title: The risk of death among adult participants in trials of antipsychotic drugs in schizophrenia.
abstract: In this paper we investigate mortality in short-term placebo-controlled trials conducted to demonstrate efficacy and safety of atypical antipsychotic drugs for the treatment of schizophrenic patients in the acute phase of illness. Arguments are provided, why short-term placebo-controlled studies are required. This is an integrated analysis of results from randomized placebo-controlled trials conducted pre-licensing for risperidone, olanzapine, quetiapine IR, ziprasidone, risperidone consta, aripiprazole, paliperidone, and quetiapine XR. Information was retrieved from study publications, EPAR, and from the FDA SBA, all in the public domain. 7553 patients were randomized in the remaining 23 short-term acute phase clinical trials. 2/5738 patients died after having been randomized to an active treatment. 5/1815 died in the placebo group. The crude odds-ratio for an increased death risk with placebo treatment is 7.92 (95% confidence interval (1.45 to 40.87), two sided P=0.0134). Death narratives show: (i) both deaths in active treatment groups occurred during randomized treatment period, (ii) two deaths in the placebo group of a trial in the elderly were observed in patients with severe co-morbidities not usually included in a randomized trial, and (iii) two further deaths in the placebo groups occurred 9 and 23 days after the end of the randomized treatment period. Under these circumstances the crude odds-ratio for an increased risk of death for patient with placebo as compared to active treatment is 1.58 (95% confidence interval (0.14-17.45), two sided P=0.71). Confidence intervals are generally wide indicating a still limited knowledge about a potential increase in mortality with placebo treatment. Unless, however, society is willing to take the risk that ineffective drugs are licensed and cause undetected harm thereafter, or is willing to restrict licensing to drugs that are superior to current treatments, short-term placebo-controlled trials in the acute phase of schizophrenia are necessary. Measures are proposed to minimize risks.
authors.affiliation: European Medicines Agency (EMEA), 7 Westferry circus, London E14 4HB, United Kingdom. maria.isaac@emea.europa.eu
authors.forename: Maria
authors.initials: M
authors.lastname: Isaac
authors.forename: Armin
authors.initials: A
authors.lastname: Koch
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects*; D017322:Clinical Trials, Phase II as Topic / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000401:mortality*; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy* / Q000401:mortality*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents