Olanzapine (OLZ), a Second-Generation Antipsychotic (SGA) widely used in the treatment of Schizophrenia (Duggan et al., 2005), has been reported to have a higher efficacy and tolerability than First-Generation Antipsychotics (FGA), at least in the short and medium term (Solmi et al., 2017). Available evidence on the clinical effects of antipsychotics mostly derives from Randomized Controlled Trials (RCTs) specifically designed for submission to regulatory authorities (Huhn et al., 2019).

Recently, a third wave of antipsychotic drugs has been released (namely aripiprazole, brexpiprazole, cariprazine, asenapine, lurasidone). Their efficacy is comparable to “older” SGAs, but with a higher tolerability; for this reason, they are sometimes referred to as Third Generation Antipsychotics (TGAs). The authors are aware of the non-univocal nomenclature used for this new wave of antipsychotics, but for simplicity decided to use the term TGA throughout the paper.

SGAs, including OLZ, which had been used as investigational drugs in RCTs designed for their development, have also been used as comparator drugs in (usually more recent) RCTs designed for the development of TGAs (Greger et al., 2021; Jindal et al., 2013). Conversely, few RCTs directly compared TGAs with FGAs (Girgis et al., 2011; Kane et al., 2010); our knowledge of differences between TGAs and FGAs is mostly derived from inferences based on comparisons of FGAs with SGAs, and SGAs with TGAs. Such indirect evidence can be affected by peculiarities in the design of those latter comparisons: differences between trials using SGAs either as investigational drugs compared with FGAs or as comparators for TGAs could distort estimates of indirect comparisons between TGAs and FGAs.

SGAs and TGAs have both been claimed to be at least as effective as, or more effective than, FGAs, and to have a higher tolerability; TGAs display a higher tolerability than SGA, especially in the long term (McDonagh et al., 2020; Leucht et al., 2013). However, the generalizability of the results derived from RCTs to real-world practice has been questioned (Katona et al., 2021; Younis et al., 2020), because of the enrollment of small and non-representative samples and of the use of fixed doses (Katona et al., 2021). In addition, the number of available RCTs with an adequately long follow-up is insufficient to draw consistent conclusions on long-term safety and tolerability (Rotella et al., 2020).

In order to obtain a complete overview of all available evidence, the results of RCTs can be combined in a meta-analysis. Heterogeneity across studies is one of the main issues of this approach, as RCTs with the same endpoint can display wide methodological differences (e.g., superiority or non-inferiority design, diversity in inclusion and exclusion criteria, different length of follow-up, the same drug used as investigational or comparator treatment, etc.).

The aim of this study is to assess the possible effect on estimates of OLZ efficacy based on the trial design, comparing studies in which OLZ was used either as an investigational drug or comparator, and adjusting for other potential confounders.