Systematic Literature Review of the Methods Used to Compare Newer Second-Generation Agents for the Management of Schizophrenia: A focus on Health Technology Assessment

The challenges of comparative effectiveness to support health technology assessment (HTA) agencies are important considerations in the choices of antipsychotic medications for the treatment of schizophrenia. Our aim was to assess the study methods used and outcomes reported in the published literature to address the question of comparative effectiveness of newer antipsychotic agents and the adequacy and availability of evidence to support HTA agencies. A systematic search of the PubMed database from 1 January 2009 to 30 September 2013 was conducted to identify studies evaluating new atypical antipsychotics reporting on comparative effectiveness. The systematic review comprised of studies on schizophrenia patients where at least two drugs were being compared and at least one treatment group received one of the following second-generation antipsychotics: risperidone, olanzapine, aripiprazole, paliperidone, asenapine, iloperidone, lurasidone, and quetiapine. The included studies were also required to have an efficacy, safety or economic outcome, such as Positive and Negative Syndrome Scale (PANSS) score, weight gain, resource utilization, or costs. Two reviewers (BW and GK) independently applied the inclusion criteria. Disagreements between reviewers were resolved by consensus, referring to the original sources. Information on the methodology and outcomes was collected for each included study. This included study description, head-to-head drug comparison, patient population, study methodology, statistical methods, reported outcomes, study support, and journal type. A total of 198 studies were identified from electronic search methods. The largest category of studies was randomized controlled trials [RCTs] (N = 73; 36.9 %), which were largely directed at the regulatory endpoint. Fewer studies were undertaken for HTA-purposes cohort studies (N = 53; 26.8 %), meta-analyses (N = 32; 16.2 %), economic studies (N = 14; 7.1 %), and cross-sectional studies (N = 13; 6.6 %). Direct head-to-head comparisons preferred by HTA were dominated by the comparison involving olanzapine and risperidone, representing 149 (75.3 %) and 119 (60.1 %) studies, respectively. RCTs, which are the primary study type for regulatory submissions, showed a lack of bias. Studies aimed at HTA were not as well performed. Cohort studies suffered from bias in the selection of comparison groups, lack of control for confounders, and differential dropout rates. As a group, cross-sectional studies scored poorly for bias, with a primary failure to identify a representative sample. Economic studies showed highly variable bias, with bias in the representation of effectiveness data, model assumptions without validation, and lack of sensitivity analyses. One limitation of this systematic review is that it only included studies from 2009 to 2013, potentially excluding some earlier comparator studies, particularly those involving first-generation antipsychotics. This review of comparative effectiveness studies of second-generation antipsychotic agents for schizophrenic patients revealed a wide range of study types, study methodologies, and outcomes. For traditional efficacy outcomes and select safety outcomes, there is strong evidence from many well-conducted studies; however, there are fewer studies of types preferred by HTA with limited head-to-head comparisons and a higher risk of bias in the execution of these studies.