Singh, Balwinder

Mood disorders are among the most disabling and complex psychiatric conditions, affecting millions worldwide and contributing substantially to morbidity, mortality, and healthcare utilization [...]

ABSTRACT Objectives To explore the clinical impact of social determinants of health (SDoH) stress in bipolar disorder (BD) course of illness and to explore potential gender differences in SDoH stress endorsement. Methods 2280 individuals living with BD type I or II (62% women; 67.5% BD‐I) participating in the Mayo Clinic Bipolar Biobank who completed a questionnaire assessing positive and negative‐valent stressors in the 12 months prior to study enrollment were included for this analysis. Six negative stressors were used as proxies of SDoH. Generalized linear models were used to test the association between SDoH stressors and markers of illness severity as well as potential differences by sex by including an interaction term. Results After adjusting for age, sex, and recruitment site, SDoH‐related stressors were significantly associated with a more severe course of illness in both men and women. Except for unemployment rates, women reported more frequently SDoH‐related stress (i.e., lack of family support, financial problems, health coverage and access problems). Conclusions The study found significant gender differences in both the endorsement of specific SDoH stressors and in the prevalence of specific illness severity markers; however, it did not directly test the predictive relationship between gender differences in SDoH and illness severity markers. Future studies aiming to achieve health equity in mental health care should continue assessing social determinants of health stressors, incorporating a gender perspective to better understand their influence on bipolar disorder.

ABSTRACT Objective Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment‐resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies. Methods The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD. Results TRBD was defined as the failure to achieve a significant and sustained clinical response after at least two approved and adequately dosed pharmacological treatments, administered for a sufficient duration with treatment adherence. For bipolar I (BD‐I) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks), lurasidone (20–120 mg/day for ≥ 6 weeks), the combination of olanzapine (6–12 mg/day) and fluoxetine (25–75 mg/day for ≥ 8 weeks), cariprazine (1.5–3 mg/day for ≥ 6 weeks), and lumateperone (42 mg/day for ≥ 6 weeks). For bipolar II (BD‐II) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks) and lumateperone (42 mg/day for ≥ 6 weeks). Conclusion This consensus definition aims to provide clarity for clinical trials, improve consistency in research, and guide treatment approaches and inform regulatory pathways. It represents a foundational step in addressing the unmet needs in TRBD and promoting the development of innovative therapeutic strategies. Future efforts will focus on adapting the definition to better align with real‐world clinical challenges and optimize patient care.

Background: Invasive and non-invasive neuromodulation in psychiatry represents a burgeoning field that leverages advanced neuromodulation techniques to address substance use disorders (SUDs). Aims: This narrative review synthesizes findings from multiple reviews to evaluate the efficacy of neuromodulation in treating SUDs. Methods: A comprehensive literature search was conducted between December 2024 and April 2025, focusing on systematic reviews and meta-analyses that examined various neuromodulation modalities, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). The selected reviews were analyzed to identify common themes, outcomes, and gaps in the current understanding of these treatments for SUDs. Results: 11 reviews met the final inclusion criteria; 5 focused on non-invasive neuromodulation (rTMS, tDCS) and 6 on invasive neuromodulation (DBS). Non-invasive neurostimulation was associated with modest improvements in craving and cognitive dysfunction in individuals with SUDs. Similarly, invasive neuromodulation (DBS), through high-frequency stimulation of the bilateral nucleus accumbens, appeared to reduce cravings and improve comorbid psychiatric symptoms in both preclinical and human studies. Importantly, small sample sizes, heterogeneity in targets and stimulation protocols, and short follow-up periods significantly limit the generalizability of current findings from both non-invasive and invasive neuromodulation studies. Conclusions: As novel and more effective therapies for the treatment of SUD are desperately needed, procedural interventional psychiatry holds promise. However, despite encouraging results, existing evidence is still preliminary, and larger, rigorously designed studies are warranted to further establish the safety and efficacy of neuromodulatory interventions for SUD treatment.

Abstract Purpose/Background Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Abstract Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.