Polygenic scores for precision psychiatry: a study on the effect heterogeneity of antidepressants.

Importance: Antidepressants are recommended as the initial choice of treatment for moderate and severe depression, but the choice of antidepressant class can be challenging, with the possibility of serious adverse events such as increased suicidality with antidepressant initiation. Objective: To evaluate the utility of polygenic scores in predicting heterogeneous effects of antidepressants on suicidal thoughts. Design: Using genetic and clinical data on both children and adults with major depressive disorder from the All of Us Research Program, we used a target trial emulation framework to evaluate the heterogeneous effects of antidepressants on suicidal thoughts across genetic characteristics. Setting: Longitudinal cohort from the All of Us Research Program. Participants: More than 7,000 patients, both children and adults, with major depressive disorder. Interventions: The initiation of selective serotonin reuptake inhibitors (SSRIs), compared to the initiation of serotonin and norepinephrine reuptake inhibitors (SNRIs) and bupropion. Main Outcomes and Measures: The effects of antidepressants on suicidal thoughts, as well as subgroup effects across polygenic scores (PGSs) of various psychiatric disorders. Results: Patients with higher PGS for psychiatric disorders, particularly for attention deficit-hyperactivity disorder (ADHD), were more likely than those with lower scores to experience suicidal thoughts with the initiation of SSRIs, relative to bupropion (hazard ratio 1.66, 95%CI, 1.30-2.12, for participants with ADHD PGS higher than median vs. hazard ratio 1.06, 95%CI, 0.81-1.38, for participants with ADHD PGS lower than median; P-for-interaction, 0.01). We observed a similar trend for schizophrenia, although the interaction was not statistically significant (hazard ratio 1.52, 95%CI, 1.19-1.93, for participants with schizophrenia PGS higher than median vs. hazard ratio 1.1.17, 95%CI, 0.89-1.53, for participants with ADHD PGS lower than median; P-for-interaction, 0.16). We did not observe differences in the effects of SSRIs relative to SNRIs across PGSs. Conclusions and Relevance: The genetic predisposition to psychiatric disorders may, at least partially, underlie the heterogeneity in the risk of suicidal thoughts with antidepressant use. In the personalized medicine framework, PGSs for various psychiatric disorders may help tailor antidepressants to each patient to avoid serious adverse effects such as suicidal thoughts.