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Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (<jats:italic>n<\/jats:italic>\u2009=\u2009122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.32, <jats:italic>p<\/jats:italic>\u2009=\u20090.0023, <jats:italic>n<\/jats:italic>\u2009=\u200988) and remission (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.31, <jats:italic>p<\/jats:italic>\u2009=\u20090.0037, <jats:italic>n<\/jats:italic>\u2009=\u200988), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (<jats:italic>p<\/jats:italic>\u2009=\u20090.00072, <jats:italic>n<\/jats:italic>\u2009=\u200988) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (<jats:italic>p<\/jats:italic>\u2009=\u20090.036, <jats:italic>n<\/jats:italic>\u2009=\u200988) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.<\/jats:p>","DOI":"10.1038\/s41398-024-02842-x","type":"journal-article","created":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T13:01:33Z","timestamp":1709384493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A genetic risk score to predict treatment nonresponse in psychotic depression"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7079-8335","authenticated-orcid":false,"given":"Sophie E.","family":"ter Hark","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieke J. 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