Frye, Mark

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

ABSTRACT Background Higher time in sedentary behavior and insufficient physical activity are very common in bipolar disorder (BD). Whereas physical activity and exercise offer significant benefits across mental health, brain health, and heart health in BD. The International Society for Bipolar Disorders Nutrition and Exercise Task Force (NExT) synthesized evidence to evaluate the impacts of sedentary behavior, physical activity, and exercise on illness course, physical health, and treatment outcomes. Methods A best‐evidence synthesis was conducted using a question‐and‐answer format. We searched PsycINFO, SPORTDiscus, Embase, PubMed, and Web of Science from inception to March 1st, 2026, supplemented by reference lists and existing guidelines. Search terms included combinations of physical activity, exercise, sedentary behavior, and bipolar disorder‐related terms. Results Observational studies show that individuals with BD exhibit significantly higher sedentary behavior and lower physical activity compared to the general population, with notable discrepancies between self‐reported and objective measurements. Evidence on physical activity's protective role against BD onset is mixed, with some prospective and Mendelian randomization studies suggesting reduced risk, while others report bidirectional or null associations. Preliminary findings from clinical trials indicate that exercise improves overall functioning, reduces mood episode frequency and hospitalizations, and alleviates depressive symptoms, with one pilot study showing an 82% antidepressant response rate. Exercise also shows potential to reduce anxiety and improve sleep, though robust data are limited. Conclusions Despite limited high‐quality evidence, physical activity and exercise demonstrate promising physical and mental health benefits for individuals with BD. Future research should prioritize multicenter randomized controlled trials, enhanced assessment tools, and accessible, tailored programs to integrate physical activity into routine BD management.

ABSTRACT Objective To provide expert recommendations for the development of a specialty bipolar clinic that promotes best clinical practices for the delivery of safe and effective care. Methods Members of the National Network of Depression Centers (NNDC) Bipolar Clinics Work Group met in a series of 1‐h monthly video calls over 18 months to discuss all aspects of their respective institution's bipolar clinics, including services provided, administrative processes, staffing models, characteristics of patients treated, patient volumes, finances, and research. The group also invited psychiatrists from outside of the NNDC who ran large bipolar clinics to contribute their thoughts and experiences on the subject. In addition, the NNDC sent a 20‐question survey to all 27 sites asking clinic directors specific questions about their bipolar clinics, if applicable. Further meetings and discussions incorporating results from the survey took place to produce a comprehensive set of recommendations. Results Twenty‐one of 27 NNDC sites (81%) responded to the survey. Twelve of 21 (57%) sites had a specific bipolar clinic, and another 4 (19%) were looking to start one. Clinics were based in university settings. The meetings, clinic survey, and discussions resulted in 10 recommendations describing services and operations for bipolar specialty clinics. Conclusions Given the complexity of bipolar disorder, specialty clinics are important to enhance care. Clinics with a wide array of services that include consultation, medication management, bipolar‐specific psychotherapies, and patient/family psychoeducation provide the most comprehensive care. Challenges to these clinics include maintaining ongoing patient access as well as ensuring long‐term financial stability.

ABSTRACT Background This study aimed to explore the effect of family history (FH) and polygenic risk scores (PRS) for multiple psychiatric disorders on lithium response in bipolar disorder (BD). Method The sample included patients from the Mayo Clinic BD Biobank. FH in first‐degree relatives was obtained via the patient questionnaire. Linear regression models tested the association of FH and PRS for BD, major depressive disorder (MDD), schizophrenia (SCZ), alcohol use disorder (AUD), anxiety disorder (ANX), and attention‐deficit/hyperactivity disorder (ADHD) with lithium response measured by the Alda A score adjusted for the Alda B sum score. Post hoc models additionally adjusted for clinical covariates (age at onset, rapid cycling, and BD subtype). Results 716 patients had Alda scores for lithium response (61.9% females, mean age = 43.4 years). FH‐BD ( β = −0.57, p = 0.015), AUD ( β = −0.44, p = 0.045), and ANX ( β = −0.61, p = 0.050) were associated with worse lithium response. After adjusting for clinical covariates, associations for FH‐BD and FH‐ANX were no longer significant. PRS‐BD was associated with better response ( β = 0.22, p = 0.041), while PRS‐MDD ( β = −0.28, p = 0.01) and PRS‐ADHD ( β = −0.24, p = 0.028) were associated with worse response, with effects largely unchanged after adjusting for clinical covariates. In the combined model considering all FHs simultaneously, only FH‐BD remained significantly associated with worse lithium response ( β = −0.71, p = 0.039). In the combined model for PRS, only PRS‐BD ( β = 0.31, p = 0.008; better response) and PRS‐MDD ( β = −0.29, p = 0.020; worse response) showed significant associations. Conclusions In this exploratory study, FH‐BD, AUD, and ANX were associated with poor response, though only FH‐AUD remained significant after adjusting for clinical factors. PRS‐BD predicted better response, while PRS‐MDD was associated with worse response. These findings suggest independent and potentially complementary roles of FH and PRS. Integrating both familial and genetic risk measures may improve personalized treatment strategies and outcomes for BD patients.

ABSTRACT Introduction Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), initially developed for type 2 diabetes, have shown promise in improving renal outcomes in patients with and without diabetes. However, their effect on lithium‐associated kidney dysfunction remains unknown. Methods This historical cohort study included patients from Mayo Clinic (2001–2023) with mood disorders who received lithium for ≥ 6 months and later used SGLT2i for ≥ 1 month. Data on SGLT2i use and lithium treatment were extracted from electronic health records. Serum creatinine values were used to calculate estimated glomerular filtration rate (eGFR) trajectories. Linear mixed‐effects models with piecewise linear splines were used to estimate eGFR slopes before and after SGLT2i initiation, adjusted for age and sex. Results Fifty‐six patients (mean age 57.4 years, 46.4% female), predominantly with bipolar disorder (87.5%), were included. The mean eGFR, measured nearest to SGLT2i initiation, was 77.9 ± 26.0 mL/min/1.73 m 2 , and the mean duration of SGLT2i use was 19.5 ± 17.8 months. Before SGLT2i initiation, eGFR declined at a rate of −1.43 mL/min/1.73 m 2 per year ( p < 0.001). After initiation, eGFR increased by 0.69 mL/min/1.73 m 2 per year, reflecting a + 2.13 change ( p = 0.025). Sensitivity analyses, including only patients on lithium at SGLT2i initiation ( n = 22) or who had > 1 year of SGLT2i use ( n = 29) showed similar, though non‐significant, changes in slopes. Conclusion SGLT2i treatment was associated with a significant improvement in eGFR trajectory in patients with mood disorders who received long‐term lithium therapy. These findings suggest a potential role for SGLT2is in mitigating lithium‐associated kidney dysfunction and highlight the need for randomized controlled trials in this population.

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.

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 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 The lack of a molecular understanding of mood disorders has impeded progress in diagnosis and treatment. Glycosylation may provide insights into the complex mechanisms underlying these conditions. We conducted N-glycoproteomic analysis on dorsolateral prefrontal cortex samples from individuals with major depressive disorder (MDD) and bipolar disorder (BD), in depressive or manic states at death. Additionally, we examined depression prevalence in congenital disorders of glycosylation (CDG) through a literature review and assessment of 110 CDG patients. Glycoproteomic analysis revealed a significant increase in protein glycosylation in individuals with MDD relative to both controls and individuals with BD. Depression prevalence was lower in our pediatric and adult cohort of individuals with CDG. These results suggest brain glycosylation changes may play a role in mood disorder pathology and highlight the distinct biology of unipolar and bipolar depression. Our findings propose that impaired glycosylation may confer resilience to depression, offering potential therapeutic insights.

ABSTRACT Background Despite the classic Kraepelinian dichotomy between bipolar disorder (BD) and schizophrenia (SZ), contemporary evidence suggests shared antecedent risk factors and similarities in the early course. This study aimed to identify distinct trajectories leading to first‐episode mania (FEM) and first‐episode psychosis (FEP) by examining antecedent psychopathology, including psychiatric diagnoses, symptoms, substance use, and psychotropic medication exposure. Methods Individuals born after 1985 who resided in Olmsted County, Minnesota, USA, and had FEM/FEP were identified through the Rochester Epidemiology Project. Latent class analysis (LCA) was used to identify subgroups based on antecedent psychopathology incorporating 57 dichotomous antecedent measures before FEM/FEP. Results A total of 202 individuals ( BD n = 73, SZ n = 129; 26.7% female, mean age 20.8 ± 3.7 years) were included. A 3‐class LCA model optimally fits the data. Class 1 (Neurodevelopmental, 29.7%) had a high prevalence of neurodevelopmental disorders, behavioral symptoms, and ADHD medication use. Class 2 (Depressive‐Anxious, 31.2%) included depressive and anxiety disorders, mood‐related symptoms, and SSRI / SNRI use. Class 3 (Minimal Psychiatric Morbidity, 39.1%) had a low prevalence of antecedent diagnoses and symptoms, with comparable substance use to other classes. There were significant diagnostic differences, with SZ being more common in the Neurodevelopmental (71.7%) and Minimal Psychiatric Morbidity (70.9%) classes, while BD was more common in the Depressive‐Anxious class ( p = 0.007). Neurodevelopmental and Minimal Psychiatric Morbidity classes had higher proportions of males (85.0% and 82.3%, respectively) compared to the Depressive‐Anxious class (50.8%, p < 0.001). The Neurodevelopmental class showed an earlier age at first mental health visit (9.5 ± 5.5 years) and a longer antecedent illness duration (10.8 ± 6.1 years) than the other classes ( p < 0.001). Conclusion This study identified three distinct pathways to FEM and FEP, offering a transdiagnostic perspective on the antecedent illness trajectories of BD and SZ. Future research should validate these categories that are more inclusive than the classic BD versus SZ dichotomy and explore their potential for predicting illness course and guiding personalized early interventions.