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Introduction: Untreated bipolar disorder in pregnancy is associated with adverse maternal and neonatal outcomes. Despite advances in clinical management, there is concern among obstetric providers and patients about the safety of pharmacological agents for the treatment of bipolar disorder in pregnancy. Recent studies have shown atypical antipsychotics and lamotrigine to have a favorable safety profile; however, little information is published on lurasidone. Objectives: The objective of this retrospective chart review was to evaluate pregnancy and neonatal outcomes in obstetric patients with bipolar disorder who are untreated, compared to those treated with lurasidone, other atypical antipsychotics, and lamotrigine at a tertiary teaching institution. Methods: This retrospective cohort study included neonates whose mothers had a diagnosis of bipolar disorder and were referred to the Maternal & Fetal Care Clinic with two documented visits after January 1, 2014, with delivery by October 31, 2017, within an SSM health‐system hospital. Results: In this study, women with untreated bipolar disorder (not on any mood stabilizer) in pregnancy had significantly higher rates of premature delivery and low birth weight compared to women on mood stabilizers of lamotrigine, lurasidone, and other atypical antipsychotics. No difference was observed for pregnancy or neonatal outcomes between patients taking any of the mood stabilizers. Conclusions: This study suggests that the use of lurasidone, other atypical antipsychotics, and lamotrigine have better neonatal outcomes than untreated bipolar disorder in pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Few studies have addressed medication adherence in adolescents and young adults (AYAs) with bipolar disorder (BD). This 6‐month prospective randomized‐controlled trial (RCT) tested customized adherence enhancement for adolescents and young adults (CAE‐AYA), a behavioral intervention for AYAs versus enhanced treatment as usual (ETAU). Methods: Inclusion criteria were AYAs age 13–21 with BD type I or II with suboptimal adherence defined as missing ≥20% of medications. Assessments were conducted at Screening, Baseline, and weeks 8, 12 and 24. Primary outcome was past 7 day self‐reported Tablets Routine Questionnaire (TRQ) validated by electronic pillbox monitoring (SimpleMed). Symptom measures included the Hamilton Depression Rating Scale (HAM‐D) and Young Mania Rating Scale (YMRS). Results: The mean sample age (N = 36) was 19.1 years (SD = 2.0); 66.7% (N = 24) female, BD Type I (81%). The mean missed medication on TRQ for the total sample was 35.4% (SD = 28.8) at screening and 30.4% (SD = 30.5) at baseline. Both CAE‐AYA and ETAU improved on TRQ from screening to baseline. Baseline mean missed medication using SimpleMed was 51.6% (SD = 38.5). Baseline HAM‐D and YMRS means were 7.1 (SD = 4.7) and 6.0 (SD = 7.3), respectively. Attrition rate at week 24 was 36%. Baseline to 24‐week change on TRQ, adjusting for age, gender, educational level, living situation, family history, race, and ethnicity, showed improvement favoring CAE‐AYA versus ETAU of 15%. SimpleMed interpretation was limited due to substantial missing data. There was a significant reduction in depression favoring CAE‐AYA. Conclusions: CAE‐AYA may improve adherence in AYAs with BD, although conclusions need to be made cautiously given study limitations. Clinical Trials Registration: ClinicalTrials.gov identifier: NCT04348604. [ABSTRACT FROM AUTHOR]

Background: Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20‐year period. Methods: We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran–Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20‐year period. Results: Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20‐year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20‐year period. Conclusions: Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic‐induced constipation. [ABSTRACT FROM AUTHOR]

Objectives: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well‐characterized individuals with BD in North America, Europe, and Australia. Methods: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta‐analyses with generalized linear mixed methods were conducted to identify prescription patterns. Results: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD‐I (60%; vs. BD‐II = 33%). Cross‐sectionally, mood‐stabilizing anticonvulsants (44%), second‐generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First‐generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD‐II (47%) compared to BD‐I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. Conclusions: Mood‐stabilizing anticonvulsants, second‐generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first‐generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence‐based guidelines to help improve treatment practices in BD. [ABSTRACT FROM AUTHOR]

Introduction: The management of pediatric bipolar disorder (PBD) requires pharmacotherapy to control acute symptoms, reduce relapse, prevent suicide, and improve psychosocial functioning. The purpose of this study was to investigate prescribing patterns among PBD patients discharged from two public mental hospitals in Taiwan, from 2006 to 2019. Methods: PBD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 420), were included in the analysis. Prescribed drugs at discharge, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second‐ and first‐generation antipsychotics, SGAs and FGAs), and antidepressants, were explored. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Time trends of each prescribing pattern were analyzed using the Cochran‐Armitage Trend test. Results: The most commonly prescribed psychotropic agents were SGAs (76.0%), followed by valproate (65.7%) and FGAs (24.8%). The prescription rates of SGAs, antidepressants, antidepressant plus antipsychotic, and antidepressant without mood stabilizer significantly increased over time, whereas the prescription rates of mood stabilizers, lithium, and FGAs significantly decreased. Discussions: Prescribing patterns changed greatly for PBD patients over time. However, much more evidence supporting the effectiveness of psychotropic agents in PBD patients is required. [ABSTRACT FROM AUTHOR]

Objectives: People with bipolar disorder have an elevated risk of mortality. This study evaluated associations between the use of mood stabilizers and the risks of all‐cause mortality, suicide, and natural mortality in a national cohort of people with bipolar disorder. Methods: In this nationwide cohort study, we used data from January 1, 2000, to December 31, 2016, collected from Taiwan's National Health Insurance Research Database and included 25,787 patients with bipolar disorder. Of these patients, 4000 died during the study period (including 760 and 2947 from suicide and natural causes, respectively). Each standardized mortality ratio (SMR) was calculated as the ratio of observed mortality in the bipolar cohort to the number of expected deaths in the general population. Multivariable Cox proportional hazards regression with a time‐dependent model was performed to estimate the hazard ratio (HR) of each mood stabilizer with each mortality outcome. Results: The SMRs of all‐cause mortality, suicide, and natural mortality in the bipolar disorder cohort were 5.26, 26.02, and 4.68, respectively. The use of mood stabilizers was significantly associated with decreased risks of all‐cause mortality (adjusted HR [aHR] = 0.58, p< 0.001), suicide (aHR = 0.60, p < 0.001), and natural mortality (aHR = 0.55, p < 0.001) within a 5‐year follow‐up period after index admission. Among the individual mood stabilizers, lithium was associated with the lowest risks of all‐cause mortality (aHR = 0.38, p < 0.001), suicide (aHR = 0.39, p < 0.001), and natural mortality (aHR = 0.37, p < 0.001). Conclusion: In addition to having protective effects against suicide and all‐cause mortality, mood stabilizers also exert a substantial protective effect against natural mortality, with lithium associated with the lowest risk of mortality. [ABSTRACT FROM AUTHOR]

Objective: Medications for the treatment of bipolar disorder (BD) could affect patients' cognitive function. Patients with BD present with neurocognitive impairment even in a remission state. Little research is available on the daily functioning, especially driving performance, of stable outpatients with BD under pharmacological treatment. Methods: In total, 58 euthymic outpatients with BD undergoing real‐world pharmacotherapy and 80 sex‐ and age‐matched healthy controls (HCs) were enrolled. Three driving tasks using a driving simulator—road‐tracking, car‐following, and harsh‐braking—and three cognitive tasks—Continuous Performance Test, Wisconsin Card Sorting Test, and Trail‐Making Test—were evaluated. Symptom assessment scales—Young Mania Rating Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory‐II, Social Adaptation Self‐evaluation Scale, and Stanford Sleepiness Scale—were also completed. Results: Car‐following and road‐tracking performance were significantly impaired in patients with BD compared with HCs after adjusting for demographic variables, but these performances generally overlapped. Broad neurocognitive functions were significantly lower in the patients with BD compared to HCs, but car‐following performance was significantly negatively correlated with sustained attention only. Although most patients received multiple medications rather than monotherapy, no relationship between prescriptions and driving performance was found. Conclusion: Euthymic patients with BD under steady‐state pharmacotherapy had impaired driving performance compared with HCs, but the overlapping distributions of driving performance suggested that driving performance is not always deteriorated in patients with BD. Therefore, attentional function may be a useful clinical feature for judging driving aptitude in patients with BD. [ABSTRACT FROM AUTHOR]

Aims: Patients with brain diseases have been associated with several retinal abnormalities. This study aimed to assess the risk of retinal diseases in patients with bipolar disorder (BD). Methods: This nationwide cohort of 73,271 patients with BD was enrolled between 2001 and 2009. To identify newly diagnosed retinal diseases, the patients were followed to the end of 2011. The control group included 293,084 patients, matched for demographic characteristics and medical and ophthalmological comorbidities. The Kaplan–Meier method was used to estimate incidence rates of retinal diseases. Cox regression was applied to calculate the hazard ratios (HRs) with 95% confidence intervals (CIs) after adjusting for confounders. Results: Patients with BD had higher incidence rates of any retinal disease than the controls (1.27% vs 0.48%, P < 0.001), and retinal diseases were diagnosed at a young age (54.23 years [±12.68 years] vs 57.01 years [±13.12 years], P < 0.001). After adjusting for demographic characteristics, physical and ophthalmological comorbidities, and medications, the HR was 3.24 (95% CI, 2.18–4.82) for retinal detachment, 2.35 (95% CI, 1.83–3.03) for primary retinopathy, 2.26 (95% CI, 1.91–2.68) for diabetes retinopathy, 2.39 (95% CI, 1.49–3.82) for hypertensive retinopathy, and 3.46 (95% CI, 2.45–4.89) for retinal vascular complications in patients with BD vs controls. The cumulative daily dose of bipolar medications was not associated with the incidence of any retinal disease. Conclusion: Patients with BD were associated with a higher risk of retinal detachment, primary retinopathy, diabetes retinopathy, hypertensive retinopathy, and retinal vascular complications than the controls. Further studies are needed to examine the mechanisms mediating these retinal diseases in patients with BD. [ABSTRACT FROM AUTHOR]

Objective: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case‐control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics. Methods: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five‐year lag time and diagnosis of dementia was assessed by conditional logistic regression models. Results: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First‐ and second‐generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06–3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10–2.67; p = 0.02 and OR 1.84; 1.03–3.32; p = 0.04, respectively). Conclusion: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them. [ABSTRACT FROM AUTHOR]

Objectives: A systematic review and meta‐analysis of double‐blind, randomized placebo‐controlled trials were conducted to examine how soon an increase in recurrence risk could be observed among bipolar I disorder (BDI) patients who were clinically stable with the combination therapy of mood stabilizers with second‐generation antipsychotics (SGA+MS) treatment following second‐generation antipsychotics discontinuation (i.e., MS alone) compared with SGA+MS maintenance. Methods: Embase, PubMed, and CENTRAL databases were used for systematic literature searches until May/22/2020. The primary outcome was the recurrence rate of any mood episode at 6 months. The secondary outcomes were the recurrence rates of manic/hypomanic/mixed and depressive episodes and all‐cause discontinuation at 6 months. The recurrence rates at 1, 2, 3, 9, and 12 months were also investigated. Results: Eight studies (mean study duration = 58.25 ± 33.63 weeks) were identified (SGA+MS group [n = 1,456: 3 aripiprazole+MS studies, 1 lurasidone+MS study, 1 olanzapine+MS study, 2 quetiapine+MS studies, 1 ziprasidone+MS study] and placebo+MS group [n = 1,476]). Pooled SGA+MS exhibited lower recurrence rates of any mood episode, manic/hypomanic/mixed episodes, and depressive episodes as well as reduced all‐cause discontinuation at every observational point. The risk ratios (95% confidence interval) of the recurrence rate at 6 months were 0.51 (0.39–0.86) for any mood episode, 0.42 (0.30–0.59) for manic/hypomanic/mixed episodes, and 0.39 (0.28–0.54) for depressive episodes. The RR for all‐cause discontinuation was 0.67 (0.50–0.89). Both aripiprazole+MS and quetiapine+MS outperformed placebo+MS in the recurrence of any mood, manic/hypomanic/mixed, and depressive episodes at 6 months. Conclusions: SGA+MS prevented recurrence for up to 12 months for BDI compared with placebo+MS. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) poses a significant public health concern, with roughly one‐quarter of sufferers attempting suicide. BD is characterized by manic and depressive mood cycles, the recurrence of which can be effectively curtailed through lithium therapy. Unfortunately, the most frequently employed lithium salt, lithium carbonate (Li2CO3), is associated with a host of adverse health outcomes following chronic use: these unwanted effects range from relatively minor inconveniences (e.g., polydipsia and polyuria) to potentially major complications (e.g., hypothyroidism and/or renal impairment). As these undesirable effects can limit patient compliance, an alternative lithium compound with a lesser toxicity profile would dramatically improve treatment efficacy and outcomes. Lithium orotate (LiC5H3N2O4; henceforth referred to as LiOr), a compound largely abandoned since the late 1970s, may represent such an alternative. LiOr is proposed to cross the blood–brain barrier and enter cells more readily than Li2CO3, which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns. This review addresses the controversial history of LiOr, complete with discussions of experimental and clinical efficacy, putative mechanisms of action, adverse effects, and its potential future in therapy. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to describe the pre‐diagnostic and post‐diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. Methods: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. Results: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%‐90% of the patients received any psychotropic drug while 12%‐26% received treatment with an antidepressant without overlapping treatment with a mood‐stabilizing drug. Conclusion: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment‐resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood‐stabilizing properties are concerning. [ABSTRACT FROM AUTHOR]

Objective: In this paper, we aimed at reviewing evidence‐based treatment options for bipolar mania and proposed tentative evidence‐based clinical suggestions regarding the management of a manic episode, especially regarding the choice of the proper mood stabilizer and antipsychotic medication. Method: A narrative review was undertaken addressing 'treatment of bipolar mania'. Findings have been synthesized and incorporated with clinical experience into a model to support different treatment choices. Results: To date, there is solid evidence supporting the use of several medications, such as lithium, divalproex, and carbamazepine, and antipsychotics, such as chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, inhaled loxapine, asenapine, and cariprazine in acute mania, and some evidence supporting the use of clozapine or electroconvulsive therapy in treatment‐refractory cases. However, in clinical practice, when making decisions about treatment, personalized treatment is needed, according to the different clinical presentations and more complex clinical situations within the manic episode and considering a long‐term view and with the objective of not only a symptomatic but also functional recovery. After remission from acute mania, psychoeducation strategies are useful to ensure adherence. Discussion: Despite the evidence forefficacy of many currently available treatments for mania, the majority of RCTs provide little direction for the clinician as to what steps might be optimal in different presentations of mania as well as in the presence of specific patient characteristics. Manic episodes should be managed on a personalized basis considering the clinical course and patient criteria and with the expectation of maintaining that treatment in the long‐term. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: For the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and in combination. Methods: As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non‐randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy. Results: In eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not. Conclusions: The results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register‐based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: We aimed to investigate the characteristics of pregnant women who required either mood stabilizer or antipsychotic treatment. These women requiring such treatment are likely to be more mentally unwell and thus carry a higher burden of comorbidities associated with poor pregnancy outcomes. Methods: This retrospective review investigated the common characteristics of pregnant women who were prescribed with antipsychotics or mood stabilizers under a major city's public maternal mental health service. Demographic data, pregnancy factors and prenatal care, stressors and support, concurrent medical and substance abuse problems, and ongoing maternal mental health issues were recorded. Results: Most pregnancies were unplanned. Commonly, social stressors, medical problems, and substance use were identified. The most common diagnosis was bipolar disorder. Discussion: Pregnant women requiring treatment with mood stabilizers or antipsychotics are a complex clinical population, with multiple risk factors for negative pregnancy outcome, before even considering the potential risk from psychotropic agents and mental illness itself. Obtaining reliable data about substance use and medication compliance remains problematic. [ABSTRACT FROM AUTHOR]

Study Objective: Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform–specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy. Design: Cross‐sectional observational study. Setting: Clinical research services center at an academic center. Patients: Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months. Interventions: A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75‐g oral glucose tolerance test. Measurements and Main Results: Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation‐sensitive high‐resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed. Conclusion: Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Objectives We examined differences in treatment outcome between Diagnostic and Statistical Manual Fourth Edition (DSM-IV)-defined rapid cycling and average lifetime-defined rapid cycling in subjects with bipolar II disorder. We hypothesized that, compared with the DSM-IV definition, the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment. Methods Subjects ≥18 years old with a bipolar II major depressive episode (n=129) were categorized into DSM-IV- and average lifetime-defined rapid cycling and prospectively treated with either venlafaxine or lithium monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. Results These exploratory analyses found moderate agreement between the two rapid-cycling definitions (κ=0.56). The lifetime definition captured subjects with more chronic courses of bipolar II depression, whereas the DSM-IV definition captured subjects with more acute symptoms of hypomania. There was no difference between rapid-cycling definitions with respect to the response to acute venlafaxine or lithium monotherapy. However, the lifetime definition was slightly superior to the DSM-IV definition in identifying subjects who went on to experience hypomanic symptoms during continuation therapy. Conclusions Although sample sizes were limited, the findings suggest that the lifetime definition of rapid cycling may identify individuals with a chronic rapid-cycling course and may also be slightly superior to the DSM-IV definition in identifying individuals with hypomania during relapse-prevention therapy. These findings are preliminary in nature and need replication in larger, prospective, bipolar II studies. [ABSTRACT FROM AUTHOR]

Objectives This analysis of screening and baseline data from an ongoing trial examined self-report versus automated adherence monitoring and assessed the relationship between bipolar disorder (BD) symptoms and adherence in 104 poorly adherent individuals. Methods Adherence was measured with the Tablets Routine Questionnaire (TRQ) and the Medication Event Monitoring System (MEMS). Symptoms were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Brief Psychiatric Rating Scale (BPRS). Results The mean age of the sample was 46.3 years [standard deviation (SD) = 9.41 years], with 72% (n = 75) women and 71% (n = 74) African American subjects. Adherence improved from screening to baseline, with a mean missed drug proportion measured by TRQ of 61.43% (SD = 26.48%) versus a baseline mean of 46.61% (SD = 30.55%). The mean proportion of missed medication using MEMS at baseline was 66.43% (SD = 30.40%). The correlation between TRQ and MEMS was 0.47. The correlation between a single index drug and all BD medications was 0.95. Symptoms were generally positively correlated with TRQ (worse adherence = more severe symptoms), but in most instances was only at a trend level (p > 0.05), with the exception of the correlations between baseline TRQ and MADRS and BPRS, which were positive ( r = 0.20 and r = 0.21, respectively) and significant (p ≤ 0.05). Conclusions In patients with BD, monitoring increased adherence by 15%. MEMS identified 20% more non-adherence than self-report. Using a standard procedure to identify a single index drug for adherence monitoring may be one way to assess global adherence in patients with BD receiving polypharmacy treatment. Greater BD symptom severity may be a clinical indicator to assess for adherence problems. [ABSTRACT FROM AUTHOR]

Background Optimal successive treatment decisions are not well established after an initial medication nonresponse in major depressive disorder or bipolar disorder. While practice guidelines offer consensus-based expert treatment recommendations, little is known about "real world" pharmacology decision making by practicing psychopharmacologists. Materials and Methods We surveyed via Internet the national membership of the American Society of Clinical Psychopharmacology (ASCP) to study preferred pharmacotherapy strategies and factors that influence medication choices for patients with mood disorders. Results Surveys were returned by 154/752 ASCP members (21%). After nonresponse to a serotonin reuptake inhibitor in major depressive disorder, participants equally favored switching within or across antidepressant classes. After a partial response, adjunctive bupropion was the preferred intervention, followed by changing antidepressant classes. Atypical antipsychotic augmentation was only a fourth-line consideration, even though moderate or marked efficacy was perceived in most instances with olanzapine, aripiprazole, and quetiapine. Respondents favored avoiding antidepressants in bipolar I patients with mixed/cycling features or prior antidepressant-associated mania/hypomania. In rapid cyclers, they advocated antidepressant cessation and preferred the use of atypical antipsychotics and lamotrigine. Conclusions Participating psychopharmacologists treating adults with mood disorders report prescribing medications that largely mirror the evidence base with only a few notable exceptions, in consideration of the characteristics of definable clinical subpopulations. [ABSTRACT FROM AUTHOR]

Objective Valproic acid (VPA), a mood stabilizer used for treating bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant ( Ki) of 25 mM. Inhibition may account for VPA's ability to reduce AA turnover in brain phospholipids of unanesthetized rats and to be therapeutic in BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non-teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4. Methods Rat Acsl4-flag protein was expressed in Escherichia coli. We used Michaelis-Menten kinetics to characterize and quantify the ability of VCD to inhibit conversion of AA to AA-CoA by recombinant Acsl4 in vitro. Results Acsl4-mediated activation of AA to AA-CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM. Conclusions VCD's ability to uncompetitively inhibit AA activation to AA-CoA by Acsl4, at a lower Ki than VPA, suggests that, like VPA, VCD may reduce AA turnover in rat brain phospholipids. If so, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD. [ABSTRACT FROM AUTHOR]

Background Although long-term treatment is a core aspect of the management of children and adolescents with bipolar disorder ( BD), most clinical recommendations are based on results from short-term studies or adult data. In order to guide clinical practice, we review the efficacy and safety profile of mood stabilizers, antipsychotics, and other pharmacological strategies for the long-term treatment of BD in pediatric patients. Methods A MEDLINE, EMBASE, Cochrane and PsycInfo search (inception through November 2013) was performed to identify prospective studies longer than 12 weeks assessing the use of pharmacological strategies for the long-term treatment of BD in pediatric patients (0-18 years of age). Results Four randomized controlled trials ( RCT) [three placebo-controlled (assessing aripiprazole (2) and flax oil), and one head-to-head comparison of lithium vs. divalproex], and thirteen noncontrolled studies (six open-label studies assessing lithium or anticonvulsants, five assessing second-generation antipsychotics ( SGAs) and four assessing combination strategies) were included in the review. Aripiprazole has shown efficacy for relapse prevention in children with pediatric bipolar disorder ( PBD) 4-9 years of age in one placebo-controlled RCT. Positive results have been reported in noncontrolled studies with quetiapine and lithium for relapse prevention, as well as with lithium, quetiapine, ziprasidone, and the combination of risperidone and divalproex or lithium for long-term symptom reduction in PBD. The most frequently reported adverse events in children and adolescents treated with lithium and anticonvulsants are gastrointestinal and neurological, whereas use of SGAs is mainly related to weight gain and sedation. Conclusion According to the limited empirical evidence, aripiprazole can be useful for relapse prevention in children with PBD. Given the lack of consistent efficacy data, clinical decision making should be based on individual clinical aspects and safety concerns. [ABSTRACT FROM AUTHOR]

ABSTRACT Bipolar disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5-HT1A) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5-HT1A levels correlates with antidepressant medication outcome. Forty-one medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode had brain PET scans performed using [11C]WAY-100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BPF (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and nonremitters. Thirty-four patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and nonremitters did not differ in age, sex, or recent medication history with serotonergic medications. Remitters had higher [11C]WAY-100635 BPF across all brain regions compared with nonremitters ( P = 0.02). Higher pretreatment brain 5-HT1A receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment. Synapse 67:773-778, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The Japanese Society of Mood Disorders established a committee for treatment guidelines of mood disorders, which created the first edition of a treatment guideline for bipolar disorders on 10 March 2011. The committee has now created a second edition, which we report here. In creating this treatment guideline, the first step was to have several bipolar disorder specialists review well-conducted studies and meta-analyses. Based on this evidence, and with a consensus among the specialists, treatment procedures that were considered optimal were compiled and the strength of recommendation for each treatment method was determined. The first draft, prepared in this manner, was further revised through a process of critical investigation by all committee members to produce the final edition. [ABSTRACT FROM AUTHOR]

Identifying the biological pathways mediating the action of a therapeutic compound may help the development of more specific treatments while also increasing our understanding of the underlying disease pathology. Salts of the metal lithium are commonly used as a front-line mood stabilizing treatment for bipolar disorder. Lithium's action has been variously linked to inositol phosphate metabolism and the WNT/Glycogen Synthase Kinase 3β (GSK3β)/β-Catenin signalling cascade, but, to date, little is known about which of these provides the principal therapeutic benefit for patients and, more specifically, which constituent genes, through presumed sequence variation, determine differences in patient response to treatment. Here, we describe a functional screen in which SH-SY5Y neuroblastoma cells were randomly mutated through genomic integration of the pMS1 poly A 'gene trap' plasmid vector. Lithium normally induces differentiation of neuroblastoma cells, but a small proportion of mutated cells continued to proliferate and formed colonies. Rapid amplification of cDNA ends (RACE)-PCR was used to identify the 'trapped' gene in each of these lithium-resistant colonies. Heterozygous, gene trap integrations were identified within ten genes, eight of which are likely to produce loss-of-function mutations including MED10, MSI2 and three long intergenic non-coding (LINC) RNAs. Both MED10 and MSI2 have been previously linked with WNT/GSK3β/β-Catenin pathway function suggesting that this is an important mediator of lithium action in this screen. The methodology applied here provides a rapid, objective and economic approach to define the genetic contribution to drug action, but could also be readily adapted to any desired in vitro functional selection/screening paradigm. [ABSTRACT FROM AUTHOR]

Nielsen J, Kane JM, Correll CU. Real-world effectiveness of clozapine in patients with bipolar disorder: results from a 2-year mirror-image study. Bipolar Disord 2012: 14: 863-869. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Clozapine remains the drug of choice for treatment-resistant schizophrenia but the evidence for its use in severe bipolar disorder (BD) remains sparse. Methods: A pharmaco-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine in BD patients (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image design. Results: A total of 21473 patients with a lifetime diagnosis of International Classification of Diseases-10 (ICD-10) BD were identified, of which only 326 (1.5%) were treated with clozapine and were included in the mirror-image analysis. The mean follow-up time was 544 ± 280 days, the mean clozapine dose was 307.4 mg [95% confidence interval (CI): 287.9-328.2], and 39.3% were male. During clozapine treatment, the mean number of bed-days decreased from 177.8 (95% CI: 149.4-211.6) to 34.6 (95% CI: 24.8-48.2) (p < 0.001). The mean number of admissions was reduced from 3.2 (95% CI: 2.9-3.7) to 2.0 (95% CI: 1.6-2.4) (p < 0.001). Overall, 240 patients (73.6%) had reduced bed-days and 130 (39.9%) were not admitted while treated with clozapine. Moreover, the number of psychotropic co-medications was reduced from 4.5 defined daily doses (DDD) (25-75 percentiles: 2.4-8.2) to 3.9 DDD (25-75 percentiles: 2.4-6.1) (p = 0.045). Somatic hospital visits for intentional self-harm/overdose reduced significantly from 8.3% to 3.1% (p = 0.004). However, non-psychotropic co-medication use for medical conditions did not increase; 0.7 DDD (25-75 percentiles: 0.0-2.9) to 0.8 DDD (25-75 percentiles: 0.1-2.89) (p = 0.3). Conclusions: Clozapine use for BD was associated with a significant and clinically relevant reduction in the number of bed-days, psychiatric admissions, psychotropic co-medications, and hospital contact for self-harm/overdose, without increased medical treatments. Clozapine seems to be an appropriate choice for treatment-resistant BD and should be investigated in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Recent data suggest that brain-derived neurotrophic factor ( BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD-I) or type II (BPD-II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ2 = 6.18, df = 2, P = 0.046; allele: χ2 = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64-0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD-I and BPD-II separately. For BPD-I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers ( t = −2.27, df = 144, P = 0.025); for BPD-II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers ( t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD-II patients ( N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD-I and BPD-II. [ABSTRACT FROM AUTHOR]

Malhi GS, Chengappa KNR, Gershon S, Ghaemi SN. Atypical mood stabilizers: a new role for neuroleptics? Bipolar Disord 2011: 13: 583-586. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. [ABSTRACT FROM AUTHOR]

Yu Z, Ono C, Kim HB, Komatsu H, Tanabe Y, Sakae N, Nakayama KI, Matsuoka H, Sora I, Bunney WE, Tomita H. Four mood stabilizers commonly induce FEZ1 expression in human astrocytes. Bipolar Disord 2011: 13: 486-499. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Mood stabilizers influence the morphology, chemotaxis, and survival of neurons, which are considered to be related to the mood-stabilizing effects of these drugs. Although previous studies suggest glial abnormalities in patients with bipolar disorder and an effect of mood stabilizers on certain genes in astrocytes, less is known about the effects of mood stabilizers in astrocytes than in neurons. The present study identifies a common underlying response to mood stabilizers in astrocytes. Methods: Human astrocyte-derived cells (U-87 MG) were treated with the four most commonly used mood stabilizers (lithium, valproic acid, carbamazepine, and lamotrigine) and subjected to microarray gene expression analyses. The most prominently regulated genes were validated by qRT-PCR and western blot analysis. The intercellular localization of one of these regulated genes, fasciculation and elongation protein zeta 1 (FEZ1), was evaluated by immunofluorescence staining. Results: The microarray data indicated that FEZ1 was the only gene commonly induced by the four mood stabilizers in human astrocyte-derived cells. An independent experiment confirmed astrocytic FEZ1 induction at both the transcript and protein levels following mood stabilizer treatments. FEZ1 localized to the cytoplasm of transformed and primary astrocytes from the human adult brain. Conclusions: Our data suggest that FEZ1 may play important roles in human astrocytes, and that mood stabilizers might exert their cytoprotective and mood-stabilizing effects by inducing FEZ1 expression in astrocytes. [ABSTRACT FROM AUTHOR]

Sajatovic M, Gildengers A, Al Jurdi RK, Gyulai L, Cassidy KA, Greenberg RL, Bruce ML, Mulsant BH, Ten Have T, Young RC. Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report. Bipolar Disord 2011: 13: 294-302. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. This is a multisite, 12-week, open-label trial of lamotrigine augmentation in 57 older adults (≥ 60 years; mean ± SD age = 66.5 ± 6.7 years) with either type I or type II bipolar depression. Primary outcome measure was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule II (WHO-DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess side effects. A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression. [ABSTRACT FROM AUTHOR]

Ghaemi SN. From BALANCE to DSM-5: taking lithium seriously. Bipolar Disord 2010: 12: 673-677. © 2010 The Author. Journal compilation © 2010 John Wiley & Sons A/S. [ABSTRACT FROM AUTHOR]

Safer DJ. Mood swing and mood stabilizer: how specific are these terms? Bipolar Disord 2010: 12: 685-690. © 2010 The Author. Journal compilation © 2010 John Wiley & Sons A/S. In the DSM-IIIR in 1987, the category title for depressive and bipolar disorders was changed from affective disorders to mood disorders. Within a short period of time thereafter, mood swing and mood stabilizer became very commonly used terms in psychiatry with bipolar implications. Terms and definitions in recent texts, articles, and dictionaries pertaining to mood fluctuations have been reviewed. The term mood was seldom part of psychiatric terminology until the late 1970s. Mood swing and mood stabilizer as used in the psychiatric literature are primarily nonspecific and often misleading concepts-particularly as a basis for treatment decisions. Affective fluctuations and shifts to irritability and/or anger in persons with personality and depressive disorders are being viewed by many in the mental health field as cyclically biphasic-between depressed to elated-which is clearly at variance with research findings. More data-based research on mood variations is needed to authoritatively remedy this situation. [ABSTRACT FROM AUTHOR]

Malhi GS. The king is dead, long live the king! The restoration of BALANCE. Bipolar Disord 2010: 12: 681-684. © 2010 The Author. Journal compilation © 2010 John Wiley & Sons A/S. [ABSTRACT FROM AUTHOR]

Bilszta JLC, Meyer D, Buist AE. Bipolar affective disorder in the postnatal period: investigating the role of sleep. Bipolar Disord 2010: 12: 568–578. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Psychotic disorders have a high rate of relapse in the postpartum period for reasons that are unclear, but may be related to changes in sleep patterns that occur during pregnancy and after birth. Understanding of the influence of sleep on postpartum psychosis presentation is limited. The aim of the current study was to investigate changes in sleep/wake activity during pregnancy and the postpartum period in women with a history of psychosis. Methods: Women with a history of bipolar disorder and/or postpartum psychosis (HxW) were recruited (n = 23) together with a control population (CtW) (n = 15). Data on demographic and psychosocial factors, mental health status, and sleep/wake activity were collected at seven timepoints—the last week of each trimester of pregnancy and four times during the postpartum (weeks 1, 4, and 8, and at month 6). Longitudinal data were analysed using an HLM version 6 repeated-measures multilevel model. Results: No significant differences were noted in sleep/wake activity between HxW and CtW. None of the HxW who were taking a mood stabilizer during their pregnancy, including at delivery, relapsed during the study. Of those taking an antidepressant or antipsychotic, or no medication, 3 relapsed within the first six months and 2 within the first two months. HxW were more likely to report a poor partner relationship than CtW. Conclusion: Results suggest that during the perinatal period, there is no difference in sleep/wake activity in women with a history of a psychotic disorder. Use of mood stabilizer during pregnancy and at delivery appears important in preventing psychotic relapse in the postpartum. [ABSTRACT FROM AUTHOR]

Objective The use of atypical antipsychotics (AAPs) for the treatment of unipolar and bipolar depression has been more and more frequently evaluated, and aripiprazole showed positive effects in the treatment of unipolar depression. However, no placebo-controlled studies of adjunctive aripiprazole for the treatment of bipolar depression have been performed yet. Methods In this prospective, double-blind, placebo-controlled, randomized trial, 23 inpatients with bipolar depression according to DSM-IV criteria were included. Before randomization, patients had to be on a constant mood stabilizer treatment with lithium or valproate for at least 1 week. After inclusion, all patients were openly treated with additional citalopram and with additional aripiprazole or placebo for 6 weeks. The primary outcome parameter was the reduction in depressive symptoms according to the Hamilton Depression Rating Scale (HDRS) within 6 weeks. Results After 6 weeks of treatment, the HDRS score decreased in both groups. There was no significant difference between both the groups at any point of time with respect to the HDRS. Conclusions Derived from this small pilot study, adjunctive aripiprazole does not seem to be a promising strategy for the acute treatment of bipolar depression. However, this lack of additional benefit seems to stem from the already good effectiveness of the control group, namely the treatment with citalopram. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: The goal of the present study was to evaluate the efficacy of risperidone combined with mood stabilizers for treating bipolar mixed state. Methods: The present study was a 24-week, open-label, combination, prospective investigation of the efficacy of risperidone in combination with mood stabilizers. Risperidone (1–6 mg/day) was given in combination with mood stabilizers in flexible doses according to clinical response and tolerability for 114 patients in mixed or manic episode. Results: Forty-four patients met our criteria for mixed state bipolar disorder and 70 met the criteria for pure mania. Mean age for the subjects was 39.0 ± 11.0 years and 55.3% were female. The combination of risperidone with mood stabilizers significantly improved the scores on the Young Mania Rating Scale (YMRS), 17-item Hamilton Rating Scale for Depression (HAMD), 18-item Brief Psychiatric Rating Scale (BPRS), Global Assessment Scale (GAS), and Clinical Global Impression Scale for use in bipolar illness Severity (CGI-BP) at 24 weeks ( P < 0.0001). Analysis of the YMRS, BPRS, GAS, and CGI-BP scores showed significant improvement in both the manic and mixed groups. The rate of response in YMRS scores was 84.2% ( n = 96) and the rate of YMRS remission was 77.2% ( n = 88) at week 24 in the total population. Seventy-four patients met both YMRS ≤ 12 and HAMD ≤ 7 at week 24 (64.9%). Risperidone was well tolerated, and adverse events were mostly mild. Conclusion: The combination of risperidone with mood stabilizers was an effective and safe treatment for manic symptoms and coexisting depressive symptoms of bipolar disorder. [ABSTRACT FROM AUTHOR]

Objective Multiple psychotropic medications are routinely prescribed to treat bipolar disorder, creating complex medication regimens. This study investigated whether the daily number of psychotropic medications or the daily number of pills were associated with self-reported adherence with taking a mood stabilizer. Methods Patients self-reported their mood and medications taken daily for about 6 months. Adherence was defined as taking at least one pill of any mood stabilizer daily. Univariate general linear models (GLMs) were used to estimate if adherence was associated with the number of daily medications and the number of pills, controlling for age. The association between mean daily dosage of mood stabilizer and adherence was also estimated using a GLM. Results Three hundred and twelve patients (mean age 38.4 ± 10.9 years) returned 58,106 days of data and took a mean of 3.1 ± 1.6 psychotropic medications daily (7.0 ± 4.2 pills). No significant association was found between either the daily number of medications or the daily number of pills and adherence. For most mood stabilizers, patients with lower adherence took a significantly smaller mean daily dosage. Conclusions The number of concurrent psychotropic medications may not be associated with adherence in bipolar disorder. Patients with lower adherence may be taking smaller dosages of mood stabilizers. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium’s neurotrophic effects since Cade’s original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium’s neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium’s neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium’s molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses. [ABSTRACT FROM AUTHOR]

Clonazepam, first used for seizure disorders, is now increasingly used to treat affective disorders. We summarize the use of clonazepam to improve the management of depression. Clonazepam is useful for treatment-resistant and/or protracted depression, as well as for acceleration of response to conventional antidepressants. Clonazepam is at this time recommended for use in combination with SSRIs (fluoxetine, fluvoxamine, sertraline) as an antidepressant, and should be used at a dosage of 2.5–6.0 mg/day. If clonazepam is effective, a response should be observed within 2–4 weeks. It is significantly more effective for unipolar than for bipolar depression. Low-dose, long-term treatment with clonazepam exhibits a prophylactic effect against recurrence of depression. Although the mechanism of action of clonazepam has not yet been established, some investigators have been suggested that it involves enhancement of anti-anxiety effects, anticonvulsant effects on subclinical epilepsy, increase in 5-HT/monoamine synthesis or decrease in 5-HT receptor sensitivity mediated through the GABA system, and regulate in GABA activity. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

PURPOSE. Bipolar II disorder is often misdiagnosed as major depressive disorder. This paper addresses accurate diagnosis, proper treatment, and the chronic nature of the illness. CONCLUSIONS. Key factors in treatment success are early and accurate diagnosis and the patient's acceptance of a chronic psychiatric illness. Once the diagnosis of bipolar II disorder and need for long-term treatment are accepted, a successful outcome is more likely ( Keck, 2003 ). PRACTICE IMPLICATIONS. The psychiatric advanced practice nurse contributes to successful treatment of bipolar II disorder through accurate diagnosis, evidence-based treatment, community referrals, coordination of care, professional organization participation, and patient advocacy. [ABSTRACT FROM AUTHOR]

Objectives: Patients with bipolar disorder have changes in brain structures but it is unclear if these are present at disease onset and thus predispose subjects to develop the disorder, or whether they develop during the course of the disorder, either due to the effects of multiple episodes or as a consequence of treatment with psychotropic agents. Studies in first-episode (FE) manic patients have the potential to provide answers to these questions. Methods: Voxel-based morphometry (VBM) was used to assess magnetic resonance imaging scans of 15 FE manic patients and 15 matched healthy controls. Results: Using a priori defined statistical criteria, no significant differences in brain structures were noted between the two groups. However, there was approximately a 6% reduction in left anterior cingulate, left precuneus and right posterior cingulate volume in FE patients and these reductions were significant (p ≤ 0.002) at uncorrected levels. Conclusions: First-episode manic patients have reductions in left anterior, right posterior cingulate as well as left precuneus volumes, but these reductions are smaller and likely worsen with further mood episodes in bipolar patients. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effect of age at onset on the phenomenology of Cotard's syndrome (CS) as a recent study reported a high rate of occurrence of bipolar disorder (BD) in adolescents and young adults with CS followed up for ≥2 years. Methods: We reviewed all cases of CS reported since it was first described. A statistical analysis was carried out to determine the effect of age at onset on CS phenomenology. Results: We found 138 cases including 21 cases aged 25 years or younger. In these younger CS patients, BD was more frequent, and the risk of associated BD was increased nine times (p < 0.0001). Within the BD sub-group (n = 27), admixture analysis identified two sub-groups with mean ages at onset of 18.7 years [standard deviation (SD) = 3.2] and 50.5 years (SD = 11.7). Conclusions: Young people with CS should be monitored carefully for the onset of BD, and families should be educated about this risk. Treatment with mood stabilizers can be helpful for those who develop BD. Within BD associated with CS, early versus late onset should be distinguished. [ABSTRACT FROM AUTHOR]

Classic Kraepelian observations and contemporary epidemiological studies have noted a high prevalence rate between bipolar disorder and alcoholism. The extent to which these two illnesses are comorbid (i.e., two distinct disease processes each with an independent course of illness), genetically linked, or different phenotypic expressions of bipolar illness itself continues to be investigated. It is increasingly clear that co-occurring alcohol abuse or dependence in bipolar disorder phenomenologically changes the illness presentation with higher rates of mixed or dysphoric mania, rapid cycling, increased symptom severity, and higher levels of novelty seeking, suicidality, aggressivity, and impulsivity. It is very encouraging that interest and efforts at evaluating pharmacotherapeutic compounds has substantially increased over the past few years in this difficult-to-treat patient population. This article will review the clinical studies that have evaluated the effectiveness of conventional mood stabilizers (lithium, carbamazepine, divalproex, and atypical antipsychotics) in the treatment of alcohol withdrawal and relapse prevention in patients with alcoholism and in the treatment of bipolar disorder with comorbid alcoholism. A number of add-on, adjunctive medications, such as naltrexone, acamprosate, topiramate, and the atypical antipsychotics quetiapine and clozapine, may be candidates for further testing. [ABSTRACT FROM AUTHOR]

Objective: Depressive symptoms of bipolar disorder have more negative impact on a patient's life than manic symptoms. This review focused on the emerging efficacy data for treatments in bipolar depression. Methods: English-language literature cited in Medline was searched with terms bipolar depression, clinical trial, and trial. Randomized, placebo-controlled trials of newer studies with older agents and all studies with newer or novel agents were prioritized. Open-label studies of novel agents presented at major scientific meetings were also included. Results: Olanzapine, olanzapine–fluoxetine combination (OFC), and quetiapine were superior to placebo in the acute treatment of bipolar depression. Lamotrigine only significantly reduced core symptoms of depression compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood stabilizer (MS) had superiority to placebo in reducing depressive symptoms. Topiramate augmentation of an MS was equally as effective as Bupropion-SR. Patients treated with an MS responded well to the addition of agomelatine, a melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol and repetitive transcranial magnetic stimulation did not separate from placebo. Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to placebo in preventing depressive relapses. All agents were relatively well tolerated. Conclusions: Olanzapine, OFC, and quetiapine are effective in the acute treatment of bipolar depression. Compared with lithium and divalproex, lamotrigine is more effective in preventing bipolar depression. Larger controlled studies of the other agents in the acute and maintenance treatment of bipolar depression are warranted. [ABSTRACT FROM AUTHOR]

Pavuluri MN, Henry DB, Carbray JA, Naylor MW, Janicak PG. Divalproex sodium for pediatric mixed mania: a 6-month prospective trial.Bipolar Disord 2005: 7: 266–273.© Blackwell Munksgaard, 2005This prospective 6-month open trial examined the effectiveness and safety of divalproex sodium (DVPX) in pediatric mixed mania.Thirty-four subjects with a mean age of 12.3 (SD = 3.7) years, DSM-IV diagnosis of a current mixed episode and a baseline Young Mania Rating Scale (YMRS) score>20 were treated with DVPX monotherapy. The primary outcome measures were the YMRS and the Child Depression Rating Scale-Revised. Secondary measures were the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and the Children's Global Assessment of Functioning Scale (C-GAS). Measures of safety and tolerability were also administered.Effect size (Cohen'sd) based on change scores from baseline was 2.9 for the YMRS and 1.23 for the CDRS-R. Response rate (≥50% change from baseline YMRS score and≤40 score on CDRS-R at the end of study) was 73.5%. The remission rate (≥50% change from baseline on YMRS,≤40 on CDRS-R, CGI-BP-Improvement subscale of≤2, and≥51 CGAS score) was 52.9%. Significant improvements (p < 0.001) from baseline were seen for mean scores on all outcome measures (i.e., YMRS, CGI-BP, CDRS-R, and C-GAS). DVPX was safe and well tolerated with no serious adverse events during the 6-month trial.This study provides evidence for the effectiveness and safety of DVPX in the treatment of pediatric mixed mania over a 6-month period. Placebo-controlled, randomized trials involving larger samples will ultimately shed light on the efficacy of this agent. [ABSTRACT FROM AUTHOR]

Carney SM, Goodwin GM. Lithium– a continuing story in the treatment of bipolar disorder.Acta Psychiatr Scand 2005: 111 (Suppl. 426): 7–12.© Blackwell Munksgaard 2005.To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety.A selective literature review.Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies.Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use. [ABSTRACT FROM AUTHOR]

Objectives: Current guidelines provide little practical information on the clinical characteristics of bipolar I patients who are likely to benefit from the combination of a mood stabilizer and an antidepressant. Rather, guidelines simply state that an adjunctive antidepressant is recommended in cases of ‘severe’ depression. Our objective was to evaluate the clinical and demographic differences between patients who remitted on a mood stabilizer alone and patients who subsequently required an adjunctive antidepressant to achieve stabilization. Methods: We retrospectively compared the pharmacological treatment strategies of 39 patients with bipolar I disorder who were in a current depressive episode. Patients who did not respond to mood stabilizer monotherapy were prescribed an adjunctive antidepressant. We evaluated the clinical differences at baseline and week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer alone and patients that did not remit until they subsequently received an adjunctive antidepressant. Results: Patients who required an adjunctive antidepressant had significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer monotherapy were more likely to be married, achieved stabilization in less time, presented with higher Young Mania Rating Scale (YMRS) scores, and experienced the previous episode of depression more recently than patients who required an antidepressant. Conclusions: Our findings suggest that rapid improvement after achieving a therapeutic dose of a mood stabilizer is clinically significant and represents a surrogate endpoint in the treatment of bipolar I depression. Larger, prospective, and controlled studies are needed to verify our results and to identify additional indicators for a mood stabilizer and antidepressant combination treatment strategy. [ABSTRACT FROM AUTHOR]

Defines the concept of mood stabilizer. Treatment of phases of affective illness, mania, prophylaxis and depression; Efficacy of mood stabilizer for acute mood episodes without causing affective switch; Distinction between typical neuroleptic and standard antidepressant agents from lithium.

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management. Methods: A literature search was conducted using keywords ‘bipolar disorder’, ‘depression’, ‘drug therapy’, ‘antidepressants’, ‘lithium’, and ‘anticonvulsants’. Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate. Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided. [ABSTRACT FROM AUTHOR]

The answers to a questionnaire on the practical prescription in mood disorders from 298 Japanese psychiatrists was obtained. As the first-line treatment, a majority of respondents chose newer tricyclic agents (TCA) or non-TCA for moderate depression and older TCA for severe depression both with and without psychotic features. Combination therapy with antidepressants and anxiolytics was fairly popular in moderate depression, while antidepressant/neuroleptic combination was more common in severe psychotic depression. Sulpiride was the most favored drug for dysthymia. Although lithium was the most popular for bipolar mania, respondents were divided on the treatment of bipolar depression. [ABSTRACT FROM AUTHOR]

The authors reviewed the literature on the pharmacotherapy of geriatric mood disorders. Based on the evidence available, we have proposed: (i) that although any antidepressant is assumedly equal in antidepressive efficacy, ones with weak anticholinergic and antialpha1 effects are preferable in geriatric patients; (ii) that augmentation therapy with lithium and methylphenidate has modest evidence of efficacy in this population; (iii) that modified electroconvulsive therapy is safe and effective for severe and psychotic depression in the elderly; and (iv) that lithium remains the first choice for geriatric bipolar disorder, although its optimal serum level may he lower than in youger adults. [ABSTRACT FROM AUTHOR]