Antipsychotic Dose Reduction or Discontinuation Can Lead to Severe Relapse

Antipsychotic dose reduction or discontinuation increases the risk of severe relapse in people with schizophrenia or other psychotic disorders, according to a new study led by Joanna Moncrieff, MD, of the division of psychiatry at University College London.¹

Due to antipsychotic drug’s adverse effects—such as increasing risk of diabetes, heart disease, tardive dyskinesia, sedation, akathisia, emotional blunting, and sexual dysfunction—Moncrieff and colleagues wanted to see if the drug dosage could be safely lowered in treated patients.

Ultimately, the team wanted to see if lowering the antipsychotic dose in people with schizophrenia or other psychotic disorders would improve social functioning, and to figure this out, they conducted the open, parallel-group, randomized RADAR trial.

“It has been suggested that antipsychotic discontinuation might itself be a risk factor for relapse,” investigators wrote. “Although some evidence suggests that gradual reduction might reduce this risk, our findings do not support this.”

Participants were selected from 19 National Health Service Trusts in England. Eligible patients were aged >18 years old, with a diagnosis of a recurrent psychotic disorder with a prescription of an antipsychotic.

Throughout the trial, the median dose reduction was 67% in the reduction group and 0% in the maintenance group. The dose was lowered every 2 months. The study had follow-up assessments after 6, 12, and 24 months.

The primary outcome of the study was to look at social functioning when lowering the medication dosage, using the Social Functioning Scale. The secondary outcome was looking at severe relapse and how many participants needed to be admitted to the hospital.

Other secondary outcome scales included the Positive and Negative Syndrome Scale (PANSS), measuring mental state, and Manchester Short Assessment, measuring quality of life.

To measure adverse effects, the team used the self-reported Glasgow Antipsychotic Side-effect Scale (GASS). Then, the self-reported Arizona Sexual Experiences Scale (ASEX) measured bodyweight and sexual dysfunction. Participants also had to take the following assessments: self-reported questionnaire about the Process of Recovery (QPR), the self-reported Client Satisfaction Questionnaire (CSQ), and the self-reported Medication Adherence Rating Scale (MARS).

In total, 4157 people were screened; 253 patients were enrolled in the assessment. There were 168 (66%) men, 83 (32%) women, and 3 (1%) transgender people. Mean patient age was 46 years.

Two-thirds (n = 171 [67%]) of participants were reported White; 52 (21%) were reported Black; 16 (6%) were reported Asian; and 12 (5%) were reported another ethnicity.

Per the Social Functioning Scale the team found no difference between the reduction group and the maintenance group at 24 months (β, 0.19; 95%, CI -1.94 to 2.33; P = .86).

“Our trial does not show any benefits to people from reducing antipsychotic medication in terms of improving social functioning or reducing adverse effects, including bodyweight, in the short to medium term,” the team wrote.

The reduction group had 93 serious adverse effects, affecting 49 individuals. Meanwhile, the maintenance group had 64 adverse effects, affecting 29 individuals.

“The lack of alleviation of adverse effects is surprising in view of the lower dose reached in the reduction group and the findings of the qualitative analysis,” the investigators wrote.

In the reduction group, 5 deaths were caused by natural causes: an accidental drug overdose; adverse effects of antipsychotic medication; and a trio of deaths caused by unknown factors. In the maintenance group, 2 deaths were caused by natural causes, one being an accidental overdose, and the other a suicide.

The team continued to find after the 2-year follow-up the gradual antipsychotic dose reduction did not affect social functioning.

Moncrieff and colleagues found in previous meta-analyses that reducing or discontinuing antipsychotic medication increases rates of relapse; however, many trials did not focus on a gradual dose reduction approach nor include long-term follow-up.

“In people with recurrent psychosis or schizophrenia, we found no evidence to support our hypothesis that a gradual reduction of antipsychotic medication improved social functioning at 2-year follow-up,” the team wrote. “Antipsychotic reduction increased the risk of relapse compared with continuing maintenance treatment, although most people did not relapse.”

Thirty-two (25%) people from the reduction group severely relapsed while only 17 (13%) in the maintenance group relapsed (odds ratio [OR], 2.20; 95% CI, 1.15 – 4.22).

In the reduction group, there was less time before a severe relapse than the maintenance group (hazard ratio [HR], 2.2; 95% CI 1.2 – 4.0; P = .007). Thus, reducing antipsychotic medication dosage has increased the risk for severe relapse—and the gradual dosage reducing did not help.

“It has been suggested that it might take years for the brain to adapt slowly to lower levels of a drug that has been taken for a long period,” the team wrote. “Future studies could also explore whether additional psychological and social support could reduce the excess risk of relapse associated with antipsychotic dose reduction and discontinuation.”

References

1. ^{Moncrieff J, Crellin N, Stansfeld J, et al. Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial [published online ahead of print, 2023 Sep 28]. Lancet Psychiatry. 2023;S2215-0366(23)00258-4. doi:10.1016/S2215-0366(23)00258-4}