Long-Term Antipsychotic Treatment Tapered in 2-Year Trial

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Tapering the dosage of long-term antipsychotic medication treatment for schizophrenia or recurrent psychosis was more likely to result in relapse of symptoms than maintaining the dose in a 2-year trial, despite individualized and gradual reduction over several months.¹

In the open, parallel-group, randomized Research into Antipsychotic Discontinuation and Reduction (RADAR) trial, investigators had anticipated that social functioning would improve with reduced or discontinued antipsychotic medication. They were also hopeful that the very gradual dose reduction, along with continued consultation with the treating psychiatrist and the option of psychological therapy as clinically indicated, would mitigate against relapse.

Dosage was reduced incrementally every 2 months at rates that varied with the baseline dose and patient response, toward potential discontinuation within 12 to 18 months. The investigators hypothesized that no more than 10% of those receiving reduced dosage would have a serious relapse—corresponding to their criteria for non-inferiority of tapering versus maintaining dose.

The reduced dose was not as well tolerated as had been hoped, however, with severe relapse requiring hospitalization in 25% of those in the reduction group compared with 13% of the maintenance group. There was also no difference in social functioning between the groups at baseline or at study completion, with no measurable improvement associated with reducing the antipsychotic dose. Most participants with reduced dose did not relapse, however, and several were successful in discontinuing the antipsychotic without relapse in the 2-year period.

“It was still the case that the majority of people in the reduction arm didn't relapse, and that people in the reduction arm were not worse off at the end of the study in terms of their social functioning, quality of life or any other factors, even though they did have higher rates of relapse,” the trial report lead author Joanna Moncrieff, MD, Division of Psychiatry at the University College London, commented to Psychiatric Times.

In her blog about the RADAR trial, Moncrieff expressed her disappointment that the incidence of relapse echoed results of prior dose reduction studies which had not applied comparably gradual and lengthy tapering.²

“Yet relapse was far from inevitable and the qualitative analysis showed that some people felt empowered by the opportunity to reduce their medication with official support, regardless of the outcome,” Moncrieff said.

Running the RADAR Trial

“Running the RADAR study is by far the most difficult thing I have done in my professional career,” Moncrieff acknowledged in her blog.

“Understandably, people who are already on antipsychotics often have strong views about whether they want to stay on them or not. So despite our best efforts, we did not recruit as many patients as we had originally intended,” she noted.

Moncrieff and colleagues randomized 126 participants to the reduction group and 127 to the maintenance group from over 4000 patients screened throughout the UK between April 2017 and March 2020. The cohort included 66% men, 32% women, and 1% transgender individuals aged 18 years and older; mean age of 46 years. Exclusion criteria included having had a mental health crisis or hospital admission within past month and being considered a serious risk to themselves or others.

Participants and their clinicians were aware of their treatment group, while that was masked from the study evaluators. The primary outcome was social functioning, measured on the Social Functioning Scale (SFS). The investigators explained choosing this as the primary outcome, “to reflect outcomes that are important to patients and society.”

The principal secondary outcome was severe relapse requiring hospital admission. Other secondary outcomes included mental state, measured by the Positive and Negative Syndrome Scale (PANSS); and quality of life, measured by self-report on the Manchester Short Assessment of quality of life (MANSA), and the Objective Social Outcomes Index (SIX), which is derived from it.

Although the length of time in contact with mental health services was determined (33% exceeding 20 years, 9% with 3 years or less), the duration of antipsychotic treatment was not obtained. “Because we didn’t think people could recall it accurately enough. But from the other data we can assume it would be a long time on average,” Moncrieff commented.

A 67% median dose reduction was attained at some point during the trial, and at the 2-year study completion, the median dose reduction was 33% less than at baseline. The investigators reported that 34 (27%) of those randomized to reduction stopped their antipsychotic medication sometime during the study, with 13 (10%) remaining off the antipsychotic at study end.

At 2-years, 32 participants (25%) in the reduction group had at least 1 severe relapse compared with 17 (13%) in the maintenance group (odds ratio 2.20 [95% CI 1.15-4.22]), which did not meet the criteria of 10% relapse with dose reduction for non-inferiority to maintaining dosage. Twenty participants (16%) in the reduction group and 11 (9%) in the maintenance group had a non-severe relapse. The total having any degree of relapse was 52 (41%) in the reduction group and 28 (22%) in the maintenance group. Both serious and non-serious adverse events were more common in the reduction group.

RADAR Results are Qualitative and Quantitative

Moncrieff and colleagues concluded that the gradual reduction did not lead to benefits in social functioning and was more likely to lead to relapse than continuing maintenance dosage. In a separately published report of the qualitative findings from the RADAR trial, however, the investigators indicated that most patients in the reduced dosage group had experienced a reduction in antipsychotic medication-related adverse effects, including mental clouding, emotional blunting, and sedation.³

Although there was not a significant difference between the groups in measures of social functioning at the 2-year follow-up, the investigators found some positive impacts in the reduction group in social functioning and sense of self. They also describe a range of experiences with reducing dosage.

“Some participants were highly engaged with reduction processes and despite difficulties including relapses, developed novel perspectives on medication, dose optimization, and how to manage their mental health,” the investigators recounted. “Others were more ambivalent about reduction or experienced less overall impact.”

In an editorial⁴ accompanying the RADAR trial report, Stefan Leucht, MD, Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, and colleagues note that optimal dose and duration of antipsychotic medications have been debated since their introduction, and complicated by variability in the course of schizophrenia and in the consequences of relapse.

Leucht et al noted that the RADAR trial had avoided “the important bias of dose reductions being too rapid.” They also expressed appreciation that qualitative findings had been reported. "Such qualitative studies yield different insights than comparisons of averages in randomized controlled trials and should be conducted more often," they indicated.

Leucht and colleagues did speculate that there might have been some selection bias for patients with relatively mild illness, as the investigators had provided little explanation for the small cohort of 253 obtained from over 4000 screened. The size of the cohort was more likely a reflection of the difficulty in recruiting than in seeking those with milder illness, however, as Moncrieff indicated in comments to Psychiatric Times.

"Ideally, I would like to do a trial in which we select people with less severe and more stable conditions, including those discharged to primary care—who we could not include in the RADAR trial," Moncrieff said.

The clinical lessons to take from the RADAR trial and from similar findings in previous studies of antipsychotic dosage reduction,⁵ according to Leucht et al, are "that all patients should be informed that a substantial dose reduction or discontinuation of antipsychotics is associated with an increased risk of relapse, and that reductions in side-effects are unclear.”

“Individual decisions should be based on patients' wishes, the side effect that they currently have, and their life situation—eg, whether their job is at risk, or whether there are any relatives who would notice an impending relapse in time,” they advised.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Moncreiff 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, randomized controlled trial. Lancet Psychiatry. 2023;10(11):848-859.

2. Moncreiff J. Lessons from the RADAR trial. Critical Psychiatry Network Website. October 2, 2023. Accessed January 10, 2024. https://joannamoncrieff.com/2023/10/02/lessons-from-the-radar-trial/

3. Morant N, Long M, Jayacodi S, et al. Experiences of reduction and discontinuation of antipsychotics: a qualitative investigation within the RADAR trial. EClinicalMedicine. 2023;64:102135.

4. Leucht S, Bighelli I, Siafis S, et al. Antipsychotic dose reduction: unclear benefits but certain risks. Lancet Psychiatry. 2023;10(11):819-821.

5. Wunderink L, Nieboer RM, Wiersma D, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013;70(9):913-920.