bipolar disorder and dopamine


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(Updated 8/25/04)

Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin M, Linnoila M, Hare TA, Shaywitz BA, Cohen DJ.
CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls.
Am J Psychiatry 1984 Dec;141(12):1533-40
"A total of 114 subjects (41 depressed, 20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed patients, particularly those over 40 years of age, had lower levels of GABA than did controls, and that their level of HVA increased with age, while controls' decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic subjects tended to have higher levels of HVA and MHPG. Age-associated changes were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations." [Abstract]

Tandon R, Channabasavanna SM, Greden JF.
CSF biochemical correlates of mixed affective states.
Acta Psychiatr Scand 1988 Sep;78(3):289-97
"To evaluate the question of whether "mixed" bipolar disorder is a distinct entity, we compared selected cerebrospinal fluid (CSF) biochemical parameters from patients with bipolar disorder, mixed, to those with mania and major depression. Fourteen patients in each category (DSM-III) were studied with regard to CSF HVA, 5HIAA, sodium, potassium, calcium, and magnesium levels under carefully controlled conditions. CSF HVA, 5HIAA, and sodium were found to be significantly higher in manics than in major depressives. Discriminant analysis of the biochemical variables of the mixed affective group identified two biochemically distinct and clinically different subgroups of seven patients each, one resembling the manic group and the other the major depressive group." [Abstract]

Joyce PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J.
Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder.
J Affect Disord 1995 Apr 4;33(4):233-43
"Over the course of 1 year, a patient with a rapid cycling bipolar affective disorder was followed at weekly intervals to examine whether plasma hormones and urinary catecholamines could predict current or future mood. Higher cortisol levels were found to predict depressed mood 3 days after blood sampling, higher urinary dopamine predicted a manic mood 3 days after blood sampling, urinary norepinephrine was associated with severity of current mood and prolactin was lower with concurrent depressed mood. In multivariate analyses of mood against cortisol, prolactin and three urinary catecholamines, > 50% of the variance in mood state in 3 days was explained by combinations of these biologic measures, especially cortisol and urinary dopamine, while all five biologic variables contributed to explaining 50% of the variance in current mood state. Based on the interrelationships between urinary dopamine, norepinephrine and mood, we postulate the existence of an overcompensating mechanism which is reflected in opposing correlations between urinary dopamine and norepinephrine with mood, despite the two urinary catecholamines being positively correlated." [Abstract]

Chou JC, Czobor P, Tuma I, Charles O, Bebe R, Cooper TB, Chang WH, Lane HY, Stone DL.
Pretreatment plasma HVA and haloperidol response in acute mania.
J Affect Disord. 2000 Jul;59(1):55-9.
"INTRODUCTION: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation." [Abstract]

Fortunati F, Mazure C, Preda A, Wahl R, Bowers M Jr.
Plasma catecholamine metabolites in antidepressant-exacerbated mania and psychosis.
J Affect Disord 2002 Apr;68(2-3):331-4
"We measured plasma free HVA and MHPG in 39 cases of psychosis or mania judged to be caused by antidepressant exacerbation of symptoms. A total of 24 of patients had been receiving selective serotonin reuptake inhibitors (SSRI's). The SSRI group showed a pattern of increased plasma HVA similar to a comparison group of patients with a psychotic/manic relapse secondary to medication non-compliance." [Abstract]

Mazure CM, Bowers MB.
Pretreatment plasma HVA predicts neuroleptic response in manic psychosis.
J Affect Disord 1998 Feb;48(1):83-6
"Elevated pretreatment plasma free homovanillic acid (HVA) predicted acute response to neuroleptic treatment in patients with manic psychosis. These findings suggest that plasma HVA may be a useful predictor of a successful short-term response in manic as well as schizophrenic psychoses, and that elevated pre-synaptic dopaminergic release may play a role in more than one group of psychotic disorders." [Abstract]

Post RM, Jimerson DC, Bunney WE Jr, Goodwin FK.
Dopamine and mania: behavioral and biochemical effects of the dopamine receptor blocker pimozide.
Psychopharmacology (Berl) 1980;67(3):297-305
"Although recent data suggest that pimozide has effects at other neurotransmitter receptor sites, it is one of the more specific neuroleptics in its effects on dopamine receptors. We report that in manic patients pimozide produces substantial clinical improvement with a magnitude and time course similar to that observed with the more routinely used phenothiazines chlorpromazine and thioridazine. Pimozide did not significantly increase probenecid-induced accumulations of the dopamine metabolite homovanillic acid (HVA) compared to pretreatment values. Higher HVA values were observed in manic than in nonmanic patients, however. These clinical and biochemical data add to a growing body of indirect evidence that a dopaminergic alteration may be associated with some components of the manic syndrome." [Abstract]

Gerner RH, Post RM, Bunney WE Jr.
A dopaminergic mechanism in mania.
Am J Psychiatry 1976 Oct;133(10):1177-80
"The authors present a case study that explores the relationship of dopamine function and manic illness through the use of two drugs with relatively specific effects in stimulating and blocking dopamine receptors--piribedil (ET--495) and pimozide, respectively. Piribedil, as well as d-amphetamine, was associated with manic episodes, while pimozide had an antimanic effect. These observations suggest that dopaminergic mechanisms may be involved in the mediation of manic episodes in at least some patients." [Abstract]

Anand, Amit, Verhoeff, Paul, Seneca, Nicholas, Zoghbi, Sami S., Seibyl, John P., Charney, Dennis S., Innis, Robert B.
Brain SPECT Imaging of Amphetamine-Induced Dopamine Release in Euthymic Bipolar Disorder Patients
Am J Psychiatry 2000 157: 1108-1114
"In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder." [Abstract]

Wieck A, Davies RA, Hirst AD, Brown N, Papadopoulos A, Marks MN, Checkley SA, Kumar RC, Campbell IC.
Menstrual cycle effects on hypothalamic dopamine receptor function in women with a history of puerperal bipolar disorder.
J Psychopharmacol. 2003 Jun;17(2):204-9.
"Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder." [Abstract]

Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos MB, Jack RM, Dugaw KA, Paddock MN, Parson WW.
Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
Neurology 2001 Aug 14;57(3):410-6
"OBJECTIVE: To investigate catecholamine phenotypes and the effects of a tyrosine hydroxylase inhibitor in individuals with the 22q11.2 deletion syndrome and low-activity catechol-O-methyltransferase (COMT). BACKGROUND: Many persons with the 22q11.2 deletion syndrome suffer severe disability from a characteristic ultrarapid-cycling bipolar disorder and associated "affective storms." One etiologic hypothesis for this condition is that deletion of the COMT gene from one chromosome 22 results in increased catecholamine neurotransmission, particularly if the undeleted chromosome 22 encodes a variant of COMT with low activity. METHODS: In a preliminary study, plasma, urine, and CSF catecholamines and catecholamine metabolites were measured in four teenage patients with a neuropsychiatric condition associated with 22q11.2 deletion and the low-activity COMT polymorphism on the nondeleted chromosome. In these four patients, and an additional institutionalized adult with the condition, an uncontrolled, open-label trial of metyrosine was administered in an attempt to lower catecholamine production and to alleviate symptoms. RESULTS: Mild elevations of baseline CSF homovanillic acid (HVA) were found in three of four patients and a moderate reduction in CSF HVA after metyrosine treatment in the patient with the highest pretreatment concentration. The course of the five patients during the clinical trial is described. CONCLUSIONS: In patients with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of pharmacologic agents that decrease catecholamine production, block presynaptic catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT, are warranted."

Linnoila M, Karoum F, Potter WZ.
Effects of antidepressant treatments on dopamine turnover in depressed patients.
Arch Gen Psychiatry 1983 Sep;40(9):1015-7
"Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional." [Abstract]

Swann AC, Koslow SH, Katz MM, Maas JW, Javaid J, Secunda SK, Robins E.
Lithium carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites and treatment outcome.
Arch Gen Psychiatry 1987 Apr;44(4):345-54
"Treatment of manic patients with lithium carbonate was associated with significant decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary norepinephrine excretion. These measures, before treatment, were higher in manic patients than in either depressed or normal subjects and correlated significantly with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic acid did not correlate with severity or with change during lithium carbonate treatment. Responders (about 70% of the patients) did not differ from nonresponders in pretreatment mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine excretion were reduced during lithium carbonate treatment in both responders and nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher during treatment in nonresponders than in responders and correlated with several indexes of symptom severity. These results support a relationship between mania and increased noradrenergic function. Treatment outcome, however, was not related exclusively to the reduction of noradrenergic indexes by lithium carbonate since reductions were similar in both responders and nonresponders. Reduced noradrenergic activity may therefore be necessary but not sufficient for successful outcome during lithium carbonate treatment." [Abstract]

Post RM.
Time course of clinical effects of carbamazepine: implications for mechanisms of action.
J Clin Psychiatry 1988 Apr;49 Suppl:35-48
"The relatively acute time course of antimanic efficacy may be related to the above-mentioned mechanisms or to other effects related to systems postulated to be altered in the manic syndrome. These effects might include carbamazepine's ability to increase acetylcholine in the striatum, decrease probenecid-induced levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals, decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity (in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA turnover, or act as a vasopressin agonist." [Abstract]

Swann AC, Secunda S, Davis JM, Robins E, Hanin I, Koslow SH, Maas JW.
CSF monoamine metabolites in mania.
Am J Psychiatry 1983 Apr;140(4):396-400
"As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function." [Abstract]

Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.
Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):313-7. Epub 2002 Dec 20.
"The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins." [Abstract]

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Recent Bipolar Disorder & Dopamine Research

1) Ha CM, Park D, Han JK, Jang JI, Park JY, Hwang EM, Seok H, Chang S
Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 and plays a role in dopamine receptor internalization.
J Biol Chem. 2012 Jul 26;
Calcyon, once known for interacting directly with the dopamine D1 receptor (D1DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder and ADHD. Although its direct interaction with D1DR has been shown to be misinterpreted, it still plays important roles in the D1DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D1DR through PSD-95. Calcyon is phosphorylated on Ser169 by the PKC activator PMA or by the D1DR agonist SKF81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D1DR at the cell surface was enhanced by PMA and SKF81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of caclyon and the internalization of the surface D1DR are tightly correlated. Our results suggest that calcyon regulates D1DR trafficking by forming a ternary complex with D1DR through PSD-95 and thus, possibly linking a glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

2) Risbood V, Lee JR, Roche-Desilets J, Fuller MA
Lurasidone: an atypical antipsychotic for schizophrenia.
Ann Pharmacother. 2012 Jul;46(7-8):1033-46.
[PubMed Citation] [Order full text from Infotrieve]

3) Coppola M, Mondola R
Methoxetamine: From drug of abuse to rapid-acting antidepressant.
Med Hypotheses. 2012 Jul 20;
Methoxetamine is a dissociative anaesthetic showing pharmacodynamic similarities with its analogue ketamine, a medication with demonstrated rapid-acting antidepressant effects. Like ketamine and other arylcyclohexylamine compounds, methoxetamine is thought to be both a noncompetitive NMDA receptor antagonist and a dopamine reuptake inhibitor. Furthermore, it acts as an agonist at dopamine D2, serotonin 5HT2, muscarinic cholinergic, sigma-1, opioid mu and k receptors. The hypothesis is that methoxetamine can produce rapid antidepressant effects in patients with resistant and non-resistant unipolar and bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

4) Kovtun O, Tomlinson ID, Sakrikar DS, Chang JC, Blakely RD, Rosenthal SJ
Visualization of the cocaine-sensitive dopamine transporter with ligand-conjugated quantum dots.
ACS Chem Neurosci. 2011 Jul 20;2(7):370-8.
The presynaptic dopamine (DA) transporter is responsible for DA inactivation following release and is a major target for the psychostimulants cocaine and amphetamine. Dysfunction and/or polymorphisms in human DAT (SLC6A3) have been associated with schizophrenia, bipolar disorder, Parkinson's disease, and attention-deficit hyperactivity disorder (ADHD). Despite the clinical importance of DAT, many uncertainties remain regarding the transporter's regulation, in part due to the poor spatiotemporal resolution of conventional methodologies and the relative lack of efficient DAT-specific fluorescent probes. We developed a quantum dot-based labeling approach that uses a DAT-specific, biotinylated ligand, 2-?-carbomethoxy-3-?-(4-fluorophenyl)tropane (IDT444), that can be bound by streptavidin-conjugated quantum dots. Flow cytometry and confocal microscopy were used to detect DAT in stably and transiently transfected mammalian cells. IDT444 is useful for quantum-dot-based fluorescent assays to monitor DAT expression, function, and plasma membrane trafficking in living cells as evidenced by the visualization of acute, protein-kinase-C (PKC)-dependent DAT internalization. [PubMed Citation] [Order full text from Infotrieve]

5) Russo E, Citraro R, Davoli A, Gallelli L, Donato Di Paola E, De Sarro G
Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.
Neuropharmacology. 2012 Jul 2;
Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D(2) dopamine receptors and serotonin 5-HT(1A) and 5-HT(7) receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT(6) receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

6) Stefano GB, Králíčková M, Ptacek R, Kuzelova H, Esch T, Kream RM
Low dose morphine adjuvant therapy for enhanced efficacy of antipsychotic drug action: Potential involvement of endogenous morphine in the pathophysiology of schizophrenia.
Med Sci Monit. 2012 Jun 28;18(7):HY23-26.
Major thematic threads linking extensive preclinical and clinical efforts have established a working mechanistic scheme whereby atypical antipsychotic drugs ameliorate negative DSM IV diagnostic criteria by effecting relatively potent blockade of serotonin (5-HT)(2A) receptors coupled with weaker antagonism of dopamine D(2) receptors in frontal cortical areas. These contentions are more or less supported by in vitro binding experiments employing cloned receptors on cultured cells, although significant functional involvement of 5-HT(2C) receptors has also been proposed. It is interesting that a key statistical analysis indicates a major shift in usage back to typical antipsychotic agents for management of schizophrenia from 1995-2008, whereas off-label usage of atypical antipsychotic agents was markedly increased or expanded for bipolar affective disorder. Importantly, meta-analyses generally did not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. A critical examination of putative functional linkages of morphine and its type-selective mu opioid receptor to higher order cortical regulation of cognitive processes may provide novel insights into human behavioral processes that are severely impaired in schizophrenia spectrum disorders.
[PubMed Citation] [Order full text from Infotrieve]

7) Björkholm C, Jardemark K, Marcus MM, Malmerfelt A, Nyberg S, Schilström B, Svensson TH
Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.
Eur Neuropsychopharmacol. 2012 Jun 23;
Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D(2) receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D(2) receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60nM) and reboxetine (20nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D(1) receptor antagonist SCH23390. We conclude that concomitant NET-inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D(2) occupancy. [PubMed Citation] [Order full text from Infotrieve]

8) Chakravarty MM, Felsky D, Tampakeras M, Lerch JP, Mulsant BH, Kennedy JL, Voineskos AN
DISC1 and Striatal Volume: A Potential Risk Phenotype For mental Illness.
Front Psychiatry. 2012;3:57.
Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2) receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281) and Ser704Cys (rs821618) single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in 54 healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p?=?0.017; right striatum: p?=?0.016). From the exploratory analyses we found that the Phe carriers also had larger left hemisphere volumes (p?=?0.0074) and right occipital lobe surface area (p?=?0.014) compared to LeuLeu homozygotes. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1's effects on the striatum. [PubMed Citation] [Order full text from Infotrieve]

9) Soeiro-de-Souza MG, Machado-Vieira R, Soares Bio D, Do Prado CM, Moreno RA
COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder.
Bipolar Disord. 2012 Aug;14(5):554-64.
Soeiro-de-Souza MG, Machado-Vieira R, Soares Bio D, Do Prado CM, Moreno RA. COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disord 2012: 14: 554-564. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective:? The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol-O-methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Methods:? Seventy-two symptomatic, medication-free subjects with bipolar I disorder (BD-I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Results:? Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Conclusions:? Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state-dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings. [PubMed Citation] [Order full text from Infotrieve]

10) Savitz JB, Drevets WC
Neuroreceptor imaging in depression.
Neurobiol Dis. 2012 Jun 9;
The in vivo study of receptor binding potential in the human brain is made possible by positron emission tomography (PET) imaging. Here we review PET studies of neuroreceptor function in mood disorders - specifically, major depressive disorder (MDD) and bipolar disorder (BD). We concentrate on the most widely studied receptors of the serotonergic and dopaminergic systems. Specifically, the serotonin 1A (5-HT(1A)), serotonin 2A (5-HT(2A)), serotonin 1B (5-HT(1B)), dopamine 1 (D1), and dopamine 2/3 (D2/3) receptors. We also review PET studies of the serotonin transporter (5-HTT), the dopamine transporter (DAT), monoamine oxidase A (MAO-A), and the muscarinic 2 receptor (M2). On the basis of the PET literature as well as supporting genetic studies, postmortem data, and preclinical models of depression, and several models of how monoaminergic function is altered in mood disorders are discussed with respect to inflammation, endocrine dysfunction, depression subtypes, and altered neurocircuitry. [PubMed Citation] [Order full text from Infotrieve]

11) Hudepohl NS, Nasrallah HA
Antipsychotic drugs.
Handb Clin Neurol. 2012;106:657-67.
Neuroleptic medications, now referred to as antipsychotic drugs, were serendipitously discovered in the early 1950s when the phenothiazine chlorpromazine, which was used as an antihistaminic adjunct during surgery on mentally ill patients, was observed to ameliorate psychotic symptoms. Dozens of phenothiazine, and later many nonphenothiazine, antipsychotics were developed and all of them were noted to cause extrapyramidal movement disorders, which instigated the theory that schizophrenia is related to increased dopamine activity. The poor tolerability to, and nonadherence with, the first-generation antipsychotics due to akathisia, dystonia, dyskinesia, and parkinsonism led eventually to the development of the second-generation antipsychotics with more serotonin 5-HT(2) than D(2) receptor antagonism, resulting in far fewer acute and tardive movement disorders but more metabolic adverse effects, including obesity, hyperglycemia, and hyperlipidemia. Both generations have multiple effects on various organ systems, but the second-generation agents are now indicated or used not only in primary psychotic disorders and neurologically induced psychotic symptoms, but also in nonpsychotic conditions such as bipolar disorder and major depression. Future antipsychotic drugs may transcend the model of dopamine antagonism to one of glutamate modulation. [PubMed Citation] [Order full text from Infotrieve]

12) Caccia S, Pasina L, Nobili A
Critical appraisal of lurasidone in the management of schizophrenia.
Neuropsychiatr Dis Treat. 2012;8:155-68.
Lurasidone is a new atypical antipsychotic in the benzoisothiazoles class of chemicals. Like most second-generation antipsychotics it is a full antagonist at dopamine D(2) and serotonin 5-HT(2A) receptors, and is a partial agonist at 5-HT(1A) receptors, a property shared by some but not all older agents. It has much greater affinity for 5-HT(7) subtype receptors than other atypical antipsychotics. Pharmacokinetic studies showed that lurasidone is reasonably rapidly absorbed, with bioavailability appearing to be increased by food. Lurasidone undergoes extensive metabolism to a number of metabolites, some of which retain pharmacological activities. Metabolism is mainly by CYP3A4, resulting in steady-state concentrations that vary between individuals and are potentially affected by strong inducers and inhibitors of this enzyme. Short-term clinical trials have demonstrated the efficacy of lurasidone in acute schizophrenia, with doses of 40 and 80 mg/day giving significant improvements from baseline in the PANSS and BPRS scores. The most common adverse events are nausea, vomiting, akathisia, dizziness, and sedation, with minimal increases in the risk of developing metabolic syndrome. Lurasidone did not raise the risk of QTc interval prolongation, although additional studies are required. Long-term trials are also needed to assess the risk of new-onset diabetes. Ongoing trials in patients with bipolar disorder are being completed but, again, efficacy and safety have been investigated only in a few short-term clinical trials. [PubMed Citation] [Order full text from Infotrieve]

13) Kittel-Schneider S, Kenis G, Schek J, van den Hove D, Prickaerts J, Lesch KP, Steinbusch H, Reif A
Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes.
Front Psychiatry. 2012;3:33.
Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. Conclusion: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants. [PubMed Citation] [Order full text from Infotrieve]

14) Cuellar NG
The Psychopharmacological Management of RLS in Psychiatric Conditions: A Review of the Literature.
J Am Psychiatr Nurses Assoc. 2012 Apr 22;
BACKGROUND: Restless legs syndrome (RLS) is a movement disorder treated with dopamine agonists. RLS is often diagnosed as a comorbid condition with psychiatric disorders, which are treated with dopamine antagonists or antidepressants resulting in onset or exacerbation of RLS symptoms. OBJECTIVES: The objectives of this article are to provide a review of the literature to (a) describe the comorbidity of psychiatric disorders associated with RLS, (b) identify the treatment of psychiatric disorders that cause or exacerbate symptoms of RLS, and (c) provide clinical recommendations for psychiatric health care providers. DESIGN: A review of the literature of English articles included the databases of Medline, Pubmed, PsychINFO, and CINAHL for "Restless Legs Syndrome" with major psychiatric disorders including mood disorders (depression and bipolar), schizophrenia, and anxiety disorders (anxiety, panic disorder, obsessive compulsive disorder). The PRISMA guidelines were used to improve the reporting of the review of the literature. RESULTS: There were 61 articles that met the inclusion and exclusion criteria identified for the review of the literature, including RLS with mood disorders (n = 36), schizophrenia (n = 9), and anxiety disorders (n = 16). CONCLUSIONS: Clinical trials are lacking on the best treatment for persons with RLS and psychiatric disorders; the most rigorous research found in the literature related to depression and anxiety. Studies lack evidence to document the best practice for persons with RLS and comorbid psychiatric disorders. Psychiatric health care providers should be aware of RLS, which is influenced by psychiatric medications. [PubMed Citation] [Order full text from Infotrieve]

15) Sanford M, Keating GM
Quetiapine: a review of its use in the management of bipolar depression.
CNS Drugs. 2012 May 1;26(5):435-60.
Quetiapine (Seroquel®) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600?mg/day (or quetiapine XR 300?mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300?mg/day and 600?mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600?mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600?mg/day and quetiapine XR 300?mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest. [PubMed Citation] [Order full text from Infotrieve]

16) Huang CC, Chang YH, Lee SY, Chen SL, Chen SH, Chu CH, Huang SY, Tzeng NS, Lee IH, Yeh TL, Yang YK, Lu RB
The interaction between BDNF and DRD2 in Bipolar II disorder but not in bipolar i disorder.
Am J Med Genet B Neuropsychiatr Genet. 2012 Jul;159(5):501-7.
Bipolar I (BP-I) and bipolar II (BP-II) disorders are the two most common subtypes of bipolar disorder. However, most studies have not differentiated bipolar disorder into BP-I and BP-II groups, for which the underlying etiology differentiating these two subtypes remains unclear. The genetic association between both subtypes is essential for improving our understanding. The dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1), one of the dopaminergic pathways, as well as the brain-derived neurotrophic factor (BDNF) gene, were reported as candidate genes in the etiology of bipolar disorder. Therefore, we examined the contribution of the BDNF and DRD2/ANKK1 genes and their interaction to the differentiation of BP-I and BP-II. Seven hundred ninety-two participants were recruited: 208 with BP-I, 329 with BP-II, and 255 healthy controls. The genotypes of the BDNF and DRD2/ANKK1 Taq1A polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism predicted BP-II patients. The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP-II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP-II disorder and that BP-I and BP-II are genetically distinct. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

17) Stoner SC, Pace HA
Asenapine: a clinical review of a second-generation antipsychotic.
Clin Ther. 2012 May;34(5):1023-40.
[PubMed Citation] [Order full text from Infotrieve]

18) Langlois X, Megens A, Lavreysen H, Atack J, Cik M, Te Riele P, Peeters L, Wouters R, Vermeire J, Hendrickx H, Macdonald G, De Bruyn M
Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D2 Antagonist for the Treatment of Schizophrenia.
J Pharmacol Exp Ther. 2012 Jul;342(1):91-105.
All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N- [1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [?(1), ?(2), H(1), muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or d-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

19) Amsterdam JD, Newberg AB, Soeller I, Shults J
Greater striatal dopamine transporter density may be associated with major depressive episode.
J Affect Disord. 2012 Apr 4;
BACKGROUND: We examined striatal dopamine transporter (DAT) distribution volume ratio (DVR) values in subjects with unipolar or bipolar major depressive episode (versus non-depressed healthy volunteers) using the selective DAT radioligand [(99m)Tc]TRODAT-1 and single photon emission computed tomography (SPECT). We hypothesized that striatal DVR values would be greater in depressed versus non-depressed subjects, and that greater DVR values may represent a possible clinical biomarker of depression. METHODS: [(99m)Tc]TRODAT-1 spect images were acquired from 39 depressed and 103 non-depressed drug-free subjects. The primary outcome measure was the DVR value of [(99m)Tc]TRODAT-1 binding for the putamen region and the combined putamen plus caudate region. RESULTS: DVR values were significantly correlated across all striatal regions within both subject groups (p<0.005). Depressed subjects had significantly greater DVR values (versus non-depressed subjects) in the putamen (p<0.0005) and the combined putamen plus caudate (p<0.0005) regions. There was no difference in DVR values between unipolar (n=24) and bipolar (n=15) depressed subjects, and no difference in DVR values for depressed subjects with or without prior antidepressant exposure. The predictive probability of the putamen or combined putamen plus caudate DVR value to distinguish depressed from non-depressed subjects was significant (p<0.0005). LIMITATIONS: DAT values could potentially be influenced by age, gender, diagnosis, prior psychotropic dug exposure, illness length, or symptom severity. CONCLUSION: Results confirm prior observations of greater striatal DAT density in depressed versus non-depressed subjects, and suggest that greater DVR values may possibly represent a potential diagnostic biomarker for distinguish depressed from non-depressed individuals. [PubMed Citation] [Order full text from Infotrieve]

20) Arraf Z, Amit T, Youdim MB, Farah R
Lithium and oxidative stress lessons from the MPTP model of Parkinson's disease.
Neurosci Lett. 2012 May 10;516(1):57-61.
Lithium has been successfully employed therapeutically for treatment of bipolar depressive illness; however, its mechanism of action is poorly understood. Recently, it has been demonstrated by us that lithium can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) dopaminergic neurotoxicity in mice. From analyzing the pattern of protection in various parameters, we suggest that lithium protects against MPTP-induced depletion of striatal dopamine (DA) by preventing free radical-induced inactivation of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. Possible neuroprotective effect of lithium against H(2)O(2)-induced cell death was assessed in human neuroblastoma; SH-SY5Y cell line. Pretreatment with LiCl (2mM and 4mM) for 7 days protected against H(2)O(2) neurotoxicity in a dose-dependent manner. However, this protection could not be achieved through short-term incubation with LiCl. In agreement; we found that lithium lacks immediate antioxidant activity using the in vitro lipid peroxidation essay indicating that not acute but chronic treatment with lithium allows cells to deal better with oxidative stress. [PubMed Citation] [Order full text from Infotrieve]