Antipsychotic maintenance treatment in schizophrenia and the importance of preventing relapse

The paper by Correll et al1 critically reviews the literature pertaining to maintenance antipsychotic treatment in schizophrenia. This is a highly important, but poorly understood topic. The paucity of well‐conducted long‐term studies makes it difficult to draw firm conclusions regarding the risk to benefit ratio of ongoing antipsychotic treatment. However, this paper provides a comprehensive overview of the pros and cons of that treatment. Clinicians would do well to read the paper carefully.

Despite its demonstrated benefits, it is well recognized that long‐term antipsychotic treatment is associated with substantial safety risks, adverse effects and inconveniences. For these reasons, patients and clinicians continue to entertain the possibility of stopping treatment at some stage. While the option of successfully discontinuing antipsychotics once a favourable response has been achieved would be highly desirable, the reality is that no current strategies can realistically be expected to achieve this goal. Despite our best efforts, the illness remains often characterized by chronicity, recurrence of psychotic symptoms when treatment is discontinued, and enduring deficits with negative effects on functionality, autonomy and independent living, as well as quality of life2.

There are several important aspects concerning the nature of relapse events that clinicians and patients should be aware of when considering antipsychotic treatment discontinuation. First, relapse rates are higher than usually recognized when antipsychotics are discontinued, even after a single episode of psychosis. A recent systematic review reported a weighted mean one‐year recurrence rate of 77%, and by two years the risk of recurrence had increased to over 90%3.

Second, there are no clinically useful predictors of which individuals are likely to successfully discontinue antipsychotic treatment. Indeed, one study in a small sample found that, counterintuitively, patients who respond most favourably to treatment might be at particular risk of relapse4.

Third, there are no reliable warning signs of imminent relapse, and early rescue medication interventions may not effectively prevent full‐blown illness recurrence5. Evidence suggests that, once a first psychotic episode has occurred, there is a reduced threshold for illness recurrence. Unlike the first episode, where the onset of illness is frequently gradual and prodromal symptoms emerge over months and even years, the second and subsequent episodes tend to occur abruptly, with no reliable early warning signs and with rapid return of symptom severity levels similar to those of the previous episode6. Consequently, treatment discontinuation, even with careful follow‐up and immediate re‐initiation of treatment, runs the risk of exposing patients to the consequences of full‐blown psychosis. This means that the often cited strategy of “targeted discontinuation” – i.e., carefully monitoring patients while treatment is reduced and discontinued, with immediate re‐introduction of treatment at the first signs of recurrence – may not be effective.

Fourth, a longer period of treatment prior to discontinuation does not reduce the risk of relapse. Studies in which treatment was continued for two years before discontinuation reported similar relapse rates to those in which patients were treated for six months before discontinuation7. Although longer term discontinuation studies have not been conducted, there is no reason to believe that treating patients for a longer period will reduce their chance of illness recurrence once medication is discontinued.

Finally, no discontinuation strategies have been demonstrated to improve the chance of successfully stopping antipsychotic treatment. As pointed out by Correll et al1, while psychosocial interventions are effective adjunctive therapies, they cannot be regarded as an alternative to antipsychotic medication. Furthermore, other approaches – such as gradual dose reduction followed by discontinuation of antipsychotic treatment – have not been successful.

There are serious psychosocial risks associated with illness recurrence. For example, there is a risk of self‐harm and harm to others. In addition, relapses may disrupt friendships and relationships, and impact negatively on education and employment. They may also restrict autonomy, contribute to stigma, and cause patients and their families immense distress. Furthermore, relapses add hugely to the overall economic burden of treating schizophrenia.

In addition to these negative psychosocial consequences of relapse, there may be an additional risk of biological harm. While the treatment response when antipsychotics are re‐initiated after relapse is variable, some patients exhibit protracted impairment of response and, importantly, treatment failure emerges in a subgroup of about one in six patients. Treatment failure occurs irrespective of whether it is the first or a subsequent relapse, and even when treatment is re‐introduced immediately after the first signs of illness recurrence8.

Given all of these potential hazards associated with illness recurrence, together with the clear‐cut evidence for efficacy of antipsychotics in relapse prevention studies9, it is understandable that clinicians continue to prioritize relapse prevention via continuous antipsychotic treatment as a treatment goal. This is despite the substantial adverse effect burden associated with antipsychotic medication. This burden can be reduced by judicious selection of the best tolerated antipsychotic according to the individual patient's profile, and at the lowest effective dose. There is also a need for the development of new antipsychotic medications that are better tolerated and at the same time more effective in providing uninterrupted treatment, including long‐acting injectable formulations.

Finally, there is an urgent need for further studies aimed at better identifying individuals who are more likely to successfully discontinue treatment, as well as at characterizing clinically useful early warning signs of impending relapse and developing treatment strategies more likely to result in successful discontinuation.

In the meantime, recommending ongoing maintenance treatment with the safest and best tolerated antipsychotic at the lowest therapeutic dose is the best option for achieving optimal outcomes.

Robin Emsley
Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa