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Meta-Analysis Finds Antipsychotics Help Prevent Relapse in Schizophrenia

16 May 2012. Antipsychotic drugs significantly reduce the likelihood that a patient with schizophrenia will relapse, according to a new meta-analysis appearing online May 3 in Lancet. The study, led by Stefan Leucht of Universität München, Germany, suggests that maintenance of antipsychotic therapy for up to a year after the illness has stabilized is beneficial to patients.

The findings are consistent with earlier conclusions about antipsychotic drugs, write Jim van Os of Maastricht University, The Netherlands, and Oliver Howes of King’s College London, U.K., in an accompanying commentary. They note also that, "[t]he present review breaks a trend, because systematic re-evaluations in the past two years have cast doubt on the perceived effectiveness of both pharmacological (e.g., antidepressant drugs) and non-pharmacological treatments (e.g., cognitive behavioral therapy in depression) in psychiatry…." However, van Os and Howes caution that the data, which were limited in terms of study durations and other "real-world" data, do not allow for a complete picture of the effects of antipsychotic drugs in schizophrenia.

Assessing benefits and risks
The five-year relapse rate of schizophrenia is around 80 percent (Robinson et al., 1999), meaning that one-fifth of patients won’t experience another episode during that time. Although the effect of antipsychotics on long-term survival is presently unclear, with both increases and decreases in mortality rates reported (see SRF related news story and SRF news story), neuroleptics are accompanied by severe side effects. Adverse effects include weight gain, sedation, and tardive dyskinesia, and can produce long-term health effects, create stigma, and be detrimental to quality of life. Determining the length of time patients should take antipsychotics after illness stabilization is an important and much-debated subject. In the present meta-analysis, researchers aimed to inform the debate by quantifying the effect of antipsychotics on relapse rate.

Leucht and colleagues combed through data from 65 clinical trials over the last 50 years that included a total over 6,000 patients, with a median of 47 patients per study and a median study duration of 26 weeks. A variety of definitions of relapse were used, with clinician judgment, need of medication, and rating scale score being the most common. Indeed, in their discussion, Leucht and colleagues write that, "Universally accepted definitions of relapse and stability of symptoms are urgently needed."

Nonetheless, the results of the meta-analysis were robust—fewer study participants on antipsychotics relapsed between seven and 12 months than those on placebo, and this was true for all time points studied. Some studies tracked relapse as well as hospital readmission (indicative of severe cases). In these trials, nearly 70 percent of the placebo group, but only one-quarter of those on antipsychotics, relapsed. Readmission to a hospital was recorded for 25 percent of placebo patients but only 10 percent of patients on antipsychotics. The length of time patients were stable before entering into the trial did not affect relapse rate, although the difference between the placebo and antipsychotic groups decreased with increasing study length, suggesting that antipsychotics may lose effectiveness over time. However, as noted by the authors, this effect could be due to decreased compliance over time, and thus, longer-lasting studies that more carefully monitor adherence are needed.

Antipsychotics seem to benefit other aspects of the illness besides relapse. At the end of the trials, there were fewer patients with unimproved or worse illness symptoms in the antipsychotic group than in the placebo, and drug treatment was associated with less aggressive behavior than placebo. In the small number of studies that looked at quality of life, an improvement was also seen in the neuroleptic group. But the effects of antipsychotics weren’t all positive. Not surprisingly, patients taking drugs experienced more side effects than those on placebo, including weight gain, sedation, and movement disorders (with the exception of dyskinesia, which was present more often in the placebo group than the antipsychotic group, possibly because of "rebound dyskinesia" from abrupt withdrawal of drugs). There was no overall effect on mortality, although the relatively short duration of follow-up would have made detection of such an effect difficult.

Parsing out the population
The authors also performed subgroup analyses to assess differences among drugs, finding that depot (long-lasting injection) preparations were better than oral forms at preventing relapse. However, in their discussion, the authors write that this finding is in question, and that direct comparisons between depot and oral versions of the same medicine are required.

No difference between first-generation and second-generation antipsychotics was found, and, interestingly, there was also no difference in relapse rates between tapered and abrupt drug withdrawal. This goes against the theory of supersensitivity psychosis (Chouinard et al., 1978), which suggests that long-term antipsychotic treatment increases dopamine receptor sensitivity such that sudden drug withdrawal causes a rebound psychosis and early relapse. In their commentary, van Os and Howes weigh in on the implications for supersensitivity psychosis, calling Leucht and colleagues’ data “reassuring.”

Van Os and Howes also raise important points about the other "real-world" implications of these data. They note that studies with lengthier follow-up periods are needed to provide a thorough cost-benefit analysis of long-term antipsychotic use. Moreover, they caution that “no evidence that other, more disabling, domains of psychopathology such as cognitive alterations or motivational impairment are similarly alleviated is available.”—Allison A. Curley.

Reference:
Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012 May 2. Abstract

Van Os J, Howes OD. Antipsychotic drugs for prevention of relapse. Lancet . 2012 May 2. Abstract

 
Comments on News and Primary Papers
Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 23 May 2012 Posted 23 May 2012

Since the John Davis meta-analysis in the 1970s (the second meta-analysis in medicine; see Davis, 1975), there is little doubt that drug beats placebo in relapse prevention. What is terrific here are the details on aspects of course that are addressed and more information on the risk side to complement benefit. I will comment on two findings. First, depot beats oral. Especially in the United States, we need to move depot into an attractive option and first-line approach (assuming oral administration of the same compound supports safety in the individual). Second, I have thought that there is little evidence for second-generation antipsychotics being superior to first-generation antipsychotics (clozapine excepted) in efficacy and effectiveness, and that the strongest case for second-generation antipsychotics was better relapse prevention. This meta-analysis failed to support this supposed advantage, and I have to adjust my view in this regard.

The van Os and Howes commentary merits a serious and thoughtful read. It gives...  Read more


View all comments by William Carpenter

Comment by:  Wolfgang Gaebel
Submitted 21 June 2012 Posted 22 June 2012
  I recommend the Primary Papers

Antipsychotics are (generally) effective in relapse prevention—however, evidence-based indicators for more individualized treatment are needed.

Leucht and colleagues (Leucht et al., 2012) conducted a new, highly comprehensive, but also very differentiated meta-analysis on the relapse preventive efficacy of antipsychotic drugs as compared to placebo, which is now published in The Lancet. In addition, detailed comments are provided by van Os and Howes (van Os and Howes, 2012) in the same issue. As in former reviews addressing this topic, the results clearly underline that antipsychotics are (generally) effective in preventing relapse in schizophrenia compared to placebo with average one-year relapse rates of 27 percent versus 64 percent, an estimated risk ratio of 0.4, and a number of 3 needed to treat (to benefit) patients. On the other hand, and despite this high-grade evidence, many patients with schizophrenia still show cognitive, affective, motivational, or "functional"...  Read more


View all comments by Wolfgang Gaebel
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