Singh, Balwinder

Abstract Background Anxiety disorders (ANX) affect 30–60% of individuals with bipolar disorder (BD), yet limited research has systematically examined clinical characteristics and treatment patterns in this comorbid population. This study investigated demographic, clinical, and pharmacotherapeutic differences between individuals with BD with and without comorbid ANX. Methods Cross-sectional data from 2,225 adults with BD enrolled in the Mayo Clinic Bipolar Disorder Biobank were analyzed. Participants were assessed for comorbid ANX, demographics, clinical characteristics, medication use, and treatment response using the Alda-A scale. Results Overall, 61% (n = 1,366) had comorbid ANX. Individuals with BD + ANX were younger (40.4 vs. 43.6 years, p < 0.001), more likely female (66.6% vs. 54.8%, p < 0.001), and exhibited higher rates of rapid cycling (64.2% vs. 45.2%, p < 0.001), suicide attempts (40.4% vs. 24.8%, p < 0.001), substance use disorders (63.5% vs. 54.8%, p < 0.001), and somatic comorbidities (MCIRS: 6.68 vs. 5.42, p < 0.001). Pharmacotherapeutically, BD + ANX individuals were less likely to receive lithium (37.1% vs. 47.8%, p = 0.005) and valproic acid (21.7% vs. 29.6%, p = 0.047), but more likely to receive antidepressants (53.8% vs. 39.5%, p < 0.001), benzodiazepines (39.9% vs. 26.6%, p < 0.001), and gabapentinoids (8.5% vs. 4.5%, p < 0.001). Notably, 17.3% of BD + ANX individuals received antidepressants without mood stabilizer coverage. Treatment response (Alda-A) scores were significantly lower in BD + ANX for lithium (4.91 vs. 6.05, p < 0.001), mood-stabilizing anticonvulsants (5.09 vs. 6.22, p < 0.001), and second-generation antipsychotics (4.67 vs. 5.73, p < 0.001). Similar patterns were observed in both BD-I and BD-II subtypes. Conclusions Individuals with BD + ANX represent a more severely affected subgroup with distinct prescribing patterns favoring antidepressants over mood stabilizers and attenuated mood stabilizers response. These findings highlight the need for anxiety-informed treatment algorithms recognizing anxiety comorbidity as a negative prognostic factor.

Background: Depression affects approximately 5.7% of adults worldwide, and around one-third of these individuals develop treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (administered IV or intranasally (IN)) are novel treatment options for TRD; however, only IN esketamine currently holds FDA approval. Objectives: Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD. Design: Mantel–Haenszel random-effects meta-analysis of head-to-head studies. Response and remission at study end point were co-primary outcomes, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses explored the impact of diagnosis, study type, and publication format; heterogeneity was quantified with I 2 . Data sources and methods: MEDLINE, Embase, Cochrane, APA Psycinfo, and Scopus were searched from inception through 19 March 2025. Eligible studies enrolled adults with unipolar or bipolar depression directly comparing IV ketamine with esketamine and reporting response or remission. Results: Screening 1089 records identified eight studies ( n = 978). Seven observational studies ( n = 915) comparing IV ketamine with IN esketamine were included in the meta-analysis, while one randomized controlled trial (RCT) comparing IV formulations was summarized qualitatively. Pooled response from six studies gave OR = 1.26 (95% CI, 0.92–1.71; p = 0.15) and remission from seven studies gave OR = 1.31 (95% CI, 0.93–1.86; p = 0.12), both nonsignificantly favoring IV ketamine with negligible heterogeneity ( I 2 = 0%). Sensitivity analyses excluding bipolar depression or abstract-only reports yielded similar effect estimates, reinforcing the robustness of the findings. Evidence across three studies for faster onset with IV ketamine ranged from significant in one study to modest trends in two. Conclusion: Based on the currently available comparative evidence, which is almost entirely observational, IV ketamine and IN esketamine show comparable acute response and remission rates, though IV ketamine may act faster. Large head-to-head RCTs are needed to confirm these findings. Trial registration: The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev .

Background: Lithium is a mainstay treatment for bipolar disorder, but its narrow therapeutic index and susceptibility to pharmacokinetic interactions make appropriate monitoring crucial. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are increasingly prescribed for type 2 diabetes and weight management. Scarce evidence exists on the potential interaction between semaglutide and lithium. Methods: We present 3 cases involving patients on stable lithium regimens who were initiated on semaglutide, reviewing potential mechanisms underlying the interaction between them. Findings: In 2 cases, lithium levels increased significantly, leading to toxicity despite stable renal function and no changes in concurrent medications. In the third case, preemptive reductions in lithium dosage mitigated toxicity, although lithium levels remained higher than anticipated. Mechanistic hypotheses that might contribute to semaglutide-associated elevated lithium levels include altered kidney function, dehydration from reduced oral intake, vomiting, or diarrhea, and delayed gastric emptying. Conclusions: To our knowledge, this is one of the first documented case series describing a potential interaction between semaglutide and lithium in the medical literature. These cases underscore the importance of vigilant monitoring when combining lithium with semaglutide, and potentially other GLP-1 RAs. Baseline renal function, hydration status, and lithium levels should be assessed before initiating semaglutide, and lithium levels should be monitored more frequently during therapy. Clinicians prescribing semaglutide to patients on lithium should exercise caution, monitor for signs of toxicity, and provide appropriate patient education. Further research is needed to elucidate the mechanisms of this potential interaction and its clinical significance.

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

Introduction Bipolar disorder (BD) is a chronic illness affecting approximately 2-3% adults worldwide. Mood stabilizers, such as lithium, valproate, carbamazepine, and lamotrigine are mainstays of the treatment. Despite their benefits, mood stabilizers carry a risk of side effects, which can lead to treatment discontinuation and non-adherence rates ranging from 10 to 60% in BD patients (Dols et al. Int Clin Psychopharmacol 2013; 28, 287-296). Dermatologic side effects, also known as cutaneous adverse drug reactions, are particularly distressing, often impacting patients’ self-esteem and social interactions, and contributing to non-compliance. These reactions can range in severity from mild rashes, acneiform eruptions, hair loss and psoriasis to severe, life-threatening conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (Mitkov et al. Psychosomatics 2014; 55, 1-20).Objectives Despite the well-documented association between mood stabilizers and dermatologic adverse effects (AE), the overall prevalence of these reactions across mood stabilizers remains unclear. This systematic review and meta-analysis aims (1) to estimate the prevalence of dermatologic AE associated with mood stabilizer (lithium, valproate, carbamazepine and lamotrigine) use in patients with BD, and (2) to summarize the available evidence on the onset and timing of these reactions.MethodsWe searched Ovid MEDLINE®, Embase, Cochrane Library, Web of Science, Scopus, and PsycINFO from 1970 onward for studies on dermatologic AEs in BD patients treated with lithium, valproate, carbamazepine, or lamotrigine (CRD42022357268). Study selection, data extraction, and bias risk assessment were performed by two reviewers. Meta-analyses were conducted to estimate the prevalence rates for dermatologic AEs.ResultsThe initial database searches yielded 5,354 studies. 47 articles were deemed relevant and included in this systematic review. Study designs included 16 randomized controlled trials, 10 non-randomized open-label trials, 12 cohort studies, and 9 cross-sectional studies. Lithium was associated with acneiform eruptions in 4.4% (95% CI: 1.0-17.0%), rash in 1.8% (95% CI: 0.7-4.8%), and hair loss in 1.7% (95% CI: 0.4%-6.4%) of patients. For valproate, hair loss was observed in 4.6% of patients (95% CI: 3.0-6.7%) and rash in 2.9% (95% CI: 1.6-5.3%). Carbamazepine was associated with rash in 6.0% of patients (95% CI: 4.4-7.6%), but severe reactions such as SJS and TEN were not reported. Lamotrigine had the highest rash prevalence with 9.2% (95% CI: 7.2-11.8%), while severe reactions were rare (0.04%, 95% CI: 0.00-0.63%).Conclusions Mood stabilizers showed varying levels of dermatologic AEs, but severe reactions were rare. Future studies should explore factors influencing these outcomes, their impact on quality of life and treatment participation, and potential management strategies.Disclosure of InterestNone Declared

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.

Abstract Background: Responsiveness to mood-stabilizing pharmacotherapy varies in bipolar disorder (BD). We investigated clinical correlates of second-generation antipsychotic (SGA) treatment response and conducted the first genome-wide association study (GWAS), including exploratory polygenic scores (PGS), of SGA pharmacogenomic treatment response in BD. Methods: Treatment response was quantified using the Alda scale, and GWAS was performed using Alda-A score, controlling for sex, genotyping batch, and the genomic principal components. Results: The cohort included 2,159 adults with BD (1,416 BD-I, 691 BD-II, 51 schizoaffective BD), mean age 41.8 years, 62% female, 84% white, and 14% Hispanic. Nearly half (48%) were treated with SGAs. Current SGA users were younger (41.2±14.7 vs. 42.5±15.3 years, p =0.040), more likely to be Hispanic (14% vs. 11%, p =0.047), had a higher body mass index (BMI; 30.4±7.6 vs. 29.5±7.1 kg/m 2 , p =0.005). Lifetime comorbidity patterns for current SGA users include higher rates of manic psychosis (29% vs. 17%, p <0.001) and eating disorders — Anorexia Nervosa (7% vs. 4%, p =0.003), Bulimia Nervosa (7% vs. 4%, p =0.003), and Binge Eating Disorder (14% vs. 11%, p =0.030). We detected a genome-wide significant association between SGA Alda-A scores and GAS7 variants (top variant: rs202127418, β =-2.998, p =4.96E-08). However, SGA response was not significantly associated with PGS for schizophrenia, BD, and major depression (FDR>0.05). Conclusions: SGAs are frequently utilized as mood stabilizers in patients with BD and are associated with manic psychosis and eating disorders. GAS7 variants may predict SGA response, but larger, more diverse cohorts are needed for validation.