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The search for biomarkers has been a leading endeavor in biological psychiatry. To analyze its evolution over the years, we performed a systematic review to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main features of studies proposing them as biomarkers and (c) whether their patterns of variation are similar across disorders. Of the six molecules most commonly studied as plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across diagnoses. An analysis of this literature showed that, while 66% of studies compared patients and controls, only 34% were longitudinal, and only 10% presented a measure of diagnostic or prognostic efficacy. Meta-analyses showed variation in the levels of these molecules to be robust across studies, but similar among disorders, suggesting them to reflect transdiagnostic systemic consequences of psychiatric illness. Based on this, we discuss how current publication practices have led to research fragmentation across diagnoses, and suggest approaches to face this issue.

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Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed out as potential biomarkers of bipolar disorder. Indeed, recent studies have shown that bipolar disorder involves microglial activation in the hippocampus and alterations in peripheral cytokines, suggesting a potential link between neuroinflammation and peripheral toxicity. These abnormalities may also be the biological underpinnings of outcomes related to neuroprogression, such as cognitive impairment and brain changes. Additionally, astrocytes may have a role in the progression of bipolar disorder, as these cells amplify inflammatory response and maintain glutamate homeostasis, preventing excitotoxicity. The present review aims to discuss neuron-glia interactions and their role in the pathophysiology and treatment of bipolar disorder.

| 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 |

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.

Objective: To review the current evidence for efficacy of cannabidiol in the treatment of mood disorders. Methods: We systematically searched PubMed, Embase, Web of Science, PsychInfo, Scielo, ClinicalTrials.gov , and The Cochrane Central Register of Controlled Trials for studies published up to July 31, 2019. The inclusion criteria were clinical trials, observational studies, or case reports evaluating the effect of pure cannabidiol or cannabidiol mixed with other cannabinoids on mood symptoms related to either mood disorders or other health conditions. The review was reported in accordance with guidelines from Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. Results: Of the 924 records initially yielded by the search, 16 were included in the final sample. Among them, six were clinical studies that used cannabidiol to treat other health conditions but assessed mood symptoms as an additional outcome. Similarly, four tested cannabidiol blended with Δ-9-tetrahydrocannabinol in the treatment of general health conditions and assessed affective symptoms as secondary outcomes. Two were case reports testing cannabidiol. Four studies were observational studies that evaluated the cannabidiol use and its clinical correlates. However, there were no clinical trials investigating the efficacy of cannabidiol, specifically in mood disorders or assessing affective symptoms as the primary outcome. Although some articles point in the direction of benefits of cannabidiol to treat depressive symptoms, the methodology varied in several aspects and the level of evidence is not enough to support its indication as a treatment for mood disorders. Conclusions: There is a lack of evidence to recommend cannabidiol as a treatment for mood disorders. However, considering the preclinical and clinical evidence related to other diseases, cannabidiol might have a role as a treatment for mood disorders. Therefore, there is an urgent need for well-designed clinical trials investigating the efficacy of cannabidiol in mood disorders.

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