Abstract: Background: Differences among antipsychotics in terms of effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second generation antipsychotics (SGAs) are scarce. We aimed to compare the clinical effectiveness in the short-term of Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode schizophrenia-spectrum disorders. Method: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. 202 first-episode drug-naïve patients were randomly assigned to Aripiprazole (N = 78), Ziprasidone (N = 62), or Quetiapine (N = 62) and followed-up for 3 months. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat populations was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3 months was small (13.86%). The treatment discontinuation rate differed significantly between treatment groups (Aripiprazole = 23.1%, Ziprasidone = 37.1% and Quetiapine = 61.3%) (?2 = 21.334; p b 0.001). Insufficient efficacy in the group of Quetiapine is the main reason for discontinuation rate differences (?2 = 20.223; p b 0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank = 23.467 p b 0.001). Aripiprazole and Quetiapine were associated with a greater depressive symptoms improvement (p = 0.043). The profile of side-effects varies between treatments. Patients on Quetiapine were less likely to be prescribed hypnotics. Conclusions: Patients treated with Quetiapine had a higher risk of treatment discontinuation in the short-term after a first episode due to insufficient efficacy. Establishing differences between SGAs may help clinicians in prescribing decisions for the treatment of individuals presenting with first-episode schizophrenia.

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