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Purposeof Review: Old age bipolar disorder (OABD), increasingly common as the population ages, presents unique diagnostic and treatment challenges. This selective review focuses on issues especially relevant to outpatient management., Recent Findings: People with OABD may have similar frequency and severity of mood episodes compared to younger adults. Depression predominates, and mixed symptoms in both depressive and manic episodes are common. Comorbidity and excess mortality are high, with a particular bidirectional association with cerebrovascular disease. Lithium may outperform valproic acid and second-generation antipsychotics in efficacy. Tolerability and long-term safety can be improved with relatively lower target drug therapeutic levels. Outpatient clinicians treating OABD should take an active role in the recognition and management of medical comorbidities. A careful history and examination might reveal subtle signs of bipolar disorder or mixed features and change treatment. A primary target for treatment is to reduce polypharmacy when appropriate. Further trials are needed to make specific and clear recommendations in OABD., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bipolar disorder (BD) has been linked to accelerated aging processes, with many studies suggesting that drugs used to treat BD may modulate pathways related to aging. This systematic review aimed to determine whether FDA-approved pharmacotherapies for BD have reported effects on aging biomarkers across clinical and preclinical studies. We conducted searches in PubMed and PsychINFO and followed PRISMA guidelines. Out of 6400 records identified, 19 studies met the inclusion criteria. Most preclinical studies tested the effects of BD drugs, especially lithium, on lifespan and telomere biology in cell and animal models. Clinical studies predominantly focused on lithium, evaluating aging markers like telomere length, telomerase, mitochondrial DNA copy number, and epigenetic age acceleration in individuals with BD. Findings indicate that chronic lithium treatment is associated with modulatory effects on aging biomarkers, particularly increased telomere length and telomerase activity. Conversely, some negative results were also reported. Limited evidence suggests potential aging-modulating properties of other mood stabilizers like valproic acid and lamotrigine, evidencing that further investigation is required. Despite variability across studies, the overall findings support the notion that pharmacotherapies used in BD present many effects of aging biomarkers. However, the field is still developing, with a clear emphasis on lithium and a lack of standardized methods to evaluate aging biomarkers in clinical samples. Further research exploring the anti-accelerated aging effects of BD drugs beyond lithium, their mechanisms of action, and potential synergistic effects is warranted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gabriel R. Fries reports financial support was provided by National Institute of Mental Health and Milken Institute, and Tatiana Barichello reports financial support was provided by the National Institute on Aging, the Texas Alzheimer's Research and Care Consortium, and The National Football League Players Association. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Bipolar disorder (BD) often necessitates hospitalization, especially during manic episodes. Long-acting injectable antipsychotics (LAIs) are theorized to enhance treatment adherence and decrease rehospitalization rates compared to oral medications. This study aimed to evaluate the real-world effectiveness of LAIs in reducing rehospitalizations among BD patients admitted for bipolar mania., Methods: We conducted a retrospective cohort study using data from a tertiary psychiatry hospital in Taiwan spanning January 1st, 2006, to December 31st, 2017. We analyzed 2212 hospitalizations among 945 patients with bipolar mania. A mixed-effects Cox regression model compared rehospitalization hazards between LAIs, mood stabilizer plus oral antipsychotic (MS + OAP), and mood stabilizer only (MS) groups. Sensitivity analyses assessed robustness across various subgroup criteria., Results: LAI treatment significantly reduced the hazard of rehospitalization within one year post-discharge compared to MS + OAP (HR = 2.29, 95 % CI = 1.56-3.36) and MS alone (HR = 2.66, 95 % CI = 1.68-4.21). This effect was consistent across different rehospitalization types-all-cause, bipolar disorder-specific, and bipolar mania-specific. Each additional previous hospitalization was associated with higher hazard of rehospitalization across the three rehospitalization types. Sensitivity analyses suggested LAIs' efficacy in manic episodes with and without psychotic symptoms and for patients with frequent hospitalizations. The LAIs included in the analysis are haloperidol, risperidone, fluphenazine, flupentixol, and zuclopenthixol., Conclusion: Our findings suggest that the addition of LAIs for bipolar mania during acute inpatient treatment is associated with reduced rehospitalizations, particularly among patients with recurrent hospitalizations, making it a valuable option. However, the lack of outpatient prescription data limits our ability to further substantiate this concept, warranting future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2024 The Author(s). Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically., Methods: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk., Results: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies., Limitations: Substantial heterogeneity among the studies precluded performing a meta-analysis., Conclusion: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention., Competing Interests: Declaration of competing interest ME's spouse is an employee of Sanofi. MAF has received grant support from Assurex Health and Mayo Foundation, received CME travel and honoraria from Carnot Laboratories and American Physician Institute, and has Financial Interest / Stock ownership / Royalties from Chymia LLC. All other authors report no financial relationships with commercial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Pharmacotherapy remains crucial for treating bipolar disorder (BD), but knowledge on the treatments actually used by newly diagnosed patients in real-world settings is sparse., Methods: Individuals newly diagnosed with BD during 1996-2018, aged 15-65 years, were identified from national Finnish registers. The patients' use of different drug classes (mood stabilizers, antipsychotics and antidepressants) or combinations of these drug classes were followed from initial pharmacotherapy (first line) after BD diagnosis until the fifth line of treatment or until the two-year follow-up time ended. Clinical and sociodemographic factors associated with antidepressants-only as the first treatment line were assessed with logistic regression., Results: 82.6 % of all patients used BD medication during the follow-up. 33.9 % had antidepressants-only as the first, 22.9 % as the second and 19.7 % as the third treatment line. Use of combinations of mood stabilizers, antipsychotics and antidepressants increased by successive treatment lines. Factors associated with antidepressants-only as the first treatment line included older age (>45 years aOR 2.20, 95% CI: 2.01-2.40, 25-45 years: 1.55, 1.42-1.68, compared with those aged <25), diabetes (1.35, 1.17-1.55) and female sex (1.29, 1.21-1.37). BD diagnosis registered in 2016-2018 (0.48, 0.42-0.55) and substance abuse (0.77, 0.71-0.83) were associated with decreased odds., Limitations: Due to the register-based nature of this study, not all potentially important clinical factors influencing medication use could be controlled for., Conclusions: A large proportion of patients with bipolar disorder are not treated according to treatment guidelines, as use of antidepressants alone is common. Reasons for not following evidence-based recommendations need to be further researched., Competing Interests: Declaration of competing interest Drs Tiihonen, Tanskanen, and Taipale have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. Dr. Tiihonen has been a consultant to HLS Therapeutics, Orion and WebMed Global; has received honoraria for lectures from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Sunovion. Dr. Taipale reports personal fees from Gedeon Richer, Janssen-Cilag, Lundbeck and Otsuka. Dr. Lähteenvuo is a board member of Genomi Solutions Ltd., Springflux Ltd. and Nursie Health Ltd., has received honoraria from Camurus, Lundbeck, Janssen, Janssen-Cilag, Orion Pharma, Otsuka, and Sunovion, and research funding from the Finnish Medical Foundation and the Emil Aaltonen Foundation and participated in research funded by Janssen-Cilag. Other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Mood stabilizers are psychotropic drugs mainly used to treat bipolar disorder in the acute phase or for maintenance therapy to prevent relapse. In clinical practice, mood stabilizers are commonly prescribed for conditions other than bipolar disorder. This study investigated the distribution of mood stabilizer prescriptions for different psychiatric diagnoses and studied differences in the drugs, dosage, and plasma concentration in 10 Asian countries including Taiwan, South Korea, Malaysia, China, Thailand, India, Pakistan, Singapore, Indonesia, and Myanmar., Methods: Patients prescribed mood stabilizers (lithium, carbamazepine, valproic acid, or lamotrigine) for a psychiatric condition other than bipolar disorder (codes F31.0-F31.9 in the International Classification of Diseases, 10th Edition, Clinical Modification) were recruited through convenience sampling. A website-based data entry system was used for data collection., Results: In total, 1557 psychiatric patients were enrolled. Schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F20-F29, 55.8 %) was the most common diagnosis, followed by non-bipolar mood disorders (F30, F31- F39, 25.3 %), organic mental disorder (F00-F09, 8.8 %), mental retardation (F70-F79, 5.8 %) and anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders (F40-F48, 4.4 %). The most frequently targeted symptoms (>20 %) were irritability (48 %), impulsivity (32.4 %), aggression (29.2 %), anger (20.8 %), and psychosis (24.1 %). Valproic acid was the most frequently used medication., Conclusions: Clinicians typically prescribe mood stabilizers as empirically supported treatment to manage mood symptoms in patients with diagnoses other than bipolar disorders, though there is on official indication for these disorders. The costs and benefits of this add-on symptomatic treatment warrant further investigation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in reporting this study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2022 John Wiley & Sons Australia, Ltd.)

Introduction: Lithium treatment is considered the gold standard for the long-term management of bipolar disorder and recurrent unipolar depression. It is also extremely effective in other psychiatric conditions characterized by impulsivity and aggression, and for the prevention of suicidal behaviours., Areas Covered: This paper provides a scoping review and an expert commentary regarding the use of lithium in adult patients. Available information about efficacy, tolerability, dosing, and switching is analyzed, and the strategies that may be most useful in real-world clinical settings are highlighted., Expert Opinion: Lithium is effective on different domains of bipolar disorder, including the long-term prevention of recurrences of affective episodes, management of acute mania as well as in the prophylaxis of all affective episodes. Lithium has been defined a 'forgotten drug,' since its use in routine clinical practice has been declined over the last 20 or 30 years. Reasons for this trend include lack of adequate training on the management of lithium side effects. Considering its efficacy, use of lithium in ordinary clinical practice should be promoted. Several strategies, such as using slow-release formulations, can be easily implemented in order to minimize lithium side effects and improve its tolerability profile.

Pregnancy in women with bipolar disorder (BD) can be considered a high-risk pregnancy in view of several clinical and pharmacotherapeutic considerations. Pharmacological treatment during pregnancy requires a careful weighing of psychotropic drug exposure against the risk of BD relapse. An untreated bipolar illness can negatively affect the health of mother as well as unborn child in the event of a relapse. Availability of well balanced, latest information on safety of prophylactic drugs for BD is crucial for making informed decisions. The review provides an evidence-based update (2015-2021) on the drug safety considerations involved in providing care for women with BD who are either pregnant or planning to conceive in near future. Literature review based on systematic reviews, meta-analyses, and data available from studies based on large-scale cohorts and birth registries has been synthesized and presented along with clinically relevant recommendations., Competing Interests: None

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., (© 2022 The Authors Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

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., (© 2022 The Authors. Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups., Methods: We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months., Results: We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54-0.70, 5) for any mood episode, 0.72 (0.60-0.87, 13) for depressive episodes, and 0.45 (0.36-0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61-0.82, 6)., Conclusions: Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

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 (Li 2 CO 3 ), 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 (LiC 5 H 3 N 2 O 4 ; 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 Li 2 CO 3 , 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., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mood stabilizers with disparate chemical structures are approved for treating bipolar disorder, but their mechanisms of action are not agreed on. However, when administered to unanesthetized rats at clinically relevant doses, they modulate neurotransmission involving arachidonic acid and brain activity of COX-2, which oxidizes arachidonic acid within the arachidonic acid metabolic cascade., Hypothesis: Inhibiting COX-2 directly might enhance mood stabilizer effects in bipolar disorder patients., Observations: This paper reviews randomized controlled trials that showed that celecoxib, a selective COX-2 inhibitor, or low-dose aspirin, which inhibits COX-1 and inhibits/acetylates COX-2, reduced bipolar symptoms in patients on mood stabilizers. More convincing are two population based pharmacoepidemiological studies that each demonstrated that chronic low dose aspirin reduced bipolar severity markers in patients on mood stabilizers., Conclusions: This clinical evidence is consistent with the hypothesis that low-dose chronic aspirin and celecoxib, which can inhibit COX-2 and enter brain, can be repurposed in bipolar disorder to enhance mood stabilizer effects on arachidonic acid metabolism and neurotransmission., (Published by Elsevier Ltd.)

Lithium intoxication may induce neurological complications, initially characterised by a conscience alteration and an encephalopathy clinical picture with a risk of death or sever long-term consequences. With an occurrence sometimes atypical and possibly without initial hyperlitemia, the diagnosis delay of these complications might be important. Moreover, no specific guidelines focused on these complications are available. The aim of this article is to propose an update on diagnosis and treatment of neurological complications attributable to lithium, as encephalopathy., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: Mixed presentations in bipolar disorder have long posed clinical and nosological challenges. The DSM-5 mixed features specifier was developed to provide a more flexible and clinically relevant definition of mixed presentations compared with narrowly defined DSM-IV mixed episodes. However, there is little guidance on treating such presentations. Here, we summarize the evidence for biological treatments of DSM-5 and similarly defined mixed features (MFs)., Recent Findings: The literature on treating MFs is almost exclusively based on post hoc analyses. Within this limited evidence base is preliminary positive data for aripiprazole, asenapine, cariprazine, olanzapine, risperidone, and ziprasidone in treating acute mania with MFs, and cariprazine, lurasidone, olanzapine, and ziprasidone for depressive symptoms in depression with MFs. Divalproex may also be efficacious for acute mania with MFs. The few extant maintenance studies suggest that divalproex and olanzapine may have long-term efficacy in those with index MFs or for the prevention of MFs, respectively. The existing evidence suggests that clinicians consider atypical antipsychotics and divalproex for treating acute mixed presentations. However, adequately powered treatment trials-and studies of maintenance and neurostimulation therapies-are needed. Additionally, data-driven techniques to identify relevant symptom clusters may help improve our conceptualization of mixed presentations.

It is recognized that d-amphetamine (AMPH)-induced hyperactivity is thought to be a valid animal model of mania. In the present study, we investigated whether a proinflammatory oxidative gene indoleamine-2,3-dioxygenase (IDO) is involved in AMPH-induced mitochondrial burden, and whether mood stabilizers (i.e., lithium and valproate) modulate IDO to protect against AMPH-induced mania-like behaviors. AMPH-induced IDO-1 expression was significantly greater than IDO-2 expression in the prefrontal cortex of wild type mice. IDO-1 expression was more pronounced in the mitochondria than in the cytosol. AMPH treatment activated intra-mitochondrial Ca 2+ accumulation and mitochondrial oxidative burden, while inhibited mitochondrial membrane potential and activity of the mitochondrial complex (I > II), mitochondrial glutathione peroxidase, and superoxide dismutase, indicating that mitochondrial burden might be contributable to mania-like behaviors induced by AMPH. The behaviors were significantly attenuated by lithium, valproate, or IDO-1 knockout, but not in IDO-2 knockout mice. Lithium, valproate administration, or IDO-1 knockout significantly attenuated mitochondrial burden. Neither lithium nor valproate produced additive effects above the protective effects observed in IDO-1 KO in mice. Collectively, our results suggest that mood stabilizers attenuate AMPH-induced mania-like behaviors via attenuation of IDO-1-dependent mitochondrial stress, highlighting IDO-1 as a novel molecular target for the protective potential of mood stabilizers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Objectives: Bipolar spectrum disorder (BSD) is an extended concept of bipolar disorder (BD) that includes conditions that do not fulfill the criteria. There is no recommendation today about its treatment. We reviewed relevant literature focusing on pharmacological treatments, looking for high-strength evidence leading to guidelines., Methodology: A literature search was conducted using MedLine / PubMed database and Google Scholar up to September 2018. Search words were related to BSD and pharmacological treatment., Results: The literature search yielded 621 articles. Out of these, 35 articles met our selection criteria. There was limited high quality data. Only one randomized control trial (RCT) and one randomized open label trial were found. Most studies used different definition of BSD., Conclusions: There is a considerable lack of data and no evidence supporting efficacy of pharmacological treatment for BSD. There is a need for a consensus on the definition of BSD and more evidence studies to evaluate drug's effectiveness in this condition., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The study compared treatment failure when using three therapeutic strategies in bipolar disorders: (i) mood stabilizers (MSs: lithium, valpromide, divalproate, carbamazepine, lamotrigine) without second-generation antipsychotic (SGAP); (ii) SGAPs (aripiprazole, olanzapine, risperidone, quetiapine) without MS; (iii) combination of MSs and SGAPs., Methods: A historical cohort study was conducted using the French national healthcare databases in 20,086 outpatients aged 21+, newly treated with one of the three treatment strategies in 2011-2012, and diagnosed with a bipolar disorder. A composite outcome was based on indicators of treatment failure identified over 12 months: treatment discontinuation, switch or addition, psychiatric hospitalisation, suicide attempt, and death. For each strategy, the cumulative incidence of treatment failure was calculated while adjusting for covariates by propensity score weighting., Results: A total of 8,225 patients (40.9%) were newly dispensed MSs, 9,342 (46.5%) SGAPs, and 2,519 (12.5%) both MSs and SGAPs. The one-year adjusted cumulative incidence of treatment failure was 75.7% (95%CI 74.9;76.3) in patients using MSs, 75.3% (74.6;76.0) in patients using SGAPs, and 60.5% (58.3;62.6) in patients with the combination. The adjusted difference in incidence for SGAPs compared with MSs was -0.40% (-1.4;0.6 p = 0.4) in the whole population, -2.2% (-3.3; -1.2 p < 0.002) in patients under 65 years and +6.7% (4.1;9.1 p < 0.002) in patients 65 years and over., Limitations: Combinations of MSs and SGAPs could not be directly compared with MS or SGAP monotherapies., Conclusions: One-year treatment failure was high. Overall, no difference in treatment failure was observed between MS or SGAP strategy but differences might exist depending on age., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: People with bipolar disorder require long-term treatment but it is estimated that 40% of these people do not adhere to prescribed medication regimens. Non-adherence increases the risk of relapse, hospitalisation and suicide. Some evidence syntheses report barriers to mental health treatment adherence but rarely delineate between modifiable and non-modifiable barriers. They also fail to distinguish between the patients' perspective and that of other stakeholders such as clinicians despite of their different understanding and priorities about adherence. Facilitators of adherence, which are also important for informing adherence intervention design, are also lacking from syntheses and few syntheses focus on medications for bipolar disorder.This systematic review aims to identify modifiable barriers and facilitators (determinants) of medication adherence in bipolar disorder. We also plan to report determinants of medication adherence from perspectives of patients, carers, healthcare professionals and other third parties. A unique feature of this systematic review in the context of mental health is the use of the Theoretical Domains Framework (TDF) to organise the literature identified determinants of medication adherence., Methods and Analysis: The protocol adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and ENhancing Transparency in REporting the synthesis of Qualitative research (ENTREQ) guidelines. This review will include both qualitative and quantitative primary studies exploring determinants of medication adherence in bipolar disorder. We will search the following databases using a preplanned strategy: CINAHL, Cochrane Library (CENTRAL), Embase, LiLACS, Medline, PsychINFO, PubMed without date restrictions. We will report the quality of included studies. We will use framework synthesis using the TDF as an a priori 'framework'. We will map the literature identified modifiable determinants to the domains of TDF., Ethics and Dissemination: Ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication., Prospero Registration Number: CRD42018096306., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To compare pharmacogenetic test predictions with self-reported treatment experience and side effect tolerability among patients with depression taking psychotherapeutic medications., Methods: Subjects completed a survey recalling medication effectiveness and side effects and then underwent pharmacogenetic testing., Results: Our 15 gene pharmacogenetic panel predicted efficacy (p < 0.001) but did not predict side effect tolerability (p = 0.70) in a group of 352 patients. The pharmacogenetic panel and reported efficacy corresponded 60% of the time and medication tolerability agreed 71% of the time., Conclusion: Pharmacogenetic testing may be a useful adjunct to predict efficacy of medications used to treat depression.

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., (© 2017 John Wiley & Sons Australia, Ltd.)

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., (© 2018 Pharmacotherapy Publications, Inc.)

Objective: Depression and brief periods of manic symptoms are linked to a significant risk of progression to bipolar disorder (BD) in children who have a first-degree relative with BD I or II. However, little evidence exists to guide the pharmacologic management of children with these high-risk phenotypes. We propose a pharmacological treatment algorithm for high-risk youth and present results on its use in a study of children with a first-degree relative with BD., Methods: Subjects were 40 youth (mean 12.7 years, range 9-17 years) who had (1) a first-degree relative with lifetime history of BD I or II, (2) DSM-IV-TR diagnoses of BD not otherwise specified, major depressive disorder or cyclothymic disorder, and (3) active symptoms of depression, mania, or hypomania. Participants and their families were enrolled in a randomized trial examining the effects of two psychosocial interventions on the 1-year course of mood disorder. At study intake, participants received a psychiatric evaluation and were offered medications or had existing medications optimized to decrease symptom severity. During the 1-year study, psychiatrists treated participants using a medication algorithm to treat depressive or manic symptoms as well as comorbid anxiety and/or attention-deficit/hyperactivity disorder., Results: At study entry, 25 of 40 (62.5%) of the participants were taking at least one psychiatric medication. At 1 year, nearly an identical proportion were taking medications (22 of 35, 63%). Independent ratings indicated that in 84.7% of the study visits, physicians maintained adherence to the algorithm. No patients experienced antidepressant- or stimulant-induced mania during the study., Conclusions: An algorithmic approach to pharmacologic interventions may aid in the management of youth (i.e., age <18) at high risk for BD. Future studies should compare outcomes in high-risk patients receiving algorithm-prescribed treatment versus those receiving treatment as usual., Clinical Trial Registration Information: Early Family-Focused Treatment for Youth at Risk for Bipolar Disorder; www.clinicaltrials.gov/ ; NCT00943085.

Introduction: The goal of this paper is to provide a practical, clinically oriented review of lithium, a salt widely used to treat mania since the 1870s and formally approved as a mood stabilizer in 1970. Although lithium is still considered a first-line treatment for bipolar mania in most practice guidelines, its use may be overshadowed by newer psychotropic medications. Areas covered: This paper addresses the historical use of lithium, modern indications for its use, guidelines for prescribing and monitoring continued lithium use, drug-drug interactions, and pharmacodynamics/pharmacokinetic properties. The paper also reviews the unique properties of lithium and their potential clinical importance. Expert opinion: While the use of lithium does involve some unique risks to the patient, it may also has some unique advantages in certain patient populations. Two major findings that make lithium unique are its potential neuroprotective benefits and decreased risk of suicide in patients with mood disorders.

Background: The present research aimed to investigate the efficacy of a multifaceted intervention that included motivational interviewing (MI) and psychoeducation in improving medication adherence (MA) among patients with bipolar disorder (BD)., Method: A multicenter, cluster randomized, observer-blind, controlled, parallel-group trial was conducted in ten academic centers in Iran. Patients with BD were randomly assigned to the experimental group (EXP; n = 136) or the usual care group (UC; n = 134). The EXP group received five sessions of MI and psychoeducation together with their family members. The primary outcome measure was changes in scores on the Medication Adherence Rating Scale from baseline to 6 months post-intervention. Other outcome measures included serum levels of mood stabilizers, clinical symptoms, quality of life, as well as measures of intention, beliefs about medicine, perceived behavioral control, automaticity, action and coping planning, and adverse reactions., Results: Medication adherence improved over time in both groups, but patients in the EXP group improved more (baseline score: 6.03; score at the sixth month: 9.55) than patients in the UC group (baseline score: 6.17; score at the sixth month: 6.67). In addition, patients in the EXP group showed greater improvement than patients in the UC group in almost all secondary outcomes 6 months following the intervention., Conclusions: Multifaceted interventions that include motivational-interviewing and psychoeducation can significantly improve MA and clinical and functional outcomes in patients with BD., Trial Registration Number: The trial was registered with theClinicalTrials.gov database (NCT02241863) https://clinicaltrials.gov/ct2/show/NCT02241863.

Bipolar disorders belong to the spectrum of mood disorders and represent a serious psychiatric comorbidity. Behaviors adopted by bipolar patients can foster cancer occurrence but also impact its management, especially during acute depressive or manic episode. Oncologists must adapt their protocols in order to obtain the best compliance for treatment and avoid any possible mood destabilization, with the inherent risk of suicidal attempt. Potential interactions between mood-stabilizing agents (lithium, divalproate, atypical antipsychotics, and anticonvulsivants) and oncologic treatment (chemotherapy, targeted therapy, immunotherapy, corticotherapy) will be particularly watched. To do so, a closely collaboration with the oncopsychiatrist but also with the referent or liaison psychiatry team is necessary during the patient's oncologic care. Some clinical vignettes will illustrate the modalities of care of bipolar disorders in oncology., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: We evaluated the effectiveness of Electroconvulsive Therapy (ECT) in the treatment of Bipolar Disorder (BD) in a large sample of bipolar patients with drug resistant depression, mania, mixed state and catatonic features., Method: 522 consecutive patients with DSM-IV-TR BD were evaluated prior to and after the ECT course. Responders and nonresponders were compared in subsamples of depressed and mixed patients. Descriptive analyses were reported for patients with mania and with catatonic features., Results: Of the original sample only 22 patients were excluded for the occurrence of side effects or consent withdrawal. After the ECT course, 344 (68.8%) patients were considered responders (final CGIi score ≤2) and 156 (31.2%) nonresponders. Response rates were respectively 68.1% for BD depression, 72.9% for mixed state, 75% for mania and 80.8% for catatonic features. Length of current episode and global severity of the illness were the only statistically significant predictors of nonresponse., Conclusion: ECT resulted to be an effective and safe treatment for all the phases of severe and drug-resistant BD. Positive response was observed in approximately two-thirds of the cases and in 80% of the catatonic patients. The duration of the current episode was the major predictor of nonresponse. The risk of ECT-induced mania is virtually absent and mood destabilization very unlikely. Our results clearly indicate that current algorithms for the treatment of depressive, mixed, manic and catatonic states should be modified and, at least for the most severe patients, ECT should not be considered as a "last resort".

Background: Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder., Methods: We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders., Results: A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST., Conclusion: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the "bipolar-like" behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.

Background: No previous study has focused on the association between use of antipsychotic drugs and the development of cataracts in patients with bipolar disorder (BD); hence, we aimed to examine this association in the present study., Methods: We conducted a retrospective nested case-control study using data from the National Health Insurance Database of Taiwan between 2000 and 2011. A total of 3292 BD patients, 1684 with cataracts and 1608 controls matched for age, sex, and index date, were included. Antipsychotic drug exposure was categorized by type of drug and duration of use. A conditional logistic regression analysis was used to analyze the association., Results: Among BD patients, we found significantly reduced odds ratio (OR) of cataract development among past (adjusted OR (AOR), 0.74; 95% confidence interval (CI), 0.62-0.89; p=0.001) and continuous users (AOR, 0.71; 95% CI, 0.59-0.85; p<0.001) of atypical antipsychotics. No association was found between the odds of cataract development and typical antipsychotics. Besides, concomitant use of antidepressants (AOR, 1.23; 95% CI, 1.06-1.43; p=0.007) and mood stabilizers (AOR, 1.23; 95% CI, 1.06-1.42; p=0.007) were associated with increased odds of cataract development., Limitations: Some important contributors to cataract development such as family history of cataract, smoking and alcohol exposure could not be measured from the claims data and this may confound the results., Conclusions: Reduced odds of cataract were found in patients with BD taking atypical antipsychotics. However, given that BD patients often have risk factors for developing cataract, regular ocular evaluations are recommended for those treated with antipsychotics drugs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response., Methods/design: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response., Discussion: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost., Trial Registration: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Aim: In view of the potential effects of psychiatric drugs on DNA methylation, we investigated whether medication use in bipolar disorder is associated with DNA methylation signatures., Experimental Procedures: Blood-based DNA methylation patterns of six frequently used psychotropic drugs (lithium, quetiapine, olanzapine, lamotrigine, carbamazepine, and valproic acid) were examined in 172 bipolar disorder patients. After adjustment for cell type composition, we investigated gene networks, principal components, hypothesis-driven genes and epigenome-wide individual loci., Results: Valproic acid and quetiapine were significantly associated with altered methylation signatures after adjustment for drug-related changes on celltype composition., Conclusion: Psychiatric drugs influence DNA methylation patterns over and above cell type composition in bipolar disorder. Drug-related changes in DNA methylation are therefore not only an important confounder in psychiatric epigenetics but may also inform on the biological mechanisms underlying drug efficacy.

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Mood stabilizer (MS) plus antipsychotic (AP) co-treatment is common in patients with acute bipolar disorder (BD), but adverse effects (AEs) of this strategy have not been systematically reviewed., Areas Covered: We conducted a systematic review searching PubMed/MEDLINE and PsycINFO on April 1, 2015 for randomized trials in ≥ 20 adults with acute manic/mixed or depressed BD comparing MS or AP monotherapy with their combination that reported quantitative AE data. Pooled together, MS+AP versus MS monotherapy (studies = 18, n = 4419) was associated with significantly higher burden regarding 21/53 (39.6%) individual AEs, particularly weight gain-related (5/5 = 100%), extrapyramidal (5/12 = 41.7%) and glucose/lipid-related AEs (3/8 = 37.5%). AP+MS versus AP monotherapy (studies = 3, n = 397) was associated with significantly higher burden regarding 4/21 (19.0%) individual AEs (≥ 1 AE, tremor, sedation/somnolence, vomiting)., Expert Opinion: Efficacy advantages of AP+MS co-treatment versus monotherapy should be balanced with its greater AE burden. AE risk is higher for adding AP to MS (17 additional AEs) than adding MS to an AP, including the particularly concerning cardiometabolic AEs. More data are needed, as only one or two studies provided data for 21/21 (100%) AEs of MS augmentation of AP, and 13/53 (24.5%) AEs of AP augmentation of MS, and as sparse data suggest clinically relevant AE differences across individual AP+MS combinations.

A great deal of evidence suggests that virtually all antidepressant treatments induce a dopaminergic behavioral supersensitivity. We have suggested that this effect may play a key role not only in the antidepressant effect of these treatments, but also in their ability to induce a switch from depression to mania. In 2003-4 we found that the sensitization of dopamine receptors induced by imipramine is followed, after imipramine withdrawal, by a desensitization of these receptors associated with a depressive-like behavior assessed in the forced swimming test. The dopamine receptor sensitization can be prevented by MK-801, an NMDA receptor antagonist, but not by currently used mood stabilizers (lithium, carbamazepine, valproate). These observations led us to suggest - and later confirm - with preliminary clinical observations that memantine may have an acute antimanic and a long-lasting mood-stabilizing effect in treatment-resistant bipolar disorder patients. Here we present data showing that memantine prevents not only the dopamine receptor sensitization induced by imipramine, as observed with MK-801, but also the ensuing desensitization and the associated depressive-like behaviorq observed after antidepressant withdrawal., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The association between Toxoplasma gondii seropositivity and respectively Bipolar Disorder (BD) and Schizophrenia/Schizoaffective disorder (SZ) is one of the most studied link between one pathogen and psychiatric disorders. The aim of the present study was thus to retrospectively determine if the administration of an antipsychotic and/or a mood stabilizer having known in vitro Anti-Toxoplasmic Activity (TATA+) was associated with a better clinical outcome in a population of 152 BD or 114 SZ patients and seropositive for T. gondii infection compared to patients receiving a treatment without anti-toxoplasmic activity (TATA-)., Methods: This multicenter study was conducted in an academic public hospital during a 3-years period between 2009 and 2011. All consecutive inpatients and outpatients with SZ or BD diagnosis with a stable treatment for more than 4 weeks were recruited. socio-demographic and clinical characteristics measured with validated scales as well as a serological status for toxoplasmic infection were included. Treatments were classified according to their in vitro antitoxoplasmic activity. A multivariate model was used to determine the clinical characteristics that were significantly different between patients receiving a treatment with no antitoxoplasmic activity compared to others., Results: BD patients with positive serum antibodies against T. gondii presented more lifetime depressive episodes (p = 0.048) after adjustment for age, sex and sociodemographic characteristics when treated by drug having no anti-toxo activity, compared to patients having received drugs with anti-toxo activity. A significant difference was not found in BD toxonegative patients and in SZ toxopositive or toxonegative patients., Conclusions: It seems to be of importance to consider prescribing a drug with a clear anti-toxoplasmic activity (TATA+) for BD patients seropositive to T. gondii, in particular valproate that was found as the mood stabilizer with the highest antitoxoplasmic activity. Prospective randomized controlled trials are warranted to confirm this preliminary data., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology., Areas Covered: This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca²⁺) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca²⁺ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients., Expert Opinion: Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.

Objective: Despite the close relationship between the functional polymorphism C(-1019)G (rs6295) of the serotonergic 1A receptor (5-HT1A) and mood, few studies have investigated the relationship between rs6295 and bipolar disorder., Aims: In this study, we aimed to investigate whether rs6295 is associated with clinical prognosis and treatment response in patients with bipolar I disorder acute manic episodes., Methods: One hundred twenty-eight patients with bipolar I disorder and one hundred sixty-eight healthy controls were recruited. Associations between patients with bipolar I disorder and healthy controls were compared. In addition, age at onset, number of admissions, and treatment response, including response rate, mean changes in manic symptoms, number of anti-manic agents and the total dosage of mood stabilizers for acute manic symptoms were compared between the rs6295 GG and CG+ CC groups in patients with bipolar I disorder. We conducted a separate subgroup analysis according to gender., Results: There were no differences in frequency between patients and controls. In patients with bipolar disorder, clinical prognosis and treatment response were no different between GG and CG+ CC groups. However, in a subgroup analysis according to gender, male, but not female, patients in the GG group had a longer duration of illness and a greater number of both previous episodes and psychiatric ward admissions than did the GC+ CC group., Conclusions: Further studies should investigate the relationship between 5-HT1A polymorphisms and bipolar disorder in terms of mood episode and gender.

Introduction: Bipolar disorder (BD) is the seventh leading cause of disability per year of life among all diseases in the population aged 15 to 44. It is a group of heterogeneous diseases, with frequent comorbid psychiatric or somatic disorders, variable treatment response and frequent residual symptoms between episodes. The major impairment associated with this disorder is related to the high relapse and recurrence rates, the functional impact of comorbidities and cognitive impairment between episodes. The prognosis of the disease relies on the efficacy of relapse and recurrence prevention interventions. Given the heterogeneity of the disorder, relapse and recurrence prevention needs to develop a personalized care plan from the start of the acute phase. In such a complex situation, guideline-driven algorithms of decision are known to improve overall care of patients with bipolar disorder, compared to standard treatment decisions. Although guidelines do not account for all the situations encountered with patients, this systematic approach contributes to the development of personalized medicine., Methods: We present a critical review of recent international recommendations for the management of manic phases. We summarize treatment options that reach consensus (monotherapy and combination therapy) and comment on options that differ across guidelines., Results: The synthesis of recent international guidelines shows a consensus for the initial treatment for manic phases. For acute and long-term management, the anti-manic drugs proposed are traditional mood stabilizers (lithium or valproate) and atypical antipsychotics (APA - olanzapine, risperidone, aripiprazole and quetiapine). All guidelines indicate stopping antidepressant drugs during manic phases. International guidelines also present with some differences. First, as monotherapy is often non sufficient in clinical practice, combination therapy with a traditional mood stabilizer and an APA are disputed either in first line treatment for severe cases or in second line. Second, mixed episodes treatment is not consensual either and some guidelines propose in first line valproate, carbamazepine and some APA, and advice not to use lithium. On the other hand, some guidelines do not propose specific treatment for mixed episodes and group them with manic episodes management. Duration of treatment is unclear., Conclusion: Guidelines utilization has shown that the systemic use by clinicians of decision algorithms in comparison to "treatment as usual" modality improves the overall care of patients with BD. Future data from cohorts of patients seem necessary to complement the existing data from clinical trials. These cohort studies will help to take into account the different individual profiles of BD and thus may help to propose a more personalized medicine., (Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.)

Background: Several lines of evidence have suggested that has-mir-206 (miRNA-206) may regulate brain-derived neurotrophic factor (BDNF) protein synthesis. The primary aim of this study was to determine whether miRNA-206 gene (MIR206) may confer susceptibility to bipolar disorder type I (BD-I) and treatment response to mood stabilizers. Also, we intended to verify the hypothesis that a potential interplay of MIR206 and BDNF may influence the genetic risk for BD-I and treatment response., Methods: The MIR206 rs16882131 and BDNF rs6265 polymorphisms were genotyped in 280 BD-I patients and 288 healthy controls. Treatment response to lithium and valproate was retrospectively determined., Results: No association was observed in the individual polymorphism with regards to risk of BD-I and treatment response. Our results showed a significant gene to gene interaction between the MIR206 rs16882131 and BDNF rs6265 polymorphisms that contribute to BD-I susceptibility and treatment response. Further analysis showed a significant interaction between MIR206 and BDNF on treatment score (F3, 138=8.61, P=0.046), and individuals with MIR206 T/T+TC and BDNF A/A genotypes had a significantly lower mean treatment score than those with MIR206 CC and BDNF A/A+A/G as well as those with MIR206 CC and BDNF G/G genotypes (P=0.018 and 0.013, respectively)., Limitation: This is a preliminary investigation with relatively small sample size., Conclusion: Our findings provide initial evidence of the gene-to-gene interaction of MIR206 and BDNF in regards to the risk for BD-I as well as treatment response to mood stabilizers., (Copyright © 2014 Elsevier B.V. All rights reserved.)