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.

TRIAL REGISTRATION: EudraCT number: 2017-002406-12.