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The risks and benefits of standard antidepressants for patients with bipolar disorder are not well understood. In this randomized, placebo-controlled trial of patients with bipolar disorder, all of whom received a mood stabilizer, adjunctive treatment with an antidepressant did not reduce the symptoms of bipolar depression or increase the risk of mania. In patients with bipolar disorder, all of whom received a mood stabilizer, adjunctive treatment with an antidepressant did not reduce the symptoms of bipolar depression or increase the risk of mania. Bipolar disorder, the sixth-leading cause of disability worldwide, 1 is a chronic and recurrent psychiatric illness with a lifetime prevalence of just under 4% 2 and annual costs that exceed those of diabetes or recurrent (unipolar) major depressive disorder. 3 Although abnormal mood elevation is the cardinal diagnostic feature that distinguishes bipolar disorder from recurrent major depressive disorder, depression that alternates with manic episodes (bipolar depression) is the leading cause of impairment and death among patients with bipolar disorders. 4 – 6 Two main limitations related to standard antidepressant medications hamper their use in the treatment of bipolar depression. First, though these agents have proved . . .

BackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy; adjunctive treatment is often used to address this unmet need. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with manic, mixed, or depressive episodes of bipolar I disorder, is under investigation as adjunctive therapy for patients with MDD.MethodsThis randomized, double-blind, phase 3 placebo (PBO)-controlled study assessed the efficacy, safety, and tolerability of CAR 1.5 and 3 mg/d as an adjunct to ADT in adult patients with MDD (18–65 years) and inadequate response to ADT alone (NCT03738215). The primary endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions (CGI) were also assessed. Treatment response was defined as at least 50% decrease in MADRS total score at week 6.ResultsPatients (n=751) in the modified intent-to-treat population were randomly assigned to CAR 1.5 mg/d+ADT (n=250), CAR 3 mg/d+ADT (n=252), or PBO+ADT (n=249). Mean age was 44.8 years and 73.4% were female; mean baseline total scores were: MADRS=32.5, HAMD-17=25.9, HAM-A= 21.4. Overall, 89.7% of patients completed the study; rates of discontinuation due to adverse events (AEs) and lack of efficacy were 3.6% and 0.5%, respectively. The difference in MADRS total score change from baseline to week 6 was statistically significant after multiplicity adjustment for CAR 1.5 mg/d vs PBO (-14.1 vs -11.5; adjusted P=.0050), but not for CAR 3 mg/d (-13.1; P=.0727). Differences for CAR 1.5 mg/d vs PBO were observed by week 2 (nominal P=.0453) and maintained at weeks 4 (nominal P<.0001) and 6 (nominal P=.0025). At week 6, more CAR 1.5 mg/d patients (44%) than PBO patients (34.9%) responded to treatment (nominal P=.0446). Greater improvement in the CGI-I scores was observed for CAR 1.5 (nominal P=.0026) and 3 mg/d (nominal P=.0076) vs PBO. At week 6, improvement in HAMD-17 total score reached nominal significance for CAR 1.5 mg/d vs PBO (-13.1 vs -11.1; nominal P=.0017), but not for CAR 3 mg/day (-12.2; P=.0783). HAM-A improvement was greater for CAR 1.5 mg/d vs PBO (nominal P=.0370). There were no deaths; 2 serious AEs occurred in each group (CAR: kidney infection, social stay hospitalization; PBO: depression, multiple sclerosis). The most common CAR AEs (≥5% and twice PBO) were akathisia and nausea.ConclusionCariprazine 1.5 mg/d was effective as adjunctive treatment in adults with MDD and inadequate response to ADT. Cariprazine was generally well tolerated, with a safety profile that was consistent with other indications. Together with results from a prior flex-dose study, these results suggest that adjunctive cariprazine may be an effective option for patients with inadequate response to ADT alone.FundingAbbVie

Pamela Sklar and colleagues report a genome-wide association study of bipolar disorder and identify variants in the genes encoding ankyrin-3 and the alpha-1C subunit of the L-type voltage-gated calcium channel as increasing risk. To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 × 10 −9 ) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 × 10 −8 , rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Evidence indicates that quality of life is subnormal in patients with bipolar disorder and that it differs across mood states. However, the pattern of specific deficits has not been well studied, and the role of potential confounders has received no attention. We investigated the self-reported quality of life, Medical Outcomes Study 36-Item Short Form (SF-36), and Quality of Life Enjoyment and Satisfaction (QLESQ) at baseline across the clinical states of the first 2000 participants enrolled in Systematic Treatment Enhancement Program for Bipolar Disorder. Bivariate analyses indicated significant differences across mood state, with depressive symptoms predicting lower SF-36 mental and physical scores and QLESQ overall score. However, adjustment for relevant clinical and demographic variables erased the difference in the SF-36 physical score. Notably, covariate adjustment removed the apparently “supranormal” SF-36 mental and QLESQ scores among those with mania/hypomania compared with those euthymic. Depressive symptoms are a strong predictor of quality of life, yet covariate adjustment has an impact as well. Clinically, this indicates the need for addressing these factors if quality of life is to be maximized. Such factors should also be taken into account in future naturalistic and clinical trials research on quality of life in bipolar disorder.

Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.

Importance This study employs artificial intelligence methods to predict mood phases in patients with bipolar disorder, addressing the issue of poor prognosis caused by recurrent episodes and uncertainty in mood phases. Objective To explore the patterns of mood transitions in patients with bipolar disorder, we developed a mood phase transition model using a Transformer model to investigate whether predicting mood changes can improve prognosis. Design We conducted cohort follow-up assessments of patients with bipolar disorder. At each visit, patients were evaluated using the Hamilton Depression Rating Scale (HAMD) and the Young Mania Rating Scale (YMRS) as clinician-rated assessments, along with the BDCC self-rating scale. We then input these data into several different AI models for training and validated the models’ performance using the data. Setting The study was conducted through online medical platforms and offline follow-up evaluations. Participants The study included 812 patients diagnosed with bipolar disorder according to DSM-5 criteria, who had at least one BDCC assessment result and at least one depressive episode meeting HAMD criteria and one manic/hypomanic episode meeting YMRS criteria. Result In the experiment utilizing current self-assessment scales for rapid identification of affective states, the best performance was observed with the Transformer and RF models, with AUCs for affective state identification of 0.83 (95% CI 0.77–0.89) for the Transformer model, and 0.88 (95% CI 0.83–0.93) for the RF model. In experiments predicting the next affective state, the AUC for the Transformer prediction was 0.76 (95% CI 0.65–0.87), and for the RF model, it was 0.78 (95% CI 0.68–0.88). In predictions of affective states 90 days later, the Transformer model performed best, with accuracies of 82.76%, 79.31%, 58.62%, and 41.38% for the Transformer, CNN, RF, and SVM models, respectively. Conclusions and relevance To some extent, the AI model can predict patients’ mood phase transition patterns, achieving an AUC greater than 0.8. Decision Curve Analysis (DCA) indicates that patients may obtain clinical benefits based on this predictive model. Additionally, the model demonstrates optimal predictive performance at 180 days. Trial registration http://ClinicalTrials.gov under the identifier NCT02015143

The impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder. To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning. A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year. A current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over I year of prospective study. The negative impact was greater with multiple anxiety disorders. Anxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.

Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone. Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months. The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.

Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life. To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes. In a double-blind randomised maintenance trial, patients received either olanzapine or lithium monotherapy for 1 year. Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms. The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse. Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse (relative risk 4.67, P<0.001). Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms (RR=2.51, P<0.001 and RR=2.35, P=0.03 respectively). These findings help to identify patients at increased risk of affective relapse and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent.