Depression continues to be a major contributor to the global burden of diseases. Antidepressants are recommended as the initial choice of treatment for moderate and severe depression among adults, but the choice of antidepressant class can be challenging, as efficacies of commonly used antidepressants are generally comparable between classes. As such, to determine which medication to prescribe to each patient, clinicians often rely on the adverse effect profile of antidepressants. One of the most discussed adverse effects is the possibility of increased suicidality with antidepressant initiation, a rare but serious adverse event. Efforts to predict this have mostly relied on clinical and sociodemographic characteristics of patients, but we do not yet have a clear picture. A promising avenue is to use patients' genetic data, but the evidence on its utility has so far been mixed, and few large scale databases have both clinical and genetic data that can evaluate its utility. Here, using genetic and clinical data on more than 7,000 patients, both children and adults, with major depressive disorder from the All of Us Research Program, we show that the genetic predisposition for psychiatric disorders may underlie the substantial heterogeneity in the risk of suicidal thoughts with antidepressant use. Specifically, using a target trial emulation framework, we show that patients with higher polygenic risk scores for psychiatric disorders, particularly for attention deficit-hyperactivity disorder, are more likely than those with lower scores to experience suicidal thoughts with the use of selective serotonin reuptake inhibitors, relative to bupropion. In the personalized medicine framework, PRSs for various psychiatric disorders may help tailor antidepressants to each patient to avoid serious adverse effects such as suicidal thoughts.

The authors have declared no competing interest.

R.G. receives funding from Knight-Hennessy Scholars, the Japan Foundation for Pediatric Research (22-001), and Chernobyl-Fukushima Medical Foundation for other work not related to this study. K.I. receives research support from the Japan Society for the Promotion of Science (23KK0240), the Japan Agency for Medical Research and Development (AMED; JP22rea522107), the Japan Science and Technology (JST PRESTO; JPMJPR23R2), and the Program for the Development of Next-generation Leading Scientists with Global Insight (L-INSIGHT) sponsored by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA \#: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The All of Us Research Program has been approved by the All of Us Institutional Review Board.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data used in this study are available through the All of Us Research Program.