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The present systematic review was aimed at critically summarizing the evidence about treatment-emergent manic/hypomanic and depressive switches during the course of bipolar disorder (BD). A systematic search of the MEDLINE, EMBASE, CINAHL, Web of Science, and PsycInfo electronic databases was conducted until March 24th, 2021, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Observational studies clearly reporting data regarding the prevalence of treatment-emergent mood switches in patients with BD were considered for inclusion. Thirty-two original studies met the inclusion criteria. In the majority of cases, manic switches were analyzed; only 3 papers investigated depressive switches in type I BD. Treatment-emergent mania/hypomania in BD subjects ranged from 17.3% to 48.8% and was more frequent with antidepressant monotherapy compared to combination treatment with mood stabilizers, especially lithium, or second-generation antipsychotics. A higher likelihood of mood switch has been reported with tricyclics and a lower rate with bupropion. Depressive switches were detected in 5-16% of type I BD subjects and were associated with first-generation antipsychotic use, the concomitant use of first- and second-generation antipsychotics, and benzodiazepines. The included studies presented considerable methodological heterogeneity, small sample sizes and comparability flaws. In conclusion, many studies, although heterogeneous and partly discordant, have been conducted on manic/hypomanic switches, whereas depressive switches during treatment with antipsychotics are poorly investigated. In BD subjects, both antidepressant and antipsychotic medications seems to play a role in the occurrence of mood switches, although the effects of different pharmacological compounds have yet to be fully investigated., Competing Interests: Conflict of interests G.M. received travel grants from Janssen (unrelated to the present work). N.V. has received financial support for CME activities and travel funds from the following entities (unrelated to the present work): Angelini, Janssen-Cilag, Lundbeck, Otsuka. I.P. has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag and Lundbeck (unrelated to the present work). A.T. received research support from Lundbeck and served as speaker for Angelini and Lundbeck (unrelated to the present work). E.V. has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Generalitat de Catalunya (PERIS), the Spanish Ministry of Science and Innovation (CIBERSAM), EU Horizon 2020, and the Stanley Medical Research Institute. G.P. acted as consultant to Lundbeck, Angelini, FB-Health; he received a scholarship / research support from Lundbeck and Angelini and he is a member of the speaker / advisory board of Sanofi-Aventis, Lundbeck, FB-Health, Angelini (unrelated to the present work). Other authors have no affiliation or financial interest in any organization that may constitute a conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Resistance and worsening of depression in response to antidepressants (ADs) are major clinical challenges. In a large international sample of patients with major depressive disorder (MDD), we aim to explore the possible associations between different patterns of response to ADs and bipolarity. A total of 2811 individuals with a major depressive episode (MDE) were enrolled in the BRIDGE-II-MIX study. This post-hoc analysis included only 1329 (47%) patients suffering from MDD. Patients with (TRD-MDD, n = 404) and without (NTRD-MDD, n = 925) history of resistance to AD treatment and with (n = 184) and without (n = 1145) previous AD-induced irritability and mood lability (AIM) were compared using Chi-square, t-Student's test and logistic regression models. TRD-MDD patients resulted significantly associated with higher rates of AIM, psychotic features, history of suicide attempts, emotional lability and impulsivity, comorbid borderline personality disorder and polipharmacological treatment, compared to NTRD-MDD group. In comparison to NAIM-MDD patients, subjects in the AIM-MDD group showed significantly higher rates of first-degree family history for BD, previous TRD, atypical features, mixed features, psychiatric comorbidities, lifetime suicide attempts and lower age at first psychiatric symptoms. In addition, patients with AIM presented more often almost all the hypomanic symptoms evaluated in this study. Among these latter symptoms, logistic regressions showed that distractibility, impulsivity and hypersexuality were significantly associated with AIM-MDD. In conclusion, in MDD patients, a lifetime history of resistance and/or irritability/mood lability in response to ADs was associated with the presence of mixed features and a possible underlying bipolar diathesis., (Copyright © 2019. Published by Elsevier B.V.)

According to the DSM-5, "reduction in the need for sleep" is the only sleep-related criteria for mixed features in depressive episodes. We aimed at studying the prevalence, clinical correlates and the role of hypersomnia in a sample of acutely depressed patients. Secondarily, we factors significantly increasing the odds of hypersomnia were studied. We conducted a post-hoc analysis of the BRIDGE-II-Mix study. Variables were compared between patients with hypersomnia (SLEEP+) and with insomnia (SLEEP-) with standard bivariate tests. A stepwise backward logistic regression model was performed with SLEEP+ as dependent variable. A total of 2514 subjects were dichotomized into SLEEP+ (n = 423, 16.8%) and SLEEP- (n = 2091, 83.2%). SLEEP+ had significant higher rates of obese BMI (p < 0.001), BD diagnosis (p = 0.027), severe BD (p < 0.001), lifetime suicide attempts (p < 0.001), lower age at first depression (p = 0.004) than SLEEP-. Also, SLEEP+ had significantly poorer response to antidepressants (AD) such as (hypo)manic switches, AD resistance, affective lability, or irritability (all 0<0.005). Moreover, SLEEP+ had significantly higher rates of mixed-state specifiers than SLEEP- (all 0 < 0.006). A significant contribution to hypersomnia in our regression model was driven by metabolic-related features, such as "current bulimia" (OR = 4.21) and "overweight/obese BMI (OR = 1.42)". Globally, hypersomnia is associated with poor outcome in acute depression. Hypersomnia is strongly associated with mixed features and bipolarity. Metabolic aspects could influence the expression of hypersomnia, worsening the overall clinical outcome. Along with commonly used screening tools, detection of hypersomnia has potential, costless discriminative validity in the differential diagnosis unipolar and bipolar depression., (Copyright © 2019. Published by Elsevier B.V.)