bipolar disorder diagnostic issues


Attention Valued Visitor: A Drug Reference Page for FDA Approved General Anesthetics is now available!
Shawn Thomas ( is working to summarize the mechanisms of action of every drug approved by the FDA for a brain- related condition. In addition, new pages with more automated content will soon replace some of the older pages on the web site. If you have suggestions about content that you would like to see, e-mail if you have anything at all to share.



(Updated 1/12/04)

[Note that research conducted prior to 2002 is not included on this page.]

Bowden CL.
Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II.
MedGenMed. 2002 Aug 16;4(3):17.
"Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered." [Full Text]

Judd LL, Akiskal HS, Schettler PJ, Coryell W, Maser J, Rice JA, Solomon DA, Keller MB.
The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders?
J Affect Disord. 2003 Jan;73(1-2):19-32.
"BACKGROUND: The present analyses were designed to compare the clinical characteristics and long-term episode course of Bipolar-I and Bipolar-II patients in order to help clarify the relationship between these disorders and to test the bipolar spectrum hypothesis. METHODS: The patient sample consisted of 135 definite RDC Bipolar-I (BP-I) and 71 definite RDC Bipolar-II patients who entered the NIMH Collaborative Depression Study (CDS) between 1978 and 1981; and were followed systematically for up to 20 years. Groups were compared on demographic and clinical characteristics at intake, and lifetime comorbidity of anxiety and substance use disorders. Subsets of patients were compared on the number and type of affective episodes and the duration of inter-episode well intervals observed during a 10-year period following their resolution of the intake affective episode. RESULTS: BP-I and BP-II had similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II had a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. Intake episodes of BP-I were significantly more acutely severe. BP-II patietns had a substantially more chronic course, with significantly more major and minor depressive episodes and shorter inter-episode well intervals. BP-II patients were prescribed somatic treatment a substantially lower percentage of time during and between affective episodes. LIMITATIONS: BP-I patients with severe manic course are less likely to be retained in long-term follow-up, whereas the reverse might be true for BP-II patients who are significantly more prone to depression (i.e., patients with less inclination to depression and with good prognosis may have dropped out in greater proportions); this could increase the gap in long term course characteristics between the two samples. The greater chronicity of BP-II may be due, in part, to the fact that the patients were prescribed somatic treatments substantially less often both during and between affective episodes. CONCLUSIONS: The variety in severity of the affective episodes shows that bipolar disorders, similar to unipolar disorders, are expressed longitudinally during their course as a dimensional illness. The similarities of the clinical phenotypes of BP-I and BP-II, suggest that BP-I and BP-II are likely to exist in a disease spectrum. They are, however, sufficiently distinct in terms of long-term course (i.e., BP-I with more severe episodes, and BP-II more chronic with a predominantly depressive course), that they are best classified as two separate subtypes in the official classification systems." [Abstract]

Judd LL, Schettler PJ, Akiskal HS, Maser J, Coryell W, Solomon D, Endicott J, Keller M.
Long-term symptomatic status of bipolar I vs. bipolar II disorders.
Int J Neuropsychopharmacol. 2003 Jun;6(2):127-137.
"Weekly affective symptom severity and polarity were compared in 135 bipolar I (BP I) and 71 bipolar II (BP II) patients during up to 20 yr of prospective symptomatic follow-up. The course of BP I and BP II was chronic; patients were symptomatic approximately half of all follow-up weeks (BP I 46.6% and BP II 55.8% of weeks). Most bipolar disorder research has concentrated on episodes of MDD and mania and yet minor and subsyndromal symptoms are three times more common during the long-term course. Weeks with depressive symptoms predominated over manichypomanic symptoms in both disorders (31) in BP I and BP II at 371 in a largely depressive course (depressive symptoms=59.1% of weeks vs. hypomanic=1.9% of weeks). BP I patients had more weeks of cyclingmixed polarity, hypomanic and subsyndromal hypomanic symptoms. Weekly symptom severity and polarity fluctuated frequently within the same bipolar patient, in which the longitudinal symptomatic expression of BP I and BP II is dimensional in nature involving all levels of affective symptom severity of mania and depression. Although BP I is more severe, BP II with its intensely chronic depressive features is not simply the lesser of the bipolar disorders; it is also a serious illness, more so than previously thought (for instance, as described in DSM-IV and ICP-10). It is likely that this conventional view is the reason why BP II patients were prescribed pharmacological treatments significantly less often when acutely symptomatic and during intervals between episodes. Taken together with previous research by us on the long-term structure of unipolar depression, we submit that the thrust of our work during the past decade supports classic notions of a broader affective disorder spectrum, bringing bipolarity and recurrent unipolarity closer together. However the genetic variation underlying such a putative spectrum remains to be clarified." [Abstract]

Serretti A, Mandelli L, Lattuada E, Cusin C, Smeraldi E.
Clinical and demographic features of mood disorder subtypes.
Psychiatry Res. 2002 Nov 15;112(3):195-210.
"The aim of this study was to investigate demographic, clinical and symptomatologic features of the following mood disorder subtypes: bipolar disorder I (BP-I); bipolar disorder II (BP-II); major depressive disorder, recurrent (MDR); and major depressive episode, single episode (MDSE). A total of 1832 patients with mood disorders (BP-I=863, BP-II=141, MDR=708, and MDSE=120) were included in our study. The patients were assessed using structured diagnostic interviews and the operational criteria for psychotic illness checklist (n=885), the Hamilton depression rating scale (n=167), and the social adjustment scale (n=305). The BP-I patients were younger; had more hospital admissions; presented a more severe form of symptomatology in terms of psychotic symptoms, disorganization, and atypical features; and showed less insight into their disorder than patients in the other groups. Compared with the major depressive subgroups, BP-I patients were more likely to have an earlier age at onset, an earlier first lifetime psychiatric treatment, and a greater number of illness episodes. BP-II patients had a higher suicide risk than both BP-I and MDSE patients. MDSE patients presented less severe symptomatology, lower age at observation, and a higher number of males. The retrospective approach and the selection constraints due to the inclusion criteria are the main limitations of the study. Our data support the view that BP-I disorder is quite different from the remaining mood disorders from a demographic and clinical perspective, with BP-II disorder having an intermediate position to MDR and MDSE, that is, as a less severe disorder. This finding may help in the search for the biological basis of mood disorders." [Abstract]

Benazzi F.
Clinical differences between bipolar II depression and unipolar major depressive disorder: lack of an effect of age.
J Affect Disord. 2003 Jul;75(2):191-5.
"BACKGROUND: Inconsistent clinical differences were reported in bipolar II versus unipolar depression. Age difference may be a confounding factor. Study aims were to describe the clinical and family history features of bipolar II versus unipolar depression, and to control for the possible confounding effect of age on clinical features. METHODS: Consecutive 126 unipolar and 187 bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Variables studied were gender, age, age of onset, MDE recurrences, axis I comorbidity, MDE severity, psychotic, melancholic, and atypical features, depression chronicity, melancholic, atypical, and hypomanic symptoms, depressive mixed state-DMX3 (MDE+three or more concurrent hypomanic symptoms), and mood disorders family history. The effect of age on clinical differences was controlled by logistic regression (by adding age as an independent variable after each independent variable). RESULTS: Bipolar II had significantly lower age, lower age of onset, more recurrences, more atypical features, more DMX3, more family history of bipolar II and MDE. Almost all the clinical differences found significant in the first analysis resulted still significant when controlled for age. LIMITATIONS: Single interviewer, non-blind, cross-sectional assessment, bipolar II diagnosis based on history. CONCLUSIONS: Results confirmed previous findings, and showed that bipolar II-unipolar MDE clinical differences were not related to age." [Abstract]

Dorz S, Borgherini G, Conforti D, Scarso C, Magni G.
Depression in inpatients: bipolar vs unipolar.
Psychol Rep. 2003 Jun;92(3 Pt 1):1031-9.
"162 depressed inpatients were divided into three diagnostic groups to compare patterns of sociodemographic characteristics, psychopathology, and psychosocial: 35 had a single episode of major depression, 96 had recurrent major depression, and 31 had a bipolar disorder. Psychopathology and psychosocial functioning were measured by clinician-rated scales, Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, Clinical Global Impression, and self-rating scales, Symptom Checklist-90, Social Support Questionnaire, Social Adjustment Scale. The three groups were comparable on sociodemographic variables, with the exception of education. Univariate analyses showed a similar social impairment as measured by Social Support Questionnaire, Social Adjustment Scale, and no significant differences were recorded for the psychopathology when the total test scores (Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, Clinical Global Index, Symptom Checklist-90) were evaluated. Some differences emerged for single items in the Montgomery-Asberg Depression Rating Scale and Symptom Checklist-90. These findings suggest a substantial similarity among the three groups. Results are discussed in terms of the clinical similarities between unipolar and bipolar patients during a depressive episode as well as the limitations of cross-sectional study implies." [Abstract]

Benazzi F.
Bipolar II disorder and major depressive disorder: continuity or discontinuity?
World J Biol Psychiatry. 2003 Oct;4(4):166-71.
"AIM: To find if bipolar II disorder (BPII) and major depressive disorder (MDD) were distinct categories or overlapping syndromes. METHODS: 308 BPII and 236 MDD outpatients, presenting for major depressive episode (MDE) treatment, were interviewed with the Structured Clinical Interview for DSM-IV. History of mania and hypomania, and hypomanic symptoms present during MDE, were systematically investigated. Presence of zones of rarity between BPII and MDD depressive syndromes was assessed. Atypical and hypomanic symptoms were chosen because atypical features and depressive mixed state (ie, MDE plus more than 2 concurrent hypomanic symptoms, according to Akiskal and Benazzi 2003) were often reported to distinguish BPII from MDD depressive syndromes (more common in BPII). If BPII were a distinct category, distributions of these symptoms should show zones of rarity between BPII and MDD depressive syndromes. Histograms and Kernel density estimate were used to study distributions of these symptoms. RESULTS: BPII had significantly more atypical features and depressive mixed state than MDD. Histograms and Kernel density estimate curves of distributions of atypical and hypomanic symptoms in the entire sample did not show zones of rarity. CONCLUSIONS: Finding no zones of rarity supports a continuity between BPII and MDD (meaning partly overlapping disorders without clear boundaries)." [Abstract]

Benazzi F.
Bipolar II versus unipolar chronic depression: a 312-case study.
Compr Psychiatry 1999 Nov-Dec;40(6):418-21
"Differences between bipolar II depression and unipolar depression have been reported, such as a lower age at onset and more atypical features in bipolar II depression. The aim of the present study was to compare chronic/nonchronic bipolar II depression with chronic/nonchronic unipolar depression to determine whether the reported differences are present when chronicity is taken into account. Three hundred twelve outpatients in a bipolar II/unipolar major depressive episode were assessed with the Structured Clinical Interview for DSM-IV-Clinician Version (SCID-CV), the Montgomery and Asberg Depression Rating Scale (MADRS), and the Global Assessment of Functioning (GAF) Scale. No significant difference was found between chronic bipolar II and chronic unipolar depression (age at intake and onset, gender, duration of illness, recurrences, psychosis, atypical features, axis I comorbidity, and severity). A significantly lower age at onset and more atypical features were observed when comparing chronic/nonchronic bipolar II with nonchronic unipolar depression. These findings suggest that differences reported between bipolar II and unipolar depression are mainly due to nonchronic unipolar depression. Chronic unipolar depression may be a subtype intermediate between bipolar II depression and nonchronic unipolar depression." [Abstract]

Ducrey S, Gex-Fabry M, Dayer A, Pardos ER, Roth L, Aubry JM, Bertschy G.
A Retrospective Comparison of Inpatients with Mixed and Pure Depression.
Psychopathology. 2003 [Epub ahead of print]. Epub 2003 Nov 27.
"Some authors advocate a broadening of the narrow concept of mixed episodes in the direction of mania leading to the concept of mixed mania, and in the direction of depression leading to the concept of mixed depression. The latter has been little investigated so far. In the present article, we retrospectively compare 49 patients with pure depression with 51 patients with mixed depression in terms of socio-demographic and clinical variables in order to contribute to the validation of the distinction between mixed and pure depression. Supporting this distinction, we observed that mixed depressive patients more frequently had past histories of bipolar disorder and alcohol abuse and had longer durations of hospital stay. These last two points remain significant even when we control for the effect of the association with bipolarity." [Abstract]

Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W.
Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania.
J Affect Disord. 2003 Jan;73(1-2):133-46.
"BACKGROUND: The boundaries of bipolarity have been expanding over the past decade. Using a well characterized epidemiologic cohort, in this paper our objectives were: (1). to test the diagnostic criteria of DSM-IV hypomania, (2). to develop and validate criteria for the definition of softer expressions of bipolar-II (BP-II) disorder and hypomania, (3). to demonstrate the prevalence, clinical validity and comorbidity of the entire soft bipolar spectrum. METHODS: Data on the continuum from normal to pathological mood and overactivity, collected from a 20-year prospective community cohort study of young adults, were used. Clinical validity was analysed by family history, course and clinical characteristics, including the association with depression and substance abuse. RESULTS: (1). Just as euphoria and irritability, symptoms of overactivity should be included in the stem criterion of hypomania; episode length should probably not be a criterion for defining hypomania as long as three of seven signs and symptoms are present, and a change in functioning should remain obligatory for a rigorous diagnosis. (2). Below that threshold, 'hypomanic symptoms only' associated with major or mild depression are important indicators of bipolarity. (3). A broad definition of bipolar-II disorder gives a cumulative prevalence rate of 10.9%, compared to 11.4% for broadly defined major depression. A special group of minor bipolar disorder (prevalence 9.4%) was identified, of whom 2.0% were cyclothymic; pure hypomania occurred in 3.3%. The total prevalence of the soft bipolar spectrum was 23.7%, comparable to that (24.6%) for the entire depressive spectrum (including dysthymia, minor and recurrent brief depression). LIMITATION: A national cohort with a larger number of subjects is needed to verify the numerical composition of the softest bipolar subgroups proposed herein. CONCLUSION: The diagnostic criteria of hypomania need revision. On the basis of its demonstrated clinical validity, a broader concept of soft bipolarity is proposed, of which nearly 11% constitutes the spectrum of bipolar disorders proper, and another 13% probably represent the softest expression of bipolarity intermediate between bipolar disorder and normality." [Abstract]

Benazzi F, Akiskal HS.
The dual factor structure of self-rated MDQ hypomania: energized-activity versus irritable-thought racing.
J Affect Disord. 2003 Jan;73(1-2):59-64.
"BACKGROUND: Bipolar II is diagnosed in a clinically depressed patient by documenting history of hypomania. Therefore, it is of great significance for both clinical and research purposes to characterize the factor structure of hypomania. METHODS: Among consecutive depressive outpatients-126 major depressives and 187 bipolar II-diagnosed by the Structured Clinical Interview for DSM-IV (Clinician Version), 181 who had clinically recovered from depression were administered the Mood Disorder Questionnaire (MDQ of. Am. J. Psychiatry 157, 1873). The MDQ is a newly developed, psychometrically validated self-report screening instrument for bipolar spectrum disorders. It screens for lifetime history of manic/hypomanic symptoms by including yes/no items covering all DSM-IV symptoms of mania/hypomania. The MDQ symptom interrelationships were studied by principal component analysis with varimax rotation. RESULTS: Hypomanic symptoms occurring in >50% were racing thoughts, increased energy and social activity, and irritability. Factor analysis revealed two factors: 'Energized-Activity' (eigenvalue=3.1) and 'Irritability-Racing Thoughts' (eigenvalue=1.5). LIMITATIONS: Cross-sectional assessment. CONCLUSIONS: Self-assessment of past hypomanic symptoms by patients, during clinical remission from depression, revealed two independent hypomanic factors, neither of which comprised euphoria. Hypomanic behavior appears to be more fundamental for the diagnosis of hypomania than elated mood accorded priority in DSM-IV; of hypomanic moods, irritability had greater significance than elation. It would appear that self-report of euphoria is less likely when hypomanias are brief (>or=2 vs. >or=4 days). The main implication for busy clinical practice is that energized activity and irritable mood associated with racing thoughts represent the modal experiences of hypomania among bipolar II outpatients; euphoria is neither sensitive, nor pathognomonic, in the diagnosis of these patients. These conclusions accord with recommendations made many years ago for the diagnosis of hypomania among cyclothymic patients [. Am. J. Psychiatry 134, 1227]." [Abstract]

Akiskal HS, Azorin JM, Hantouche EG.
Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy.
J Affect Disord. 2003 Jan;73(1-2):7-18.
"BACKGROUND: Although the construct of depression has been subjected to numerous factor analytic studies and phenomenological subtypes of clinical relevance have been delineated, this is not the case for mania. The few available studies have reported at least two factors, which consist of euphoric versus dysphoric-hostile subtypes. Our objective was to replicate and further enrich this literature. METHODS: In the EPIMAN French National Study we systematically evaluated 104 DSM-IV hospitalized manic patients in four university centers in different regions of France. Psychiatrists completed the Beigel-Murphy Manic State Rating Scale (MSRS), as well as the HAM-D(17), affective temperament scales, and the GAF Axis V from DSM-IV. Categorization of patients into pure versus dysphoric mania was made on the basis of clinical diagnosis, independent from psychometric measures. RESULTS: On principal component analysis of the MSRS, three factors explained the largest variance: a global manic (23.3% variance), paranoid-hostile (14.8% variance), and psychotic (9.1% variance). After varimax rotation, we obtained seven independent factors: F1 Disinhibition-instability, F2 Paranoia-hostility, F3 Deficit, F4 Grandiosity-psychosis, F5 Elation-euphoria, F6 Depression, and F7 (Hyper)sexuality. We could not demonstrate significant correlations between the individual factors and impaired functioning on GAF. However, depressive and, to some extent, cyclothymic temperaments correlated with F6 Depression. Finally, intergroup comparisons between pure versus dysphoric mania diagnosed clinically showed high levels of F3 Deficit and F5 Elation in the pure, and of F6 Depression in dysphoric, mania; F2 Paranoia-hostility did not discriminate these two clinical forms of mania. LIMITATIONS: Although the present analyses on the Beigel-Murphy represent the largest sample studied to date, they are still underpowered and do not guarantee a stable factorial structure. Our findings are cross-sectional and require prospective validation. CONCLUSIONS: Our data suggest that 'dysphoria' as used in the literature to qualify mania is insufficiently precise, and is best further specified as 'depressive' versus 'irritable.' Moreover, our data extend the rich multidimensional phenomenology of mania beyond the existing literature: we submit that disinhibition-instability (a core 'activation' component) can, on the one hand, be associated with distinct emotional presentations (euphoric, depressive, or irritable-hostile), as well as psychotic and deficit symptomatology on the other." [Abstract]

Gonzalez-Pinto A, Ballesteros J, Aldama A, Perez de Heredia JL, Gutierrez M, Mosquera F, Gonzalez-Pinto A.
Principal components of mania.
J Affect Disord. 2003 Sep;76(1-3):95-102.
"OBJECTIVE: An alternative to the categorical classification of psychiatric diseases is the dimensional study of the signs and symptoms of psychiatric syndromes. To date, there have been few reports about the dimensions of mania, and the existence of a depressive dimension in mania remains controversial. The aim of this study was to investigate the dimensions of manic disorder by using classical scales to study the signs and symptoms of affective disorders. METHODS: One-hundred and three consecutively admitted inpatients who met DSM IV criteria for bipolar disorder, manic or mixed were rated with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HDRS-21). A principal components factor analysis of the HDRS-21 and the YMRS was carried out. RESULTS: Factor analysis showed five independent and clinically interpretable factors corresponding to depression, dysphoria, hedonism, psychosis and activation. The distribution of factor scores on the depressive factor was bimodal, whereas it was unimodal on the dysphoric, hedonism and activation factors. Finally, the psychosis factor was not normally distributed. LIMITATIONS: Patients of the sample were all medicated inpatients. CONCLUSIONS: Mania seems to be composed of three core dimensions, i.e. hedonism, dysphoria and activation, and is frequently accompanied by a psychotic and a depressive factor. The existence of a depressive factor suggests that it is essential to evaluate depression during mania, and the distribution of the depressive factor supports the existence of two different states in mania." [Abstract]

Meyer TD, Hautzinger M.
The structure of affective symptoms in a sample of young adults.
Compr Psychiatry. 2003 Mar-Apr;44(2):110-6.
"Symptoms of bipolar disorders include depression and mania. The term "bipolar" implies states that are opposite to each other. Construing scales that define mania and depression as opposite ends of one dimension cannot account for the existence of mixed symptoms. One self-report instrument, the Internal State Scale (ISS), combines both dimensions in one measure. However, the ISS only assesses internal subjective states and does not tap other typical and more objective symptoms of (hypo-) mania. To explore the factorial structure of affective symptoms in a general population sample, we extended the Center for Epidemiologic Studies-Depression Scale (CES-D), adding items to assess manic symptoms as described in DSM-IV. The scale was completed by 2,059 young adults. The results for the original CES-D are comparable to prior studies. Factor-analysis for the extended CES-D revealed two factors in women and men: most manic symptoms loaded high on a factor "euphoria-activation," whereas the other factor included all typical dysphoric-depressive symptoms, but also included the "manic symptoms" of distractibility and irritability. Our results support a two-factor model of bipolar symptoms in the general population with irritability being more closely associated with dysphoria than euphoria. The implications and limitations of the present results are discussed." [Abstract]

Benazzi F, Akiskal HS.
Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania.
J Affect Disord. 2003 Jan;73(1-2):33-8.
"BACKGROUND: The prevalence of bipolar II disorder in depressed outpatients is much higher than previously reported, a finding probably related to systematic probing for past hypomania by trained clinicians. Our objective was to further refine the strict SCID-CV guidelines for hypomania in depressed outpatients. METHODS: 168 consecutive outpatients presenting with major depression were systematically interviewed with the SCID-CV about all past hypomanic behavior, irrespective of duration and initial negative response to the screening question on mood. Once typical hypomanic behaviors were elicited, the patient was re-questioned about mood change. RESULTS: The prevalence of bipolar II was 61.3%. Bipolar II, so-defined, was indistinguishable at age of onset, recurrence, and atypical features from a previous sample of 251 BP-II patients interviewed by the same clinician (FB) without the present modification of the stem question on mood, and which had yielded a prevalence of 45% in the same outpatient clinic. LIMITATIONS: Single interviewer, and cross-sectional assessment. CONCLUSIONS: Systematic probing for all past hypomanic symptoms and behaviors, independently of the answer to the screening question on mood, can elicit hypomanic features that would otherwise be discarded by strict adherence to the SCID-CV. A net gain of 16% in the diagnosis of BP-II can thereby be achieved." [Abstract]

Solomon DA, Leon AC, Endicott J, Coryell WH, Mueller TI, Posternak MA, Keller MB.
Unipolar mania over the course of a 20-year follow-up study.
Am J Psychiatry. 2003 Nov;160(11):2049-51.
"OBJECTIVE: Using data from a longitudinal study of the mood disorders, the investigators address the phenomenon of unipolar mania. METHOD: Subjects diagnosed as having Research Diagnostic Criteria mania at intake into the study were prospectively followed for up to 20 years. RESULTS: Twenty-seven subjects had the diagnosis of unipolar mania at the time they entered the study and had no history of major depression before enrolling in the study. Seven of these subjects did not suffer any episodes of major depression during the 15- to 20-year follow-up. CONCLUSIONS: These data support the diagnostic validity of unipolar mania." [Abstract]

Yazici O, Kora K, Ucok A, Saylan M, Ozdemir O, Kiziltan E, Ozpulat T.
Unipolar mania: a distinct disorder?
J Affect Disord. 2002 Sep;71(1-3):97-103.
"BACKGROUND: This study aimed to identify the differences between unipolar mania and classical bipolar disorder. METHODS: Patients with at least four manic episodes and at least 4 years of follow-up without any depressive episodes were classified as unipolar mania. This group was compared to other bipolar-I patients defined according to DSM-IV regarding their clinical and socio-demographic variables. RESULTS: The rate for unipolar mania as defined by the study criteria was found to be 16.3% in the whole group of bipolar-I patients. Unipolar manic patients tended to have more psychotic features and be less responsive to lithium prophylaxis compared to other bipolar-I patients. LIMITATIONS: Because it was a retrospective study, there may be some minor depressive episodes left unrecorded in the unipolar mania group despite careful and thorough investigation. In addition, even with our fairly strict criteria for the diagnosis of unipolar mania, the possibility of a future depressive episode cannot be excluded. CONCLUSIONS: Unipolar mania may be the presentation of a nosologically distinct entity." [Abstract]

Akiskal HS, Hantouche EG, Allilaire JF, Sechter D, Bourgeois ML, Azorin JM, Chatenet-Duchene L, Lancrenon S.
Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II).
J Affect Disord. 2003 Jan;73(1-2):65-74.
"BACKGROUND: According to DSM-IV and ICD-10, hypomania which occurs solely during antidepressant treatment does not belong to the category of bipolar II (BP-II). METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 144 (29.2%) fulfilled the criteria for bipolar II with spontaneous hypomania (BP-II Sp), and 52 (10.5%) had hypomania associated solely with antidepressants (BP-H AA). RESULTS: BP-II Sp group had earlier age at onset, more hypomanic episodes, and higher ratings on cyclothymic and hyperthymic temperaments, and abused alcohol more often. The two groups were indistinguishable on the hypomania checklist score (12.2+/-4.0 vs. 11.4+/-4.4, respectively, P=0.25) and on rates of familial bipolarity (14.1% vs. 11.8%, respectively, P=0.68). But BP-H AA had significantly more family history of suicide, had higher ratings on depressive temperament, with greater chronicity of depression, were more likely to be admitted to the hospital for suicidal depressions, and were more likely to have psychotic features; finally, clinicians were more likely to treat them with ECT, lithium and mood stabilizing anticonvulsants. LIMITATION: Naturalistic study, where treatment was uncontrolled. CONCLUSION: BP-H AA emerges as a disorder with depressive temperamental instability, manifesting hypomania later in life (and, by definition, during pharmacotherapy only). By the standards of clinicians who have taken care of these patients for long periods of time, BP-H AA appears as no less bipolar than those with prototypical BP-II. We submit that familial bipolarity ('genotypic' bipolarity) strongly favors their inclusion within the realm of bipolar II spectrum, as a prognostically less favorable depression-prone phenotype of this disorder, and which is susceptible to destabilization under antidepressant treatment. These considerations argue for revisions of DSM-IV and ICD-10 conventions. BP-HAA may represent a genetically less penetrant expression of BP-II; phenotypically; it might provisionally be categorized as bipolar III." [Abstract]

Meyer TD, Keller F.
Is there evidence for a latent class called 'hypomanic temperament'?
J Affect Disord. 2003 Aug;75(3):259-67.
"BACKGROUND: Affective disorders belong to the most common psychiatric disorders. Several risk factors have been postulated and empirically investigated. Researchers like Akiskal [Interpersonal Factors in the Origin and Course of Affective Disorders, Gaskell, London, 1996] have pointed out the associations between sub-affective temperaments and affective disorders. However, no study has dealt with the issue whether there is a latent class of such sub-affective temperaments or if such temperaments are best conceptualized as fully dimensional. We investigated whether the Hypomanic Personality Scale [J. Abnorm. Psychol. 121 (1986) 214-222] as an indicator of hyperthymia is taxonic in structure. METHODS: We chose two different samples to address this issue: A sample of young adults (n = 1,966) and another sample of adolescents (n = 4,045). We ran MAXCOV-HITMAX analyses based on identical subsets of items in both samples. RESULTS: Neither in the sample of young adults nor in the sample of adolescents there was evidence for a latent class called 'hypomanic temperament'. LIMITATION: Only one indicator for vulnerability and one procedure to test for latent classes was used. Furthermore, we do not know how many of our sample had a life-time history or current affective disorders. CONCLUSIONS: The hypomanic-hyperthymic temperament is best conceptualized as a dimension in the general population. However, before drawing final conclusions about the taxonicity of the risk for affective disorders, more research is needed using different measures, samples and methods to resolve this question of the dimensionality of vulnerability. Additionally, the question remains open how to conceptualize mania itself." [Abstract]

Altshuler LL, Gitlin MJ, Mintz J, Leight KL, Frye MA.
Subsyndromal depression is associated with functional impairment in patients with bipolar disorder.
J Clin Psychiatry. 2002 Sep;63(9):807-11.
"BACKGROUND: The purpose of this study was to assess whether a relationship exists between mild depressive symptoms and overall functioning in subjects with bipolar disorder. METHOD: Twenty-five male subjects with bipolar I disorder (DSM-III-R criteria), who had not experienced a DSM-III-R episode of mania, hypomania, or major depression for 3 months as determined using the Structured Clinical Interview for DSM-III-R, were evaluated for degree of depressive symptoms using the Hamilton Rating Scale for Depression (HAM-D) and for overall functional status using the Global Assessment of Functioning (GAF, DSM-IV Axis V). RESULTS: GAF scores were significantly negatively correlated with HAM-D scores (r = -0.61, df = 23, p = .001), despite the fact that no patient had a HAM-D score high enough to be considered clinically depressed. CONCLUSION: The results of this study support a relationship between subsyndromal depressive symptoms and functional impairment in bipolar subjects, despite their not meeting threshold criteria for a major depressive episode. These findings raise the possibility that in some patients with bipolar disorder subsyndromal depressive symptoms might contribute to ongoing functional impairment." [Abstract]

Wittchen HU, Mhlig S, Pezawas L.
Natural course and burden of bipolar disorders This paper is a revised version of a presentation held at the CINP International Workshop, St Tropez, France, 36 September 2001.
Int J Neuropsychopharmacol. 2003 Jun;6(2):145-54.
"Despite an abundance of older and more recent retrospective and considerably fewer prospective-longitudinal studies in bipolar disorders I and II, there are still remarkable deficits with regard to our knowledge about the natural course and burden. The considerable general and diagnosis-specific challenges posed by the nature of bipolar disorders are specified, highlighting in particular problems in diagnostic and symptom assessment, shifts in diagnostic conventions and the broadening of the diagnostic concept by including bipolar spectrum disorders. As a consequence it still remains difficult to agree on several core features of bipolar disorders, such as when they begin, how many remit spontaneously and how many take a chronic course. On the basis of clinical and epidemiological findings this paper summarizes (i) a significant need to extend the study of the natural course of bipolar disorder in clinical samples beyond the snapshot of acute episodes to the study of the mid-term and long-term symptom course, associated comorbidities and the associated burden of the disease. (ii) In terms of epidemiological studies, that are also of key importance for resolving the critical issues of threshold definitions in the context of the bipolar spectrum concept, there is a clear need for identifying the most relevant risk factors for the first onset and those for the further illness progression in early stages. Since there are some indications that these critical processes might start as early as adolescence, such studies might concentrate on young cohorts and clearly before these prospective patients come to clinical attention. (iii) The value of both types of studies might be enhanced, if beyond the use of standardized diagnostic interview, special attempts are made to use prospective life- and episode-charting methods for bipolar illnesses." [Abstract]

Hennen J.
Statistical methods for longitudinal research on bipolar disorders.
Bipolar Disord. 2003 Jun;5(3):156-68.
"OBJECTIVES: Outcomes research in bipolar disorders, because of complex clinical variation over-time, offers demanding research design and statistical challenges. Longitudinal studies involving relatively large samples, with outcome measures obtained repeatedly over-time, are required. In this report, statistical methods appropriate for such research are reviewed. METHODS: Analytic methods appropriate for repeated measures data include: (i) endpoint analysis; (ii) endpoint analysis with last observation carried forward; (iii) summary statistic methods yielding one summary measure per subject; (iv) random effects and generalized estimating equation (GEE) regression modeling methods; and (v) time-to-event survival analyses. RESULTS: Use and limitations of these several methods are illustrated within a randomly selected (33%) subset of data obtained in two recently completed randomized, double blind studies on acute mania. Outcome measures obtained repeatedly over 3 or 4 weeks of blinded treatment in active drug and placebo sub-groups included change-from-baseline Young Mania Rating Scale (YMRS) scores (continuous measure) and achievement of a clinical response criterion (50% YMRS reduction). Four of the methods reviewed are especially suitable for use with these repeated measures data: (i) the summary statistic method; (ii) random/mixed effects modeling; (iii) GEE regression modeling; and (iv) survival analysis. CONCLUSIONS: Outcome studies in bipolar illness ideally should be longitudinal in orientation, obtain outcomes data frequently over extended times, and employ large study samples. Missing data problems can be expected, and data analytic methods must accommodate missingness." [Abstract]

Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, Solomon DA, Leon AC, Keller MB.
A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.
Arch Gen Psychiatry. 2003 Mar;60(3):261-9.
"BACKGROUND: This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II). METHODS: Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. RESULTS: Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (> or =7 days) hypomanias were not significantly different on any measure. CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process." [Abstract]

Post RM, Denicoff KD, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Rush AJ, Keck PE Jr, McElroy SL, Luckenbaugh DA, Pollio C, Kupka R, Nolen WA.
Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method.
J Clin Psychiatry. 2003 Jun;64(6):680-90; quiz 738-9.
"BACKGROUND: A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive treatment with mood stabilizers and adjunctive agents have previously not been well delineated. METHOD: 258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year. RESULTS: Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry. CONCLUSION: A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed." [Abstract]

Tohen M, Zarate CA Jr, Hennen J, Khalsa HM, Strakowski SM, Gebre-Medhin P, Salvatore P, Baldessarini RJ.
The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence.
Am J Psychiatry. 2003 Dec;160(12):2099-107.
"OBJECTIVE: Since improved prediction of illness course early in bipolar disorder is required to guide treatment planning, the authors evaluated recovery, first recurrence, and new illness onset following first hospitalization for mania. METHOD: Bipolar disorder patients (N=166) were followed 2-4 years after their first hospitalization for a manic or mixed episode to assess timing and predictors of outcomes. Three aspects of recovery were measured: syndromal (DSM-IV criteria for disorder no longer met), symptomatic (Young Mania Rating Scale score </=5 and Hamilton Depression Rating Scale score </=8), and functional (regaining of premorbid occupational and residential status). Rates of remission (syndromal recovery sustained >/=8 weeks), switching (onset of new dissimilar illness before recovery), relapse (new episode of mania within 8 weeks of syndromal recovery), and recurrence (new episode postremission) were also assessed. RESULTS: By 2 years, most subjects achieved syndromal recovery (98%, with 50% achieving recovery by 5.4 weeks); 72% achieved symptomatic recovery. Factors associated with a shorter time to syndromal recovery for 50% of the subjects were female sex, shorter index hospitalization, and lower initial depression ratings. Only 43% achieved functional recovery; these subjects were more often older and had shorter index hospitalizations. Within 2 years of syndromal recovery, 40% experienced a new episode of mania (20%) or depression (20%), and 19% switched phases without recovery. Predictors of mania recurrence were initial mood-congruent psychosis, lower premorbid occupational status, and initial manic presentation. Predictors of depression onset were higher occupational status, initial mixed presentation, and any comorbidity. Antidepressant treatment was marginally related to longer time to recovery and earlier relapse. CONCLUSIONS: Within 2-4 years of first lifetime hospitalization for mania, all but 2% of patients experienced syndromal recovery, but 28% remained symptomatic, only 43% achieved functional recovery, and 57% switched or had new illness episodes. Risks of new manic and depressive episodes were similar but were predicted by contrasting factors." [Abstract]

Baldessarini RJ, Tondo L, Hennen J.
Treatment-latency and previous episodes: relationships to pretreatment morbidity and response to maintenance treatment in bipolar I and II disorders.
Bipolar Disord. 2003 Jun;5(3):169-79.
"OBJECTIVE: To clarify relationships of treatment delay and pretreatment episode count with pretreatment morbidity and responses to maintenance treatments in bipolar disorders. METHODS: In 450 DSM-IV bipolar I (n = 293) or II (n = 157) patients (280 women, 170 men), we evaluated correlations of latency from illness-onset to starting maintenance treatment and pretreatment episode counts with pretreatment morbidity and treatment response. We considered morbidity measures before and during treatment, and their differences. RESULTS: Latency averaged 7.8 years, with 9.0 episodes per patient, before various maintenance treatments started. Morbidity (percentage of time-ill, episodes per year, first wellness-interval, or proportion of subjects hospitalized or having no recurrences) during maintenance treatment averaging 4.2 years was unrelated to treatment latency or pretreatment episode count. However, pretreatment morbidity was greater with shorter latency, resulting in larger relative reduction of morbidity after earlier treatment. CONCLUSIONS: Greater treatment latency and pretreatment episode count were not followed by greater morbidity during treatment, although longer delay yielded smaller during-versus-before treatment reduction in morbidity. Predictions that longer treatment delay or more pretreatment episodes lead to poorer responses to various maintenance treatments in bipolar I or II disorder were not supported." [Abstract]

Baethge C, Tondo L, Bratti IM, Bschor T, Bauer M, Viguera AC, Baldessarini RJ.
Prophylaxis latency and outcome in bipolar disorders.
Can J Psychiatry. 2003 Aug;48(7):449-57.
"OBJECTIVE: To analyze new and reviewed findings to evaluate relations between treatment response and latency from onset of bipolar disorder (BD) to the start of mood-stabilizer prophylaxis. METHOD: We analyzed our own new data and added findings from research reports identified by computerized searching. RESULTS: We found 11 relevant studies, involving 1485 adult patients diagnosed primarily with BD. Reported latency to prophylaxis averaged 9.6 years (SD 1.3), and follow-up in treatment averaged 5.4 years (SD 3.1). Greater illness intensity and shorter treatment latency were closely associated, resulting in a greater apparent reduction in morbidity with earlier treatment. However, this finding was not sustained after correction for pretreatment morbidity, and treatment latency did not predict morbidity during treatment. Therefore, assessments based on improvement with treatment, or without correction for pretreatment morbidity, can be misleading. CONCLUSIONS: Available evidence does not support the proposal that delayed prophylaxis may limit response to prophylactic treatment in BD and related disorders." [Abstract]

Goldberg JF, Ernst CL.
Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder.
J Clin Psychiatry. 2002 Nov;63(11):985-91.
"BACKGROUND: Whether delays in the initiation of appropriate pharmacotherapy for bipolar illness negatively affect course, outcome, or lifetime suicide risk remains at issue. METHOD: Lifetime affective syndromes and the initial emergence of affective symptoms were assessed by lifecharting in 56 DSM-IV bipolar patients. Lifetime treatment interventions were recorded by clinical interview with corroboration via record reviews. Lag times to the initiation of a mood stabilizer (after initial symptom onset and/or first lifetime affective episode) were assessed relative to functional outcome and lifetime suicide attempts. RESULTS: Mean +/- SD lag time from initial affective symptoms until first mood stabilizer treatment was 9.8 +/- 9.4 years. A greater number of years from symptom onset to first mood stabilizer was associated with poorer past year social functioning (r = -0.35, p =.008), more annual hospitalizations (r = 0.38, p =.004), and a greater likelihood for making a lifetime suicide attempt (odds ratio = 7.26, 95% confidence interval = 1.62 to 32.59; Wald chi2 = 6.69, df = 1, p =.010). Delayed mood stabilizer initiation was linked with poorer outcomes in these domains regardless of initial index episode polarities of mania versus depression. Prolonged delays to bipolar diagnoses and mood stabilizer initiation were associated with earlier ages at affective symptom onset (p <.03) and milder severity of initial symptoms (p =.003). Psychotherapy initiation often preceded mood stabilizer introduction by >/= 8 years. CONCLUSION: Delays in the initiation of mood stabilizer pharmacotherapy at illness onset, even for relatively mild symptoms at illness onset and regardless of index episode polarity, may confer an elevated risk for suicidal behavior, poorer social adjustment, and more hospitalizations in bipolar disorder. Greater surveillance screening for bipolar illness in patients who first present for psychotherapy may help to diminish these adverse outcomes." [Abstract]

Ghaemi N, Sachs GS, Goodwin FK.
What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness.
World J Biol Psychiatry. 2000 Apr;1(2):65-74.
"BACKGROUND: In recent years, much progress has been made in the diagnosis and treatment of schizophrenia and depression. Bipolar disorder, however, remains frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is the case? What is to be done about it? METHODS: We critically review studies in the nosology of bipolar disorder and the effects of antidepressant agents. RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as unipolar major depressive disorder. Antidepressants are probably overused and mood stabilisers underused. Reasons for underdiagnosis include patients' impaired insight into mania, failure to involve family members in the diagnostic process, and inadequate understanding by clinicians of manic symptoms. We propose using a mnemonic to aid in diagnosis, obtaining family report, and utilising careful clinical interviewing techniques given the limitations of patients' self-report. We recommend aggressive use of mood stabilisers, and less emphasis on antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to manic criteria is necessary and the current pattern of use of antidepressant use in bipolar disorder needs to change." [Abstract]

Hirschfeld RM, Lewis L, Vornik LA.
Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder.
J Clin Psychiatry. 2003 Feb;64(2):161-74.
"OBJECTIVE: To assess the experience of selected individuals living with bipolar disorder and compare this experience with that of a similar group of individuals sampled in 1992. METHOD: In June 2000, 4192 self-administered questionnaires were sent to National Depressive and Manic-Depressive Association chapters for distribution to support group participants diagnosed with bipolar disorder. By July 31, 2000, the first 600 completed surveys were analyzed. RESULTS: Over one third of respondents sought professional help within 1 year of the onset of symptoms. Unfortunately, 69% were misdiagnosed, with the most frequent misdiagnosis being unipolar depression. Those who were misdiagnosed consulted a mean of 4 physicians prior to receiving the correct diagnosis. Over one third waited 10 years or more before receiving an accurate diagnosis. Despite having underreported manic symptoms, more than half believe their physicians' lack of understanding of bipolar disorder prevented a correct diagnosis from being made earlier. In 2000, the respondents reported a greater negative impact of bipolar disorder on families, social relationships, and employment than did the respondents in 1992. Overall, respondents were satisfied with their current treatment, which often included medication, talk therapy, and support groups. Respondents who were highly satisfied with their treatment provider had a more positive outlook on their illness and their ability to cope with it. CONCLUSION: Individuals with bipolar disorder reported that the illness manifests itself early in life but that accurate diagnosis lags by many years. The illness exacts great hardships on the individual and the family and has a profoundly negative effect on careers. These findings are very similar to those reported nearly a decade ago." [Abstract]

Akiskal HS.
Validating 'hard' and 'soft' phenotypes within the bipolar spectrum: continuity or discontinuity?
J Affect Disord. 2003 Jan;73(1-2):1-5.
"The unitary Kraepelian concept of manic-depressive illness which incorporated attenuated forms, personal dispositions to mood instability, as well as much of the terrain of remitting depressions, may be considered by many to be too broad. On the other hand, the presently preferred unipolar-bipolar dichotomy in official nosology fails to account for the very common occurrence of clinical and subclinical conditions in the interface of major depressive disorders and bipolarity. The emerging concept of the bipolar spectrum represents a provocative working hypothesis to account for these conditions." [Abstract]

Jackson A, Cavanagh J, Scott J.
A systematic review of manic and depressive prodromes.
J Affect Disord. 2003 May;74(3):209-17.
"BACKGROUND: This paper explores whether individuals with a mood disorder can identify the nature and duration of depressive and manic prodromes. METHODS: Seventy-three publications of prodromal symptoms in bipolar and unipolar disorders were identified by computer searches of seven databases (including MEDLINE and PsycLIT) supplemented by hand searches of journals. Seventeen studies (total sample=1191 subjects) met criteria for inclusion in a systematic review. RESULTS: At least 80% of individuals with a mood disorder can identify one or more prodromal symptoms. There are limited data about unipolar disorders. In bipolar disorders, early symptoms of mania are identified more frequently than early symptoms of depression. The most robust early symptom of mania is sleep disturbance (median prevalence 77%). Early symptoms of depression are inconsistent. The mean length of manic prodromes (>20 days) was consistently reported to be longer than depressive prodromes (<19 days). However, depressive prodromes showed greater inter-individual variation (ranging from 2 to 365 days) in duration than manic prodromes (1-120 days). LIMITATIONS: Few prospective studies of bipolar, and particularly unipolar disorders have been reported. CONCLUSIONS: Early symptoms of relapse in affective disorders can be identified. Explanations of the apparent differences in the recognition and length of prodromes between mania and bipolar depression are explored. Further research on duration, sequence of symptom appearance and characteristics of prodromes is warranted to clarify the clinical usefulness of early symptom monitoring." [Abstract]

Henry C, Swendsen J, Van den Bulke D, Sorbara F, Demotes-Mainard J, Leboyer M.
Emotional hyper-reactivity as a fundamental mood characteristic of manic and mixed states.
Eur Psychiatry. 2003 May;18(3):124-8.
"BACKGROUND: The relationship between depression and mania remains poorly understood and is responsible for much of the confusion about mixed states. The difficulty in conceptualizing opposite states such as euphoric and depressive moods during the same episode may account for the considerable differences in reported frequencies of mixed states, among acutely manic patients. It is possible that the fundamental mood characteristic of mania is not tonality of mood (e.g. euphoric, irritable or depressed mood), but rather the intensity of emotions. METHOD: We interviewed 30 patients hospitalized for a manic episode, asking about their symptoms during the episode, using the list of symptoms for manic and depressive episode of the DSM-IV criteria. Emotional hyper-reactivity, defined as an increase in the intensity of all emotions, was assessed using the Hardy Scale. Manic symptoms were also assessed by a clinician using the Beck-Rafaelsen Mania Scale. RESULTS: This study showed that most of the manic episodes presented many dysphoric symptoms, more particularly depressive mood (33%), irritability (53%), anxiety (76%), and recurrent thoughts of death or suicidal ideation (33%). However, only 10% of our sample met the criteria for mixed state. The other symptoms reported by patients and included in the DSM-IV criteria for depressive mood are common between depressive and manic episodes. All patients (100%) reported that they felt all their emotions with an unusual intensity. CONCLUSION: We suggest that the most appropriate way to define mood in manic states is as a function of intensity, and not as a function of tonality. This definition circumvents the arbitrary dichotomy between mania and mixed state. With this definition, manic episodes can be described as being more or less dysphoric, with the actual characteristics of dysphoria encompassing irritability, anxiety, or depressive affect. This point could be extremely helpful in discriminating mixed state or dysphoric mania from depression." [Abstract]

Myin-Germeys I, Peeters F, Havermans R, Nicolson NA, DeVries MW, Delespaul P, Van Os J.
Emotional reactivity to daily life stress in psychosis and affective disorder: an experience sampling study.
Acta Psychiatr Scand. 2003 Feb;107(2):124-31
"OBJECTIVE: To investigate the emotional reactivity to small disturbances in daily life in patients with non-affective psychosis (NAP), bipolar disorder (BD) and major depression [major depressive disorder (MDD)]. METHOD: Forty-two patients with NAP, 38 with BD, 46 with MDD, and 49 healthy controls were studied with the experience sampling method to assess (i) appraised subjective stress of small disturbances in daily life and (ii) emotional reactivity, reflected in changes in positive affect (PA) and negative affect (NA). RESULTS: Multilevel regression analyses showed an increase in NA in MDD, a decrease in PA in BD and both an increase in NA and a decrease in PA in NAP in association with the subjectively stressful situations, compared with the control subjects. CONCLUSION: Individuals with NAP, MDD and BD display differences in emotional stress reactivity. Type of mood disorder may exert a pathoplastic effect on emotional reactivity in individuals with MDD and BD. Individuals with NAP may be most vulnerable to the effects of daily life stress." [Abstract]

Potash JB, Chiu YF, MacKinnon DF, Miller EB, Simpson SG, McMahon FJ, McInnis MG, DePaulo JR Jr.
Familial aggregation of psychotic symptoms in a replication set of 69 bipolar disorder pedigrees.
Am J Med Genet. 2003 Jan 1;116B(1):90-7.
"We found evidence previously of familial aggregation of psychotic symptoms in 65 bipolar disorder pedigrees. This finding, together with prior evidence from clinical, family, neurobiological, and linkage studies, suggested that psychotic bipolar disorder may delineate a valid subtype. We sought to replicate this finding in 69 new bipolar disorder pedigrees. The presence of psychotic symptoms, defined as hallucinations or delusions, during an affective episode was compared in families of 46 psychotic and 23 non-psychotic bipolar I probands ascertained at Johns Hopkins for the NIMH Bipolar Disorder Genetics Initiative. There were 198 first-degree relatives with major affective disorder including 90 with bipolar I disorder. Significantly more psychotic proband families than non-psychotic proband families (76% vs. 48%) contained at least one affected relative with psychotic symptoms. Psychotic symptoms occurred in 35% of relatives of psychotic probands and in 22% of relatives of non-psychotic probands (P = 0.10). Both psychotic affective disorder generally and psychotic bipolar I disorder clustered significantly in families. These results are consistent with our prior report although the magnitude of the predictive effect of a psychotic proband is less in the replication families. Our findings provide modest support for the validity of psychotic bipolar disorder as a subtype of bipolar disorder. This clinically defined subtype may prove more homogeneous than the disorder as a whole at the level of genetic etiology and of neuropathology/pathophysiology. Families with this subtype should be used to search for susceptibility genes common to bipolar disorder and schizophrenia, and for biological markers that may be shared with schizophrenia." [Abstract]

Maj M, Pirozzi R, Magliano L, Bartoli L.
Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome.
Am J Psychiatry. 2003 Dec;160(12):2134-40.
"OBJECTIVE: The study aimed to explore how prevalent agitated depression is in bipolar I disorder, whether it represents a mixed state, and whether it differs from nonagitated depression with respect to course and outcome. METHOD: From 313 bipolar I patients with an index episode of major depression, the authors selected those fulfilling Research Diagnostic Criteria for agitated depression. These 61 patients were compared to 61 randomly recruited bipolar I patients with an index episode of nonagitated depression and 61 randomly recruited bipolar I patients with an index episode of mania regarding demographic, historical, and clinical features. The two depressive groups were also compared regarding time to recovery from the index episode, treatment received for that episode, percentage of time spent in an affective episode during a prospective observation period, and 5-year outcome. RESULTS: Patients with agitated depression were consistently not elated or grandiose, but one-fourth had the cluster of symptoms with racing thoughts, pressured speech, and increased motor activity, and one-fourth had the paranoia-aggression-irritability cluster. Compared to patients with nonagitated depression, they had a longer time to 50% probability of recovery from the index episode, were more likely to receive standard antipsychotic drugs during that episode, and spent more time in an affective episode during the observation period. CONCLUSIONS: The occurrence of agitated depression in bipolar I disorder is not rare and has significant prognostic and therapeutic implications. Whether the co-occurrence of a major depressive syndrome with one or two of these symptomatic clusters makes up a "mixed state" remains unclear." [Abstract]

Benazzi F, Helmi S, Bland L.
Agitated depression: unipolar? Bipolar? Or both?
Ann Clin Psychiatry. 2002 Jun;14(2):97-104.
"The classification of agitated depression (major depressive episode (MDE) plus psychomotor agitation) in mood disorders is unclear. DSM-IV is neutral on this point. As antidepressants may increase agitation, a better understanding of agitated depression is important for clinical practice. Study aim was to find if agitated depression was closer to bipolar or to unipolar disorders, by studying its association with variables typically related to bipolar disorders (early onset, many recurrences, more atypical features, more bipolar family history), and by studying its association with bipolar II disorder. Consecutive 151 unipolar and 226 bipolar II psychoactive drug-free MDE outpatients were interviewed with the Structured Clinical Interview for DSM-IV, when presenting for MDE treatment. Agitated MDE patients were compared with nonagitated MDE patients. Statistics were t test for means, two-sample test of proportion, and logistic regression (STATA 7). Agitated MDE was present in 85 patients (22.5%). It had significantly more bipolar II disorder patients (80.0% vs. 54.1%, p = 0.0000), more females, lower age at onset, longer duration of illness, more MDE recurrences, more atypical features, more MDE symptoms, and more family history of bipolar disorders, than nonagitated MDE. To control for the possible confounding effect of bipolar II disorder, logistic regression was used. All the significant differences became nonsignificant. Results might suggest that agitated MDE might be closer to the bipolar spectrum than to unipolar disorder, because it was associated with variables typically distinguishing bipolar from unipolar disorders, and with bipolar II disorder. Further studies on this topic are needed." [Abstract]

Benazzi F.
Highly recurrent unipolar may be related to bipolar II.
Compr Psychiatry. 2002 Jul-Aug;43(4):263-8.
"Unipolar and bipolar disorders may be subgroups of a single mood disorder, of which the key feature is not polarity, but the episodic, recurrent course. The aim of this study was to determine whether highly recurrent unipolar was related to bipolar II, by comparing clinical and family history features. Eighty-nine consecutive unipolar and 151 consecutive bipolar II outpatients, presenting for major depressive episode (MDE) treatment, were interviewed using the Structured Clinical Interview for DSM-IV (SCID) and the Family History Screen. Unipolar patients were divided into highly recurrent (>4 MDEs) (HRUP) and low recurrent (</=4 MDEs) (LRUP). HRUP had significantly fewer atypical features and less bipolar II family history than bipolar II, while age at onset, axis I comorbidity, and depression chronicity were not significantly different. HRUP had statistically significant lower age at onset, more axis I comorbidity, more depression chronicity, and clinically significant more atypical features and more bipolar II family history than LRUP. Results suggest that HRUP could be midway between bipolar II and LRUP. Pages and Dunner (1997) view that recurrent unipolar and bipolar II could be part of a single mood disorder, and Goodwin and Jamison (1990) view that recurrence is the key feature of mood disorders are partly supported by the findings." [Abstract]

apadimitriou GN, Dikeos DG, Daskalopoulou EG, Soldatos CR.
Co-occurrence of disturbed sleep and appetite loss differentiates between unipolar and bipolar depressive episodes.
Prog Neuropsychopharmacol Biol Psychiatry. 2002 Oct;26(6):1041-5.
"The aim of this study was to examine whether the co-occurrence of disturbed sleep and appetite loss, two commonly encountered somatic symptoms of depression, can differentiate the clinical expression of depressive episodes between bipolar (BP) and unipolar patients (UP). Forty BP and 40 UP outpatients were interviewed through the Schedules for the Clinical Assessment in Neuropsychiatry (SCAN) and the presence of sleep disturbance and appetite loss during their most severe depressive episode was determined. Other variables studied were patients' gender and age, clinical characteristics related to the course of the disease (age at onset, duration of illness, and number and frequency of depressive and manic episodes), severity of the worst major depressive episode, and presence or absence of certain associated symptoms during that episode (loss of energy, low interest, feelings of guilt and/or self-reproach, impaired concentration, suicidal ideation, and agitation or retardation). Appetite loss was found to be more frequently present in UP (78%) than BP patients (55%, P<.05). No significant difference in the occurrence of sleep disturbance was found between the two groups. Among BP patients, appetite loss was present in 73% of those with sleep disturbance vs. 33% of those without (P<.02), while no such difference in co-occurrence of sleep disturbance and appetite loss was noticed among UP patients (74% vs. 85%, respectively, n.s.); this finding did not seem to be related to differences in severity of depression among UP and BP patients. Furthermore, those BP patients with co-occurrence of the two somatic symptoms complained also of loss of energy and low interest more often than those without (P<.01 and P<.05, respectively). No similar differences were observed among UP patients. The results of the present study suggest that the pathophysiological mechanisms underlying depressive episodes may differ between BP and UP affective disorder, and that those BP patients with simultaneous occurrence of sleep disturbance and appetite loss can be considered to belong to a particular nosologic subgroup with potential therapeutic and prognostic implications." [Abstract]

Gassab L, Mechri A, Gaha L, Khiari G, Zaafrane F, Zougaghi L.
[Bipolarity correlated factors in major depression: about 155 Tunisian inpatients]
Encephale. 2002 Jul-Aug;28(4):283-9.
"The distinction between the depressive troubles according to their inclusion in bipolar disorders or in recurrent depressive disorders offers an evident practical interest. In fact, the curative and mainly the preventive treatment of these troubles are different. So it is necessary to identify the predictive factors of bipolar development in case of inaugural depressive episode. In 1983, Akiskal was the first who identified those factors: pharmacological hypomania, puerperal depression, onset at early age (<25 years), presence of psychotic characteristics, hypersomnia and psychomotor inhibition. Through this study, the authors try to compare the epidemiological, clinical and evolution characteristics of major depression in bipolar disorders to recurrent depressive disorders in order to indicate the correlated factors with bipolarity. It is a retrospective and comparative study based on about 155 inpatients for major depressive episode during the period between January 1994 and December 1998. These patients were divided into two groups according the DSM IV criteria: bipolar group (96 patients) and recurrent depressive group (59 patients). Both groups were compared according to socio-demographic data, life events in childhood, personal and family history, clinical and evolution characteristics of the index depressive episode. The predictive factors proposed by Akiskal were systematically examined. It was found out that the following factors were correlated with bipolarity: high rate of separation and divorce (17.7% versus 5.1%; p=0.02), family history of psychiatric disorders (56.3% versus 35.6%; p=0.012) especially bipolar ones (29.2% versus 3.4%; p=0,00008), onset at early age (mean age of onset: 24.8 8.2 years versus 34.1 12.6 years; p=0.000004), number of affective episode significantly more frequent (mean 3.6 versus 2.5; p=0.03), sudden onset of depressive episode (44.8% versus 15.9%; p=0.0003) and presence of psychotic characteristics (69.8% versus 16.7%; p=0.0001) catatonic characteristics (37.3% versus 20.3%; p=0.03), hypersomnia (51% versus 20.3%; p=0.03) and psychomotor inhibition (83.3% versus 42.4%; p=0.00007). Negatively correlated factors of bipolar depression were: somatic comorbidity such as diabetes, hypertension and rhumatismal diseases (12.5% versus 28.8%; p=0.012) and association with dysthymic disorders (2.2% versus 12.1%; p=0.029). No correlation was found between bipolarity and life events in childhood, seasonal character, alcoholic dependence and suicide attempt. Concerning the validity of predictive factors of bipolarity proposed by Akiskal, we found: history of bipolar disorders (Sensibility: 29.2%, specificity: 96.6%, Positive Predictive Value (PPV): 93%), hypersomnia (Sensibility: 51%, specificity: 80%, PPV: 80%), onset before the age of 25 years (Sensibility: 62.5%, specificity: 70%, PPV: 77%), psychomotor inhibition (Sensibility: 83.3%, specificity 58%, PPV: 76%), and psychotic characteristics (Sensibility: 69.8%, specificity: 62.7%, PPV: 75%). In spite of methodological differences, our results tallied with the other studies. We focus on the importance of the bipolar family history criterion, which has the highest PPV, and the limits of psychotic characteristics criterion which has the lowest PPV. This may be explained by the frequency of these characteristics of affective disorders in our cultural context. The association of the hypersomnia and psychomotor inhibition in one criterion in order to increase their diagnostic power. Our study helps us to identify the factors that would predict the bipolar evolution of a depressive episode allowing the use of specific treatment and ensuring the improvement of prognostic." [Abstract]

Swann AC, Pazzaglia P, Nicholls A, Dougherty DM, Moeller FG.
Impulsivity and phase of illness in bipolar disorder.
J Affect Disord. 2003 Jan;73(1-2):105-11.
"BACKGROUND: Impulsivity is prominent in bipolar disorder, but there is little quantitative information relating it to phase of illness. METHODS: We measured impulsivity in patients with bipolar disorder who had not met episode criteria for at least 6 months, patients who were manic, and healthy control subjects. Impulsivity was measured using the Barratt Impulsiveness Scale (BIS) and performance on the computerized Immediate Memory-Remote Memory Task (IMT-DMT), based on the Continuous Performance Test, which has been shown to reflect risk of impulsivity in other populations. RESULTS: BIS scores in euthymic and manic bipolar subjects were identical, and were significantly elevated compared to controls. Commission errors (impulsive responses) on the IMT-DMT were elevated in manic subjects but were identical to controls in euthymic subjects. Measures of impulsivity did not appear related to depressive symptoms. LIMITATIONS: The number of subjects was too small for detailed investigation of the role of comorbidities; subjects were receiving pharmacological treatments. CONCLUSIONS: Impulsivity has state- and trait-related aspects in bipolar disorder." [Abstract]

Maj M, Pirozzi R, Magliano L, Bartoli L.
The prognostic significance of "switching" in patients with bipolar disorder: a 10-year prospective follow-up study.
Am J Psychiatry. 2002 Oct;159(10):1711-7.
"OBJECTIVE: This study explored whether "switching" (i.e., the direct transition from one mood polarity to the other) has significant prognostic implications in patients with bipolar disorder. METHOD: Bipolar disorder patients (N=97) whose first prospectively observed episode included at least one mood polarity switch and 97 bipolar disorder patients whose index episode was monophasic were compared with respect to several demographic and historical variables, symptomatic features of the index episode, time to recovery from the index episode, time spent in an affective episode during a prospective observation period, and psychopathological and psychosocial outcome at a 10-year follow-up interview. RESULTS: Patients whose index episode included at least two mood polarity switches spent significantly more time in an affective episode during the observation period and had a significantly worse psychopathological and psychosocial outcome 10 years after recruitment than those whose index episode included only one mood polarity switch or was monophasic. Patients whose polyphasic index episode started with depression spent a significantly higher proportion of time in an affective episode and had a significantly worse 10-year outcome than those whose polyphasic index episode started with mania or hypomania. Retention of the switching pattern throughout the observation period was seen in 42.4% of patients whose index episode started with mania and in 65.2% of those whose index episode started with depression. CONCLUSIONS: An index episode including at least two mood polarity switches, especially if starting with depression, is associated with a poor long-term outcome in patients with bipolar disorder. This pattern represents a significant target for new pharmacological and psychosocial treatment strategies." [Abstract]

Gitlin M, Boerlin H, Fairbanks L, Hammen C.
The effect of previous mood states on switch rates: a naturalistic study.
Bipolar Disord. 2003 Apr;5(2):150-2.
"OBJECTIVES: A recent study suggested that post-manic depressions (post-MD) may differ from post-euthymia depression (post-ED). The goal of this study was to compare the switch rates and length of depressive episodes stratified by the pre-depression mood states. METHODS: The course of 72 prospectively observed depressions in 28 patients with Bipolar I depressions were divided into post-MD versus ED. The two groups, both all episodes and first observed episode, only were compared in their switch rates and length of episode. RESULTS: Almost two-thirds (65%) of episodes were rated as ED. There was no difference in switch rates between the two groups, whether analysed by all episodes, first episodes only, or episodes not treated with antidepressants. Length of depressive episodes were also not significantly different between the two groups. DISCUSSION: These findings do not suggest different switch characteristics between post-MD and post-ED." [Abstract]

Bellivier F, Golmard JL, Rietschel M, Schulze TG, Malafosse A, Preisig M, McKeon P, Mynett-Johnson L, Henry C, Leboyer M.
Age at onset in bipolar I affective disorder: further evidence for three subgroups.
Am J Psychiatry. 2003 May;160(5):999-1001.
"OBJECTIVE: Preliminary data suggested that there are three subgroups of bipolar affective disorder based on age at onset. The authors sought to replicate those findings and determine the cut-off age of each subgroup. METHOD: Admixture analysis was used to determine the best-fitting model for the observed ages at onset of 368 consecutively admitted patients. The results obtained were compared with those of the previously described model. The authors also investigated whether affected siblings are more likely to belong to the same theoretical age-at-onset subgroup as identified by admixture analysis. RESULTS: The existence of three subgroups defined by age at onset was confirmed. The mean ages estimated in this model were 17.4 years (SD=2.3), 25.1 years (SD=6.2), and 40.4 years (SD=11.3). Affected siblings were more likely to belong to the same theoretical subgroup. CONCLUSIONS: There are three age-at-onset subgroups of bipolar patients, and specific familial vulnerability factors might underlie each subgroup." [Abstract]

Engstrom C, Brandstrom S, Sigvardsson S, Cloninger R, Nylander PO.
Bipolar disorder. II: personality and age of onset.
Bipolar Disord. 2003 Oct;5(5):340-8.
"OBJECTIVES: The aim of this study was to examine whether personality i.e. temperament and character interacts with age of onset in bipolar disorder. METHODS: Bipolar patients were recruited among in- and outpatients from lithium dispensaries of northern Sweden. Patients were diagnosed according to DSM-IV criteria for bipolar disorder type I and II. Temperament and Character Inventory (TCI) was used for measuring personality. TCI was administered to 100 lithium treated bipolar patients and 100 controls. RESULTS: Treatment response was significantly lower (p = 0.005) in patients with early onset compared with late onset. Family history (p = 0.013) and suicide attempts (p = 0.001) were also significantly more common in patients with early onset. Further, patients with early onset were significantly higher (p = 0.045) in the temperament factor harm avoidance (HA) than patients with late onset, but the difference was weak. Patients with early onset had more fear of uncertainty (HA2; p = 0.022) and were more shy (HA3; p = 0.030). Bipolar I patients showed similar results as those in the total bipolar group (I and II), with significantly higher HA (p = 0.019, moderate difference), HA2 (p = 0.015) and HA3 (p = 0.043) in patients with early onset compared with late onset. Bipolar II patients showed no differences between early and late age of onset but the groups are small and the results are therefore uncertain. CONCLUSIONS: Early age of onset in bipolar disorder was correlated to an increase in severity, family history, poorer treatment response and poorer prognosis. Early onset was also correlated to personality." [Abstract]

Schurhoff F, Bellivier F, Jouvent R, Mouren-Simeoni MC, Bouvard M, Allilaire JF, Leboyer M.
Early and late onset bipolar disorders: two different forms of manic-depressive illness?
J Affect Disord 2000 Jun;58(3):215-21
"BACKGROUND: Conflicting results in genetic studies of bipolar disorders may be due to the clinical and genetic heterogeneity of the disease. Age at onset of bipolar disorders may be a key indicator for identifying more homogeneous clinical subtypes. We tested whether early onset and late onset bipolar illness represent two different forms of bipolar illness in terms of clinical features, comorbidity and familial risk. METHODS: Among a consecutively recruited sample of 210 bipolar patients, we compared early onset (n=58) and late onset (n=39) bipolar patients; the cut-off points were age at onset before 18 years and after 40 years for the two subgroups. The subgroups were compared by independent t tests and a contingency table by raw chi-square test. Morbid risk among first-degree relatives was measured by the survival analysis method. RESULTS: The early onset group had the most severe form of bipolar disorder with more psychotic features (P=0.03), more mixed episodes (P=0.01), greater comorbidity with panic disorder (P=0.01) and poorer prophylactic lithium response (P=0.04). First degree relatives of early onset patients also had a higher risk of affective disorders (P=0.0002), and exhibit the more severe phenotype, i.e bipolar disorder. CONCLUSION: Our data suggest that early and late onset bipolar disorders differ in clinical expression and familial risk and may therefore be considered to be different subforms of manic-depressive illness." [Abstract]

Benazzi F.
Early- versus late-onset bipolar II disorder.
J Psychiatry Neurosci 2000 Jan;25(1):53-7
"OBJECTIVE: To compare the clinical features and the outcome between patients with early- and late-onset bipolar II disorder. DESIGN: Case series. SETTING: Outpatient private practice. PATIENTS: One hundred and seventy-nine consecutive outpatients with bipolar II disorder presenting for treatment of a major depressive episode. OUTCOME MEASURES: Duration of illness, severity of depression, recurrences, psychosis, chronicity, atypical features and comorbidity. RESULTS: Patients with early-onset (before 20, 25 or 30 years of age) bipolar II disorder had a significantly longer duration of illness and more recurrences compared with patients with late-onset (after 20, 25 or 30 years of age) bipolar II disorder. All other variables were not significantly different between the 2 groups. CONCLUSIONS: Indicators of worse outcome (severity of depression, psychosis, chronicity, comorbidity) were not significantly different between patients with early- and late-onset bipolar II disorder." [Abstract]

Moorhead SR, Young AH.
Evidence for a late onset bipolar-I disorder sub-group from 50 years.
J Affect Disord. 2003 Feb;73(3):271-7.
"BACKGROUND: Age of onset has been used to identify aetiological sub-groups in complex inherited disorders such as Alzheimer's disease and osteoarthritis. We examined the relationship between age of onset and family history in bipolar-I disorder in an attempt to identify subgroups. METHODS: All patients discharged from a district in-patient service diagnosed with bipolar disorder in a 7-year period were ascertained from a case register (n=277). Diagnosis by DSM-IIIR criteria was confirmed; family history and age of first admission were recorded from case notes. RESULTS: Age of first admission in those with a negative family psychiatric history was significantly older (P=0.029) with a skewed age distribution. This non-familial group contained significantly more subjects with first admission from the age of 50 years (P=0.007). CONCLUSIONS: Patients with bipolar-I disorder whose age of first admission is 50 years or above may belong to a different aetiological sub-group." [Abstract]

Sajatovic M.
Aging-related issues in bipolar disorder: a health services perspective.
J Geriatr Psychiatry Neurol. 2002 Fall;15(3):128-33.
"Among the elderly, bipolar disorder is a significant public health problem, often leading to functional impairment and substantial use of health care resources. There has been a growing awareness regarding the manifestations of bipolar disorder among older adults owing to both changes in national demographics and developing sophistication in the treatment of bipolar illness. Bipolar disorder accounts for 5% to 19% of mood disorder presentations in the elderly, although a clear picture of the exact prevalence of bipolar disorder among older adults in the community is still lacking. Data from treatment centers give a somewhat unreliable picture of the true prevalence and manifestations of bipolar disorder in the general population as elderly patients tend to underuse mental health systems, under-report psychiatric symptoms, and are often treated in nonhospital/clinic settings, such as nursing homes. Factors of particular relevance in late-life bipolar disorder include age of onset, symptom presentation/recognition, secondary mania, psychiatric and medical comorbidity, and response to treatment. Future mental health services research must further explore these issues to optimize care for older adults with bipolar disorder." [Abstract]

Hirschfeld RM, Calabrese JR, Weissman MM, Reed M, Davies MA, Frye MA, Keck PE Jr, Lewis L, McElroy SL, McNulty JP, Wagner KD.
Screening for bipolar disorder in the community.
J Clin Psychiatry. 2003 Jan;64(1):53-9.
"BACKGROUND: Our goal was to estimate the rate of positive screens for bipolar I and bipolar II disorders in the general population of the United States. METHOD: The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II disorders, was sent to a sample of 127,800 people selected to represent the U.S. adult population by demographic variables. 85,358 subjects (66.8% response rate) that were 18 years of age or above returned the survey and had usable data. Of the nonrespondents, 3404 subjects matched demographically to the 2000 U.S. Census data completed a telephone interview to estimate nonresponse bias. RESULTS: The overall positive screen rate for bipolar I and II disorders, weighted to match the 2000 U.S. Census demographics, was 3.4%. When adjusted for the nonresponse bias, the rate rose to 3.7%. Only 19.8% of the individuals with positive screens for bipolar I or II disorders reported that they had previously received a diagnosis of bipolar disorder from a physician, whereas 31.2% reported receiving a diagnosis of unipolar depression. An additional 49.0% reported receiving no diagnosis of either bipolar disorder or unipolar depression. Positive screens were more frequent in young adults and low income households. The rates of migraine, allergies, asthma, and alcohol and drug abuse were substantially higher among those with positive screens. CONCLUSION: The positive MDQ screen rate of 3.7% suggests that nearly 4% of American adults may suffer from bipolar I and II disorders. Young adults and individuals with lower income are at greater risk for this largely underdiagnosed disorder." [Abstract]

Judd LL, Akiskal HS.
The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases.
J Affect Disord. 2003 Jan;73(1-2):123-31.
"BACKGROUND: Despite emerging international consensus on the high prevalence of the bipolar spectrum in both clinical and community samples, many skeptics contend that narrowly defined bipolar disorder with a lifetime rate of about 1% represents a more accurate estimate of prevalence. This may in part be due to the fact that higher figures proposed for the bipolar spectrum (5-8%) have not been based on national data and have not included all levels of manic symptom severity. In the present secondary analyses of the US National Epidemiological Catchment Area (ECA) database, we provide further clarification on this fundamental public health issue. METHODS: All respondents in the first wave (first interview) of the ECA household five site sample (n=18252) were classified on the basis of DSM-III criteria into lifetime manic and hypomanic episodes, as well as those with at least two lifetime manic/hypomanic symptoms below the threshold for at least 1 week duration (subsyndromal manic symptoms [SSM] group). Odds ratios were calculated on lifetime service utilization for mental health problems, measures of adverse psychosocial outcome, and suicidal behavior compared to subjects with no mental disorders or manic symptoms. RESULTS: As originally reported nearly two decades ago by the primary investigators of the ECA, the lifetime prevalence for manic episode was 0.8%, and for hypomania, 0.5%. What is new here is the inclusion of subthreshold SSM subjects, which accounted for 5.1%, yielding a total of 6.4% lifetime prevalence for the bipolar spectrum. All three (manic, hypomanic and SSM) groups had greater marital disruption. There were significant increases in lifetime health service utilization, need for welfare and disability benefits and suicidal behavior when the SSM, hypomanic and manic subjects were compared to the no mental disorder group. Suicidal behavior was non-significantly highest in the hypomanic (bipolar II) group. Otherwise, hypomanic and manic groups had comparable level of service utilization and social disruption. LIMITATIONS: Comorbid disorders, which might influence functioning, were not included in the present analyses. CONCLUSION: These secondary analyses of the US National ECA database provide convincing evidence for the high prevalence of a spectrum of bipolarity in the community at 6.4%, and indicate that subthreshold cases are at least five times more prevalent than DSM-based core syndromal diagnoses at about 1%. These SSM subjects, who met the criteria of "caseness" from the point of view of harmful dysfunction, are of great theoretical and public health significance." [Abstract]

Daniels BA, Kirkby KC, Mitchell P, Hay D, Bowling A.
Heterogeneity of admission history among patients with bipolar disorder.
J Affect Disord. 2003 Jul;75(2):163-70.
"BACKGROUND: Patients on a first admission for bipolar disorder often have a history of other psychiatric diagnoses for previous admissions. AIMS: The current study examines the time course and diagnoses of psychiatric admissions prior and subsequent to a first hospitalisation for a diagnosis of bipolar disorder. METHOD: The prior admission histories (over the period 1965-1989) of 1167 patients who had been hospitalised in state mental health facilities with their first admission with diagnosis of bipolar disorder between 1983 and 1989 were examined. RESULTS: A total of 542 (46.4%) patients had at least one previous hospitalisation with a psychiatric diagnosis other than bipolar disorder. Two prominent groups emerged; one group which had primarily a history of prior admissions with diagnoses of depression over 1-3 years, and a second which mainly had previous admissions for schizophrenia, over a period longer than for those with a primarily depressive history. The group with a history of schizophrenia was significantly younger and had a greater number of admissions prior to the first bipolar disorder diagnosis than the depression group. LIMITATIONS: This was a record-based study which did not examine cases which were not hospitalised. CONCLUSIONS: There appeared to be three distinct patterns of prior presentations in those patients admitted with a diagnosis of bipolar disorder." [Abstract]

Morselli PL, Elgie R; GAMIAN-Europe.
GAMIAN-Europe/BEAM survey I--global analysis of a patient questionnaire circulated to 3450 members of 12 European advocacy groups operating in the field of mood disorders.
Bipolar Disord. 2003 Aug;5(4):265-78.
"OBJECTIVES: GAMIAN-Europe is a pan-European federation of national patient organizations from 30 European countries covering the whole spectrum of psychiatry. To gain a better understanding of what it is like to live with bipolar disorder (BD), GAMIAN-Europe undertook a detailed patient-based questionnaire, known as 'GAMIAN-Europe/BEAM Survey', examining a variety of aspects. METHODS: The questionnaire was mailed to 3450 patients from 12 member organizations in 11 countries. A total of 1760 completed questionnaires were received but 28 were ruled out as inappropriate. Of the remainder, 1041 respondents stated that they had been, or were, suffering from BD. The remainder stated that they were suffering from depression, dysthymia or atypical depression. RESULTS: The findings indicate that, on average, a bipolar patient is expected to wait for 5.7 years for a correct diagnosis from the first onset of symptoms. Many patients have a family history of mood and anxiety disorders. They experience a high degree of stigmatization from all quarters. This is reflected in the difficulties they experience in obtaining employment despite high academic achievement. Most patients receive combination therapy. Compliance problems resulting from adverse side-effects are less significant than in the past. Overall, the level of satisfaction with pharmacotherapy was high yet, paradoxically, patients had reservations about dependency issues and possible long-term side-effects. CONCLUSIONS: There was a clear need for more patient education about pharmacological and psychosocial interventions, despite material progress having been made over the past decade. There is an urgent need for more information and education for both relatives and the public in most European countries to improve awareness and understanding of BDs and other mood disorders and the doctor-patient dialogue." [Abstract]

Birnbaum HG, Shi L, Dial E, Oster EF, Greenberg PE, Mallett DA.
Economic consequences of not recognizing bipolar disorder patients: a cross-sectional descriptive analysis.
J Clin Psychiatry. 2003 Oct;64(10):1201-9.
"BACKGROUND: This retrospective study compared treatment patterns and costs for patients with recognized and unrecognized bipolar disorder with those of depressed patients without a bipolar disorder claim. METHOD: Claims data for 7 large national employers covering 585,584 persons aged less than 65 years were used to identify patients diagnosed with depression and initially treated with antidepressants. Data on employees, as well as spouses and dependents, for the period 1998 to mid-2001 were used. Patients were identified as bipolar based on the criteria of a bipolar diagnosis claim (ICD-9 codes: 296.0, 296.1, 296.4-296.8) and/or a mood stabilizer prescription claim. Of the patients identified as bipolar, unrecognized bipolar disorder (unrecognized-BP) patients met the criteria after antidepressant initiation, while recognized bipolar disorder (recognized-BP) patients met the criteria at or before initiation. The remaining patients in the sample were non-bipolar depressed (non-BP) patients. Outcome measures included treatment patterns and monthly medical costs in the 12 months subsequent to initiation of antidepressant treatment. RESULTS: Of the 9009 patients treated for depression with antidepressants, there were 8383 non-BP patients (93.1%), 293 recognized-BP patients (3.3%), and 333 unrecognized-BP patients (3.7%). Use of combination therapies varied among the non-BP (11%), unrecognized-BP (32%), and recognized-BP patients (44%) (all pairwise p <.01). Use of mood stabilizers was less frequent among unrecognized-BP patients (14%) than recognized-BP patients (34%) (p <.0001). Unrecognized-BP patients incurred significantly greater (p <.05) mean monthly medical costs ($1179 US dollars) in the 12 months following initiation of antidepressant treatment compared with recognized-BP patients ($801 US dollars) and non-BP patients ($585 US dollars). Monthly indirect costs were significantly greater (p <.05) for unrecognized-BP ($570 US dollars) and recognized-BP ($514 US dollars) employees compared with non-BP employees ($335 US dollars) in the 12 months following antidepressant initiation. CONCLUSIONS: Patterns of medication treatment for bipolar disorder were suboptimal. Accurate and timely recognition of bipolar disease was associated with lower medical costs and lower indirect costs due to work loss." [Abstract]

















->Back to Home<- //->Back to Bipolar Disorder Index<-

Recent Bipolar Disorder Diagnostic Research

1) Schöttle D, Schimmelmann BG, Conus P, Cotton SM, Michel C, McGorry PD, Karow A, Naber D, Lambert M
Differentiating schizoaffective and bipolar I disorder in first-episode psychotic mania.
Schizophr Res. 2012 Jul 28;
OBJECTIVE: This study aims to differentiate schizoaffective disorder (SAD) and bipolar-I-disorder (BD) in first-episode psychotic mania (FEPM). METHODS: All 134 patients from an epidemiological first-episode psychosis cohort (N=786) with FEPM and an 18-month follow-up final diagnosis of SAD (n=36) or BD (n=98) were assessed with respect to pre-treatment, baseline and outcome differences. Second, patients with baseline BD who shifted (shifted BD) or did not shift to SAD (stable BD) over the follow-up period were compared regarding pre-treatment and baseline differences. RESULTS: SAD patients displayed a significantly longer duration of untreated psychosis (DUP; effect size r=0.35), a higher illness-severity at baseline (r=0.20) and more traumatic events (Cramer-V=0.19). SAD patients displayed a significantly higher non-adherence rate (Cramer-V=0.19); controlling for time in treatment and respective baseline scores, SAD patients had significantly worse illness severity (CGI-S; partial ?(2)=0.12) and psychosocial functioning (GAF; partial ?(2)=0.07) at 18-months, while BD patients were more likely to achieve remission of positive symptoms (OR=4.9, 95% CI=1.8-13.3; p=0.002) and to be employed/occupied (OR=7.7, 95% CI=2.4-24.4, p=0.001). The main discriminator of stable and shifted BD was a longer DUP in patients shifting from BD to SAD. CONCLUSIONS: It is difficult to distinguish BD with psychotic symptoms and SAD in patients presenting with FEPM. Longer DUP is related to SAD and to a shift from BD to SAD. Compared to BD, SAD had worse outcomes and higher rates of non-adherence with medication. Despite these differences, both diagnostic groups need careful dimensional assessment and monitoring of symptoms and functioning in order to choose the right treatment. [PubMed Citation] [Order full text from Infotrieve]

2) Gershon A, Thompson WK, Eidelman P, McGlinchey EL, Kaplan KA, Harvey AG
Restless Pillow, Ruffled Mind: Sleep and Affect Coupling in Interepisode Bipolar Disorder.
J Abnorm Psychol. 2012 Jul 30;
Disturbances in sleep and affect are prominent features of bipolar disorder, even during interepisode periods. Few longitudinal studies have prospectively examined the relationship between naturally occurring sleep and affect, and no studies to date have done so during interepisode periods of bipolar disorder and using the entire set of "gold standard" sleep parameters. Participants diagnosed with bipolar I disorder who were interepisode (n = 32) and healthy controls (n = 36) completed diagnostic and symptom severity interviews, and a daily sleep and affect diary, as well as an actigraphy sleep assessment, for eight weeks (M = 54 days, ± 8 days). Mutual information analysis was used to assess the degree of statistical dependence, or coupling, between time series data of sleep and affect. As measured by actigraphy, longer sleep onset latency was coupled with higher negative affect more strongly in the bipolar group than in the control group. As measured by sleep diary, longer wakefulness after sleep onset and lower sleep efficiency were coupled with higher negative affect significantly more strongly in the bipolar group than in the control group. By contrast, there were no significant differences between groups in the degree of coupling between any measures of sleep and positive affect. Findings support the coupling of sleep disturbance and negative affect during interepisode bipolar disorder. Ongoing monitoring of sleep-affect coupling may provide an important target for intervention in bipolar disorder. (PsycINFO Database Record (c) 2012 APA, all rights reserved). [PubMed Citation] [Order full text from Infotrieve]

3) Bohman H, Jonsson U, Päären A, von Knorring L, Olsson G, von Knorring AL
Prognostic significance of functional somatic symptoms in adolescence: a 15-year community-based follow-up study of adolescents with depression compared with healthy peers.
BMC Psychiatry. 2012 Jul 27;12(1):90.
ABSTRACT: BACKGROUND: The lack of population based long-term longitudinal studies of functional physical/somatic symptoms has been stressed in previous research. Little is known about the long-term outcome or whether associated depression is a risk factor or a consequence. This study follows up adolescents with depression and non-depressed controls with or without functional somatic symptoms in a community sample during 15 years. METHODS: The total population of 16-17 year olds, in the city of Uppsala, Sweden, was screened for depression in 1991-1993. Adolescents with positive screening and the same number of healthy controls took part in a semi-structured diagnostic interview. In addition, 21 different self-rated somatic symptoms were assessed. The participants were followed up with a structured interview 15 years later, 64% participated. RESULTS: The number of concurrent somatic symptoms in adolescents with depression predicted adverse adult mental health outcomes in a stepwise manner. The quarter of the depressed adolescents with most somatic symptoms (greater than or equal to 5) subsequently developed recurrent depression (68%), panic disorder (44%), chronic depression (30%), somatoform disorders (26%), bipolar disorder (22%), suicide attempts (16%), and psychotic disorders (8%). Abdominal pain was a strong independent predictor for depression and anxiety.Somatic symptoms predicted adult mental disorders in non-depressed controls. CONCLUSIONS: Somatic symptoms precede depression and predict future mental disorders. The number of somatic symptoms concurrent with adolescent depression is related to subsequent poor mental health in a stepwise manner. Treatment guidelines for individuals with somatic symptoms are needed. [PubMed Citation] [Order full text from Infotrieve]

4) Swann AC, Lijffijt M, Lane SD, Steinberg JL, Moeller FG
Antisocial personality disorder and borderline symptoms are differentially related to impulsivity and course of illness in bipolar disorder.
J Affect Disord. 2012 Jul 24;
BACKGROUND: Interactions between characteristics of bipolar and Axis II cluster B disorders are clinically and diagnostically challenging. Characteristics associated with personality disorders may be dimensional aspects of bipolar disorder. We investigated relationships among antisocial personality disorder (ASPD) or borderline personality disorder symptoms, impulsivity, and course of illness in bipolar disorder. METHODS: Subjects with bipolar disorder were recruited from the community. Diagnosis was by structured clinical interview for DSM-IV (SCID-I and -II), psychiatric symptom assessment by the change version of the schedule for affective disorders and schizophrenia (SADS-C), severity of Axis II symptoms by ASPD and borderline personality disorder SCID-II symptoms, and impulsivity by the Barratt impulsiveness scale (BIS-11). RESULTS: ASPD and borderline symptoms were not related to clinical state or affective symptoms. Borderline symptoms correlated with BIS-11 impulsivity scores, and predicted history of suicide attempts independently of the relationship to impulsivity. ASPD symptoms were more strongly related to course of illness, including early onset, frequent episodes, and substance-related disorders. These effects persisted after allowance for gender and substance-use disorder history. CONCLUSIONS: Personality disorder symptoms appear to be dimensional, trait-like characteristics of bipolar disorder. ASPD and Borderline symptoms are differentially related to impulsivity and course of illness. [PubMed Citation] [Order full text from Infotrieve]

5) Raven M, Parry P
Psychotropic marketing practices and problems: implications for DSM-5.
J Nerv Ment Dis. 2012 Jun;200(6):512-6.
The descriptive diagnostic model since DSM-III has often led to "cookbook" diagnosis and assumptions of "chemical imbalance" for psychiatric disorders. Pharmaceutical companies have exploited this in their marketing. This includes promoting self-diagnosis with online checklists. Significant overprescribing of psychotropics has resulted. DSM-5 will provide new disorders and broader diagnostic criteria that will likely exacerbate this. Most psychotropic prescribing is done by primary care physicians, who are problematically excluded from DSM-5 field trials and are influenced by industry funded key opinion leaders who may promote diagnosis of subthreshold cases. More lax criteria will increase diagnosis of subthreshold cases. Expansion of not otherwise specified (NOS) categories can be used to justify off-label promotion. Pediatric bipolar disorder, constructed within the bipolar disorder NOS category, became an "epidemic" in the United States, fuelled by diagnostic upcoding pressures. Disruptive mood dysregulation disorder may similarly cause overdiagnosis and excessive prescribing, as will other new disorders and lower diagnostic thresholds. [PubMed Citation] [Order full text from Infotrieve]

6) Álvarez MJ, Roura P, Foguet Q, Osés A, Solà J, Arrufat FX
Posttraumatic stress disorder comorbidity and clinical implications in patients with severe mental illness.
J Nerv Ment Dis. 2012 Jun;200(6):549-52.
Traumatic experiences and posttraumatic stress disorder (PTSD) are more frequent in patients with serious mental illness than in the general population. This study included 102 patients with schizophrenia, bipolar disorder, and schizoaffective disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Epidemiological and clinical data were collected using the Brief Psychiatric Rating Scale and Traumatic Life Events and Distressing Event questionnaires. We found a high number of traumatic experiences, and 15.1% of the patients met all criteria for PTSD. We found no differences based on diagnosis or sex, although there was a nonsignificant trend toward greater PTSD comorbidity in women. Among patients with serious mental illness and PTSD, 64.3% had made some attempt at suicide at some point in life, compared with 37.4% of patients without PTSD. [PubMed Citation] [Order full text from Infotrieve]

7) Castillo OA, Foneron A, Sepúlveda F, Sánchez-Salas R, Martínez V
Bladder hemangioma: case report.
Arch Esp Urol. 2012 Jul;65(6):623-625.
OBJECTIVE: Bladder hemangioma is a benign rare lesion. There are no pathognomonic clinical signs and management is controversial due to the bleeding risk. We report a bladder cavernous hemangioma resolved using bipolar transurethral resection. METHODS: We review the case of a female patient who presented with asymptomatic hematuria. On cystoscopy we discovered a reddish sessile lesion compatible with bladder hemangioma. We describe the diagnostic work up, surgical management and review other therapeutic alternatives for these lesions. RESULTS: Fifty five year old healthy female patient consulting for total painless hematuria. Cystoscopic evaluation revealed a 1 cm diameter sessile reddish elevated lesion near the bladder neck. We performed a transurethral endoscopic resection using the Gyrus Bipolar resectoscope®. Pathologic report concluded cavernous angioma. CONCLUSION: Bladder hemangiomas are benign and rare lesions. Clinical presentation has no pathognomonic signs although gross painless hematuria is the most frequent complain. Management is controversial due to the bleeding risk of this highly vascularized lesion. However, it appears that small lesions could be treated using transurethral resection. Although they have a benign course, follow up is mandatory to detect recurrence or residual disease. [PubMed Citation] [Order full text from Infotrieve]

8) Comte I, Kotagiri P, Szele FG
Regional Differences in Human Ependymal and Subventricular Zone Cytoarchitecture Are Unchanged in Neuropsychiatric Disease.
Dev Neurosci. 2012 Jul 20;
Much work has focused on the possible contribution of adult hippocampal neurogenesis to neuropsychiatric diseases. The hippocampal subgranular zone and the other stem cell-containing neurogenic niche, the subventricular zone (SVZ), share several cytological features and are regulated by some of the same molecular mechanisms. However, very little is known about the SVZ in neuropsychiatric disorders. This is important since it surrounds the lateral ventricles and in schizophrenia ventricular enlargement frequently follows forebrain nuclei shrinkage. Also, adult neurogenesis has been implicated in pharmacotherapy for affective disorders and many of the molecules associated with neuropsychiatric disorders affect SVZ biology. To assess the neurogenic niche, we examined material from 60 humans (Stanley Collection) and characterized the cytoarchitecture of the SVZ and ependymal layer in age-, sex- and post mortem interval-matched controls, and patients diagnosed with schizophrenia, bipolar illness, and depression (n = 15 each). There is a paucity of post mortem brains available for study in these diseases, so to maximize the number of possible parameters examined here, we quantified individual sections rather than a large series. Previous work showed that multiple sclerosis is associated with increased width of the hypocellular gap, a cell-sparse region that typifies the human SVZ. Statistically there were no differences between disease groups and controls in the width of the hypocellular gap or in the density of cells in the hypocellular gap. Because ventricular enlargement in schizophrenia may disrupt ependymal cells, we quantified them, but observed no difference between diagnostic groups and controls. There are significant differences in the prevalence of neuropsychiatric illness between the sexes. Therefore, we looked for male versus female differences, but did not observe any in the parameters quantified. We next turned to a finer spatial resolution and asked if there were differences amongst the disease groups in dorsal ventral subdivisions of the SVZ. Similar to when we treated the SVZ as a whole, we did not find such differences. However, compared to the dorsal SVZ, the ventral SVZ had a wider hypocellular gap and more ependymal cells in all four groups. In contrast, cell density was similar in dorsal ventral subregions of the SVZ hypocellular gap. These results show that though there are regional differences in the SVZ in humans, neuropsychiatric disorders do not seem to alter several fundamental histological features of this adult neurogenic zone. [PubMed Citation] [Order full text from Infotrieve]

9) Bombin I, Mayoral M, Castro-Fornieles J, Gonzalez-Pinto A, de la Serna E, Rapado-Castro M, Barbeito S, Parellada M, Baeza I, Graell M, Payá B, Arango C
Neuropsychological evidence for abnormal neurodevelopment associated with early-onset psychoses.
Psychol Med. 2012 Jul 25;:1-12.
BACKGROUND: The longitudinal neuropsychological study of first-episode early-onset psychosis (EOP) patients, whose brain maturation is still in progress at the time of illness onset, provides a unique opportunity to compare their cognitive development with that of healthy subjects, in search of specific patterns resulting from the interaction between neurodevelopmental processes and the presence of psychotic disorders. Method Seventy-five first-episode EOP patients (schizophrenia n=35; bipolar disorder n=17; other forms of psychosis n=23) with a mean age of 15.53 years were assessed with a neuropsychological battery that included measures of attention, working memory, memory and executive functions within 6 months following the onset of the first psychotic symptom (baseline) and 2 years later. Psychotic symptoms were assessed at both times with the Positive and Negative Symptom Scale (PANSS). Seventy-nine healthy subjects matched for age and education served as controls. RESULTS: EOP patients showed significant cognitive impairment at both baseline and the 2-year follow-up, with no significant differences between diagnostic groups at either time. Both healthy controls and EOP patients improved in all cognitive measures, except for patient working memory. Improvement in patient attention lost significance after controlling for psychotic symptom reduction. No significant time/diagnosis interaction was found among patients (p>0.405). CONCLUSIONS: Cognitive impairment in EOP is already present at the first episode, and cognitive development seems to be arrested early in EOP patients compared to their healthy peers, at least for some cognitive functions. These and previous similar results support the neurodevelopmental hypothesis of psychosis. [PubMed Citation] [Order full text from Infotrieve]

10) Khadivi R, Shakeri M, Ghobadi S
The Efficiency of Mental Health Integration in Primary Health Care: a Ten-year Study.
Int J Prev Med. 2012 Mar;3(Suppl1):S139-S145.
OBJECTIVES: This study was conducted on the estimation of the efficiency of mental health program in primary health care in Chaharmahal and Bakhtyari province, situated in center of the Islamic Republic of Iran, from 1999 to 2009. METHODS: One of the important objectives of mental health program is screening of mental health disorders and follow up. According to the prescription of mental health program, General Practitioners (GPs) were appointed to screen under-covered individuals, treat patients and also follow-up the patients with mental health disorders who needs referring to psychiatric clinics. Diagnostic criteria of mental disorders were based on American Psychiatry Association (DSM IV1994). Patients were categorized in four groups as follows: 1 - Severe mental disorders, such as major depression, schizophrenia, bipolar disorders, etc., 2 - Mild mental disorders, such as neurosis, anxiety, etc., 3 - Convulsive disorders and 4 - Behavioral disorders. The convulsive disorders and their types were diagnosed by physical examination and electroencephalography. In order to screen mental retardation, intelligence scale (IQ) score < 70 was considered as mental retardation. During the 10 years (1999 to 2009) of conducting program, all new diagnosed cases were confirmed by psychiatrists. All data was recorded in health files by trained GPs and they were assessed and justified by psychiatrists. RESULTS: During 10 years after conducting and stabilizing integrated mental health in primary health care, 13514 patients overall were newly detected and followed. Ten years incidence of total psychiatric disorders was estimated in about 15.9 per 1000 populations. CONCLUSIONS: Integrated mental health care offers the opportunity to increase access and develop efficiency of the mental health cares. [PubMed Citation] [Order full text from Infotrieve]

11) Watson D, O'Hara MW, Naragon-Gainey K, Koffel E, Chmielewski M, Kotov R, Stasik SM, Ruggero CJ
Development and Validation of New Anxiety and Bipolar Symptom Scales for an Expanded Version of the IDAS (the IDAS-II).
Assessment. 2012 Jul 20;
The original Inventory of Depression and Anxiety Symptoms (IDAS) contains 11 nonoverlapping scales assessing specific depression and anxiety symptoms. In creating the expanded version of the IDAS (the IDAS-II), our goal was to create new scales assessing other important aspects of the anxiety disorders as well as key symptoms of bipolar disorder. Factor analyses of the IDAS-II item pool led to the creation of seven new scales (Traumatic Avoidance, Checking, Ordering, Cleaning, Claustrophobia, Mania, Euphoria) plus an expanded version of Social Anxiety. These scales are internally consistent and show strong convergent and significant discriminant validity in relation to other self-report and interview-based measures of anxiety, depression, and mania. Furthermore, the scales demonstrate substantial criterion and incremental validity in relation to interview-based measures of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) symptoms and disorders. Thus, the expanded IDAS-II now assesses a broad range of depression, anxiety, and bipolar symptoms. [PubMed Citation] [Order full text from Infotrieve]

12) Hajek T, Cullis J, Novak T, Kopecek M, Blagdon R, Propper L, Stopkova P, Duffy A, Hoschl C, Uher R, Paus T, Young LT, Alda M
Brain Structural Signature of Familial Predisposition for Bipolar Disorder: Replicable Evidence For Involvement of the Right Inferior Frontal Gyrus.
Biol Psychiatry. 2012 Jul 19;
BACKGROUND: To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS: This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS: Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS: Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations. [PubMed Citation] [Order full text from Infotrieve]

13) Sinclair D, Webster MJ, Fullerton JM, Shannon Weickert C
Glucocorticoid receptor mRNA and protein isoform alterations in the orbitofrontal cortex in schizophrenia and bipolar disorder.
BMC Psychiatry. 2012 Jul 20;12(1):84.
ABSTRACT: BACKGROUND: The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). METHODS: In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. RESULTS: We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p<0.05), while GR-1H mRNA was decreased (22.0%) in schizophrenia cases relative to controls (p<0.005). By western blotting, there were significant increases in abundance of a truncated GRalpha isoform, putative GRalpha-D1, in bipolar disorder (56.1%, p<0.005) and schizophrenia (31.5% p<0.05). Using genotype data for eleven NR3C1 polymorphisms, we found no evidence of effects of NR3C1 genotype on GR mRNA or GRalpha protein expression in the OFC. CONCLUSIONS: These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRalpha-D1 protein isoform may be up-regulated widely across the frontal cortex in psychiatric illness. [PubMed Citation] [Order full text from Infotrieve]

14) Samuel DB
Assessing Personality in the DSM-5: The Utility of Bipolar Constructs.
J Pers Assess. 2011 Jul;93(4):390-7.
All previous editions of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) have described and assessed personality solely in terms of pathological categories. Nonetheless, there is compelling evidence that normal-range personality traits also provide clinically useful information, emphasizing the importance of thoroughly assessing both adaptive and maladaptive aspects of personality within a clinical context. The proposed inclusion of a dimensional trait model in the upcoming DSM-5 represents an important shift in the understanding of personality pathology and provides an ideal opportunity to integrate the assessment of normal personality into clinical practice. Building on research conceptualizing personality disorders as maladaptive, extreme variants of general personality traits, it is proposed that both normal and abnormal personality can be assessed within the same dimensional model using bipolar constructs. The inclusion of bipolar traits, such as a continuum ranging from introversion to extraversion, would hold numerous advantages for a dimensional model. These benefits include a strong foundation of existing validity research, comprehensive coverage of personality pathology, and the ability to provide useful information about all individuals. Despite potential complexities, the adoption of bipolar constructs within DSM-5's dimensional model presents the greatest opportunity to maximize efficiency, validity, and clinical utility. [PubMed Citation] [Order full text from Infotrieve]

15) Chakraborty V, Cherian AV, Math SB, Venkatasubramanian G, Thennarasu K, Mataix-Cols D, Reddy YC
Clinically significant hoarding in obsessive-compulsive disorder: results from an Indian study.
Compr Psychiatry. 2012 Jul 13;
BACKGROUND: Hoarding is frequently conceptualized as a symptom of obsessive-compulsive disorder (OCD), but recent evidence indicates that, in most cases, hoarding may be better conceptualized as a distinct disorder that can coexist with OCD. Most of the research on hoarding is from the Western countries. This study aimed to provide data on the prevalence and correlates of clinically significant hoarding in a large sample of patients with OCD from the Indian subcontinent. METHODS: We examined 200 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition OCD for clinically significant hoarding using the Saving Inventory-Revised, followed by a clinical interview. RESULTS: Twenty patients (10%) had clinically significant hoarding. In all cases, hoarding did not appear to be related or secondary to other OCD symptoms. None of the cases consulted for their hoarding problems. Compared with nonhoarders, hoarders hailed exclusively from an urban background and had a significantly higher frequency of certain obsessions and compulsions, bipolar disorder, generalized anxiety disorder, cluster C personality disorders, and a higher number of lifetime suicidal attempts. They also had a more severe OCD along with poorer global functioning and somewhat poorer insight into obsessive-compulsive symptoms. CONCLUSIONS: The results suggest that clinically significant hoarding is relatively prevalent in Indian patients with OCD and that it appears to be largely unrelated to the OCD phenotype. However, the presence of comorbid hoarding is associated with more severe OCD, high comorbidity, more suicidal attempts, and a lower level of functioning. The results contribute to the current nosologic debate around hoarding disorder and provide a unique transcultural perspective. [PubMed Citation] [Order full text from Infotrieve]

16) Wray NR, Gottesman II
Using Summary Data from the Danish National Registers to Estimate Heritabilities for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder.
Front Genet. 2012;3:118.
Estimates of heritability of psychiatric disorders quantify the genetic contribution to their etiology. Estimation of these parameters requires affected status on probands and their family members. Traditionally, heritabilities have been estimated from families ascertained from specific hospital registers, but accumulating sufficient numbers of families can be difficult. Larger sample sizes are achievable from national registries, but calculation of heritability from individual level data from these data sets is accompanied by other problems. Here, we use published summary data from a national population-based cohort of >2.6 million persons in Denmark to estimate heritabilities of schizophrenia, bipolar disorder, and major depressive disorder (MDD). The summary data comprised cumulative incidences up to 52?years of age for schizophrenia and bipolar disorder and up to 51?years for MDD in offspring where either one or both parents were diagnosed with one of these disorders. Estimates of the heritabilities of the liability to developing schizophrenia, bipolar disorder, and MDD are 0.67 (95% confidence interval (CI) 0.64-0.71), 0.62 (95% CI 0.58-0.65), and 0.32 (95% CI 0.30-0.34) respectively. The estimates may be inflated by common environmental effects, but despite this, they are somewhat lower for schizophrenia and bipolar disorder than those estimated from contemporary twin samples. The lower estimates may reflect the diverse environments (including diagnostic interpretation) that contribute to national data, compared to twin/family studies. Our estimates are similar to those estimated previously from national data of Sweden, and they may be more representative of the international samples brought together for large-scale genome-wide association studies. We investigated the estimation of genetic correlations from these data. We used simulation to conclude that estimates may not be interpretable and so report them only in the Section "Appendix." [PubMed Citation] [Order full text from Infotrieve]

17) Nusslock R, Harmon-Jones E, Alloy LB, Urosevic S, Goldstein K, Abramson LY
Elevated Left Mid-Frontal Cortical Activity Prospectively Predicts Conversion to Bipolar I Disorder.
J Abnorm Psychol. 2012 Jul 9;
Bipolar disorder is characterized by a hypersensitivity to reward-relevant cues and a propensity to experience an excessive increase in approach-related affect, which may be reflected in hypo/manic symptoms. The present study examined the relationship between relative left-frontal electroencephalographic (EEG) activity, a proposed neurophysiological index of approach-system sensitivity and approach/reward-related affect, and bipolar course and state-related variables. Fifty-eight individuals with cyclothymia or bipolar II disorder and 59 healthy control participants with no affective psychopathology completed resting EEG recordings. Alpha power was obtained and asymmetry indices computed for homologous electrodes. Bipolar spectrum participants were classified as being in a major/minor depressive episode, a hypomanic episode, or a euthymic/remitted state at EEG recording. Participants were then followed prospectively for an average 4.7-year follow-up period with diagnostic interview assessments every 4 months. Sixteen bipolar spectrum participants converted to bipolar I disorder during follow-up. Consistent with hypotheses, elevated relative left-frontal EEG activity at baseline (a) prospectively predicted a greater likelihood of converting from cyclothymia or bipolar II disorder to bipolar I disorder over the 4.7-year follow-up period, (b) was associated with an earlier age-of-onset of first bipolar spectrum episode, and (c) was significantly elevated in bipolar spectrum individuals in a hypomanic episode at EEG recording. This is the first study to our knowledge to identify a neurophysiological marker that prospectively predicts conversion to bipolar I disorder. The fact that unipolar depression is characterized by decreased relative left-frontal EEG activity suggests that unipolar depression and vulnerability to hypo/mania may be characterized by different profiles of frontal EEG asymmetry. (PsycINFO Database Record (c) 2012 APA, all rights reserved). [PubMed Citation] [Order full text from Infotrieve]

18) Marshall DF, Walker SJ, Ryan KA, Kamali M, Saunders EF, Weldon AL, Adams KM, McInnis MG, Langenecker SA
Greater executive and visual memory dysfunction in comorbid bipolar disorder and substance use disorder.
Psychiatry Res. 2012 Jul 4;
Measures of cognitive dysfunction in Bipolar Disorder (BD) have identified state and trait dependent metrics. An influence of substance abuse (SUD) on BD has been suggested. This study investigates potential differential, additive, or interactive cognitive dysfunction in bipolar patients with or without a history of SUD. Two hundred fifty-six individuals with BD, 98 without SUD and 158 with SUD, and 97 Healthy Controls (HC) completed diagnostic interviews, neuropsychological testing, and symptom severity scales. The BD groups exhibited poorer performance than the HC group on most cognitive factors. The BD with SUD exhibited significantly poorer performance than BD without SUD in visual memory and conceptual reasoning/set-shifting. In addition, a significant interaction effect between substance use and depressive symptoms was found for auditory memory and emotion processing. BD patients with a history of SUD demonstrated worse visual memory and conceptual reasoning skills above and beyond the dysfunction observed in these domains among individuals with BD without SUD, suggesting greater impact on integrative, gestalt-driven processing domains. Future research might address longitudinal outcome as a function of BD, SUD, and combined BD/SUD to evaluate neural systems involved in risk for, and effects of, these illnesses. [PubMed Citation] [Order full text from Infotrieve]

19) Kishi T, Yoshimura R, Fukuo Y, Okochi T, Matsunaga S, Umene-Nakano W, Nakamura J, Serretti A, Correll CU, Kane JM, Iwata N
The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder.
Eur Arch Psychiatry Clin Neurosci. 2012 Jul 3;
The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (P (allele model) = 0.007 and P (recessive model) = 0.01). When divided by diagnostic subgroup (MDD = 3,119 patients and 4,380 controls or BP = 1,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: P (allele model) = 0.006, P (recessive model) = 0.01; BP: P (dominant model) = 0.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (P (allele model) = 0.0002, P (dominant model) = 0.0008, and P (recessive model) = 0.01). When divided by diagnostic subgroup (MDD = 1,013 patients and 1,728 controls or BP = 1,051 patients and 2,099 controls), rs878567 was associated with MDD (P (allele model) = 0.0007 and P (dominant model) = 0.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs. [PubMed Citation] [Order full text from Infotrieve]

20) Koek RJ, Yerevanian BI, Mintz J
Subtypes of antipsychotics and suicidal behavior in bipolar disorder.
J Affect Disord. 2012 Jun 29;
OBJECTIVE: Antipsychotics are commonly used in bipolar disorder, with newer (SGA) agents increasingly replacing FGA antipsychotics, particularly in bipolar depression. There are few data on differences between FGA and SGA antipsychotics in terms of their relationship to suicidal behavior in bipolar disorder. METHOD: This was a retrospective chart review of 161 bipolar veterans treated naturalistically with antipsychotics at a university-affiliated VA hospital and clinics for up to 8 years. Charts were reviewed to determine monthly antipsychotic use and occurrence of suicidal behavior: completed suicide, attempted suicide or hospitalization to prevent suicide. Suicidal behavior events were compared across patients during treatment with individual antipsychotics and FGAs or SGAs as a class. RESULTS: Non-lethal suicide events were more common during FGA than SGA monotherapy (9 events/110 months of exposure vs. 6 events/381 months of exposure; ?(2)=9.65, p=0.002). Suicide event rates did not differ between FGAs and SGAs when used in conjunction with mood stabilizers. Event rates were lower with lithium than anticonvulsants when used in conjunction with antipsychotics. No differences were found between olanzapine, risperidone and quetiapine. LIMITATIONS: The retrospective chart review methodology may have led to confounding by indication and diagnostic inaccuracy. No completed suicides occurred. Study participants were primarily male veterans. Results may not be generalizable to SGAs marketed since 2003. CONCLUSIONS: FGA antipsychotic monotherapy may be associated with higher suicidal behavior risk than SGA antipsychotic monotherapy. Antipsychotics used in conjunction with mood stabilizers, particularly lithium, are associated with lower rates, independent of antipsychotic subtype. [PubMed Citation] [Order full text from Infotrieve]