RADAR Trial: A Reality Check for Critics of Antipsychotics

A trial from the UK shows antipsychotic dose reduction increases risk of relapse and does not lead to benefits in social functioning

Critical discussion of antipsychotics on social media and in the blogosphere has been in a weird state for the last 15 years or so. Many assert, based on data with substantial methodological limitations, that antipsychotic medications worsen clinical outcomes in patients with schizophrenia and other psychotic disorders. That they worsen functioning, impede recovery, and even increase the risk of relapse and hospitalization. And that they do so not just in a subset, not just in cases of high doses or polypharmacy, but in the average patient with standard doses of antipsychotics. There are books and websites devoted to spreading this message as if it were an established scientific truth that the psychiatric profession has been hiding. Such platforms have become engines of confirmation bias, interpreting every new research finding through the lens of prior beliefs to which an unwarranted degree of confidence has been assigned. I do think there is a careful, complicated, nuanced story to be told here, one that requires a great degree of epistemic humility given the state of the evidence and an appreciation of what is at stake clinically, but that is not the approach taken by many critics. Many of these critics are neither researchers (they are unable to design studies or gather new data) nor clinicians (they have no skin in the game when it comes to patient outcomes), and as a result, their critiques are often disconnected from real-world considerations.

The RADAR trial is a welcome deviation from this trend. This trial was specifically designed to compare the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Unlike some other studies that have been conducted in patients with first-episode psychosis, this one recruited people with multiple psychotic episodes or recurrent psychotic conditions. 69% of subjects in the study were diagnosed with schizophrenia. Researchers hypothesized that antipsychotic reduction would improve social functioning and that any increase in the rate of serious relapse (leading to psychiatric hospitalization) would be less than 10%. Antipsychotic medications were reduced gradually over a period of months in a flexible way, with the aim of discontinuing completely if possible. In other prior trials, discontinuation has been much more rapid, over days or a few weeks. 126 patients were assigned to dose reduction and 127 to maintenance treatment. 70% of participants in the reduction group reduced their antipsychotic dose by 50% or more.

The article is open-access, and there are already some excellent discussions of it. The accompanying commentary by Stefan Leucht, et al. (aptly titled “Antipsychotic dose reduction: unclear benefits but certain risks”) is very good and I highly recommend reading it. I also recommend blog posts by George Dawson and Sandra Steingard. Given these discussions, I’ll keep my review of the study brief and bring up points that I think have been emphasized less well elsewhere.

Prior to the publication of the results, my own suspicion was that the RADAR trial would likely find a modest degree of improvement in social functioning and that there would be an increase in the risk of relapse, which would set the scene for a complicated discussion of how we can balance the two. Fortunately, not only was there no difference between the maintenance and dose reduction groups, but social functioning also remained stable during the course of the trial over 24 months. There was no worsening or improvement of social functioning with maintenance and no worsening or improvement with dose reduction. In contrast, the study found substantially higher rates of psychotic relapse in the dose-reduction group. By 24 months, 25% of the reduction group had at least one severe relapse, vs 13% of the maintenance group. 41% of the reduction group had a relapse of any severity vs 22% of the maintenance group.

“The RADAR trial found that a gradual reduction over several months in the dose of maintenance antipsychotics in people diagnosed with schizophrenia and related psychotic disorders did not lead to benefits in social functioning and was more likely to lead to relapse than continuing on maintenance treatment.” Moncrieff, et al. 2023. Lancet Psychiatry

• Time to severe relapse was also shorter in the reduction group compared with the maintenance group. Participants allocated to antipsychotic dose reduction reached a median of 67% reduction of their baseline dose at some point during the trial. The median dose at 24 months was 33% less than at baseline. The reason for this difference is not explained, but it’s likely because those who relapsed on lower doses had their medication dose adjusted again to control symptoms.

• 34 (27%) of those randomized to reduction stopped their antipsychotic medication completely at some time during the 24-month follow-up period. By 24 months, only 13 people (10%) in the reduction group were not taking antipsychotics. That is, out of the 34 who stopped their antipsychotics completely at some point, 62% had to resume taking antipsychotics.

• There was no difference in neurocognitive functioning (measured by a battery of tests that included digit span, digit symbol substitution, Rey auditory verbal learning, trail making, and verbal fluency) between the two groups. Dose reduction did not improve cognitive functioning in this group.

• There were eight deaths in the reduction group during the study and four in the maintenance group.

It is important to keep in mind that the people in the study are a carefully selected group of people with relatively low risk. The study excluded those who lacked the capacity to consent to trial, those who had been required to take the medication under the Mental Health Act, those whom the clinicians considered to be at serious risk of harm to themselves or others, and people who had had a mental health crisis or hospital admission in the past month. For such patients, who constitute a considerable portion of patients in clinical practice, the risks of antipsychotic dose reduction or discontinuation are likely to be even higher.

Patients in this study had relatively mild symptom severity, were on reasonable doses of antipsychotics (around 8-10 mg of olanzapine or equivalent), and the side effect burden was mild, which is likely why no improvement in functioning or cognition was seen with dose reduction. The situation is likely to be different for folks who are on higher than standard doses of antipsychotics, who are receiving antipsychotic polypharmacy, or who are experiencing side effects while on standard doses of medications.

In my experience, if patients are actively experiencing medication effects such as feeling mentally dull, numb, like a zombie, sedated, or if they are having adverse effects such as tremors, a dose reduction or change in medication does usually improve functioning. It is also reasonable to think that those who experience metabolic adverse effects such as weight gain or pre-diabetes/diabetes can also experience decline in functioning, and dose reduction or medication switching can help with that. If a patient is tolerating a dose of the antipsychotic medication with minimal adverse effects and minimal impact on the patient’s (self-reported) functioning, I do not think that dose reduction or discontinuation will be of any functional benefit. The clinical goal, in my opinion, is to maintain patients on a medication dose that they tolerate and that doesn’t interfere with their functioning. And this outcome is achievable for many patients.

The problem arises when the medication or the dose of the medication required for clinical stabilization is one that actively produces adverse effects. E.g., when patients require high doses, or polypharmacy, or when they don’t respond to first-line medications and require clozapine, which has more adverse effects and is less well tolerated. In such cases, we are forced to balance reducing the risk of relapse (or active symptom control) with active adverse effects. Ideally, the decision should be an informed one by the patient, but in practice, the culture when it comes to the treatment of schizophrenia spectrum disorders is extremely paternalistic. Clinicians want to minimize relapse, and other considerations are often secondary to them, even if those other considerations are more important to the patient. Resultantly, many patients are pressurized to stay on medication doses that they do not tolerate well, and patients are offered little to no support by the clinicians if they decide to reduce or discontinue the medication. Clinical decision-making here is made more complex when patients have poor insight or a poor appreciation of the risks, when there are concerns by family members about decompensation, and when, especially in places such as the US, there is a real risk of becoming homeless or being arrested. There are good reasons why clinicians who have skin in the game are so conservative in the management of psychotic disorders. While this clinical attitude of prioritizing relapse risk over functioning and tolerability keeps many patients stable, it also harms those who would’ve benefited from a personalized reduction, change, or discontinuation of medication.

The problem arises when the medication or the dose of the medication required for clinical stabilization is one that actively produces adverse effects… Ideally, the decision should be an informed one by the patient, but in practice, the culture when it comes to the treatment of schizophrenia spectrum disorders is extremely paternalistic. Clinicians want to minimize relapse, and other considerations are often secondary to them, even if those other considerations are more important to the patient. Resultantly, many patients are pressurized to stay on medication doses that they do not tolerate well, and patients are offered little to no support by the clinicians if they decide to reduce or discontinue the medication.

Some have speculated that perhaps an even more gradual reduction of the antipsychotic dose over months and years would show lower rates of relapse than have been reported in the RADAR trial. Possibly. We won’t know for sure until someone studies this properly, but based on the data we have, I am skeptical that it’ll make a substantial difference. I think antipsychotics confer a meaningful reduction in relapse risk, and beyond a certain threshold (tapering over several months), the rate of dose reduction matters less and less with regards to relapse risk. A gradual taper over months and years, however, is clinically wise if we have the luxury to do it that slowly. As mentioned previously, I think the goal for the average patient with chronic or recurrent psychosis should be to find a dose on the low end of the standard range that they tolerate well without subjective interference with functioning. Some people do okay with lower than standard doses, or possibly even discontinuation, but we don’t have a good sense of how to identify such individuals. Dose reduction below standard doses, or discontinuation, is certainly achievable in some cases, but it’s not an achievable goal for the average patient with chronic or recurrent psychosis, given the current state of non-pharmacological treatments for psychotic disorders. With the development of more effective non-pharmacological maintenance treatments, this may change.

The results of the RADAR trial are similar to an earlier, famous trial by Wunderink et al. of gradual antipsychotic dose reduction and discontinuation in people with a first episode of psychosis. In the initial RCT phase of the trial, at the 18-month follow-up, there was an increased rate of relapse with antipsychotic reduction, with no difference in social functioning. However, at 7-year naturalistic follow-up, patients originally randomized to antipsychotic dose reduction but now receiving usual care had higher functioning and recovery rates, and the risk of relapse had become equal after 2-3 years. I think that the risk of relapse equalized after 2-3 years because patients were no longer randomized and both arms were receiving treatment as usual. The discrepancy in functioning/recovery is more significant, and it is possible that early dose reduction may confer benefits many years later, but given the observational nature of the second phase of follow-up and the methodological problems that exist in such studies, it is difficult to say with high confidence. The RADAR team is planning for a follow-up observational phase similar to Wunderink et al. However, even if they replicate the finding by Wunderink et al. (and replication is not guaranteed), it is not likely to have much clinical force. We have solid evidence from randomized data that over a 2-year period, antipsychotic dose reduction or discontinuation nearly doubles the risk of relapse without improving functioning (for the average patient); clinicians will reasonably give this finding more weight compared to a finding that non-conclusively suggests possible benefits in functioning 7 years later.

Some critics point to long-term 20-year observational data from the Harrow study, but the Harrow study was so methodologically ill-equipped to reveal the causal relationships and its analyses are so confounded that I, along with most of the scientific community, find their results entirely unpersuasive (in contrast to the uncritical acceptance of the findings in critical circles).

As I have discussed above, findings from the RADAR trial still leave a lot of room for personalization of care. There are many situations where antipsychotic dose reduction and discontinuation are clinically appropriate, and patients should be empowered to make these decisions whenever possible. For those maintained on medications, the goal should be a medication and dose that they tolerate well. Qualitative data from some subjects in the RADAR trial showed that many patients found the collaborative process to be helpful and “developed novel perspectives on medication, dose optimisation, and how to manage their mental health. Others were more ambivalent about reduction or experienced less overall impact.”

What the RADAR trial doesn’t leave room for—and to be honest, the evidence never did—is the vilification of antipsychotics. Antipsychotics are effective maintenance treatments for acute as well as maintenance treatment of psychotic disorders. They substantially reduce the risk of relapse, and reducing their dose below recommended doses doesn’t, in general, improve functioning. Most people with chronic or recurrent psychosis who discontinue antipsychotics have to resume taking them. For the ‘antipsychotics make you worse, the best thing you can do is to get off them’ crowd, the RADAR trial is a powerful reality check.

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