Objectives: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided-a critical gap which the current update aims to address. Method: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results: No agents met threshold for first-line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second-line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second-line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first-line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second-line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first-line, and lithium and olanzapine identified as second-line options. Conclusion: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state. K E Y W O R D S bipolar disorder, guidelines, mixed features, pharmacotherapy TA B L E 1 Characteristics of bipolar disorder with mixed presentations Earlier age of onset Increased risk for hospitalization Higher rates of medical and psychiatric comorbidities Poorer treatment response More frequent and severe episodes (less time euthymic) Poorer response to maintenance treatments Higher risk for suicidal behavior

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IMPORTANCE Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. OBJECTIVE To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. DESIGN, SETTING, AND PARTICIPANTS This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. INTERVENTIONS Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. MAIN OUTCOMES AND MEASURES The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. RESULTS The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, −1.36 [95% CI, −8.92 to 6.19; P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. (continued) Key Points Question Is intermittent theta burst stimulation (iTBS) transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex safe and efficacious in acute bipolar depression? Findings This randomized clinical trial including 37 adults was terminated for futility. There was no evidence of antidepressant superiority for active iTBS over sham iTBS, and safety is uncertain because 1 hypomanic switch occurred with active iT...

BackgroundPatients with major depressive disorder (MDD) display cognitive deficits in acutely depressed and remitted states. Childhood maltreatment is associated with cognitive dysfunction in adults, but its impact on cognition and treatment related cognitive outcomes in adult MDD has received little consideration. We investigate whether, compared to patients without maltreatment and healthy participants, adult MDD patients with childhood maltreatment display greater cognitive deficits in acute depression, lower treatment-associated cognitive improvements, and lower cognitive performance in remission.MethodsHealthy and acutely depressed MDD participants were enrolled in a multi-center MDD predictive marker discovery trial. MDD participants received 16 weeks of standardized antidepressant treatment. Maltreatment and cognition were assessed with the Childhood Experience of Care and Abuse interview and the CNS Vital Signs battery, respectively. Cognitive scores and change from baseline to week 16 were compared amongst MDD participants with (DM+, n = 93) and without maltreatment (DM−, n = 90), and healthy participants with (HM+, n = 22) and without maltreatment (HM−, n = 80). Separate analyses in MDD participants who remitted were conducted.ResultsDM+ had lower baseline global cognition, processing speed, and memory v. HM−, with no significant baseline differences amongst DM−, HM+, and HM− groups. There were no significant between-group differences in cognitive change over 16 weeks. Post-treatment remitted DM+, but not remitted DM−, scored significantly lower than HM− in working memory and processing speed.ConclusionsChildhood maltreatment was associated with cognitive deficits in depressed and remitted adults with MDD. Maltreatment may be a risk factor for more severe and persistent cognitive deficits in adult MDD.

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| INTRODUC TI ONBipolar disorder is a chronic psychiatric illness characterized by recurrent manic and depressive episodes with a lifetime prevalence that reaches 4.4% 1 (including subthreshold cases). Bipolar disorder causes impairment in quality of life, even during periods of euthymia. 2 Patients have been found to spend one-third 3 to one half 4 of their time being symptomatic with periodic mood episodes and persistent residual symptoms, necessitating a search for novel treatments that could be used selectively in different phases of the disorder. Cariprazine is a piperazine derivative that is a partial agonist at dopamine D3 and D2 receptors. 5 Other pharmacodynamics Abstract Objectives: Cariprazine is a partial agonist at D2/D3 receptors that has been approved for the treatment of mania associated with bipolar disorder (BD). This metaanalysis aimed to assess the efficacy and tolerability of cariprazine in the treatment of BD. Methods:Randomized controlled trials investigating the efficacy of cariprazine in BD were included. Of the 391 studies yielded by search, 7 were included. The PRISMA protocol was followed and a set of analyses involving random-effects model with restricted maximum-likelihood estimator were used to synthesize effect sizes. Results:Cariprazine was associated with a moderate and significant reduction of manic symptoms based on YMRS change scores (SMD: −0.52; 95%CI: −0.82 to −0.21; P = .018). Cariprazine resulted in significantly higher remission (OR: 2.05; 95%CI:1.61-2.61; P = .006) and response rates (OR: 2.31; 95%CI: 1.35-3.95; P = .021) for manic and mixed episodes compared with placebo. Both cariprazine 1.5 mg and 3 mg doses were associated with small but significant reduction in depressive symptoms assessed with MADRS scores (SMD: −0.26, 95%CI: −0.49 to −0.02; P = .040) (SMD: −0.21, 95%CI: −0.41 to −0.01; P = .045), respectively. Cariprazine was significantly associated with the development of adverse effects but not with dropouts due to these adverse effects, when compared to placebo.Conclusion: Cariprazine appears to be safe and efficacious in the treatment of acute mania and mixed episodes associated with BD. Cariprazine at doses of 1.5-3 mg/day is efficacious in acute bipolar depression but the effect sizes were smaller. Controlled studies evaluating its efficacy for prophylaxis are needed. K E Y W O R D Santipsychotic, bipolar disorder, cariprazine, mania, meta-analysis, systematic review |

Objective Bipolar disorder (BD) is challenging to treat, and fewer treatments are available for depressive episodes compared to mania. Light therapy is an evidence-based nonpharmacological treatment for seasonal and nonseasonal major depression, but fewer studies have examined its efficacy for patients with BD. Hence, we reviewed the evidence for adjunctive light therapy as a treatment for bipolar depression. Methods We conducted a systematic review of databases from inception to June 30, 2019, for randomized, double-blind, placebo-controlled trials of light therapy in patients with BD (CRD42019128996). The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes included clinical response, remission, acceptability, and treatment-emergent mood switches. We quantitatively pooled outcomes using meta-analysis with random-effects models. Results We identified seven trials representing 259 patients with BD. Light therapy was associated with a significant improvement in Hamilton Depression Rating Scale score (standardized mean difference = 0.43, 95% confidence interval [CI], 0.04 to 0.82, P = 0.03). There was also a significant difference in favor of light therapy for clinical response (odds ratio [ OR] = 2.32; 95% CI, 1.12 to 4.81; P = 0.024) but not for remission. There was no difference in affective switches between active light and control conditions ( OR = 1.30; 95% CI, 0.38 to 4.44; P = 0.67). Study limitations included different light treatment parameters, small sample sizes, short treatment durations, and variable quality across trials. Conclusion There is positive but nonconclusive evidence that adjunctive light therapy reduces symptoms of bipolar depression and increases clinical response. Light therapy is well tolerated with no increased risk of affective switch.

Objectives: It has been proposed that different stages of bipolar disorder may be underpinned by distinct neurobiological substrates. However, structural neuroimaging studies in early stages of the illness are limited by small sample sizes yielding inconsistent findings. The purpose of this systematic review and meta-analysis, therefore, was to identify regional grey matter volume (GMV) changes that are consistently associated with first episode of mania (FEM).Methods: Following PRISMA guidelines, we conducted a systematic search of the literature to identify Voxel-Based Morphometry (VBM) studies in FEM patients compared with healthy individuals. We then conducted a voxel-wise meta-analysis using Seed-based d-Mapping technique. Finally, we performed univariate meta-regression analyses to explore the potential effects of moderator variables including age, gender, and percentage of lithium users on GMV alterations. Results:We identified 15 VBM studies and included 12 studies in the meta-analysis.Four studies found no regional differences in GM volumes while other 11 studies reported volume changes in frontal and temporal regions as well as anterior cingulate cortex (ACC), cerebellum and basal ganglia. The meta-analysis revealed a single cluster of GMV reduction in bilateral pregenual ACC in patients with FEM compared to healthy individuals (P < .001). The Egger's test showed no evidence of publication bias at peak voxel level (P = .447). Meta-regression analyses revealed no significant effects of moderators evaluated. Conclusions:Structural brain changes are evident in the early stages of bipolar disorder. GMV reduction in bilateral pregenual ACC is the most consistent finding in VBM studies of FEM.