Prevention of suicidal behavior with lithium treatment in patients with recurrent mood disorders.

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.

Risk of suicide attempt with gender diversity and neurodiversity.

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.

Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

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.

Current Status and Treatment of Rapid Cycling Bipolar Disorder.

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.

Circadian Activity Rhythms and Psychopathology in Major Depressive Episodes.

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.

Early sexual or physical abuse in female and male mood disorder patients.

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.

Second International Consensus Study of Antipsychotic Dosing (ICSAD-2).

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.

Lithium treatment versus hospitalization in bipolar disorder and major depression patients.

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.

Status of Type II vs. Type I Bipolar Disorder: Systematic Review with Meta-Analyses.

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.

Prevalence and outcomes of rapid cycling bipolar disorder: Mixed method systematic meta-review.

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.

Suicidal risk and protective factors in major affective disorders: A prospective cohort study of 4307 participants.

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.

Characteristics of rapid cycling in 1261 bipolar disorder patients.

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.

Clozapine Use for Bipolar Disorder: An Asian Psychotropic Prescription Patterns Consortium Study.

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.

Comparison of bipolar disorder type II and major depressive disorder.

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 HDRS21 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.

Prevention of Suicidal Behavior in Bipolar Disorder.

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.

Factors associated with onset-age in major affective disorders.

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.

Effects of Treatment of Acute Major Depressive Episodes in Bipolar I Versus Bipolar II Disorders With Quetiapine.

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.