The use of continuous treatment versus placebo or intermittent treatment strategies in stabilized patients with schizophrenia: a systematic review and meta-analysis of randomized controlled trials with first and second-generation antipsychotics

Background Although continuous treatment with antipsychotics is still recommended as the gold standard treatment paradigm for all patients with schizophrenia, some clinicians question whether continuous antipsychotic treatment is necessary, or even justified, for every patient with schizophrenia. Objective The primary objectives of this systematic review and meta-analysis are (1) compare relapse/hospitalization risks of stabilized patients with schizophrenia under active versus intermittent or placebo treatment conditions, (2) examine the role of several study characteristics, possibly intervening in the relationship between relapse risk and treatment condition (3) examine whether time-to-relapse is associated with antipsychotic treatment duration. Methods A systematic literature search, using the MEDLINE database (1950 until November 2014), was conducted for English-language published randomized controlled trials, covering a follow-up time period of at least 6 months, and investigating relapse/rehospitalisation and/or time-to-relapse rates with placebo or intermittent treatment strategies versus continuous treatment with first or second generation antipsychotics (FGAs/SGAs) in stabilized patients with schizophrenia. Additional studies were identified through searches of reference lists of other identified systematic reviews and Cochrane reports. Two meta-analyses (placebo versus continuous and intermittent versus continuous treatment) were performed to obtain an optimal estimation of the relapse/hospitalization risks of stabilized patients with schizophrenia under these treatment conditions and to assess the role of study caracteristics. For time-to-relapse data, a descriptive analysis was performed. Results Forty-eight reports were selected as potentially eligible. Of these, 21 met the inclusion criteria. Twenty-five records, identified through Cochrane and other systematic reviews and fulfilling the inclusion criteria, were added, resulting in a total of 46 records. Stabilized patients with schizophrenia who have been exposed to intermittent or placebo strategies, covering a follow-up time period of at least 6 months after randomization, have, respectively, a 3 (Odds ratio, OR=3.357, 95%CI: 2.36-5.45) to 6 (Odds ratio, OR=5.64, 95%CI: 4.47-7.11) times increased risk to relapse, compared to those patients on continuous treatment. The availability of rescue medication (p=0.0102) was the only study characteristic explaining systematic differences in the OR for relapse between placebo versus continuous treatment across studies. Studies reporting time-to-relapse data show that the time-to-(impending)-relapse always is statistically significantly delayed with continuous treatment, compared with placebo or intermittent treatment strategies. Although the interval between treatment discontinuation and symptom recurrence can be highly variable, mean time-to-relapse data seem to indicate a failure of clinical stability before 7-14 months with intermittent and before 5 months with placebo treatment strategies. For all reports included in this systematic review, median time-to relapse rates in the continuous treatment group were not estimable as less than 50% of the patients in this treatment condition relapsed before the end of the study. Conclusions With continuous treatment patients do not only have a lower risk to relapse, but can also be maintained relapse free for a longer period of time. Moreover, “success rates” in the intermittent treatment conditions probably are an overestimating of real outcome rates. As until now only a few and rather general valid predictors for relapse in schizophrenia are known and subsequent relapses may contribute to the functional deterioration and treatment resistance observed in patients with schizophrenia, continuous treatment remains the ‘gold standard’ for good clinical practice. Considering the importance of ensuring continuity of treatment as early as possible in the course of the illness before disease progression occurs, the availability of long-acting injectable antipsychotics can be an interesting treatment option, even in patients with a first episode.status: publishe