Antipsychotic dose reduction in recurrent psychosis: No clear benefits but increased relapse risk

Gradual antipsychotic dose reduction does not provide benefits in social functioning and is associated with an increased risk of relapse in patients with schizophrenia, the RADAR trial has shown.

Adverse effects of antipsychotics (eg, weight gain, sedation, sexual dysfunction) are burdensome. Seven-year follow-up of a randomized clinical trial showed that antipsychotic dose reduction and discontinuation were associated with a higher level of social functioning in patients with remitted first-episode psychosis. [World Psychiatry 2018;17:341-356; JAMA Psychiatry 2013;70:913-920]

“[We hypothesized that gradual] antipsychotic reduction would improve social functioning [in patients with recurrent psychosis or with schizophrenia], with only a small increase in relapse rate,” wrote the researchers. [Lancet Psychiatry 2023;doi:10.1016/S2215-0366(23)00258-4]

The researchers conducted the open-label, parallel-group, randomized RADAR trial in patients with schizophrenia or recurrent psychosis from 19 National Health Service Trusts in England to test the hypothesis. A total of 4,157 patients were screened, of whom 253 (mean age, 46 years; male, 66 percent; schizophrenia, 69 percent; other psychotic disorders, 31 percent) were randomized 1:1 to undergo gradual and flexible antipsychotic reduction overseen by treating clinicians, or to a maintenance group. Social functioning, assessed by the Social Functioning Scale (SFS), was chosen as the primary outcome due to its importance to patients and society.

“The antipsychotic dose was reduced incrementally every 2 months, focusing on one antipsychotic at a time if participants were prescribed more than one,” explained the researchers. “The rate of reduction varied according to the dose at baseline, with most schedules aiming for discontinuation within 12–18 months.”

At 24-month follow-up, the median antipsychotic dose reduction was 33 percent in the reduction group vs 0 percent in the maintenance group. There was no significant difference between the two groups in the overall SFS score (105.7 vs 106.7; β, 0.19; 95 percent confidence interval [CI], -1.94 to 2.33; p=0.86). “Other secondary outcomes showed no differences between the two groups, including measures of symptoms, quality of life, adverse effect scales, body weight and employment,” reported the researchers.

Thirty-two patients (25 percent) in the reduction group experienced ≥1 severe relapse requiring hospital admission vs 17 (13 percent) in the maintenance group. The difference in relapse rate was above the 10 percent noninferiority boundary, indicating a significantly higher relapse risk (odds ratio, 2.2; 95 percent CI, 1.2-4.0; p=0.007) in the reduction group at 24 months.

“The findings were somewhat disappointing, but it was heartening to learn from the qualitative study [embedded within RADAR] that many patients did report various benefits of antipsychotic reduction,” said Mr Jonny Benjamin, a panel member of the Lived Experience Advisory of RADAR. [Lancet Psychiatry 2023;doi.org/10.1016/S2215-0366(23)00266-3]

In the qualitative analysis, the researchers conducted semi-structured interviews (30-90 minutes) after the trial with 26 patients who underwent guided antipsychotic reduction. Some patients felt empowered or more confident in how they understood their mental health problems and medication and how they related to prescribers, while many valued fewer adverse effects, a more active or ‘normal’ life or a more complete sense of self. [eClinicalMedicine 2023;doi.org/10.1016/j.eclinm.2023.102135]

Results of RADAR help to inform decisions about antipsychotic dose reduction and highlight the need for a collaborative decision-making process based on sharing and careful consideration of all the evidence.