{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:03:23Z","timestamp":1791443003811,"version":"4.3.3"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"\n Importance<\/jats:title>\n Dose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n The Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n DRD within 12 months after remission compared with 12 months maintenance treatment.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time\u2009\u00d7\u2009condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66;\n P<\/jats:italic>\n \u2009=\u2009.04) and lower quality of life (\u03b2\u2009=\u2009\u22123.31; 95% CI, \u22126.34 to \u22120.29;\n P<\/jats:italic>\n \u2009=\u2009.03). At 3 years (\u03b2\u2009=\u20093.61; 95% CI, 0.28 to 6.95;\n P<\/jats:italic>\n \u2009=\u2009.03) and 4 years (\u03b2\u2009=\u20096.13; 95% CI, 2.03 to 10.22;\n P<\/jats:italic>\n \u2009=\u2009.003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (\n P<\/jats:italic>\n for trend\u2009=\u2009.06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n \n EudraCT number:\n 2017-002406-12<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.2525","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T15:00:54Z","timestamp":1759330854000},"page":"68","source":"Crossref","is-referenced-by-count":20,"title":["Early Dose Reduction or Discontinuation vs Maintenance Antipsychotics After First Psychotic Episode Remission"],"prefix":"10.1001","volume":"83","author":[{"given":"Iris E.","family":"Sommer","sequence":"first","affiliation":[{"name":"Center for Clinical Neuroscience and Cognition, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciska","family":"de 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