{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:08:35Z","timestamp":1793304515730,"version":"4.5.0"},"reference-count":14,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:sec id=\"ab-ybr250011-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Lithium augmentation is an effective treatment for patients with major depression after inadequate antidepressant response, but therapeutic outcomes vary considerably between individuals. Molecular studies may provide novel insights into treatment prediction and guide personalized therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the association of polygenic risk scores (PRS) for schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) with clinical outcomes after lithium augmentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This cohort study analyzed prospectively assessed treatment outcomes in patients who underwent lithium augmentation. Disorder-specific PRS were calculated using well-powered genome-wide association study summary statistics. Participants were recruited from 13 psychiatric hospitals, primarily in the greater Berlin area, between 2008 and 2020. They were patients with MDD who showed inadequate response to at least 1 antidepressant, a baseline score of 12 or more on the 17-item Hamilton Depression Rating Scale (HAMD-17), adequate treatment duration (\u22654 weeks), and no diagnostic or co-medication changes. Data analysis was conducted between June 2022 and November 2023.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-7\">\n                    <jats:title>Exposure<\/jats:title>\n                    <jats:p>Polygenic risk scores for MDD, SCZ, or BIP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-8\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>Response was defined as a 50% or greater reduction in HAMD-17 score, remission as a HAMD-17 score of 7 or less. Cox proportional hazards models, adjusted for ancestry, demographic, and clinical covariates, were used to estimate hazard ratios (HRs) for favorable outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-9\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 193 patients (mean [SD] age, 49.5 [13.4] years; 118 [61.1%] female and 75 [38.9%] male), higher BIP-PRS were associated with both response (HR, 1.29; 95% CI, 1.02-1.63;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.03) and remission (HR, 1.52; 95% CI, 1.14-2.04;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.004), explaining 2.51% and 4.53% of the variability in treatment outcomes, respectively. Individuals in the highest tertile of the BIP-PRS distribution had a 2.02-fold (95% CI, 1.15-3.53) higher likelihood of response and a 2.26-fold (95% CI, 1.17-4.36) higher chance of remission compared with those in the lowest tertile. Additionally, lower MDD-PRS was associated with better response to lithium augmentation (HR, 0.81; 95% CI, 0.66-1.00;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.048; Nagelkerke\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20091.99%). No significant associations were observed between SCZ-PRS and response (HR, 1.00; 95% CI, 0.80-1.24;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.97) or remission (HR, 1.12; 95% CI, 0.85-1.48;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.42).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ybr250011-10\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>Individuals carrying a higher polygenic burden for BIP and lower polygenic risk for MDD are more likely to benefit from lithium augmentation. Our findings suggest that disease-related PRS may aid in developing treatment prediction models for lithium augmentation response in depression, potentially informing clinical decision-making.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.2039","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T15:00:50Z","timestamp":1756911650000},"page":"1137","source":"Crossref","is-referenced-by-count":7,"title":["Polygenic Contributions to Lithium Augmentation Outcomes in Unipolar Depression"],"prefix":"10.1001","volume":"82","author":[{"given":"Julia","family":"Kraft","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Campus Mitte, Berlin, Germany"},{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"German Center for Mental Health (DZPG), partner site Berlin\/Potsdam, 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