, administration of ACP-103 to healthy volunteers was found to be safe and well tolerated, and single oral doses as low as 10 mg were found to fully saturate 5-HT2A receptors in human brain as determined by PET. [Abstract]

Garver DL, Holcomb JA, Christensen JD
Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia.
Int J Neuropsychopharmacol. 2007 Aug 21;1-13.
Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity (Dm) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) (n=8) were differentiated from poor responders (PR) (n=5) according to previously defined criteria. Differences of Dm at both baseline and following treatment were assessed using Dm distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p<0.05) of Dm, was found in the D-RS patients, with multiple regions demonstrating p<0.0005 patient-control differences. The pathological increase in Dm was reduced (p<0.03) following treatment-associated reduction of psychotic symptoms by 84%. Dm of PR patients did not differ from controls at baseline or following subacute treatment. While the pathophysiology(ies) underlying psychosis in poorly responsive (PR) schizophrenics does not appear to be related to a disordered myelin, the findings are consistent with a partially reversible disorder of myelin integrity, and may underlie a dys-synchrony of information processing in a major subgroup of drug-responsive patients with schizophrenia. An antipsychotic drug-induced cascade may partially restore myelin integrity and functional connectivity concomitant with antipsychotic effects in such D-RS patients. [Abstract]

Lapiz MD, Zhao Z, Bondi CO, O'Donnell JM, Morilak DA
Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition.
Int J Neuropsychopharmacol. 2007 Dec;10(6):827-33.
The role of alpha(2)-adrenergic autoreceptor desensitization in the delayed onset of antidepressant efficacy of selective norepinephrine (NE) reuptake inhibitors is unclear. Using the alpha(2)-antagonist yohimbine, we showed previously that chronic treatment with desipramine (DMI) did not alter autoreceptor-mediated inhibition of NE release in the cortex. However, yohimbine may have non-selective effects that could confound this interpretation. Thus, using microdialysis, we measured acute effects of the highly selective alpha(2)-antagonist atipamezole on NE release in the prefrontal cortex following chronic DMI treatment, after 0-8 d washout. Atipamezole induced a similar elevation of extracellular NE in all treatment groups, indicating no change in autoreceptor function. Further, the effect was most rapid in DMI-treated rats with 0- and 2-d washout, suggesting that autoreceptor-mediated inhibition was most prominent when NE levels were highest. This provides further evidence that autoreceptor-mediated inhibition of NE neurotransmission remains functional after chronic DMI treatment, arguing against the hypothesis that desensitization of alpha(2)-autoreceptors accounts for the delayed onset of action of selective NE reuptake inhibitors. [Abstract]

Savaskan E, Müller SE, Böhringer A, Schulz A, Schächinger H
Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients.
Int J Neuropsychopharmacol. 2007 Aug 13;1-8.
Depression is a common disorder in the elderly handicapping patients with affective and cognitive symptoms. Because of their good tolerability relative to the older tricyclic compounds, selective serotonin reuptake inhibitors (SSRIs) are increasingly used for the treatment of depression in the elderly. Little is known about their effects on cognition in elderly patients. In the present 4-wk, single-centre, randomized, open-label trial we investigated the antidepressive effects of escitalopram, an SSRI, in 18 elderly depressed patients [mean age (+/-s.e.m.) 76.2+/-1.8 yr] compared to 22 healthy age-matched controls (mean age 76.9+/-1.8 yr). Affective and cognitive symptoms were assessed using the Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), and a face portrait recognition test to assess memory for happy and angry faces. Depressed patients prior to treatment had markedly reduced memory performance. Treatment with escitalopram improved affective and cognitive symptoms significantly. Furthermore, escitalopram treatment improved memory for negative facial stimuli. Control subjects confirmed the well- established memory bias favouring recognition of identities acquired with happy expressions. Importantly, this bias was absent in depressed patients prior to, but also after treatment. In conclusion, escitalopram, even after a relatively short treatment period, was effective in treating depression in the elderly and may help improve cognitive performance for social stimuli. [Abstract]

Tanaka M, Kobayashi D, Murakami Y, Ozaki N, Suzuki T, Iwata N, Haraguchi K, Ieiri I, Kinukawa N, Hosoi M, Ohtani H, Sawada Y, Mine K
Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea.
Int J Neuropsychopharmacol. 2007 Aug 13;1-7.
Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may affect paroxetine-induced nausea. [Abstract]

Stahl SM
Novel mechanism of antidepressant action: norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism.
Int J Neuropsychopharmacol. 2007 Oct;10(5):575-8. [Abstract]

Perova T, Wasserman MJ, Li PP, Warsh JJ
Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder.
Int J Neuropsychopharmacol. 2007 Aug 6;1-12.
Substantial evidence implicates abnormalities of intracellular calcium (Ca2+) dynamics in the pathophysiology of bipolar disorder (BD). However, the precise mechanisms underlying such disturbances are poorly understood. To further elaborate the nature of altered intracellular Ca2+ signalling dynamics that occur in BD, we examined receptor- and store-operated Ca2+ responses in B lymphoblast cell lines (BLCLs), which have been found in earlier studies to 'report' BD-associated disturbances. Basal Ca2+ concentrations ([Ca2+]B), and lysophosphatidic acid (LPA)- and thapsigargin-stimulated Ca2+ responses were determined in BLCLs from 52 BD-I patients and 30 healthy comparison subjects using fura-2, and ratiometric fluorometry. ANOVA revealed a significant effect of diagnosis, but not gender, on [Ca2+]B (F1,63=4.4, p=0.04) and the rate of rise (F1,63=5.2, p=0.03) of LPA-stimulated Ca2+ responses in BLCLs from patients compared with those from healthy subjects. A significant genderxdiagnosis interaction on the LPA-induced rate of rise (F1,63=4.6, p=0.03) was accounted for by a faster rate of rise (97%) in BLCLs from BD-I males compared with healthy males but not in those from female patients compared with healthy females. A genderxdiagnosis interaction in thapsigargin-evoked Ca2+ influx (F1,61=3.8, p=0.05) resulted from a significantly higher peak [Ca2+]influx (24%) in BLCLs from female compared with male patients. The results suggest more rapid LPA-stimulated Ca2+ responses occur in BLCLs from BD-I patients compared with controls, which are probably mediated, in part, by canonical transient receptor potential type 3 (TRPC3)-like channels. Additionally, this study highlights sex-dependent differences that can occur in the pathophysiological disturbances involved in BD. [Abstract]

Amar S, Shaltiel G, Mann L, Shamir A, Dean B, Scarr E, Bersudsky Y, Belmaker RH, Agam G
Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia.
Int J Neuropsychopharmacol. 2007 Aug 6;1-9.
Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, beta-arrestin1, AKT1 and GSK-3beta are involved in the pathophysiology of schizophrenia. Lymphocytes obtained from schizophrenia and bipolar patients and healthy controls recruited from the Beer-Sheva Mental Health Center were transformed by Epstein-Barr virus (EBV) into lymphocyte-derived cell lines (LDCL). Post-mortem brain samples were obtained from the Rebecca L. Cooper Brain Bank, Parkville, Australia. The study was approved by the IRB committees of Beer-Sheva, Israel and Parkville, Australia. Levels of the specific proteins were assayed by Western blotting. beta-arrestin1 protein levels were significantly 2-fold increased in LDCL from schizophrenia patients while Par-4 protein levels were unaltered. A 63% significant decrease was found in frontal cortex phospho-Ser9-GSK-3beta protein levels in schizophrenia but not in those of AKT1, Par-4 or beta-arrestin1. Elevated beta-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3beta protein levels in post-mortem frontal cortex of schizophrenia patients vs. control groups support the possible involvement of these proteins in the pathophysiology of schizophrenia. However, since we did not find differences in beta-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3beta participates in other signalling cascades we can not rule out the possibility that the differences found reflect deviation in DRD2 signalling. [Abstract]

Cohen H, Geva AB, Matar MA, Zohar J, Kaplan Z
Post-traumatic stress behavioural responses in inbred mouse strains: can genetic predisposition explain phenotypic vulnerability?
Int J Neuropsychopharmacol. 2007 Jul 27;1-19.
Clinical studies of twin pairs and families of post-traumatic stress disorder (PTSD) patients raise questions as to possible genetic predisposition to PTSD. Studies using isogenic animal populations exposed to a stress paradigm could elucidate the relative contributions of genotype and environment to endophenotypic expression. The prevalence of individuals displaying severely compromised behavioural responses to predator scent stress (PSS) was assessed in six inbred strains of mice in an animal model of PTSD that classifies individuals into groups according to the degree of their behavioural response. The choice of strains was based on the frequent use of these mice in transgenic research. The prevalence of extreme behavioural response in the elevated plus maze and the acoustic startle response paradigms, performed in sequence, was assessed at baseline and 7 d after PSS exposure between and within strains, and compared to differences in circulating corticosterone levels. Narrow-sense trait heritability was determined by comparing the between-strain variance to the total variance. Although strain-specific differences in anxiety-like behaviours were demonstrated, the results revealed a significant degree of individual variability in response patterns within each of the inbred strains, yielding a baseline heritability factor for anxiety-like behaviours of 30%, but only 10% for response to stress exposure. Baseline anxiety-like behaviours were found not to be predictive of post-exposure behavioural responses. The response of the individual to stress is multifactorial and environmental factors play a predominant role in characterizing the individual response to stress exposure, although there are significant genetic underpinnings. [Abstract]

Kato T
Bridging pharmacology and neurodevelopment in schizophrenia.
Int J Neuropsychopharmacol. 2007 Dec;10(6):713-6. [Abstract]

Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, M Matthews P, J Cowen P
Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients.
Int J Neuropsychopharmacol. 2007 Jul 11;1-6.
Studies using proton magnetic resonance spectroscopy (1H-MRS) indicate that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in the occipital cortex. The aim of this study was to use 1H-MRS to determine if changes in occipital and frontal cortical GABA levels were present in patients with a history of depression who had recovered and were no longer taking medication. We used 1H-MRS to measure levels of GABA in both occipital cortex and anterior cingulate cortex/prefrontal cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression. Levels of GABA in both occipital and anterior cingulate cortex were significantly lower in recovered depressed subjects than healthy controls. Our data provide preliminary evidence that a history of recurrent depression is associated with decreased GABA levels in anterior cingulate cortex and occipital cortex. These changes could represent part of the neurobiological vulnerability to recurrent depressive episodes. [Abstract]

Ito T, Hiraoka S, Kuroda Y, Ishii S, Umino A, Kashiwa A, Yamamoto N, Kurumaji A, Nishikawa T
Effects of schizophrenomimetics on the expression of the CCN1 (CYR 61) gene encoding a matricellular protein in the infant and adult neocortex of the mouse and rat.
Int J Neuropsychopharmacol. 2007 Dec;10(6):717-25.
The acute systemic administration of a schizophrenomimetic phencyclidine [5 or 10 mg/kg, subcutaneously (s.c.)] markedly up-regulated the neocortical expression of the CCN1 gene encoding a secreted extracellular matrix-associated protein at postnatal day 56, but not at postnatal day 8, after 60 min in the mouse and rat. The development-dependent nature of the up-regulation between postnatal days 8 and 56 seems to be similar to that of the adult type phencyclidine-induced abnormal behaviours, which have been considered to be models of schizophrenic symptoms. In the young adult rat, 5, 10, and 20 mg/kg phencyclidine (given s.c.) induced an increase in the CCN1 gene transcripts in a dose-related and bell-shaped manner with a maximum at the dose of 10 mg/kg, 60 min post-injection. Other schizophrenomimetics, dizocilpine (1 mg/kg) and methamphetamine (4.8 mg/kg), also caused a prominent up-regulation of the neocortical expression of the CCN1 gene in adult rats. These results indicate that the CCN1 gene or protein could be implicated in a molecular cascade associated with the age-dependent onset of schizophrenia that usually occurs after puberty. [Abstract]

Thalmeier A, Dickmann M, Giegling I, Schneider B, M Hartmann A, Maurer K, Schnabel A, Kauert G, Möller HJ, Rujescu D
Gene expression profiling of post-mortem orbitofrontal cortex in violent suicide victims.
Int J Neuropsychopharmacol. 2007 Jul 3;1-12.
The neurobiological basis of suicidal behaviour is multifactorial and complex. Several lines of evidence indicate that environmental factors as well as multiple genes and interactions of both are implicated in its aetiology. The aim of this study was to establish the transcriptomic expression profile of post-mortem brain tissue of suicide victims in order to identify new candidate genes and biological patterns for suicidal behaviour. Post-mortem orbitofrontal cortex tissue was derived from 11 suicide victims and 10 non-psychiatric controls carefully selected from a brain bank of over 150 brains, and the expression of more than 23000 messenger RNAs was assessed in this case-control study. Validation experiments were carried out using quantitative RT-PCR as an independent method. A classification of the differentially expressed genes according to their biological function and statistical analyses of the data were performed in order to identify biological pathways that are over-represented in the suicide group. In total, 124 transcripts demonstrated significant changes (fold changes 1.3, p value 0.01), with 59 showing under-, and 65 over-expression in the suicide group. The results could be validated for nine particularly interesting transcripts (CDCA7L, CDH12, EFEMP1, MLC1, PCDHB5, PTPRR, S100A13, SCN2B, and ZFP36). The pathway analysis showed that the Gene Ontology categories 'central nervous system development', 'homophilic cell adhesion', 'regulation of cell proliferation' and 'transmission of nerve impulse' were significantly enriched. The differentially expressed genes and significant biological processes might be involved in the pathophysiology of suicide and warrant further attention. [Abstract]

Savitz JB, van der Merwe L, Newman TK, Solms M, Stein DJ, Ramesar RS
The relationship between childhood abuse and dissociation. Is it influenced by catechol-O-methyltransferase (COMT) activity?
Int J Neuropsychopharmacol. 2007 Jul 3;1-13.
Dissociation is a failure of perceptual, memorial and emotional integration that is associated with a variety of psychiatric disorders. Dissociative processes are usually attributed to the sequelae of childhood trauma although there are data to suggest that genetic influences are also important. Bipolar disorder (BD), a condition with a strong genetic basis, has also been associated with early psychological trauma. Since childhood trauma is a risk factor for both BD and dissociation, we tested for potential gene-childhood abuse interactions on dissociation in a pilot sample of BD probands and their affected and unaffected relatives (n=178). Dissociation was measured with the Dissociative Experiences Scale (DES II) and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). The BD and recurrent unipolar depression (MDE-R) groups showed higher levels of self-reported abuse and dissociation than their unaffected relatives. The low-activity Met allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene was associated with lower levels of self-reported dissociation. Further, the functional catechol-O-methyltransferase (COMT) Val158Met polymorphism interacted significantly with total CTQ abuse scores to impact perceived dissociation. The Val/Val genotype was associated with increasing levels of dissociation in participants exposed to higher levels of childhood trauma. The opposite was observed in people with Met/Met genotypes who displayed decreased dissociation with increasing self-reported childhood trauma. The current findings support the involvement of the COMT Val158Met polymorphism in mediating the relationship between trauma and psychopathology. [Abstract]

Haroutunian V, Davis KL
Introduction to the special section: Myelin and oligodendrocyte abnormalities in schizophrenia.
Int J Neuropsychopharmacol. 2007 Aug;10(4):499-502.
A central tenet of modern views of the neurobiology of schizophrenia is that the symptoms of schizophrenia arise from a failure of adequate communication between different brain regions and disruption of the circuitry that underlies behaviour and perception. Historically this disconnectivity syndrome has been approached from a neurotransmitter-based perspective. However, efficient communication between brain circuits is also contingent on saltatory signal propagation and salubrious myelination of axons. The papers in this Special Section examine the neuroanatomical and molecular biological evidence for abnormal myelination and oligodendroglial function in schizophrenia through studies of post-mortem brain tissue and animal model systems. The picture that emerges from the studies described suggests that although schizophrenia is not characterized by gross abnormalities of white matter such as those evident in multiple sclerosis, it does involve a profound dysregulation of myelin-associated gene expression, reductions in oligodendrocyte numbers, and marked abnormalities in the ultrastructure of myelin sheaths. [Abstract]

Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA, Pascual-Leone A, Fregni F
A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression.
Int J Neuropsychopharmacol. 2007 Jun 11;1-6.
Preliminary findings suggest that transcranial direct current stimulation (tDCS) can have antidepressant effects. We sought to test this further in a parallel-group, double-blind clinical trial with 40 patients with major depression, medication-free randomized into three groups of treatment: anodal tDCS of the left dorsolateral prefrontal cortex (active group - 'DLPFC'); anodal tDCS of the occipital cortex (active control group - 'occipital') and sham tDCS (placebo control group - 'sham'). tDCS was applied for 10 sessions during a 2-wk period. Mood was evaluated by a blinded rater using the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The treatment was well tolerated with minimal side-effects that were distributed equally across all treatment groups. We found significantly larger reductions in depression scores after DLPFC tDCS [HDRS reduction of 40.4% (+/-25.8%)] compared to occipital [HDRS reduction of 21.3% (+/-12.9%)] and sham tDCS [HDRS reduction of 10.4% (+/-36.6%)]. The beneficial effects of tDCS in the DLPFC group persisted for 1 month after the end of treatment. Our findings support further investigation on the effects of this novel potential therapeutic approach - tDCS - for the treatment of major depression. [Abstract]

Guiard BP, David DJ, Deltheil T, Chenu F, Le Maître E, Renoir T, Leroux-Nicollet I, Sokoloff P, Lanfumey L, Hamon M, Andrews AM, Hen R, Gardier AM
Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.
Int J Neuropsychopharmacol. 2007 Jun 11;1-14.
Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus. [Abstract]