REVIEW OF: Moncrieff J et al, Lancet Psychiatry 2023;10(11):848–859; Liu CC et al, Early Interv Psychiatry 2022;16(2):178–185

STUDY TYPE: RCTs
Many patients with schizophrenia or recurrent psychotic disorders want to reduce or stop their antipsychotic drugs to minimize adverse effects like sedation, weight gain, and emotional blunting, all of which can impair social functioning. While abrupt medication discontinuation raises the risk of relapse, two recent RCTs—RADAR and GARMED—explored whether gradual antipsychotic dose reduction or discontinuation could enhance social functioning without increasing relapse risk.

The RADAR trial
Moncrieff et al investigated gradual dose reduction every two months, aiming for medication discontinuation where possible, compared to maintenance treatment. The study enrolled 253 participants, most of whom were middle-aged, male, unemployed, and diagnosed with schizophrenia. Follow-ups were conducted remotely due to COVID-19 restrictions. Participants in the reduction group followed a planned schedule aiming for discontinuation within 12–18 months, with larger dose cuts occurring earlier in the trial. However, high relapse rates later in the trial led to dose increases for some participants. As a result, the median dose reduction, which had peaked at 67%, dropped to 33% by the 24-month mark.

Results after 24 months favored the maintenance group. Relapse rates were higher in the dose reduction/discontinuation group (41% vs 22%; p=0.007), as were severe relapses (25% vs 13%; p=0.007). Regarding quality of life, there were no significant improvements in the reduction group based on either the Manchester Short Assessment of Quality of Life (MANSA) or the Objective Social Outcomes Index (SIX) (p=0.86 and 0.26, respectively).

The GARMED trial
Liu et al explored a slower, personalized approach to tapering among 97 patients who had been stable for six months. The guided dose reduction (GDR) group followed a hyperbolic dose reduction schedule, where reductions became smaller as doses decreased to minimize withdrawal symptoms and relapse. Reductions were capped at 25% of the previous dose every six months, with shared decision-making to empower patients to pause tapering if needed. Follow-up included in-person visits every month during tapering and every three months after stabilization.

Results after 24 months favored the GDR group. Relapse rates were lower (12% GDR vs 17% maintenance; p=0.66). Seventy-five percent of GDR participants remained in remission, reducing doses by 40%–80%. There was also significant quality of life improvement in the GDR group, measured by the EuroQoL-5D visual analog scale (p=0.0009).

Why the discrepancy in results?  
The two studies differed in key ways. First, RADAR participants had worse baseline functioning, with 70% of participants unemployed as compared to 27% in the GARMED trial. Second, the RADAR trial aimed for complete discontinuation within 12–18 months, while GARMED focused on achieving the lowest effective dose, with no strict timeline and a gradual tapering strategy. Finally, RADAR was constrained by remote follow-ups during the pandemic, and patients were not allowed to pause tapering; in contrast, GARMED relied on frequent in-person visits and gave patients the flexibility to pause their taper.

Carlat Take
Tapering antipsychotics in patients with schizophrenia or recurrent psychotic disorders isn’t right for everyone. Weigh the risks of relapse carefully against the potential benefits and tailor your plan to each individual.

For those struggling with significant side effects, a taper may be worth considering—provided you do this cautiously and collaboratively. Ensure your patient has been stable for at least six months before starting. Taper gradually, and monitor symptoms closely. Pause the taper if your patient experiences discomfort or worsening symptoms, and return to the previous dose promptly if a relapse occurs.