Bipolar disorders are chronic psychiatric conditions characterized by recurrent episodes of mania and depression. Affecting over 1% of the global population, these disorders contribute significantly to disability and mortality, often due to suicide and cardiovascular disease. Diagnostic challenges arise from symptom overlap with unipolar depression, frequently leading to delays. Bipolar disorders are driven by complex genetic, neurobiological, and environmental factors and are commonly accompanied by psychiatric and medical comorbidities, further complicating diagnosis and treatment. Standard management strategies include mood stabilizers, antipsychotics, and selective use of antidepressants, complemented by psychosocial interventions like cognitive-behavioral therapy and psychoeducation, which are vital for relapse prevention. Despite recent advancements, the management of bipolar disorders remains challenging, constrained by clinical variability, an absence of specific biomarkers, and differences in approved treatments and treatment guidelines across regions. Emerging research underscores the potential of precision psychiatry and digital health tools to enhance diagnosis and treatment. Nonetheless, critical gaps persist, particularly in implementing equitable care worldwide. This review offers a comprehensive update on bipolar disorders, examining clinical presentation, early diagnosis, pathogenesis, therapeutic strategies, and future perspectives to guide clinicians and researchers in addressing these ongoing challenges in research and clinical practice. None.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol link), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges’g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges’ g = −0.95, 95%C.I. = −1.50, −0.39; p = 0.001; I² = 47.46%) and 2B (NR2B) (Hedges’g = −0.69, 95%C.I. = −1.35, −0.02; p = 0.043; I² = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges’g = −0.91, 95%C.I. = −1.51, −0.32; p = 0.003; I² = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges’g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I² = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders’ neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia.

Emotion dysregulation (ED) is characterized by rigid and frequent use of maladaptive emotion regulation (ER) strategies. Conceptualized as a transdiagnostic feature, ED may occur in both clinical and non-clinical populations, including people diagnosed with bipolar disorder (BD) and their first-degree relatives (FDRs), though expected to manifest with differential clinical features. To this end, we conducted a systematic review and meta-analysis of the literature comparing people with BD to healthy controls (HCs) or FDRs, from inception up to November 25, 2021, across major databases. Random-effects meta-analyses considered twenty-eight studies assessing ER/ED with a validated scale. Patients with BD differed from HCs in adopting more maladaptive ER strategies, such as rumination, risk-taking behaviors, negative focus, and less adaptive ones. Unaffected FDRs differed from people with BD, yet to a lower extent, suggesting that ED may span a continuum. ED in BD should be widely explored to better understand its course and management, with specific interventions aimed at reducing its burden on both high-risk and full-threshold populations.