The Distinct Role of Family History and Polygenic Risk Scores of Psychiatric Disorders on Lithium Response in Bipolar Disorder

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.