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OBJECTIVE: Current practice guidelines discourage use of lithium during breast-feeding, despite limited data. This study aimed to quantify lithium exposure in nursing infants. METHOD: In 10 mother-infant pairs, the authors obtained assays of lithium in maternal serum, breast milk, and infant serum and indices of infant renal and thyroid function. RESULTS: Maternal serum, breast milk, and infant serum daily trough concentrations of lithium averaged 0.76, 0.35, and 0.16 meq/liter, respectively, each lithium level lower than the preceding level by approximately one-half. No serious adverse events were observed, and elevations of thyroid-stimulating hormone, blood urea nitrogen, and creatinine were few, minor, and transient. CONCLUSIONS: Serum lithium levels in nursing infants were low and well tolerated. No significant adverse clinical or behavioral effects in the infants were noted. These findings encourage reassessment of recommendations against lithium during breast-feeding and underscore the importance of close clinical monitoring of nursing infants. [ABSTRACT FROM AUTHOR]

Objective: Bipolar disorders are prevalent major illnesses with high rates of morbidity, comorbidity, disability, and mortality. A growing number of psychotropic drugs are used to treat bipolar disorder, often off-label and in untested, complex combinations.Methods: To quantify utilization rates for psychotropic drug classes, this study used the 2002-2003 U.S. national MarketScan research databases to identify 7,760 persons with ICD-9 bipolar disorder subtypes. Survival analysis was used to estimate times until initial monotherapies were augmented, changed, or discontinued.Results: The most commonly prescribed first drug class was antidepressants (50% of patients), followed by mood stabilizers (25%: anticonvulsants, 17%, and lithium, 8%), sedatives (15%), and antipsychotics (11%). At study midpoint only 44% of patients were receiving monotherapy. Those receiving monotherapy were ranked by initial drug prescribed and percentage of patients (bipolar I and bipolar II): antidepressants (55% and 65%), lithium (51% and 41%), antipsychotics (32% and 31%), anticonvulsants (28% and 29%), and sedatives (28%, 25%). Median time to adding another psychotropic was 2.5-times less than median time to changing the initial treatment (16.4 compared with 40.9 weeks), and stopping was rare. Median weeks until therapy was changed in any way for 25% of patients was as follows: lithium, 29 weeks; antidepressants, 13; anticonvulsants, 13; antipsychotics, 13; and sedatives, 9.Conclusions: Antidepressants were the first-choice agent twice as often as mood stabilizers. Lithium was sustained longer than monotherapy with other mood stabilizers. Time to augmentation was much shorter than time to change or discontinuation. [ABSTRACT FROM AUTHOR]

Objective: Pregnancy poses major challenges for the treatment of bipolar disorder, and information to guide clinical care remains very sparse. The authors sought to determine the illness recurrence risk for women with bipolar disorder who discontinue lithium maintenance during pregnancy. Method: The authors retrospectively compared recurrence rates and survival functions for 101 women with DSM-IV bipolar disorder (68 type I, 33 type II) during pregnancy and postpartum (N=42) or during equivalent periods (weeks 1-40 and 41-64) for agematched nonpregnant subjects (N=59) after either rapid (1-14 days) or gradual (15-30 days) discontinuation of lithium. Recurrence rates also were obtained for the year before discontinuing lithium. Results: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant (52%) and nonpregnant women (58%) but had been much lower for both in the year before treatment was discontinued (21 %). Among subjects who remained stable over the first 40 weeks after lithium discontinuation, postpartum recurrences were 2.9 times more frequent than recurrences in nonpregnant women during weeks 41-64 (70% versus 24%). Depressive or dysphoric-mixed episodes were more prevalent in pregnant than nonpregnant women (63% versus 38% of recurrences). Recurrence risk was greater after rapid than after gradual discontinuation, and for patients with more prior affective episodes, but was similar for diagnostic types I and II. Conclusions: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant and nonpregnant women but then sharply increased postpartum. Risk was much lower during preceding treatment and less with gradual discontinuation. Treatment planning for potentially pregnant women with bipolar disorder should consider the relative risks of fetal exposure to mood stabilizers versus the high recurrence risks after discontinuing lithium. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study clarified the early characteristics of substance use disorders in patients with first-episode bipolar I disorder. METHOD: The authors evaluated substance use disorders, associated factors, and clinical course, prospectively, in the first 2 years of DSM-IV bipolar I disorder with standardized methods. RESULTS: Baseline substance use disorder was found in 33% (37 of 112) of the patients at baseline and in 39% at 24 months. Anxiety disorders were more frequent in the patients with than without substance use disorder (30% and 13%, respectively). Associations of alcohol dependence with depressive symptoms and cannabis dependence with manic symptoms were suggested. Patients using two or more substances had worse outcomes. CONCLUSIONS: Since substance use disorders were frequent from the beginning of bipolar I disorder and were associated with anxiety disorders and poor outcome, early interventions for substance use disorder and anxiety might improve later outcome. [ABSTRACT FROM AUTHOR]

QUESTION: In patients with schizophrenia, how do the efficacy and safety of newer antipsychotic drugs compare with that of clozapine?Data sourcesStudies were identified by searching Biological Abstracts/BIOSIS (to 1999), the Cochrane Library, EMBASE/Excerpta Medica (to 1998), Medline (to 1999), LILACS (January 1998), PsycLIT/PsycINFO (to 1999), reference lists, and conference proceedings and by contacting authors and drug companies.Study selectionStudies were selected if they were randomised controlled trials (RCTs) that compared newer antipsychotic drugs with clozapine in patients with schizophrenia or other schizophrenia like psychoses.Data extraction2 reviewers independently assessed the quality of study methods and extracted data on patient characteristics, drug regimen, trial duration, and outcomes. Disagreements were resolved by discussion.Main results8 blinded RCTs (795 patients) met the selection criteria. Follow up ranged from 4-18 weeks (mean 8.8 wks).Sample sizes ranged from 20-273 patients (mean 107 patients). The data for all atypical drugs (risperidone, remoxipride, zotepine, and olanzapine) were pooled in the comparisons with clozapine. Newer atypical antipsychotic drugs and clozapine did not differ in the number of patients who had clinically significant improvement (5 RCTs), had deterioration in mental state or relapse (6 RCTs), left the study early (6 RCTs), or were dissatisfied with treatment (3 RCTs). Negative and positive symptom scores did not differ between groups. Newer atypical antipsychotic drugs led to less fatigue, nausea/ vomiting, orthostatic dizziness, and hypersalivation but to more extrapyramidal symptoms than clozapine (table). Differences were not statistically significant for libido decrease, dry mouth, seizures, hypersomnia, sedation/drowsiness, or insomnia.ConclusionIn patients with schizophrenia, newer drugs have not yet been shown to be better than clozapine. [ABSTRACT FROM AUTHOR]

Objective: Early assessment can guide accurate diagnosis, prognosis, and treatment-planning for patients with major mental illnesses. Longitudinal studies in psychotic depression from onset are rare, encouraging the present study.Method: We followed 56 DSM-IV MDD patients with psychotic features prospectively and systematically to assess course and predictors of operationally-defined syndromal remission, syndromal recovery, symptomatic remission, functional recovery, and new episodes, and to evaluate diagnostic stability.Results: Among 49/56 cases followed for ≥2 years, 59% retained the initial diagnosis and most achieved syndromal remission (86%) and recovery (84%); 58% remitted symptomatically, and only 35% (17/49) recovered functionally. Syndromal recovery was earlier following subacute onset, lower initial depression scores, and lack of moodincongruent psychotic features. Within 2 years, 45% (22/49) experienced new episodes - earlier with younger onset and higher CGI scores. DSM diagnosis changed in 41%, to bipolar (33%), or schizoaffective disorders (12%), which followed early mania-like or schizophrenia-like features, respectively.Conclusions: Within 2 years of first-hospitalizations, 41% of patients initially diagnosed with psychotic-depression met criteria for DSM-IV bipolar or schizoaffective disorders. Of the 59% retaining the initial diagnosis for 2 years, nearly half experienced new episodes, 42% remained symptomatic, and two-thirds failed to regain their own prior functional status. [ABSTRACT FROM AUTHOR]

Background: Anticipating diagnostic change from major depressive (MDD) to bipolar disorder (BD) can support better prognosis and treatment, especially of depression but is challenging and reported research results are inconsistent. We therefore assessed clinical characteristics associated with diagnostic change from MDD to BD with antidepressant treatments., Methods: We compared characteristics of 3212 initially MDD patients who became (hypo)manic during antidepressant treatment to those with stable MDD diagnoses as well as with cases of stable, spontaneous BD, using standard bivariate and multivariate statistics., Results: Among MDD patients, 6.69% [CI: 5.85-7.61] changed to BD, mostly type II (BD2, 76.7%). BD-converters had higher rates of familial mood disorders (74.1% vs. 57.1%) or BD (33.7% vs. 21.0%) and 2.8-years younger onset than stable MDD patients. They also had more prior depressive recurrences/year, years-of-illness, mood-stabilizer treatment, divorces, fewer children, more suicide attempts and drug-abuse, and higher intake cyclothymia, YMRS and MDQ scores. Predictors independently associated with diagnostic conversion were: more familial BD, depressions/year, unemployment, cyclothymic temperament, suicidal ideation or acts, and fewer children. BD-converters vs. spontaneous BD cases had significantly more suicide attempts, BD2 diagnoses, and affected relatives. Converting to vs. spontaneous BD1 was associated with more ADHD, more suicidal ideation or behavior, MDI course, and younger onset; converting to vs. spontaneous BD2 had more episodes/year, unemployment, ADHD, substance abuse, suicidal ideation or attempts, and more relatives with BD., Conclusions: Few (6.69%) initially MDD subjects converted to BD, most (76.7%) to BD2. Independent predictive associations with diagnostic change included: familial BD, more depressions/year, unemployment, cyclothymic temperament, suicidal behavior and fewer children. Notably, several characteristics were stronger among those changing to BD during antidepressant treatment vs. others with spontaneous BD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Suicidal behavior is more prevalent in bipolar disorders than in other psychiatric illnesses. In the last thirty years evidence has emerged to indicate that long-term treatment of bipolar disorder patients with lithium may reduce risk of suicide and attempts, with possibly similar benefits in recurrent major depressive disorder. We review and update selected research literature on effects of lithium treatment in reducing suicidal behavior and consider proposals that higher levels of lithium in drinking water may be associated with lower suicide rates. We summarize results of a growing number of randomized, controlled studies of lithium treatment for suicide prevention including comparisons with placebos or alternative treatments, and comment on the severe challenges of such trials. The basis of a proposed protective effect of lithium against suicidal behaviors remains uncertain but may include protective effects against recurrences of depressive phases of mood disorders, especially with mixed features or agitation, and possibly through beneficial effects on impulsivity, agitation and dysphoric mood., (© 2024. The Author(s).)

Background: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons., Methods: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling., Results: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not., Conclusions: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There is growing concern about psychiatric illness co-occurring with gender-diversity and neurodiversity, including risk of suicidal behavior. We carried out systematic reviews of research literature pertaining to suicide attempt rates in association with gender- and neurodiversity, with meta-analysis of findings. Rates of suicidal acts ranked: gender-diverse versus controls (20.1% vs. 1.90%; highly significant) > autism spectrum disorder (4.51% vs. 1.00%; highly significant) > attention deficit-hyperactivity disorder (7.52% vs. 4.09%; not significant). Attempt rates also were greater among controls who included sexual minorities (5.35% vs. 1.41%). The rate among male-to-female transgender subjects (29.1%) was slightly lower than in female-to-male subjects (30.7%), who also were encountered 24.3% more often. In sum, suicidal risk was much greater with gender-diversity than neurodiversity. Suicide attempts rate was somewhat greater among female-to-male transgender subjects. Available information was insufficient to test whether suicidal risk would be even greater among persons with both gender- and neurodiversity., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Rapid cycling (RC) at least 4 recurrent episodes per year in bipolar disorder (BD) has been recognized since the 1970s. We now comment on our recent review of the topic and extensive RC analysis in a large clinical cohort, emphasizing therapeutics research., Comments: Prevalence of RC-BD averages 36% for any year versus 22% in the preceding year. Rapid cycling is not a consistent feature over many years, although average long-term, annual recurrence rates are greater in RC-BD patients. Risk of RC may be somewhat greater among women and with older ages. It is also associated with cyclothymic temperament, prominent depression, and mood-switching with antidepressant treatment and is associated with increased suicidal risk. Treatment of individual episodes in RC-BD and effective long-term prevention remain inadequately studied, although antidepressant treatment can worsen RC. Some research supports treatment with aripiprazole, lamotrigine, and lithium, and interest in second-generation antipsychotics is emerging. All such options are used in various inadequately evaluated combinations., Conclusions: Rapid cycling is prevalent among BD patients but seems to vary in risk over time without evidence of progressive worsening. Treatment of acute episodes in RC-BD patients and effective long-term preventive management require much more intensive investigation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Identifying suicidal risk based on clinical assessment is challenging. Suicidal ideation fluctuates, can be downplayed or denied, and seems stigmatizing if divulged. In contrast, vitality is foundational to subjectivity in being immediately conscious before reflection. Including its assessment may improve detection of suicidal risk compared to relying on suicidal ideation alone. We hypothesized that objective motility measures would be associated with vitality and enhance assessment of suicidal risk., Methods: We evaluated 83 adult-psychiatric outpatients with a DSM-5 bipolar (BD) or major depressive disorder (MDD): BD-I (n = 48), BD-II (20), and MDD (15) during a major depressive episode. They were actigraphically monitored continuously over 3 weekdays and self-rated their subjective states at regular intervals. We applied cosinor analysis to actigraphic data and analyzed associations of subjective psychopathology measures with circadian activity parameters., Results: Actigraphic circadian mesor, amplitude, day- and nighttime activity were lower with BD versus MDD. Self-rated vitality (wish-to-live) was significantly lower, self-rated suicidality (wish-to-die) was higher, and their difference was lower, with BD versus MDD. There were no other significant diagnostic differences in actigraphic sleep parameters or in self-rated depression, dysphoria, or anxiety. By linear regression, the difference between vitality and passive suicidal ideation was strongly positively correlated with mesor (p < 0.0001), daytime activity (p < 0.0001), and amplitude (p = 0.001)., Conclusions: Higher circadian activity measures reflected enhanced levels of subjective vitality and were associated with lesser suicidal ideation. Current suicidal-risk assessment might usefully include monitoring of motility and vitality in addition to examining negative affects and suicidal thinking., (© 2023 S. Karger AG, Basel.)

Early abuse has been associated with psychiatric morbidity but comparisons of bipolar (BD) and major depressive (MDD) disorder subjects with versus without early sexual or physical abuse are rare. Patients (n = 684) diagnosed with a DSM-5-TR major mood disorder were evaluated and followed for several years at mood disorder centers to compare details of history and clinical status in participants with versus without early sexual or physical abuse. Early history of sexual (16.2%) or physical abuse (11.9%) was prevalent; 5.15% reported both. Both types of abuse were much more prevalent with BD than MDD. Sexual abuse was associated with younger illness-onset and somewhat younger menarche in females; both abuse-types were associated with familial mood disorders, especially BD. Prospective, long-term illness episode-frequency, depressions or [hypo]manias/year and %-time [hypo]manic all were greater following sexual abuse but morbidity measures did not differ following physical abuse. Prevalence of suicidal behavior ranked: double (48.5%) > physical (32.1%) > sexual (30.3%) abuse, and with BD > MDD (OR = 2.31). Recall bias and not using psychometric instruments to define abuse severity or type may limit interpretation of findings. Early sexual (more than physical) abuse, led to greater morbidity and both abuses were strongly associated with familial mood disorders and greater suicidal risk, especially with double-abuse and BD diagnosis. We support a bilateral relationship between abuse and diagnosis of BD: abuse may facilitate early appearance of BD but also may result from the actions of abusive BD family members., Competing Interests: Declaration of competing interest CV, LT, AM, MP, MC, RJB have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Preventing hospitalization of major affective disorder patients is a fundamental clinical challenge for which lithium is expected to be helpful., Methods: We compared hospitalization rates and morbidity of 260 patients with DSM-5 bipolar or major depressive disorder in the 12 months before starting lithium versus 12 months of its use. We evaluated duration of untreated illness, previous treatments, substance abuse, suicidal status, lithium dose, and use of other medicines for association with new episodes of illness or of symptomatic worsening as well as hospitalization, using bivariate and multivariate analyses., Results: Within 12 months before lithium, 40.4 % of patients were hospitalized versus 11.2 % during lithium treatment; other measures of morbidity also improved. Benefits were similar with bipolar and major depressive disorders. Independently associated with hospitalization during lithium treatment were: receiving an antipsychotic with lithium, suicide attempt during lithium treatment, lifetime substance abuse, and psychiatric hospitalization in the year before starting lithium, but not diagnosis., Limitations: Participants and observation times were limited. The study was retrospective regarding clinical history, lacked strict control of treatments and was not blinded., Conclusions: This naturalistic study adds support to the effectiveness of lithium treatment in preventing hospitalization in patients with episodic major mood disorders., Competing Interests: Declaration of competing interest All authors and immediate family members declare no apparent or potential conflicts of interest in the material presented arising from financial relationships with commercial organizations. In the last two years, MP has received lecture or advisory board honoraria or engaged in clinical trial activities with Angelini Pharma, Lundbeck, Janssen, Pfizer, MSD, Rovi, Fidia and Recordati Corporations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research., Aims: This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus., Methods: We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis., Results: Survey participants ( N  = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis., Conclusions: As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Suicidal behavior is strongly associated with major affective disorders, but there is a need to quantify and compare specific risk and protective factors in bipolar disorder (BD) and major depressive disorder (MDD)., Methods: In 4307 extensively evaluated major affective-disorder participants with BD (n = 1425) or MDD (n = 2882) diagnosed by current international criteria, we compared characteristics among those with versus without suicidal acts from illness-onset through 8.24 years of follow-up., Results: Suicidal acts were identified in 11.4 % of participants; 25.9 % were violent and 6.92 % (0.79 % of all participants) were fatal. Associated risk factors included: diagnosis (BD > MDD), manic/psychotic features in first-episodes, family history of suicide or BD, separation/divorce, early abuse, young at illness-onset, female sex with BD, substance abuse, higher irritable, cyclothymic or dysthymic temperament ratings, greater long-term morbidity, and lower intake functional ratings. Protective factors included marriage, co-occurring anxiety disorder, higher ratings of hyperthymic temperament and depressive first episodes. Based on multivariable logistic regression, five factors remained significantly and independently associated with suicidal acts: BD diagnosis, more time depressed during prospective follow-up, younger at onset, lower functional status at intake, and women > men with BD., Limitations: Reported findings may or may not apply consistently in other cultures and locations., Conclusions: Suicidal acts including violent acts and suicides were more prevalent with BD than MDD. Of identified risk (n = 31) and protective factors (n = 4), several differed with diagnosis. Their clinical recognition should contribute to improved prediction and prevention of suicide in major affective disorders., Competing Interests: Declaration of competing interest AM, LT, MP, MC, RJB have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Excess mortality is a critical hallmark of bipolar disorder (BD) due to co-occurring general medical disorders and especially from suicide. It is timely to review of the status of suicide in BD and to consider the possibility of limiting suicidal risk., Methods: We carried out a semi-systematic review of recent research reports pertaining to suicide in BD., Findings: Suicide risk in BD is greater than with most other psychiatric disorders. Suicide rates (per 100,000/year) are approximately 11 and 4 in the adult and juvenile general populations, but over 200 in adults, and 100 among juveniles diagnosed with BD. Suicide attempt rates with BD are at least 20 times higher than in the adult general population, and over 50 times higher among juveniles. Notable suicidal risk factors in BD include: previous suicidal acts, depression, mixed-agitated-dysphoric moods, rapid mood-shifts, impulsivity, and co-occurring substance abuse. Suicide-preventing therapeutics for BD remain severely underdeveloped. Evidence favoring lithium treatment is stronger than for other measures, although encouraging findings are emerging for other treatments., Conclusions: Suicide is a leading clinical challenge for those caring for BD patients. Improved understanding of risk and protective factors combined with knowledge and close follow-up of BD patients should limit suicidal risk. Ethically appropriate and scientifically sound studies of plausible medicinal, physical, and psychosocial treatments aimed at suicide prevention specifically for BD patients are urgently needed.Reprinted from Bipolar Disord 2021; 23:14-23 , with permission from John Wiley and Sons. Copyright © 2021., (Copyright © 2023 by the American Psychiatric Association.)

Rapid-cycling in bipolar disorder (RC-BD) is associated with greater illness morbidity and inferior treatment response but many aspects remain unclear, prompting this systematic review of its definitions, prevalence, and clinical characteristics. We searched multiple literature databases through April 2022 for systematic reviews or meta-analyses on RC-BD and extracted associated definitions, prevalence, risk-factors, and clinical outcomes. We assessed study quality (NIH Quality Assessment Tool) and levels of evidence (Oxford criteria). Of 146 identified reviews, 22 fulfilling selection criteria were included, yielding 30 studies involving 13,698 BD patients, of whom 3777 (27.6% [CI: 26.8-28.3]) were considered RC-BD, as defined in 14 reports by ≥4 recurrences/year within the past 12 months or in any year, without considering responsiveness to treatment. Random-effects meta-analytically pooled one-year prevalence was 22.3% [CI: 14.4-32.9] in 12 reports and lifetime prevalence was 35.5% [27.6-44.3] in 18 heterogenous reports. Meta-regression indicated greater lifetime prevalence of RC-BD among women than men (p=0.003). Association of RC-BD with suicide attempts, and unsatisfactory response to mood-stabilizers was supported by strong evidence (Level 1); associations with childhood maltreatment, mixed-features, female sex, and type-II BD had moderate evidence (Level 2). Other factors: genetic predisposition, metabolic disturbances or hypothyroidism, antidepressant exposure, predominant depressive polarity (Level 3), along with greater illness duration and immune-inflammatory dysfunction (Level 4) require further study. RC-BD was consistently recognized as having high prevalence (22.3%-35.5% of BD cases) and inferior treatment response. Identified associated factors can inform clinical practice. Long-term illness-course, metabolic factors, and optimal treatment require further investigation., Competing Interests: Declaration of competing interest MS received honoraria/has been a consultant for Angelini, Lundbeck, Otsuka. MAF has received grant support from Assurex Health, Mayo Foundation, CME/Travel/Honoraria from Carnot Laboratories, American Physician Institute, and has financial interest/stock ownership/royalties in Chymia LLC. No other authors or immediate family members have financial relationships with commercial organizations that might appear to represent potential conflicts of interest with the material presented., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Learning Objectives After Participating in This Cme Activity, the Psychiatrist Should Be Better Able to: • Analyze and compare the different bipolar disorder (BD) types.• Identify markers that distinguish BD types and explain how the DSM-IV defines the disorder., Abstract: Since the status of type II bipolar disorder (BD2) as a separate and distinct form of bipolar disorder (BD) remains controversial, we reviewed studies that directly compare BD2 to type I bipolar disorder (BD1). Systematic literature searching yielded 36 reports with head-to-head comparisons involving 52,631 BD1 and 37,363 BD2 patients (total N = 89,994) observed for 14.6 years, regarding 21 factors (with 12 reports/factor). BD2 subjects had significantly more additional psychiatric diagnoses, depressions/year, rapid cycling, family psychiatric history, female sex, and antidepressant treatment, but less treatment with lithium or antipsychotics, fewer hospitalizations or psychotic features, and lower unemployment rates than BD1 subjects. However, the diagnostic groups did not differ significantly in education, onset age, marital status, [hypo]manias/year, risk of suicide attempts, substance use disorders, medical comorbidities, or access to psychotherapy. Heterogeneity in reported comparisons of BD2 and BD1 limits the firmness of some observations, but study findings indicate that the BD types differ substantially by several descriptive and clinical measures and that BD2 remains diagnostically stable over many years. We conclude that BD2 requires better clinical recognition and significantly more research aimed at optimizing its treatment., (Copyright © 2023 President and Fellows of Harvard College.)

Background: Rapid-cycling (RC; ≥ 4 episodes/year) in bipolar disorder (BD) has been recognized since the 1970s and associated with inferior treatment response. However, associations of single years of RC with overall cycling rate, long-term morbidity, and diagnostic subtypes are not clear., Results: We compared descriptive and clinical characteristics in 1261 BD patients with/without RC, based on history and prospective follow-up for several years. RC in any previous year was identified in 9.36% of BD subjects (3.74% in BD1, 15.2% BD2), and somewhat more among women than men. RC-BD subjects had 3.21-fold greater average prospective annual rates of recurrence but not hospitalizations, had less difference in %-time-ill, received more mood-stabilizing treatments, and had greater suicidal risk, lacked familial psychiatric illnesses, had more cyclothymic temperament, were more likely to be married, had more siblings and children, experienced early sexual abuse, but were less likely to abuse drugs (not alcohol) or smoke. In multivariable regression modeling, older age, mood-switching with antidepressants, and BD2 > BD1 diagnosis, as well as more episodes/year were independently associated with RC. Notably, prospective mean recurrence rates were below 4/year in 79.5% of previously RC patients, and below 2/year in 48.1%., Conclusions: Lifetime risk of RC in BD was 9.36%, more likely in women, with older age, and in BD2 > BD1. With RC, recurrence rates were much higher, especially for depression with less effect on %-time ill, suggesting shorter episodes. Variable associations with unfavorable outcomes and prospective recurrence rates well below 4/year in most previously RC patients indicate that RC was not a sustained characteristic and probably was associated with use of antidepressants., (© 2023. The Author(s).)

Background: Pharmacoepidemiological studies of clozapine use to treat bipolar disorder (BD), especially in Asia, are rare, although they can provide insights into associated clinical characteristics and support international comparisons of indications and drug dosing., Methods: We examined the prevalence and clinical correlates of clozapine treatment for BD in 13 Asian countries and regions (China, Hong Kong SAR, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, and Thailand) within an Asian Prescription Patterns Research Consortium. We compared BD patients treated with clozapine or not in initial bivariate comparisons followed by multivariable logistic regression modeling., Results: Clozapine was given to 2.13% of BD patients overall, at a mean daily dose of 275 (confidence interval, 267-282) chlorpromazine-equivalent mg/day. Patients receiving clozapine were older, more likely males, hospitalized, currently manic, and given greater numbers of mood-stabilizing and antipsychotic drugs in addition to clozapine. Logistic regression revealed that older age, male sex, current mania, and greater number of other antipsychotics remained significantly associated with clozapine treatment. Clozapine use was not associated with depressed mood, remission of illness, suicidal risk, or electroconvulsive treatment within the previous 12 months., Conclusions: The identified associations of clozapine use with particular clinical features call for vigilance in personalized clinical monitoring so as to optimize clinical outcomes of BD patients and to limit risks of adverse effects of polytherapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Compare patients diagnosed as DSM-5 type II bipolar disorder (BD2) vs. major depressive disorder (MDD)., Methods: We compared characteristics of 3246 closely and repeatedly evaluated, consenting, adult patient-subjects (n = 706 BD2, 2540 MDD) at a specialty clinic using bivariate methods and multivariable modeling., Results: Factors more associated with BD2 than MDD included: [a] descriptors (more familial psychiatric, mood and bipolar disorders and suicide; younger at onset, diagnosis and first-treatment; more education; more unemployment; fewer marriages and children; higher cyclothymic, hyperthymic and irritable temperament ratings, lower anxious); [b] morbidity (more hypomanic, mixed or panic first episodes; more co-occurring general medical diagnoses, more Cluster B personality disorder diagnoses and ADHD; more alcohol and drug abuse and smoking; shorter depressive episodes and interepisode periods; lower intake ratings of depression and anxiety, higher for hypomania; far more mood-switching with antidepressants; lower %-time depressed; DMI > MDI course-pattern in BD2; more suicide attempts and violent suicidal behavior); [c] item-scores with intake HDRS 21 higher for suicidality, paranoia, anhedonia, guilt, and circadian variation; lower somatic anxiety, depressed mood, insight, hypochondriasis, agitation, and insomnia; and [d] treatment (more lithium, mood-stabilizing anticonvulsants and antipsychotics, less antidepressants and benzodiazepines)., Conclusions: BD2 and MDD subjects differed greatly in many descriptive, psychopathological and treatment measures, notably including more familial risk, earlier onset, more frequent recurrences and greater suicidal risk with BD2. Such differences can contribute to improving differentiation of the disorders and planning for their treatment., Competing Interests: Conflict of interest AM, LT, MP, MC, RJB have no conflict of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium., Methods: We compared factors for association with recurrences of BD within 12 months of discontinuing long-term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium-discontinuation and prior treatment duration., Results: Among 227 BD subjects who received lithium for 4.47 [CI: 3.89-5.04] years and then discontinued, rapid treatment-discontinuation, and stopping for medical reasons were strongly associated with new illness-episodes within 12 months, as were diagnosis (BD-I > BD-II), greater morbidity during lithium-treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment-discontinuation. Early recurrence was not associated with treatment-duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD-I diagnosis remained significantly, independently associated with early illness after lithium-discontinuation, with no effect of treatment duration., Conclusions: Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD-I than BD-II, and following greater morbidity during lithium-treatment, but not related to dose or duration of preceding treatment exposure., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Several second-generation antipsychotic drugs (SGAs) have evidence of benefit for acute major depressive episodes in bipolar disorder (BD) patients. However, their comparative efficacy in types I vs II BD (BD1 vs BD2) remains uncertain., Methods: We carried out a systematic literature search for randomized, double-blinded, controlled treatment trials for acute major depressive episodes involving head-to-head comparisons of BD1 versus BD2 subjects, followed by meta-analyses and meta-regression modeling., Results: Seven reports met out inclusion criteria, yielding 22 comparisons of SGA versus placebo averaging 8.3 weeks in duration. All trials involved quetiapine, which was much more effective than placebo (pooled standardized mean difference [SMD] = 1.76 [95% confidence interval, 1.40-2.12], P < 0.0001). Estimated % improvement averaged 53.5% [46.5-60.5] with quetiapine vs 39.8% [34.2-45.4] with placebo ( P < 0.0001); their ratio was somewhat larger with BD1 (1.56 [1.26-1.86]) versus BD2 subjects (1.22 [1.07-1.37], P = 0.04; as was SMD (BD1: 2.35 [1.83-2.86]; BD2: SMD = 1.44 [1.05-1.82]). Meta-regression found diagnosis (BD1 > BD2) to be the only factor significantly associated with the meta-analytic outcome., Conclusions: Although data are limited, depressed BD1 patients may respond somewhat better to quetiapine than BD2. Additional head-to-head diagnostic comparisons are needed with other SGAs, as well as evaluation of monotherapy versus various combinations that include SGAs in both short- and long-term use., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Lithium salts are widely used clinically, mainly for treatment of bipolar disorder, in which it is highly effective. Various preparations have been developed and tested, including older immediate-release (IR) forms of lithium carbonate and other salts and formulations with slow-release (SR) properties, developed in hopes of increasing the tolerability of lithium treatment, adherence to its use, and possibly its efficacy. Systematic reviews of head-to-head comparisons of pharmacological and clinical properties of such preparations are lacking. Accordingly, we systematically reviewed clinical studies of both IR and SR formulations of lithium salts, seeking to compare their pharmacokinetic properties, adverse effects, clinical tolerability, and clinical effectiveness. Very few such comparative studies were identified and they are highly heterogeneous in design and findings. In 11 included reports, SR formulations appeared to be better tolerated and possibly to be associated with greater adherence to treatment. Studies of comparative clinical efficacy are lacking. Despite decades of use of various lithium salts, systematic comparisons of the pharmacological and clinical properties of IR vs. SR preparations remain rare and to be deepened, though with suggestive superiority of SR salts.

Background: Research findings on factors associated with onset-age (OA) with bipolar (BD) and major depressive disorders (MDD) have been inconsistent, but often indicate greater morbidity following early OA., Methods: We considered factors associated with OA in 1033 carefully evaluated, systematically followed mood disorder subjects with DSM-5 BD (n = 505) or MDD (n = 528), comparing rates of descriptive and clinical characteristics following early (age <18), intermediate (18-40), or later onset (≥40 years), as well as regressing selected measures versus OA. Exposure time (years ill) was matched among these subgroups., Results: As hypothesized, many features were associated with early OA: familial psychiatric illness, including BD, greater maternal age, early sexual abuse, nondepressive first episodes, co-occurring ADHD, suicide attempts and violent suicidal behavior, abuse of alcohol or drugs, smoking, and unemployment. Other features increased consistently with later OA: %-time-depressed (in BD and MDD, women and men), as well as depressions/year and intake ratings of depression, educational levels, co-occurring medical disorders, rates of marriage and number of children., Conclusions: OA averaged 7.5 years earlier in BD versus MDD (30.7 vs. 38.2). Some OA-associated measures may reflect maturation. Associations with family history and suicidal risk with earlier OA were expected; increases of time-depressed in both BD and MDD with later OA were not. We conclude that associations of OA with later morbidity are complex and not unidirectional but may be clinically useful., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care., (© 2022 World Psychiatric Association.)

Objective: To assess rates and lethality of suicidal behavior in studies of children and adolescents diagnosed with major depressive disorder (MDD) or bipolar disorder (BD)., Methods: This PROSPERO-registered protocol (CRD-42019159676) systematically reviewed reports on suicidal behavior among juveniles (age ≤ 18 years), and pooled data on risk (% of subjects) and rates (%/year), followed by random-effects meta-analysis and multivariable linear regression modeling., Results: Included were 41 reports (1995-2020) from 15 countries involving 104,801 juveniles (102,519 diagnosed with MDD, 2282 with BD), at risk for 0.80-12.5 years. Meta-analytically pooled suicide attempter-rates averaged 7.44%/year [95%CI: 5.63-9.25] with BD and 6.27%/year [5.13-7.41] with MDD. Meta-analysis of 5 studies with both diagnostic groups found significantly greater attempt risk with BD vs. MDD (OR = 1.59 [1.24-2.05], p < 0.0001). In 6 studies, suicide rate with juvenile mood disorders averaged 125 [56.9-236]/100,000/year, similar to adult rates, >30-times greater than in the general juvenile population, and higher among older adolescents. The ratio of attempts/suicides (A/S) was 52.6 among mood-disordered juveniles, indicating greater lethality than among juveniles in the general population (A/S ≥ 250), but somewhat less than in the estimated adult general population (A/S ca. 30)., Conclusions: Rates of suicide attempts in juveniles with a major mood disorder averaged 6580/100,000/year, were greater in BD versus MDD observed under the same conditions, and greater with shorter periods of observation. Lethality (fatalities per suicide attempt) was greater in juveniles diagnosed with major affective disorders than in the juvenile general population, but less than in adults., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To compare characteristics of bipolar disorder patients diagnosed as DSM-5 types I (BD-1) vs. II (BD-2)., Methods: We compared descriptive, psychopathological, and treatment characteristics in a sample of 1377 consenting, closely and repeatedly evaluated adult BD patient-subjects from a specialty clinic, using bivariate methods and logistic multivariable modeling., Results: Factors found more among BD-2 > BD-1 cases included: [a] descriptors (more familial affective disorder, older at onset, diagnosis and first-treatment, more education, employment and higher socioeconomic status, more marriage and children, and less obesity); [b] morbidity (more general medical diagnoses, less drug abuse and smoking, more initial depression and less [hypo]mania or psychosis, longer episodes, higher intake depression and anxiety ratings, less mood-switching with antidepressants, less seasonal mood-change, greater %-time depressed and less [hypo]manic, fewer hospitalizations, more depression-predominant polarity, DMI > MDI course-pattern, and less violent suicidal behavior); [c] specific item-scores with initial HDRS 21 (higher scores for depression, guilt, suicidality, insomnia, anxiety, agitation, gastrointestinal symptoms, hypochondriasis and weight-loss, with less psychomotor retardation, depersonalization, or paranoia); and [d] treatment (less use of lithium or antipsychotics, more antidepressant and benzodiazepine treatment)., Conclusions: BD-2 was characterized by more prominent and longer depressions with some hypomania and mixed-features but not mania and rarely psychosis. BD-2 subjects had higher socioeconomic and functional status but also high levels of long-term morbidity and suicidal risk. Accordingly, BD-2 is dissimilar to, but not necessarily less severe than BD-1, consistent with being distinct syndromes., (© 2022. The Author(s).)

Background: This study evaluated associations of PE with symptomatic status in mood and anxiety disorder subjects, and considered many other associated factors so as to expand on comparable previous studies., Methods: Consenting adults at a mood disorder center were assessed for associations of PE frequency ([never, past only, ≤once/week] vs. regularly at 2-3- or >3-times/week) with standard psychometric measures of depression and anxiety symptoms, selected demographic, clinical factors, using bivariate and multivariate methods., Results: Of 2190 subjects (58.8% women; mean age 42.6 years; 44.8% with major depressive, 40.6% bipolar, and 14.6% anxiety disorders), 22.5% currently engaged in regular PE. Such engagement was associated with lower morbidity ratings, youth, male sex, being unmarried, more education, higher socio-economic status (SES), less religious practice, less early abuse, younger age at illness onset and at intake, fewer years ill, lower BMI, fewer siblings, hyperthymic temperament, less time depressed before intake, and living at higher population density. Greater PE-frequency was associated with lower ratings of depression (but not anxiety), male sex, younger age, and lower BMI. Factors independently associated with PE in multivariate modeling ranked by significance: older age at intake ≥ lower BMI > more education > higher SES > male sex., Limitations: PE assessment did not include type, intensity or duration. Some information provided may be subject to recall bias, though it should not affect comparisons among subjects., Conclusion: Regularly repeated PE again appeared to be beneficial for patients with depression or anxiety and should be included in their treatment interventions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest None.

Background: Because use and dosing of mood stabilizers (MSs) to treat bipolar disorder (BD) patients in Asia are not well documented, we examined prevalence and clinical correlates of treatment of Asian BD patients with relatively high doses of MSs., Methods: We conducted a pharmacoepidemiological survey across 13 Asian countries and territory in the Research on Asian Psychotropic Prescription Patterns Consortium. Mood stabilizer doses were converted to lithium carbonate equivalents (Li-eq milligrams per day). We compared relatively high (>900 Li-eq mg/day) versus lower MS doses by bivariate comparisons, followed by multivariable linear regression to identify factors associated with higher MS doses., Results: Among 1647 participants, MS dose averaged 584 (confidence interval, 565-603 Li-eq mg/d). Preliminarily, the 13.1% of the subjects given greater than 900 mg/d versus those given lower doses were younger, male, currently hospitalized, not currently depressed, and reported lifetime suicidal ideation; they also received relatively high doses of antipsychotics, received electroconvulsive treatment within the previous 12 months, and had greater ratings of tremors and sedation. By linear regression modeling, the mean proportion given high doses of MS was associated significantly and independently with higher doses of antipsychotics, younger age, male sex, hospitalized, more years of illness, country, higher body mass index, recent electroconvulsive treatment, and being in illness remission., Conclusions: Relatively high doses of MSs for BD are prevalent, but vary markedly among Asian countries, and are particularly likely among young males, ill for many years, and given high doses of antipsychotics or ECT. These characteristics allow better identification of patient profiles that can guide treatment of BD patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)