Frye, Mark A.

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

Importance There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. Objective To address circumstances warranting psychotropic medication deprescribing. Evidence Review The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Findings Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Conclusions and Relevance Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

Background: Bipolar disorder (BD) is associated with a higher prevalence of chronic kidney disease (CKD) and increased mortality, yet individuals with both BD and CKD are less likely to receive kidney replacement therapy (KRT). Sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide renal protection in diabetes, but their long-term effects in this high-risk population remain unknown. Objectives: To evaluate whether SGLT2i use reduces the risk of KRT and all-cause mortality in adults with BD and mild-to-moderate CKD (stage ⩽ 3). Design: Observational cohort study with propensity score matching (PSM). Method: In this study using TriNetX (2009–2024) real-world database, 89,369 adults with BD and mild-to-moderate CKD were classified as SGLT2i users ( n = 12,736) or nonusers ( n = 76,633). Primary outcomes were progression to KRT and all-cause mortality over 5 years. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models, and 1:1 PSM reduced confounding. Subgroup analyses examined sex, race/ethnicity, diabetes status, CKD stage, and mood stabilizer use. Results: SGLT2i use was associated with lower risk of KRT (aHR 0.47 (95% CI, 0.42–0.53)) and all-cause mortality (aHR 0.69 (95% CI, 0.65–0.73); both p < 0.001). Protective effects were consistent across subgroups, including individuals receiving lithium, lamotrigine, valproate, or antipsychotics. After PSM (10,967 matched pairs), 5-year KRT-free survival was 94.61% versus 90.99%, and overall survival was 78.67% versus 67.53% (both p < 0.001). Given the observational design, the possibility of residual or unmeasured confounding canot be excluded. Conclusion: SGLT2i therapy in individuals with BD and mild-to-moderate CKD is associated with substantially lower risks of KRT and all-cause mortality. Prospective trials are needed to confirm these findings.

Background: Lithium, the gold standard treatment of bipolar disorder (BD), is thought to cause nephropathy in long-term users. However, the role of confounding variables linked to BD in exerting this adverse effect remains unclear. Objectives: This paper evaluates kidney function in patients with affective disorders who are taking lithium compared to patients not on lithium treatment. Design: This article is a systematic review and meta-analysis. Data sources and methods: A comprehensive search of publications up to October 2023 within Cochrane, Embase, PubMed, Scopus, Web of Science, and CINAHL databases was performed. Three assessors screened and extracted data from eligible observational studies. Risk of bias assessment was done with the ROBINS-E tool. Eligible studies were comparative studies of adult patients with diagnoses of affective disorders, including BD on lithium, with control groups not on lithium, reporting kidney function outcomes. Results: Mean estimated Glomerular filtration rate (eGFR) showed less favorable outcomes in the lithium group compared to the non-lithium group ( n = 1622, MD = −11.14 ml/min/1.73 m 2 , 95% CI: −16.61, −5.68, I 2 = 86%). The mean annual eGFR decline comparison favored the non-lithium group ( n = 13,280, MD = 0.13 ml/min/1.73 m 2 , 95% CI: 0.06, 0.20, I 2 = 0%). Serum creatinine concentration (mg/dl) was found to be higher in the lithium compared to non-lithium groups ( n = = 1704, MD = 0.05, 95% CI: 0.03, 0.07, I 2 = 3%). New or progressing chronic kidney disease events were not found to be statistically different between the lithium and control groups ( n = = 17,740, OR = 2.16, 95% CI: 0.59, 7.94, I 2 = 99%). The high heterogeneity in this meta-analysis limits the reliability and interpretability of our results. Conclusion: Kidney function, as measured by eGFR, was decreased in the lithium-taking groups versus the non-lithium groups. Continuous monitoring and discussion of risks and benefits with patients, especially those with a baseline of reduced kidney function, is imperative. Trial registration: This review was registered prospectively with PROSPERO (CRD42024517414).

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.

ABSTRACT Background Mood episodes in bipolar disorder (BD) follow a seasonal pattern in approximately 25% of patients. We aimed to examine the associations of specific seasonality patterns in BD with various clinical phenotypes and treatment‐related outcomes. Methods Patients from the Mayo Clinic Bipolar Disorder Biobank with available seasonality data were included in the study. Among those reporting any seasonality, participants were further categorized into four seasonality groups: fall/winter depression, spring/summer (hypo)mania, biphasic (fall/winter depression with spring/summer (hypo)mania), and equinoctial seasonality (any mood episode occurring in spring or fall). Regression models were used, treating seasonality patterns as the predictor of clinical phenotypes (BD subtype, early onset, history of psychosis, suicide attempt, rapid cycling), lifetime medication exposure (number of unique antidepressants, antipsychotics, and any psychotropics) and treatment response to mood stabilizers (Alda A score). Results Among 1702 patients with BD (61.5% female, mean age = 41.43 ± 14.73 years), 44.6% reported seasonal mood episodes. Individuals with any seasonality were more likely to have BD‐I (OR = 1.29, p = 0.024), early onset (OR = 1.29, p = 0.026), exposure to higher lifetime number of antipsychotics (IRR = 1.20, p < 0.001) and any psychotropics (IRR = 1.13, p < 0.001). Fall/winter depression was associated with a higher lifetime number of antidepressants (IRR = 1.18, p = 0.021), any psychotropics (IRR = 1.14, p = 0.013), worse response to lithium ( β = −0.82, p = 0.029) and all mood stabilizers ( β = −0.69, p = 0.014). Spring/summer (hypo)mania showed negative associations with rapid cycling (OR = 0.36, p < 0.001) and lifetime number of antidepressants (IRR = 0.70, p = 0.013). Equinoctial seasonality was linked to a history of psychosis (OR = 1.76, p = 0.004). Conclusion Seasonality in BD is associated with distinct clinical features and treatment‐related outcomes. Specific seasonality patterns, particularly fall/winter depression, may reflect a more complex and difficult‐to‐treat illness course. These findings highlight the need for research to better characterize seasonality subtypes beyond a binary “seasonal” vs. “non‐seasonal” classification and to explore how these patterns influence the illness course and management of BD.

Abstract Computational analysis of speech enables precise, objective measurements of a behavioral signal closely linked to manic episodes. In a prospective cohort study conducted in Rochester, MN ( ClinicalTrials.gov Identifier: NCT05956340 ) , eighteen English-speaking adults voluntarily hospitalized for a manic episode of Bipolar I Disorder between August 2023 and September 2024 were enrolled. Participants completed semi-structured research interviews during both acute episodes and remission, with manic symptom severity assessed at each session using the Young Mania Rating Scale (YMRS). Across 57 recorded interviews, temporal prosodic features were extracted using automated computational algorithms. After adjusting for individual differences and moderating effects, participant articulation rate (β = 0.24, p = 0.0038), speech rate variability (β = 0.23, p = 0.0041), floor transfer offset (β = -0.31, p = 0.007), and speaking duration (β = 0.54, p < 0.001) were significantly associated with manic symptom severity. These temporal elements classified manic (CV AUC = 0.85) and remission (CV AUC = 0.83) status, highlighting their potential as monitoring and prognostic biomarkers for manic episodes.

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.