The Importance of Antipsychotic Treatment in Severe Mental Disorders

Antipsychotics are the cornerstone of clinical management of severe psychiatric disorders. This heterogenous class of drugs has shown undoubtable efficacy in controlling illness activity in schizophrenia [1,2] and bipolar disorder [3], both in acute and maintenance phases. In addition, antipsychotics appear to significantly reduce mortality in patients with severe psychiatric disorders [4]. Even with crystal-clear evidence of such entity, there has been recent debate about whether antipsychotics could be discontinued in stable patients without psychopathological consequences.

An attempt to explore this research question came from a study by Moncrieff et al. [5], which reported the results of a randomized controlled trial (RCT), assessing the impact of gradual dose reduction in antipsychotics on functioning after 24 months in individuals with schizophrenia-spectrum disorder with multiple episodes. The study had two main findings. First, gradual dose reduction in antipsychotics did not improve functioning. Second, patients in the dose reduction arm had an over twofold increase in the risk of severe relapse (hospitalization) compared to those in the maintenance arm. Moreover, eight vs. four patients died in the dose reduction vs. standard dose arm. These results clearly support the importance of continuing antipsychotic treatment for prevention of psychotic relapses.

In addition, Moncrief et al. [5] hypothesized that most of the impairment in social functioning and quality of life experience by patients with schizophrenia spectrum disorders might be attributed to antipsychotics rather than to the detrimental effects that the disorder, especially if untreated, might exert on the person’s brain and behavior. However, despite the study design including very stable patients, which might have reduced the risk of finding increased relapse, the RCT failed to show superiority on functioning, and found a significantly increased risk of relapse. It is important to note that only 27% discontinued the antipsychotic in the dose reduction arm, suggesting that not only discontinuing, but even reducing the dose was not safe. This is consistent with previous studies showing that the most effective dose for antipsychotics should be between 0.6 and 1 defined daily dose (apart from olanzapine and perphenazine) [6].

Clearly, disentangling the drug’s effect from the detrimental impact of the disorder is extremely difficult and only longitudinal prospective studies in patient populations homogenous for stages of illness and for the type of pharmacological treatment could answer this question. Furthermore, although abrupt AP discontinuation can lead to withdrawal symptoms that may precipitate relapses, this is not true for all APs. Indeed, this class is quite heterogenous in terms of pharmacological profile, with some drugs (clozapine, quietapine, chlorpromazine) certainly more prone to producing rebound symptoms given their cholinergic affinity. But for those APs that have a simpler pharmacological profile, the most parsimonious explanation is that a reduction or suspension of the drug leads to biological reactivation of the disorder. In summary, while this study was important for exploring a difficult, yet extremely sensitive and clinically relevant, research question, we suggest caution in supporting this strategy as a beacon for clinical practice.

Overall, the RADAR trial was an important effort, an open-label trial lasting as long as 24 months that, however, substantially confirms that a dose reduction in antipsychotics not only is not beneficial on functioning but puts persons suffering from schizophrenia spectrum disorders at increased risk of relapse. Findings support the need to inform people with lived experience and their families that reducing the dose of antipsychotics might leave them at increased risk of relapse without improvement in functioning or side effects. Also, given that most antipsychotics are associated with side effects, novel medications with better tolerability profiles are becoming available and might improve long-term compliance to pharmacological treatment for schizophrenia [7].