Phenotype-by-phenome-wide association study of treatment resistant depression

Objective Treatment-resistant depression (TRD), defined as inadequate response to at least one or at least two antidepressant (AD) trials, is common in major depressive disorder (MDD). In this study, electronic health records (EHR) were used to identify clinical associations with TRD. Methods Using two biobanks, phenomes of patients with at least one MDD-related diagnostic code and one AD prescription (N=17,049) were generated using aggregated diagnostic codes (phecodes) from EHRs. Phenotype-by-phenome-wide association analyses were performed for two binary definitions of TRD, based on either one or more, or two or more, AD switches after at least 30 days but within 14 weeks, and a quantitative measure defined as the number of unique ADs prescribed for at least 30 days. Results Of the 17,049 patients with MDD, 1624 (9.5%) had at least one switch, 422 (2.5%) had at least two switches, and the number of unique antidepressant prescriptions ranged from one to twelve. After accounting for multiple testing, 142, 18, and 7 phecodes were significantly associated with the quantitative definition and the two binary definitions (≥1 AD switch or ≥2 AD switches), respectively. All three outcomes were significantly associated with known TRD risk factors including anxiety disorders, insomnia, and suicidal ideation. The quantitative measure was uniquely associated with other conditions including irritable bowel syndrome and decreased white blood cell count. Conclusions In addition to identifying known clinical associations, the quantitative measure of treatment resistance uncovered new factors potentially associated with TRD. This measure may also facilitate discovery of genetic correlates of TRD in future analyses. ### Competing Interest Statement In the last three years, Dr. Weissman has received research funds from NIMH, Templeton Foundation, Brain and Behavior and the Sackler Foundation and has received royalties for publications of books on interpersonal psychotherapy from Perseus Press, Oxford University Press, on other topics from the American Psychiatric Association Press and royalties on the social adjustment scale from MultiHealth Systems. None of these represent a conflict of interest and all other authors have no other disclosures ### Funding Statement This study was supported by the National Institute of Mental Health (NIMH) grants: R01MH121924, R01MH121923, R01MH121922, and R01MH121921. ### Author Declarations 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 current study was reviewed and approved by each site's Institutional Review Board and exempted from informed consent requirements as non-human subjects research: Mayo Clinic IRB approval 19-006227 and Mount Sinai IRB approval 07-0529. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are only available after institutional review of request of access to the electronic health record.