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.

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.

Association between peripheral biomarkers and clinical response to IV ketamine for unipolar treatment-resistant depression: An open label study.

BACKGROUND: Major Depression is the leading cause of disability worldwide. A cohort of patients do not respond adequately to available antidepressants, leading to treatment-resistant depression (TRD). We evaluated the antidepressant efficacy of an acute intravenous ketamine treatment (0.5 mg/kg) for patients with unipolar TRD, and measured peripheral blood-based biomarkers associated with response to treatment. METHODS: Fifteen adults diagnosed with TRD completed an open label study of ten infusions of subanesthetic ketamine over four weeks. Out of fifteen patients, blood was collected from eleven patients at three timepoints to analyze peripheral biomarkers in isolated plasma, including IL-6, IL-10, TNF-α, BDNF, and irisin. Irisin analysis was completed using an ELISA assay, and the remaining biomarkers were analyzed together simultaneously using a multiplex immunoassay. RESULTS: Repeated ketamine infusions produced a significant decrease in total average depressive symptoms (MADRS) at all timepoints. Improvements in depressive symptoms were significant at one week, and continued to significantly decrease until two weeks, where it was maintained. Ketamine was generally well tolerated, and we observed improvements in functional impairment, anhedonia, and psychiatric symptoms, with no increases in manic symptoms. Levels of BDNF throughout treatment inversely correlated to decreases in MADRS scores, and higher levels of baseline BDNF predicted mood responses at one- and four weeks. LIMITATIONS: The study was observational and uncontrolled, with a sample size of 15. Outpatients remained on their course of medications, unless they were pharmacological agents that have previously been identified to block ketamine's effects. CONCLUSIONS: Ketamine may be an efficacious and safe pharmacological option for the acute treatment of patients suffering from severe TRD. BDNF has the potential to function as a prognostic biomarker for predicting response to ketamine treatments.

Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis.

BACKGROUND: Racemic ketamine and esketamine have demonstrated rapid antidepressant effects. We aimed to review the efficacy and safety of racemic and esketamine for depression. RESEARCH DESIGN AND METHODS: We conducted a PRISMA-guided review for relevant randomized controlled trials of racemic or esketamine for unipolar or bipolar major depression from database inception through 2021. We conducted random-effects meta-analyses using pooled rate ratios (RRs) and Cohen's standardized mean differences (d) with their 95% confidence intervals (CI). RESULTS: We found 36 studies (2903 participants, 57% female, 45.1 +/- 7.0 years). Nine trials used esketamine, while the rest used racemic ketamine. The overall study quality was high. Treatment with any form of ketamine was associated with improved response (RR=2.14; 95% CI, 1.72-2.66; I2=65%), remission (RR=1.64; 95% CI, 1.33-2.02; I2=39%), and depression severity (d=-0.63; 95% CI, -0.80 to -0.45; I2=78%) against placebo. Overall, there was no association between treatment with any form of ketamine and retention in treatment (RR=1.00; 95% CI, 0.99-1.01; I2<1%), dropouts due to adverse events (RR=1.56; 95% CI, 1.00-2.45; I2<1%), or the overall number of adverse events reported per participant (OR=2.14; 95% CI, 0.82-5.60; I2=62%) against placebo. CONCLUSIONS: Ketamine and esketamine are effective, safe, and acceptable treatments for individuals living with depression.

Risk factors for early recurrence after discontinuing lithium in bipolar disorder.

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.

Comparative Efficacy and Tolerability of Antipsychotics for Juvenile Psychotic Disorders: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Psychotic disorders produce important morbidity and disability in children and adolescents. There have been few relevant treatment trials, encouraging assessment of research aimed at testing efficacy and safety of antipsychotics for juveniles. We aimed to compare the short- and long-term efficacy and safety of antipsychotics to treat psychotic disorders among children and adolescents. METHODS: Four major bibliographic databases (PubMed, MEDLINE, PsycINFO, and EMBASE) were searched for clinical trials of antipsychotics in children or adolescents, from database inception to May 2021. We searched for clinical trials comparing antipsychotics with control conditions for juvenile psychosis based on blinded review by 2 independent investigators (C.S.Y. and M.L.). We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and applied the Cochrane risk-of-bias tool to appraise study quality. One reviewer (A.B.) performed data abstraction which was confirmed by 2 independent, blinded reviewers (C.S.Y. and M.L.). Primary outcomes were scores rating psychosis symptoms and dichotomized retention in treatment protocols versus dropouts because of adverse events. Effect sizes were pooled using frequentist random-effects network meta-analysis modeling to generate summary rate ratios (RRs) and Cohen d standardized mean differences. RESULTS: Systematic searching generated 1330 unique records. Of these, short-term (n = 15, for 6 [3-12] weeks) and long-term (n = 10, for 12 [6-60] months) treatment trials involved 2208 (39.2% females; median age, 15.3 years), and 1366 subjects (35.0% females; median age, 15.6 years), respectively. Short-term reduction of psychosis scores ranked clozapine (d = -1.35; 95% confidence interval [CI], -1.97 to -0.73]), molindone (-1.22; 95% CI, -1.68 to -0.75), olanzapine (-1.12; 95% CI, -1.44 to -0.81), and risperidone (-0.93; 95% CI, -1.22 to -0.63) as the most effective agents. In longer-term treatment, only lurasidone was effective. Clozapine (RR, 12.8) and haloperidol (RR, 5.15) led to more all-cause and adverse event-related dropouts. There were few trials/drug (1 each for aripiprazole, asenapine, lurasidone, molindone, paliperidone, and ziprasidone, short term; aripiprazole, clozapine, haloperidol, lurasidone, and molindone, long-term). Heterogeneity and inconsistency were high, especially in long-term trials, without evidence of publication bias. CONCLUSIONS: Some antipsychotics were effective and tolerated short term, but longer-term evidence was very limited. The overall paucity of trials and of adequate controls indicates that more well-designed randomized controlled trials are required for adequate assessment of antipsychotic drug treatment for juveniles. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021232937.

Psychological symptoms, mental fatigue and behavioural adherence after 72 continuous days of strict lockdown during the COVID-19 pandemic in Argentina.

BACKGROUND: An early and prolonged lockdown was adopted in Argentina during the first wave of COVID-19. Early reports evidenced elevated psychological symptoms. AIMS: To explore if the prolonged lockdown was associated with elevated anxiety and depressive symptoms; if mental fatigue was associated with lockdown adherence (a phenomenon called 'behavioural fatigue'); and if financial concerns were associated with lockdown adherence and emotional symptoms. METHOD: The survey included standardised questionnaires to assess depressive (PHQ-9) and anxious (GAD-7) symptoms, mental fatigue, risk perception, lockdown adherence, financial concerns, daily stress, loneliness, intolerance to uncertainty, negative repetitive thinking and cognitive problems. LASSO regression analyses were carried out to predict depression, anxiety and lockdown adherence. RESULTS: The survey reached 3617 adults (85.2% female) from all provinces of Argentina after 72 days of lockdown. Data were collected between 21 May 2020 and 4 June 2020. In that period, Argentina had an Oxford stringency index of 85/100. Of those surveyed, 45.6% and 27% met the cut-offs for depression and anxiety, respectively. Mental fatigue, cognitive failures and financial concerns were correlated with psychological symptoms, but not with adherence to lockdown. In regression models, mental fatigue, cognitive failures and loneliness were the most important variables to predict depression, intolerance to uncertainty and lockdown difficulty were the most important for anxiety, and perceived threat was the most important for predicting lockdown adherence. CONCLUSIONS: During the extended lockdown, psychological symptoms increased, being enhanced by mental fatigue, cognitive difficulties and financial concerns. We found no evidence of behavioural fatigue. Thus, feeling mentally fatigued is not the same as being behaviourally fatigued.

Validation study of the Spanish brief version of TEMPS-A.

INTRODUCTION: Identifying affective temperaments could be useful both for understanding the normal behavioral variations in the general population and to establish if there is a clinical predisposition to certain disorders. Five affective temperaments have been proposed: depressive, cyclothymic, hyperthymic, irritable and anxious. Original instrument for measuring them (TEMPS-A) is a 110-item scale but many short versions in different languages have been validated. The aim of this study was to obtain a short self-administered Spanish version of TEMPS-A with good psychometric properties. MATERIALS AND METHODS: A sample of 550 students who answered the argentinean version of TEMPS-A was included, after psychometric analysis a comparison between inpatients with major depression and their matched controls by sex and age who answered the brief version was performed to get an external validation. RESULTS: The sample was composed by 298 (54.2%) women. The mean age was 23.3 year (SD=6.2). A forced five factor analysis was performed. The 7 items with the highest factorial load (more than 0.350) for each subscale were included in the brief version. The Cronbach alpha's ranged from 0.690 to .800. The most prevalent temperament was hyperthymic followed by cyclothymic for students sample. Similarities between students and controls sample were observed, but not with patients with major depression. CONCLUSIONS: This brief Spanish version of TEMPS-A (35 items) has good psychometric properties and can be used in general and clinical population.

Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium.

BACKGROUND: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear. METHODS: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes. RESULTS: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9-15]); esketamine (7 [5-10]) and lithium (5 [4-10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4-6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4-6) for esketamine, and 9 (5-106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25-10.60) for lithium and much less favorable for esketamine (0.71 [0.60-0.80]) or SGAs (0.45 [0.17-0.77]). CONCLUSIONS: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated. LIMITATIONS: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.

Long-Term Treatment of Bipolar Disorder with Valproate: Updated Systematic Review and Meta-analyses.

LEARNING OBJECTIVE: After participating in this activity, learners should be better able to:• Evaluate the evidence regarding the effectiveness of long-term treatment of bipolar disorder with valproate. BACKGROUND: Prophylactic treatment is critical for bipolar disorder (BD) patients. Valproate is commonly used for this purpose but lacks regulatory approval and carries appreciable risks. METHODS: Systematic literature searching through June 2020 sought prospective trials lasting ≥12 months with adults diagnosed with BD to support comparisons of risk of new illness episodes with valproate versus placebo or other agents. RESULTS: Included were 13 reports involving 9240 subjects treated for an average of 29.1 months (range, 12-124) in 21 trials: 9 were blinded, randomized trials (RCTs) of valproate versus placebo (n = 3), lithium (5), or olanzapine (1); 2 were unblinded RCTs versus lithium (1) or quetiapine (1); and 10 were open-label trials versus lithium (5), quetiapine (2), carbamazepine (1), lamotrigine (1), or olanzapine (1). Random-effects meta-analysis found valproate superior to placebo in 3 trials (odds ratio [OR] = 0.42 [95% confidence level (CI), 0.30-0.60]; p < .0001). In 11 trials, protective effects with valproate and lithium were similar (OR = 1.20 [CI, 0.81-1.79]; p = .36), as well in 5 comparisons versus antipsychotics quetiapine and olanzapine (OR = 0.96 [CI, 0.66-1.40]; p = .84), and 2 versus other mood-stabilizing anticonvulsants (carbamazepine and lamotrigine) (OR = 1.30 [CI, 0.75-2.26]; p = .34). Valproate was nonsignificantly more effective versus new mania than depression (χ2 = 3.03; p = .08). CONCLUSIONS: Valproate was more effective than placebo in preventing new BD episodes of mania or depression, and not significantly different from lithium, second-generation antipsychotics, or other anticonvulsants. Overall benefits were nonsignificantly greater versus mania than bipolar depression.

Ketamine for Bipolar Depression: A Systematic Review.

BACKGROUND: Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, its efficacy in bipolar depression is less clear. This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression. METHODS: We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since each database's inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies. RESULTS: We identified 6 studies, with 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials. CONCLUSIONS: There is some preliminary evidence supporting use of intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.

Subanesthetic ketamine infusions for suicide ideation in patients with bipolar and unipolar treatment refractory depression.

We evaluated the effects of repeated subanesthetic ketamine infusions on suicidal ideation (SI) in patients with major depression. 82 subjects with treatment-resistant unipolar and bipolar depression completed a two-site open-label case-series of repeated (up to four weeks) infusions of ketamine (0.5 mg/kg). Ketamine produced a significant reduction in SI as early as one hour (71.1%) and up to 1-week post-infusion (60.4%), accompanied by a reduction in overall depressive symptoms which were maintained until the 4th week. The observed anti-suicidal effect was independent of mood changes, as patients whose mood did not respond still exhibited significantly less SI than baseline.