Maintenance Treatment With Antipsychotic Drugs in Schizophrenia: A Cochrane Systematic Review and Meta-analysis

Abstract

Antipsychotic drugs are the mainstay of treatment of schizophrenia, and are known to reduce acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotics are effective for relapse prevention, compared to withdrawing these agents for people with schizophrenia or schizophrenia-like psychoses, based on evidence from randomized trials. The current report of the update of the review is focused on some newly investigated outcomes: rates of remission and recovery, change in social functioning and in quality of life. The updated review included 75 randomized controlled trials (RCTs) published from 1959 to 2017, involving 9145 participants. Although some potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear and robust to a series of sensitivity analyses. Antipsychotic drugs were more effective than placebo in preventing relapse at 1 year (drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR = 0.38, 95% CI = 0.32 to 0.45) and in reducing hospitalization (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR = 0.43, 95% CI = 0.32 to 0.57). Quality of life appeared to be better in drug‐treated participants (7 RCTs, n = 1573, SMD = −0.32, 95% CI = −0.57 to −0.07); the same for social functioning (15 RCTs, n = 3588, SMD = −0.43, 95% CI = −0.53 to −0.34). Although based on data from fewer studies, maintenance treatment apparently increased the possibility to achieve remission of symptoms (drug 53%, placebo 31%; 7 RCTs, 867 participants; RR = 1.73, 95% CI = 1.20 to 2.48) and to sustain it over 6 months (drug 36%, placebo 26%; 8 RCTs, 1807 participants; RR = 1.67, 95% CI = 1.28 to 2.19). There were no data on recovery. Antipsychotic drugs as a group were associated with more participants experiencing side effects such as movement disorders (e.g., at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI = 1.25 to 1.85) and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR = 1.69, 95% CI = 1.21 to 2.35, NNTH = 25, 95% CI = 20 to 50). For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs does not only prevent relapses and rehospitalizations, but that patients also benefit in terms of quality of life, functioning and sustained remission. These positive effects must be weighed against the backdrop of the adverse effects of antipsychotics.

Background

Schizophrenia is a frequent and generally chronic disorder, often disabling for people living with it. Relapse episodes are linked with substantial psychosocial and economic burden, implying higher risk of personal, social and occupational impairment, autonomy loss, violence events, stigma, and self-stigma. Antipsychotics are the mainstay of treatment for schizophrenia, in the acute phase as well as in the long-term perspective. The superiority of continuing these agents over drug discontinuation in preventing relapses and hospitalizations was already shown in the original version of the current work, which was published in 2012¹; however, treatment adherence is still suboptimal, and many patients and clinicians still consider the idea of withdrawing drug therapy after some time, mainly due to safety issues and consequent quality of life modifications. While therapeutic strategies involving attempts to reduce/discontinue antipsychotics and promptly reintroduce them at imminent relapse have been proven ineffective,² current clinical guidelines do not explicitly state indications beyond a 1–2 years’ timeframe^3,4; moreover, in the context of the risk-benefit ratio of maintenance medication, very few recent comprehensive data are available on the potential effects on remission/recovery, psychosocial functioning, and quality of life.

Objectives

To update systematic evidence on the efficacy and tolerability of maintenance treatment with antipsychotics for people living with schizophrenia compared to the discontinuation of these agents; in particular, new outcomes were evaluated, such as remission and recovery rates, and change in social functioning and quality of life.

Search Methods

The systematic search of the Cochrane Schizophrenia Group’s study-based register of trials was updated on October 10, 2017, July 3, 2018, and September 11, 2019. References were independently inspected by 2 reviewers; study Authors and drug companies were contacted to ask for additional data or clarifications.

Selection Criteria

Randomized controlled trials (RCTs) comparing maintenance treatment with antipsychotics and drug withdrawal/placebo for people with schizophrenia spectrum disorders were eligible for this review.

Data Collection and Analysis

Data were independently extracted by 2 researchers. Outcome measures included risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data, calculated on an intention-to-treat basis, and standardized mean differences (SMDs) for continuous data. Data synthesis was performed using a random-effects approach.

Main Results

The review includes data from 75 RCTs (9145 participants), published from 1959 to 2017. Maintenance treatment with antipsychotics was clearly more effective than placebo in preventing relapses at 1 year, with drug discontinuation associated with 3 times higher risk of recurrence (drug 24%, placebo 61%; 30 RCTs, 4249 participants; RR 0.38, 95% CI 0.32–0.45). This result was robust to a series of sensitivity analyses and consistent among different settings and types of participants, notwithstanding potential sources of bias across included studies, such as the poor reporting of allocation strategies and use of blinding. The risk of hospitalization was also reduced by maintenance treatment (21 RCTs, 3558 participants; RR 0.43, 95% CI 0.32–0.57). Although based on data from less studies, antipsychotics as a group appeared to have a positive effect on the possibility to achieve remission from symptoms (drug 53%, placebo 31%; 7 RCTs, 867 participants; RR 1.73, 95% CI 1.20–2.48) and to sustain it over 6 months (drug 36%, placebo 26%; 8 RCTs, 1807 participants; RR 1.67, 95% CI 1.28–2.19). No data were available in this perspective on the effects on recovery. Quality of life (7 RCTs, 1573 participants; SMD −0.32, 95% CI −0.57 to −0.07) and social functioning (15 RCTs, 3588 participants; SMD 3588 participants; SMD −0.43, 95% CI −0.57 to −0.07; see figure 1) were better among drug-treated subjects. No clear difference emerged in terms of mortality and suicide rates. Irrespective of follow-up duration, antipsychotics were associated with more subjects experiencing side effects, such as movement disorders (29 RCTs, 5276 participants; RR 1.52, 95% CI 1.25–1.85) and weight gain (19 RCTs, 4767 participants; RR 1.69, 95% CI 1.21–2.35).

Fig. 1.

Maintenance treatment with antipsychotic drugs vs placebo/no treatment; outcome: social functioning (across all scales and timepoints).

Authors’ Conclusions

Continuing antipsychotic drugs for up to 2 years prevents schizophrenia relapse to a greater extent than withdrawing them, among various treatment settings and populations. The advantages include better psychosocial functioning and quality of life, and more frequent clinical remission. The level of certainty in this evidence is heterogeneous across the various outcomes, and benefits should clearly be weighed against the adverse effects of these drugs. Review findings are described more in detail elsewhere.⁵

Funding

Bundesministerium für Bildung und Forschung Grant number 01KG0816 88166528, Germany; University of Hong Kong/China Medical Board (CMB) Grant, Hong Kong.