Melhuish Beaupre, Lindsay M

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 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.

ABSTRACTBackgroundInsomnia and substance use disorders (SUD) are common comorbidities of bipolar disorder (BD). Genome‐wide association studies (GWAS) have uncovered shared genetic contributions to insomnia and BD as well as SUDs and BD. Electronic health record (EHR) derived phenotypes (phecodes) and questionnaire data were used to examine the relationship between insomnia genetic liability and SUDs in BD.Methods40,839 participants from the Mayo Clinic Bipolar Disorder Biobank (BD Biobank; n = 774) and Mayo Clinic Biobank (n = 485 BD cases, n = 39,580 controls) were included in the analyses of diagnosis (phecode) outcomes (insomnia, SUD, alcohol use disorder [AUD] and tobacco use disorder [TUD]). Analyses of specific SUD outcomes obtained through the BD Biobank questionnaire included 1789 cases and considered BD subtype. Logistic regression was used to test for associations between insomnia polygenic risk scores (PRS) and insomnia and SUD outcomes in BD cases and controls.ResultsInsomnia PRS was associated with having an insomnia diagnosis (phecode) in the EHR in controls (OR = 1.19, p = 9.64e‐33) but not in BD cases (OR = 1, p = 0.95). Associations between insomnia PRS and SUD diagnoses were significant in BD cases and controls, with the association being stronger in BD cases (interaction p = 0.024). In the BD Biobank data, the insomnia PRS was associated with increased odds of AUD (OR = 1.19, p = 4.26e‐04), TUD (OR = 1.21, p = 1.25e‐05) and cannabis use disorder (OR = 1.16, p = 4.19e‐03).ConclusionThe effect of genetic predisposition to insomnia on SUD risk may be stronger in BD cases than in controls, which could have clinical care implications for individuals with BD and comorbid SUD.