Introduction
For clinicians treating first-episode psychosis (FEP), the transition from acute stabilization to long-term maintenance is one of the most challenging phases of care. While antipsychotic medications are the cornerstone of acute treatment, the optimal duration of maintenance therapy remains a subject of intense debate. Traditional guidelines often recommend at least one to two years of continuous medication following remission to prevent relapse. However, concerns regarding metabolic side effects, cognitive dulling, and the potential for ‘dopamine supersensitivity’ have led researchers to explore whether early dose reduction or discontinuation (DRD) might offer long-term functional advantages. The recently published HAMLETT (Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment) study provides critical, high-level evidence to help navigate this clinical crossroads.
Highlight
1. Short-term Vulnerability
Early dose reduction or discontinuation (DRD) within the first year of remission is associated with a significantly higher risk of relapse (OR 2.84) and a transient decrease in patient-reported quality of life.
2. Long-term Functional Gains
Despite early setbacks, patients in the DRD group exhibited significantly better researcher-rated global assessment of functioning (GAF) at the three- and four-year marks compared to those on maintenance therapy.
3. The Learning Experience Hypothesis
Because medication doses became comparable between groups after the first year, the long-term benefits of DRD are likely not due to lower drug levels alone, but rather a ‘learning experience’ that empowers patients to manage their psychotic vulnerability.
4. Critical Safety Considerations
Clinicians must remain vigilant; the study noted a higher incidence of suicide in the DRD group, emphasizing that dose reduction is a high-stakes strategy requiring intensive monitoring.
Background and Disease Burden
First-episode psychosis typically affects individuals in late adolescence or early adulthood, a critical developmental window for education, career establishment, and social integration. While antipsychotics are highly effective at suppressing positive symptoms like hallucinations and delusions, their long-term impact on functional recovery—the ability to work, socialize, and live independently—is less clear. Previous landmark studies, such as the 7-year follow-up by Wunderink et al., suggested that early dose reduction might lead to better recovery rates over time. However, subsequent trials have yielded conflicting results, leaving many psychiatrists hesitant to deviate from maintenance protocols due to the devastating impact of relapse. The HAMLETT trial was designed to resolve these discrepancies by providing a large-scale, pragmatic evaluation of DRD in a modern clinical setting.
Study Design
The HAMLETT study was a single-blind pragmatic randomized clinical trial conducted across 26 specialized psychosis units in the Netherlands. The study enrolled 347 patients who had achieved remission from FEP. Participants were randomized 1:1 into two groups: an early DRD group (reduction/discontinuation within 12 months after remission) and a maintenance treatment group (continued medication for at least 12 months).
The primary endpoint was patient-rated functioning, assessed via the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes included researcher-rated global assessment of functioning (GAF), quality of life (QoL), symptom severity (PANSS), relapse rates, and serious adverse events. This design allowed for a comprehensive view of the patient experience, balancing subjective reporting with objective clinical assessment over a four-year follow-up period.
Key Findings
Initial Challenges: Year One
The first year following randomization highlighted the risks of aggressive medication tapering. Patients in the DRD condition faced a nearly threefold increase in the risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04). This clinical instability was reflected in quality-of-life scores, which were significantly lower in the DRD group during this initial phase (β = -3.31; P = .03). Interestingly, the primary outcome measure—the patient-rated WHODAS-2—did not show a significant difference between the groups, suggesting a possible discrepancy between how patients perceive their disability and the clinical reality of their symptom burden.
The Functional Pivot: Years Three and Four
As the study progressed, a compelling trend emerged. By the third and fourth years, the early DRD group began to outperform the maintenance group in functional domains. Researcher-rated GAF scores were significantly higher for the DRD group at year three (β = 3.61; P = .03) and year four (β = 6.13; P = .003). Furthermore, a trend toward improved symptom severity (PANSS) was noted at the four-year mark (P for trend = .06).
The Paradox of Dosing
A crucial finding of the HAMLETT trial is that by the end of the first year, medication doses in both groups became largely comparable. This means the long-term functional superiority of the DRD group cannot be attributed to a lower ongoing ‘medication load’ or a reduction in current side effects. Instead, the researchers suggest a psychological or behavioral mechanism: by attempting dose reduction early, patients may have been forced to develop better coping strategies, recognize early warning signs of relapse, and take a more active role in managing their mental health. This ’empowerment’ or ‘learning effect’ appears to confer a long-term resilience that traditional maintenance therapy may inadvertently delay.
Safety and Adverse Events
While overall serious adverse events (SAEs) were similar between groups, the study recorded a sobering statistic regarding mortality. There were three confirmed deaths by suicide in the DRD group, compared to one in the maintenance group. While the sample size is too small to draw definitive statistical conclusions about suicide risk, this finding serves as a stark reminder of the potential consequences of relapse in schizophrenia-spectrum disorders. Clinicians must weigh the long-term functional promise of DRD against the immediate, life-threatening risks of clinical instability.
Expert Commentary
The HAMLETT trial represents a significant step forward in personalized psychiatry. The data suggest that we may need to rethink our definition of ‘success’ in FEP treatment. If our goal is purely relapse prevention, maintenance therapy remains the gold standard. However, if our goal is functional recovery and autonomy, a supervised, early attempt at dose reduction might be beneficial for a subset of patients.
Mechanistically, the ‘learning experience’ hypothesis aligns with the principles of recovery-oriented care. When patients are involved in the decision to reduce medication, they often become more attuned to their own mental states. However, this strategy is not without peril. The increased relapse rate and the observed suicides in the DRD group suggest that dose reduction should not be a universal recommendation but rather a carefully monitored, shared decision-making process. Future research should focus on identifying biomarkers or clinical profiles—such as cognitive reserve or social support levels—that can predict which patients are most likely to thrive after dose reduction.
Conclusion
The HAMLETT trial provides a nuanced map for the long-term management of first-episode psychosis. It confirms that while early antipsychotic dose reduction or discontinuation carries a heavy short-term price in terms of relapse and quality of life, it may pave the way for superior functional recovery years later. The finding that this benefit persists even after medication doses equalize suggests that the process of tapering itself may be a therapeutic intervention that fosters resilience. Clinicians are encouraged to engage in transparent, evidence-based discussions with their patients, balancing the immediate safety of maintenance with the long-term potential of functional independence.
Funding and Trial Registration
This trial was supported by the Netherlands Organisation for Health Research and Development (ZonMw). Trial registration: EudraCT number 2017-002406-12.
References
1. Sommer IE, de Beer F, Gangadin S, et al. Early Dose Reduction or Discontinuation vs Maintenance Antipsychotics After First Psychotic Episode Remission: A Randomized Clinical Trial. JAMA Psychiatry. 2026;83(1):68-73. doi:10.1001/jamapsychiatry.2025.2525.
2. Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation strategy vs maintenance treatment: a randomized clinical trial. JAMA Psychiatry. 2013;70(9):913-920.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year followup study of HIVCC and mortality in schizophrenia. American Journal of Psychiatry. 2020;177(6):527-536.
