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Objective: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. Method: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. Results: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. Conclusions: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.

Objective: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. Method: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. Results: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. Conclusions: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.

Objective: There is a major unmet need for effective options in the treatment of bipolar depression. Method: Five hundred forty-two outpatients with bipolar I (N-360) or II (N-182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 rag/ day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire. Results: Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week I onward. The pro portions of patients meeting response criteria ([greater than or equal to] 50% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale [less than or equal to] 12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively). Conclusions: Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.

Objective: This study compared demographic and phenomenological variables between bipolar patients with and with out rapid cycling as a function of bipolar I versus bipolar II status. Method: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health de signed to evaluate the longitudinal outcome of patients with bipolar disorder. Results: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. Conclusions: Patients with rapid cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to re fine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

Objective: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. Method: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were [greater than or equal to] 20 for inclusion, [less than or equal to] 12 for remission, and [greater than or equal to] 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. Results: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. Conclusions: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

Objective: The authors' goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients. Method: Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F]fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine ([T.sub.3]), thyroxine ([T.sub.4]), and free [T.sub.4] concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. Results: Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between [T.sub.3], [T.sub.4], or free [T.sub.4] and global or regional CBF and cerebral glucose metabolism. Conclusions: These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

Objective: This study assessed weight changes in a large cohort of patients with bipolar disorder who were treated with randomly assigned maintenance monotherapies. Method: A post hoc analysis was conducted to assess the effects of lamotrigine, lithium, and placebo administration on body weight in obese and nonobese patients with bipolar disorder from two double-blind, placebo-controlled,18-month studies. Results: Mean changes in weight among obese patients (N=155) at week 52 were -4.2, +6.1, and -0.6 kg with lamotrigine, lithium, and placebo, respectively (lamotrigine versus lithium and lithium versus placebo). Among nonobese patients (N=399), mean changes in weight (kg) at week 52 were -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo, respectively, with no significant differences among groups. Conclusions: Obese patients with bipolar I disorder lost weight while taking lamotrigine and gained weight while taking lithium.

Objective: Recognition of facial emotion was examined in manic subjects to explore whether aberrant interpersonal interactions are related to impaired perception of social cues. Method: Manic subjects with bipolar I disorder (N=8), euthymic subjects with bipolar I (N=8) or bipolar II (N=8) disorder, and healthy comparison subjects (N=10) matched pictures of faces to the words 'fear,' 'disgust,' 'anger,' 'sadness,' 'surprise,' and 'happiness.' Results: The manic subjects showed worse overall recognition of facial emotion than all other groups. They showed worse recognition of fear and disgust than the healthy subjects. The euthymic bipolar II disorder subjects showed greater fear recognition than the manic and euthymic bipolar I disorder subjects. Conclusions: Impaired perception of facial emotion may contribute to behaviors in mania. Impaired recognition of fear and disgust, with relatively preserved recognition of other basic emotions, contrasts with findings for depression and is consistent with a mood-congruent positive bias. (Am J Psychiatry 2002; 159:302-304)

IntroductionBipolar disorder (BD) is a chronic, highly disabling condition associated with psychiatric/medical comorbidity and substantive morbidity, mortality, and suicide risks. In prior reports, varying parameters have been associated with suicide risk.ObjectivesTo evaluate sociodemographic and clinical variables characterizing Italian individuals with BD with versus without prior suicide attempt (PSA).MethodsA sample of 362 Italian patients categorized as BD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) was assessed and divided in 2 subgroups: with and without PSA. Sociodemographic and clinical variables were compared between prior attempters and non-attempters using corrected multivariate analysis of variance (MANOVA).ResultsMore than one-fourth of BD patients (26.2%) had a PSA, with approximately one-third (31%) of these having>1 PSA. Depressive polarity at onset, higher number of psychiatric hospitalizations, comorbid alcohol abuse, comorbid eating disorders, and psychiatric poly-comorbidity were significantly more frequent (p<.05) in patients with versus without PSA. Additionally, treatment with lithium, polypharmacotherapy (≥4 current drugs) and previous psychosocial rehabilitation were significantly more often present in patients with versus without PSA.ConclusionsWe found several clinical variables associated with PSA in BD patients. Even though these retrospective findings did not address causality, they could be clinically relevant to better understanding suicidal behavior in BD and adopting proper strategies to prevent suicide in higher risk patients.

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IntroductionBipolar disorders (BDs) comprise different variants of chronic, comorbid, and disabling conditions, with relevant suicide and suicide attempt rates. The hypothesis that BD types I (BDI) and II (BDII) represent more and less severe forms of illness, respectively, has been increasingly questioned over recent years, justifying additional investigation to better characterize related sociodemographic and clinical profiles.MethodsA sample of 217 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)–described BD (141 BDI, 76 BDII), without a current syndromal mood episode, was recruited, and sociodemographic and clinical characteristics of BDI and II patients were compared.ResultsBDII patients had significantly more favorable sociodemographics, in relation to occupational stability, cohabitation, and marital status. However, BDII compared with BDI patients had significantly longer duration of untreated illness, more frequent lifetime anxiety disorders comorbidity, longer most recent episode duration, higher rate of depressive first/most recent episode, and more current antidepressant use. In contrast, BDI compared with BDII patients had significantly more severe illness in terms of earlier age at onset; higher rate of elevated first/most recent episode, lifetime hospitalizations, and involuntary commitments; lower Global Assessment of Functioning score; and more current antipsychotic use. BDI and II patients had similar duration of illness, psychiatric family history, lifetime number of suicide attempts, current subthreshold symptoms, history of stressful life events, and overall psychiatric/medical comorbidity.ConclusionBDII compared with BDI patients had more favorable sociodemographic features, but a mixture of specific unfavorable illness characteristics, confirming that BDII is not just a milder form of BD and requires further investigation in the field.

Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P< 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

Bipolar depression represents the most difficult-to-treat phase of bipolar disorder, mood-stabilizing compounds and second-generation antipsychotics being only partially effective, whereas the use of antidepressants is highly controversial because of risks of inefficacy, switching, rapid cycling, and increased suicidality. Among various augmentative pharmacological treatments, compounds with dopamine-enhancing activity have been shown to be variably beneficial in the treatment of bipolar depression with drug-resistance features. In particular, pramipexole – a dopamine D2D3 receptor agonist – showed antidepressant properties in bipolar depressed patients in both randomized-controlled trials and open acute and follow-up reports. The present review aims to provide an updated perspective on the use of adjunctive pramipexole in bipolar depression, taking into account randomized-controlled trials, as well as open naturalistic studies, with a specific focus on the evaluation of acute versus long-term data in terms of effectiveness and tolerability. Despite methodological differences, short-term studies support the acute efficacy and tolerabilitysafety of adjunctive pramipexole, whereas open extended observations seem to confirm the effectiveness of the compound, with some additional concern in terms of safety and tolerability issues. Adjunctive pramipexole may be a valid option in both the acute and the long-term treatment of drug-resistant bipolar depression, with possible superior tolerability in the short term.

Background: Aripiprazole, a second-generation antipsychotic, has been shown to have short- and long term efficacy in bipolar disorder as monotherapy and in two-drug combinations. However, its long-term effectiveness among patients with different degrees of pharmacotherapeutic complexity and baseline mood disturbances is not known.

To assess longer-term ziprasidone effectiveness in obese and non-obese patients with bipolar disorder (BD).

Introduction: There are limited data regarding relationships between race/ethnicity and bipolar disorder. This study assessed such relationships in patients receiving treatment in a university clinic.

We previously reported genomewide significant evidence for linkage between chromosome 6q and bipolar I disorder BPI by performing a metaanalysis of original genotype data from 11 genome scan linkage studies. We now present followup linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism SNP markers in a case–control sample N  530 cases, 534 controls and familybased sample N  256 nuclear families, 1,301 individuals. The strongest single SNP result rs6938431, P  6.72 × 10−5 was observed in the case–control sample, near the solute carrier family 22, member 16 gene SLC22A16. In a replication study, we genotyped 151 SNPs in an independent sample N  622 cases, 1,181 controls and observed further evidence of association between variants at SLC22A16and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNPwise and genebased test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder. © 2009 WileyLiss, Inc.

To identify caregivers at risk for adverse health effects associated with caregiving, the stress, coping, health and service use of 500 primary caregivers of patients with bipolar disorder were assessed at baseline, 6, and 12 months. K-means cluster analysis and ANOVA identified and characterized groups with differing baseline stress/coping profiles. Mixed effects models examined the effects of cluster, time, and covariates on health outcomes. Three groups were identified. Burdened caregivers had higher burden and avoidance coping levels, and lower mastery and social support than effective and stigmatized caregivers; stigmatized caregivers reported the highest perceived stigma (p< 0.05). Effective and stigmatized groups had better health outcomes and less service use than the burdened group over time; stigmatized caregivers had poorer self-care than effective caregivers. Cluster analysis is a promising method for identifying subgroups of caregivers with different stress and coping profiles associated with different health-related outcomes.

Few controlled studies are available to guide the clinician in treating potentially assaultive elderly individuals with psychiatric disorders. Safety concerns limit the use of benzodiazepines and antipsychotic medications in the elderly individual, making anticonvulsants an attractive alternative. This paper reviews three specific anticonvulsants for this purpose: gabapentin, oxcarbazepine and topiramate, describing safety and efficacy in elderly patients with severe agitation from psychosis or dementia. Gabapentin, renally excreted, with a half-life of 6.5 – 10.5 h, may cause ataxia. Oxcarbazapine, hepatically reduced, may cause hyponatremia, and topiramate may cause significant cognitive impairment. Nonetheless, these are important medications to consider in the treatment of agitation.

The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hocanalysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mgday (n180), quetiapine 300 mgday (n181), or placebo (n181). Number needed to treat, time to response (≥50 reduction from baseline in Montgomery–Asberg Depression Rating Scale total score) and time to remission (Montgomery–Asberg Depression Rating Scale total score ≤12) were evaluated. Response rates at week 8 were 58.2 and 57.6 for quetiapine 600 and 300 mgday, respectively, and 36.1 for placebo (P<0.001). Remission rates were 52.9 for both quetiapine groups and 28.4 for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mgday) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mgday than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mgday 2.2, quetiapine 300 mgday 3.9, and placebo 3.9). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.

ABSTRACTObjective:To assess the perceptions of clinicians in the psychiatric community about pharmacotherapy and its impact on weight gain and adverse metabolic effects in patients with bipolar disorder.Methods:In November 2005, self-administered questionnaires were sent to 7000 psychiatrists who treat bipolar disorder in their clinical practice. An additional mailing of these questionnaires was sent in January 2006 to a different group of 7000 psychiatrists who treat bipolar disorder in their clinical practice. The first 298 completed surveys were analyzed.Results:Almost half of the respondents (48%) were psychiatrists in individual private practice and 32% were in community mental health centers. About two-thirds of respondents reported that 30–60% of their bipolar patients were overweight. Thirty-eight percent of respondents reported metabolic syndrome present in 20–40% of their patients. Almost all respondents (96%) reported a 20 lb increase in patients’ weight as a troublesome potential adverse event associated with the use of some agents. After initiating a new medication, more than 80% of respondents monitored their patients’ weight, fasting plasma glucose level, and fasting lipid profile at regular intervals. However, 80% did not monitor waist circumference. Overall, respondents viewed several agents (aripiprazole, ziprasidone, carbamazepine, and lamotrigine) as not (or minimally) problematic in terms of weight gain and adverse metabolic concerns. Clozapine and olanzapine were viewed as highly problematic due to their propensity to induce weight gain and negatively influence lipid and glucose metabolism. Other agents considered to be minimally to moderately problematic in terms of weight gain and metabolic issues were quetiapine, risperidone, lithium, and valproate. Respondents reported that the profile of a bipolar agent in terms of weight gain and adverse metabolic effects was an important consideration in the management of bipolar disorder.Conclusion:Although the study is limited by a low response rate and self-selection of respondents, clinicians who did respond were concerned about the risks of weight gain and metabolic disturbances in their patients treated with bipolar agents. For most parameters, such concerns were being integrated into clinical care. However, it appears that there is a need to increase clinicians’ appreciation of the importance of abdominal obesity and the need to monitor waist circumference. A growing recognition of the differences in weight-gain potential and adverse metabolic effects among agents appears to have had a definite impact on prescribing patterns in the management of bipolar disorder.

ABSTRACTAntiepileptic drugs (AEDs) have diverse psychotropic profiles. Some AEDs have proven to be efficacious in the treatment of mood disorders, especially bipolar disorder. Others are ineffective as primary treatments but may be useful adjuncts for mood disorders or comorbid conditions. Valproate (acute mania and mixed episodes), carbamazepine (acute mania and mixed episodes), and lamotrigine (maintenance to delay recurrence) have United States Food and Drug Administration indications for the treatment of bipolar disorder. This article provides an overview of data on the use of AEDs in bipolar disorder, including acute mania and depression, prophylaxis, and rapid cycling.

The authors review current research on the safety and tolerability of anticonvulsant medications used for individuals over the age of 60 years with affective disorders, agitation and other psychiatric disorders. Three anticonvulsants currently approved in the US for treatment of bipolar affective disorder are reviewed: valproate, lamotrigine and extended-release carbamazepine. The authors discuss the pharmacokinetics, pharmacodynamics, drug–drug interactions and the impact of ageing for each drug. There are few studies of anticonvulsant medications in elderly patients with bipolar disorder or other psychiatric conditions. Therefore, the authors summarise adverse events of greatest prevalence and/or greatest severity based on data derived predominately from studies of geriatric patients with epilepsy and/or other non-psychiatric indications. Guidelines are offered for the safe use of these medications in the elderly, based on research literature.

Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.

This discussion focuses on the historical trends of carbamazepine in the treatment of acute mania, acute bipolar depression, and as maintenance treatment for bipolar disorder. Clinical implications of efficacy, safety, tolerability, and drug interactions associated with carbamazepine are discussed as well.Important progress in bipolar disorders therapeutics began in the 1970s with lithium and the conventional antipsychotics, and continued in the 1980s with carbamazepine, in the 1990s with divalproex, and in the 2000s with lamotrigine and the introduction of the atypical antipsychotics. Electroconvulsive therapy (ECT) has been used throughout these periods and still has a place in bipolar disorder, especially for severe, treatment-resistant, and very acute cases.

Although patients with bipolar disorder have been shown to benefit from psychosocial interventions, the proportion that utilizes these interventions is unknown. We set out to clarify the determinants of psychosocial service utilization in adults with bipolar disorder.

ABSTRACTTherapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect ?-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

Children and adolescents who are the biological offspring of individuals with bipolar disorder (BD) (bipolar offspring) represent a population rich in potential for revealing important aspects in the development of BD. Multiple cross-sectional assessments of psychopathology in bipolar offspring have confirmed high incidences of BD, as well as mood and behavioral disorders, and other psychopathology in this population. Longitudinal studies of offspring have begun to shed light on precursors of BD development. Other assessments of bipolar offspring have included dimensional reports of psychiatric and psychosocial functioning, temperament assessments, and descriptions of family environments and parenting styles. Neurobiological studies in bipolar offspring are just beginning to yield findings that may be related to the underlying neuropathophysiology of BD. The future holds promise for longitudinal studies of bipolar offspring incorporating all of these facets, including genetic analyses, to further elucidate the factors involved in the evolution of BD. © 2003 Wiley-Liss, Inc.

Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may “stabilize mood from below,” as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust γ-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine’s distinctive psychotropic profile.

Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 ± 128 mg for LTG and 3,987 ± 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q= 6.952, df= 2, N = 31, p= 0.031). Post hoc Qdifferences (df= 1, N = 31) were the following: LTG versus GBP (Qdiff= 5.33, p= 0.011); LTG versus PLC (Qdiff= 4.76, p= 0.022); and GBP versus PLC (Qdiff= 0.08, p= 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

We propose a new algorithm to find the corpus callosum automatically from midsagittal brain MR (magnetic resonance) images using the statistical characteristics and shape information of the corpus callosum. We first extract regions satisfying the statistical characteristics (gray level distributions) of the corpus callosum that have relatively high intensity values. Then we try to find a region matching the shape information of the corpus callosum. In order to match the shape information, we propose a new directed window region growing algorithm instead of using conventional contour matching. An innovative feature of the algorithm is that we adaptively relax the statistical requirement until we find a region matching the shape information. After the initial segmentation, a directed border path pruning algorithm is proposed in order to remove some undesired artifacts, especially on the top of the corpus callosum. The proposed algorithm was applied to over 120 images and provided promising results. © 2000 Society of Photo-Optical Instrumentation Engineers.

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug–drug interactions. 2. CBZ has multiple problematic drug–drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug–drug interactions, while the renally excreted gabapentin lacks hepatic drug–drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

Background: Several studies have demonstrated that transient self-induced sadness activates anterior paralimbic structures. To further examine the specificity of these findings and the neural substrates involved in anger and anxiety, we studied the neural correlates of the induction of anxiety and anger in healthy adults.

Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion.When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91 +/- 3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19 +/- 2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmaxwas 0.69 +/- 0.13 mmol/L for gabapentin patients and did not differ from the mean Li Cmaxof 0.72 +/- 0.15 mmol/L for placebo patients. The mean serum Li Tmaxwas 1.38 +/- 0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li T (max) of 1.5 +/- 0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder. (J Clin Psychopharmacol 1998;18:461-464)

AbstractDepressed subjects have deficits in facialemotion recognition that resemble the deficits found in persons with focal right hemisphere brain damage. To locate the brain regions responsible for this problem, the authors imaged regional cerebral blood flow (rCBF) with H2O15positron emission tomography in 10 mood-disordered patients, as well as in 10 age- and sex-matched healthy comparison subjects, while the subjects matched photographs for facial emotion or, as a control, facial identity. While matching faces for emotion, mood-disordered subjects had decreased rCBF activation bilaterally in their temporal lobes, as well as in the right insula, compared with healthy comparison subjects. Abnormal function of limbic and paraiimbic regions may partially explain the facial emotion-recognition deficits previously noted in depressed subjects.

BACKGROUND: Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability. METHODS: Eight medication-free inpatients with refractory depression received 500 μg of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a doubleblind crossover design. RESULTS: Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P&lt;.05). Responses were rapid and clinically robust, but shortlived. CONCLUSION: Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

BACKGROUND: Procaine activates limbic structures in animals. In humans, acute intravenous administration of procaine yields emotional and psychosensory experiences and temporal lobe fast activity. We studied procaine's acute effects on cerebral blood flow (CBF) in relationship to clinical responses. METHODS: Cerebral blood flow was assessed by positron emission tomography with oxygen-15—labeled water in 32 healthy volunteers. Data were analyzed with statistical parametric mapping and magnetic resonance imaging—directed regions of interest. RESULTS: Procaine increased global CBF and, to a greater extent, anterior paralimbic CBF. Subjects with intense procaine-induced fear compared with those with euphoria had greater increases in left amygdalar CBF. Absolute and normalized left amygdalar CBF changes tended to correlate positively with fear and negatively with euphoria intensity. Procaine-induced visual hallucinations appeared associated with greater global and occipital CBF increases. Absolute occipital CBF increases appeared to correlate positively with visual hallucination intensity. CONCLUSIONS: Procaine increased anterior paralimbic CBF, and different clinical responses appeared to be associated with different patterns of CBF changes.

Carbamazepine and valproic acid are anticonvulsants with mood-stabilizing properties. Basic and clinical research suggest that these medications used together may have synergistic anticonvulsant effects. Psychotropic synergy of the combination has yet to be explored systematically. We present the case of a patient with rapid-cycling bipolar disorder studied under double-blind conditions whose hypomanias and depressions were refractory to either carbamazepine or valproic acid alone, but responded dramatically to the combination. The superior response to the combination appeared to be due to pharmacodynamic rather than pharmacokinetic effects. The clinical and theoretical aspects of the use of carbamazepine and valproic acid in combination are discussed.

To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 in-patients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis. (J Clin Psychopharmacol 1992;12:431–437)

Converging evidence points to hypofunction of the left prefrontal cortex in depression. Repetitive transcranial magnetic stimulation (rTMS) activates neurons near the surface of the brain. We questioned whether daily left prefrontal rTMS might improve mood in depressed subjects and report a pilot study of such treatment in six highly medication-resistant depressed inpatients. Depression scores significantly improved for the group as a whole (Hamilton Depression Scores decreased from 23.8 ± 4.2 (s.d.) at baseline to 17.5 ± 8.4 after treatment; t 3.03, 5DF, p0.02, two-tailed paired t-test). Two subjects showed robust mood improvement which occurred progressively over the course of several weeks. In one subject, depression symptoms completely remitted for the first time in 3 years. Daily left prefrontal rTMS appears to be safe, well tolerated and may alleviate depression.

BACKGROUND: Defects in expressing or understanding the affective or emotional tone of speech (aprosodias) have been associated with right hemisphere dysfunction, while defects of propositional language have been linked to left hemisphere disease. The brain regions involved in recognition of emotional prosody in healthy subjects is less clear. OBJECTIVES: To investigate the brain regions involved in understanding emotional prosody and to determine whether these differ from those involved in understanding emotion based on propositional content. METHODS: We studied 13 healthy subjects using water labeled with radioactive oxygen 15 and positron emission tomography while they listened to 3 similar sets of spoken English sentences. In different tasks, their responses were based on the emotional propositional content, on the emotional intonation of the sentence (prosody), or on their ability to repeat the second word in the sentence (control). RESULTS: Understanding propositional content activated the prefrontal cortex bilaterally, on the left more than on the right. In contrast, responding to the emotional prosody activated the right prefrontal cortex. CONCLUSION: Neurologically healthy subjects activate right hemisphere regions during emotional prosody recognition.

• Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

The short form of the group climate questionnaire (GCQ-S) was used to evaluate process in three 12-session therapy groups for outpatient schizophrenics. Results showed no difference on the Engaged dimension between the short-term schizophrenic groups and either a normative sample of outpatient neurotic groups or the first 26 sessions of a long-term outpatient schizophrenic group. However, the short-term groups scored significantly lower (p<.001) on the Avoiding and Conflict dimensions as compared with either long-term sample. The session-to-session GCQ-S dimension pattern did not support the presence of sequential group stages, but there was a tendency for the Engaged scores to increase and the Avoiding and Conflict scores to decrease as time went on.

Summary Previous independent EEG and PET studies suggest that administration of intravenous procaine hydrochloride selectively activates limbic brain structures. To further elucidate procaine's effects and explore the relationship between quantitative EEG (qEEG) and regional cerebral blood flow (rCBF), we simultaneously recorded qEEG and sampled rCBF using O-15 water PET in 20 healthy volunteers during single-blind injections of saline (baseline condition) followed by intravenous procaine (1.84 mg/kg). After thorough screening of EEG records, a subgroup of 7 subjects with EEG data relatively free of both muscle and movement artifacts was selected for analysis. Quantitative spectral EEG data from right occipital and temporal leads were then correlated with each subject's PET rCBF values on a pixel by pixel basis, both at baseline and after procaine. The most striking finding was that the increases in occipital and temporal omega activity from baseline to procaine positively correlated with rCBF increases in the amygdala and its efferents (p<.05), in a pattern very similar to the rCBF increases seen after procaine administration. This suggests that omega activity may reflect activation of deeper brain limbic structures. Also, the convergence of EEG and PET data further supports procaine's selective limbic activation.

For more than a century, mesial cerebral structures have been candidate substrates for the mediation of emotional experience. Although limbic structures were originally conceived as forming a midline ring, emerging evidence suggests that emotional processes may be related more closely to anterior paralimbic (anterior limbic and nearby cortical) regions than to posterior limbic regions. In addition, basal ganglia-thalamocortical circuits for various cerebral processes have been proposed, including one involving anterior paralimbic structures thought to mediate emotion. Recent brain imaging studies have advanced this thesis by demonstrating anterior paralimbic activation during affective arousal in healthy volunteers. The overwhelming majority of functional imaging studies of both primary and secondary depression has demonstrated decreased anterior paralimbic and prefrontal cortical activity, the latter of which often correlated with severity of depression and resolved with symptom remission. A few studies have noted increased activity in these same regions, which may reflect heterogeneity due to particular illness subtypes. Preliminary evidence has suggested that baseline functional abnormalities in these structures may relate to diagnostic subtypes and provide differential markers of therapeutic responses. New imaging methods with greater sensitivity, spatial and temporal resolution, and biochemical specificity promise to fuel further insights into the neurobiology of normal emotion in health, subtypes of affective disorders, and perhaps even improved targeting of therapeutic interventions.

GABABmechanisms have been implicated in the antinociceptive, but not anti-consvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABABreceptors after chronic administration. The GABABagonist I-baclofen was studied in depressed patients based on two separate rationales. I-Baclofen. in doses ranging from 10–55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response. while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdraw if. These preliminary data suggest that GABABagonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABABreceptors in brain follow Mg chronic administration, suggest that GABABantagonism rather than agonism may be a fruitful clinical strategy to explore in depression.