Is a high relapse risk balanced by better functioning down the road?
STUDY: Sommer IE et al, JAMA Psychiatry 2026;83(1):68-73
STUDY TYPE: Randomized controlled trial
FUNDING: ZonMw (The Netherlands Organisation for Health Research and Development)
Background
In 2013, a paper in JAMA argued that antipsychotic dose reduction improved functioning in first episode schizophrenia. The trial began by randomizing patients to continue their antipsychotic or gradually reduce, and if possible stop it. At first, the results did not look good for the tapering group. Twice as many relapsed compared to those who stayed on the medication (43% vs 21%).
The authors followed up again 5.5 years later, managing to contact 81%. At this point, their treatment was guided by usual care, without a protocol, but those who originally attempted dose reduction were still taking lower doses overall (approx 37% lower). They also had twice the rates of functional recovery: 40% vs 18%, something not seen in the original, and thought due to either
- Lower medication doses, and lower dopamine blockade, or
- Psychological strengths. Perhaps they learned from the experience of deprescribing and were taking better care of themselves.
Other trials attempted to replicate this, but were unable to, possibly because they did not follow long enough to see this improvement in functioning. This trial, which is larger and went four years, attempted to resolve the controversy.
The Study
- 347 patients remitted for 3-6 mth from first-episode psychosis (mean age 28, 70% male) at 26 Dutch psychosis centers
- None had dangerous behavior during treatment or forced treatment.
- Randomized to gradual, hyperbolic dose reduction toward discontinuation or to continued maintenance dosing over six months, then followed for four years
- Outcomes included patient-rated functioning (WHODAS-2), clinician-rated functioning (GAF), symptoms (PANSS), quality of life, and relapse
Results
The primary outcome of self-rated functioning (WHODAS-2) didn’t differ at any point throughout the trial.
In the first year, tapering worsened outcomes. Relapse was almost three times as likely (odds ratio, 2.84) and quality of life dropped compared to maintenance. As in the earlier trial, many patients went back on their antipsychotic, having learned from the experience.
At 6-12 months, the tapering group was taking slightly less medication (2.4 to 2.8 mg less of olanzapine dose-equivalents), but after one year the two groups had similar rates of medication use.
Despite this similarity in medication rates, the tapering group still had significantly better clinician-rated functioning after three years, and a trend toward fewer symptoms (PANSS). Why? We don’t know, but we can rule out the pharmacologic hypothesis, so the authors conclude that the tapering group learned from their experience, resulting in a stronger therapeutic alliance and higher treatment adherence. However, those variables weren’t measured, so we just don’t know.
Side Effects of Tapering
Rates of self-harm, aggression, and neurological side effects were similar between groups. There were three suicide deaths in the tapering group versus one in the maintenance group.
Limitations
These findings apply to first-episode patients only; trials in multi-episode patients have found tapering brings more relapse without the later functional gains.
All of the intriguing differences were secondary outcomes, so could be chance findings. The primary outcome showed no difference between the groups at any point: self-rated functioning.
40% of patients in the continuation group actually attempted to taper their medication.
Practice Implications
- Relapse rates are higher with antipsychotic taper after first episode psychosis, a consistent finding across most discontinuation trials.
- While this replicates the intriguing finding of higher functioning many years later, the reason is not clear.
