Early Dose Reduction or Discontinuation vs Maintenance Antipsychotics After First Psychotic Episode Remission: A Randomized Clinical Trial

IMPORTANCE 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. OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS DRD within 12 months after remission compared with 12 months maintenance treatment. MAIN OUTCOMES AND MEASURES 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. RESULTS 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 × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = −3.31; 95% CI, −6.34 to −0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .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 (P for trend = .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. CONCLUSIONS AND RELEVANCE 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.