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

Population

• 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.

Interventions

• 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).

Comparators

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

Outcomes

• 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.