Effectiveness of Second-generation Antipsychotics: A Naturalistic, Randomized Comparison of Olanzapine, Quetiapine, Risperidone, and Ziprasidone

Erik Johnsen; Rune A Kroken; Tore Wentzel-Larsen; Hugo A Jørgensen


BMC Psychiatry. 2010;10:26 

In This Article


For a patient suffering from psychosis, most second-generation antipsychotics (SGAs) have been considered first-line agents based on their more favorable tolerability profiles compared with older first-generation drugs.[1–4] This particularly applies to first episode psychosis.[1,3] Most treatment guidelines are centered on schizophrenia, and the empirical evidence is very limited for non-schizophrenic psychotic disorders.[5] Differential antipsychotic efficacy of the first-line antipsychotics remains to be convincingly demonstrated despite their differing pharmacological properties. The lack of differences regarding efficacy may be caused by limitations of the evidence base. The highly selected samples and rigid experimental designs of traditional randomized, controlled trials may restrict their ability to deliver all clinically relevant information.[6] Contradictory results in studies from different sources of pharmaceutical sponsorship may also contribute to the inconclusiveness of the evidence.[7]

In recent years, several studies of the effectiveness of antipsychotics have been launched to address some of the limitations associated with traditional randomized controlled trials (RCTs) of efficacy. Effectiveness trials, also known as "naturalistic", "real-life", "pragmatic", or "practical" trials, address how a treatment works under normal clinical circumstances as distinct from the somewhat artificial settings of the efficacy trials.[6] Through pragmatic designs and more global outcome measures, these trials have been expected to supplement the base of evidence regarding effectiveness of antipsychotics. The larger studies have been financially sponsored by noncommercial sources, addressing also the problem of funding bias. In a recent systematic review of randomized head-to-head comparisons of the effectiveness of SGAs, differences among the SGAs were only consistent across trials for a limited number of outcomes.[8] In patients with chronic psychosis, olanzapine patients took a longer time to discontinuation of treatment and had better treatment adherence compared with other SGAs, but this treatment was also associated with more adverse metabolic effects. The psychopathology and most tolerability outcomes were otherwise surprisingly equal among groups. However, a significant finding in the review of effectiveness trials was a very high drug discontinuation rate in a short-term perspective for all the SGAs. About three-quarters of the patients had discontinued their allocated SGA within 18 months, with a median time until discontinuation of 5.5 months as found in the CATIE study.[9] To the authors' best knowledge, trials of the comparative effectiveness of SGAs have focused solely on the period during which the patients have used their allocated drugs. By this strategy, the results remain equivocal and do not supplement the evidence base regarding effectiveness as expected. An alternative strategy would be to assess antipsychotic effectiveness in a period extended beyond use of the first-assigned drug. Given the frequently chronic nature of schizophrenia and related disorders, and taking into account the new findings on discontinuation rates, the antipsychotic drug regimen at a given time is likely to be part of a sequence of antipsychotics. The principal question in this strategy addresses which SGA should be the starting drug in order to provide the most beneficial outcome of antipsychotic treatment.

Aims of the Study

The aim of the present study was to assess antipsychotic effectiveness in a period extending beyond the use of the first drugs.