NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2011 Dec. (CADTH Optimal Use Report, No. 1.1B.)

Cover of A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia

A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia [Internet].

Show details


When possible, CADTH builds on existing applicable Canadian and international initiatives and research. The first phase of the research process was to conduct a literature search for existing systematic reviews or guidance on AAP combination and high-dose use. National Institute for Health and Clinical Excellence (NICE) guidelines (2009),7 a Drug Effectiveness Review Project (DERP) report (2010),16 Canadian Psychiatric Association (CPA) guidelines (2004),3 American Psychological Association (APA) guidelines (2004 and 2009),17,18 and other systematic reviews on AAP combination therapy1930 and on high-dose AAPs31 were identified and assessed. None of these reports sufficiently addressed the tabled research questions; therefore, a systematic review of the primary literature was conducted.

The methodology for the systematic review is presented in detail in the project protocol.32 The full literature search strategy is presented in Appendix 1. The following databases were searched via the OVID interface: MEDLINE (1950–), MEDLINE In-Process & Other Non-Indexed Citations, Embase (1980–), PsycINFO (1967–), and The Cochrane Central Register of Controlled Trials. A parallel search was run in the CINAHL database via EBSCO. PubMed was also searched to capture additional citations not found in MEDLINE. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were each AAP drug name plus more general terms (e.g., atypical antipsychotics, second-generation antipsychotics), schizophrenia, schizoaffective disorder, drug combinations, and drug dosage. Methodological filters were applied to limit retrieval to randomized controlled trials (RCTs) or controlled clinical trials. Retrieval was not limited by publication year, but was limited to the English or French language. The Internet was searched to identify unpublished (grey) literature from websites and databases of health professional associations, health technology assessment agencies, and related entities. Bibliographies of selected studies were also reviewed. Literature alerts were monitored after completion of the primary search in June 2010. Studies published after June 2010 that met our inclusion criteria were not included in meta-analyses; however, sensitivity analyses were performed to ensure results were not significantly changed (data not reported). Manufacturers of the agents considered in this review were provided the opportunity to submit unpublished data.

Studies were selected independently by two reviewers based on criteria developed a priori, with discrepancies resolved through consensus, or the judgment of a third reviewer if agreement could not be reached.

4.1. Selection Criteria

Studies were included if they met all of the following inclusion criteria and none of the exclusion criteria:

4.2. Inclusion criteria


  • Adolescents (13 to 17 years old) or adults (≥ 18 years old) with schizophrenia or schizoaffective disorder (including the first episode of schizophrenia, acute phase or chronic phase) inadequately controlled with one or more antipsychotic (atypical or typical) monotherapy regimens.


  • Combinations consisting of one of the AAPs listed in Table 1 at a dose lower than or equal to the definition of high dose, with one or more other antipsychotic drugs (atypical or typical), or
  • AAP monotherapy at high doses (as defined in Table 1 above).


  • AAP or TAP monotherapy at any dose
  • Combinations of antipsychotic drugs at any dose.


  • Members of CERC identified outcomes of interest a priori. A compiled list of all outcomes identified was circulated to CERC members to rate the importance of each outcome on a 9-point scale: 1–3, not important; 4–6, important; and 7–9, critical. An outcome was analyzed in the review if the mean score was between 4 and 9. Included symptoms of schizophrenia (Positive and Negative Syndrome Scale [PANSS], Brief Psychiatric Rating Scale [BPRS], Clinical Global Impression — Improvement [CGI-I], Clinical Global Impression — Severity [CGI-S]), response rate, cognition, withdrawals, and serious adverse events. The outcomes of interest and their importance as rated by CERC are provided in Appendix 2. Background information on the psychiatric symptom scales considered in this review is presented in Appendix 3.

Study Design

  • RCTs (including parallel, crossover, placebo- or active-controlled).

4.3. Exclusion criteria

  • A study with a mixed population with more than 15% of participants not diagnosed with schizophrenia or schizoaffective disorder, and/or no subgroup analysis reported for patients with schizophrenia or schizoaffective disorder
  • Studies on first episode psychosis that is not specified as first episode schizophrenia
  • Studies on schizophreniform disorder
  • Studies on monotherapy comparisons between different AAPs, different TAPs, or between AAP and TAP at doses lower than the high-dose thresholds outlined in Table 1
  • Studies comparing TAP monotherapy at a recommended dose with the same TAP at high dose
  • Studies comparing TAP monotherapy at a recommended dose with a combination of the same or different TAP plus another antipsychotic
  • Studies on combination therapy with an antipsychotic agent and non-antipsychotic agent (e.g., mood stabilizer)
  • Studies published in languages other than French or English.

4.4. Quality Assessment and Data Extraction

Study quality was assessed using the Scottish Intercollegiate Guidelines Network (SIGN-50) checklist for RCTs.33 Quality assessment was performed by one reviewer and verified by a second reviewer. Disagreements were resolved through consensus, or the judgment of a third reviewer if agreement could not be reached.

Data were extracted from included studies using templates designed a priori. Data were abstracted by one reviewer with verification by a second reviewer. Disagreements were resolved through consensus, or the judgment of a third reviewer if agreement could not be reached.

4.5. Data synthesis and analysis

Some included studies administered antipsychotic agents at fixed doses, while others allowed dose titration. Antipsychotic dosing was reported variably in the included trials that permitted dose titration: average dose during the study, mean endpoint dose, and median endpoint dose. Mean endpoint doses are reported in this review where available; otherwise, median endpoint values are reported. Average doses were considered only if no measure of endpoint dose was reported.

For continuous outcome measures, meta-analysis was performed using a random effects generic inverse variance approach. Mean differences from baseline to follow-up (with corresponding measures of uncertainty), or variations thereof, were abstracted for each treatment arm from all included studies for all continuous outcome measures of interest. Where standard deviations for change scores were not reported, the approach described by Abrams et al.34 and Follett et al.35 was used where possible to impute standard deviations. This approach is based on empirical estimation of correlation where sufficient baseline and follow-up data are available from other trials with complete information on means and standard deviations at baseline, follow-up, and for change scores to permit an informed selection of a correlation value. This practice was planned to be carried out for each relevant pairwise comparison of therapies. Unfortunately, there were rarely sufficient data available for this approach. Imputation was therefore usually performed under the assumption of a moderate correlation value of 0.5 for the change scores, or by direct transfer of a standard error from another study if it was considered to be sufficiently similar.

Dichotomous outcomes, such as serious adverse events and suicidality, were meta-analyzed using relative risk as the effect measure. Dichotomous categories were defined as “no event” or “one or more events.”

The degree of heterogeneity in meta-analyses was estimated using the I2 statistic. Where heterogeneity was greater than 75%, the associated results were determined to be inappropriate for pooling and separate trial data were presented. Selected forest plots are presented in Appendix 4.

Subgroup analyses were performed, where possible, according to individual AAPs and by number of antipsychotic drugs (APDs) failed prior to the trial (i.e., ≥ 1, ≥ 2). Individual sensitivity analyses were conducted by including studies in adolescents, or by removing:

  • Studies of poor quality
  • Studies employing a crossover design
  • Studies of less than three months’ duration
  • Studies in which intention to treat (ITT) results were not reported
  • Studies that examined agents not currently available in Canada
  • Studies with clozapine (CLZ) dose less than 350 mg per day
  • Studies reported only in conference/symposium abstracts.
Copyright © 2011 Canadian Agency for Drugs and Technologies in Health.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at

Bookshelf ID: NBK169708


  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (6.0M)

Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...