Meta-analysis of Total Effect Decomposition in the Presence of Multiple Mediators: The Example of Schizophrenia Treatment

Yiwen Zhu, Franca Centorrino, John W. Jackson, Garrett M. Fitzmaurice, Linda Valeri

Research output: Contribution to journalArticlepeer-review


Background: Causal mediation analysis addresses mechanistic questions by decomposing and quantifying effects operating through different pathways. Because most individual studies are underpowered to detect mediating effects, we outlined a parametric approach to meta-analyzing causal mediation and interaction analyses with multiple mediators, compared it with a bootstrap-based alternative, and discussed its limitations. Methods: We employed fixed- and random-effects multivariate meta-analyses to integrate evidence on treatment-mediators and mediators-outcome associations across trials. We estimated path-specific effects as functions of meta-analyzed regression coefficients; we obtained standard errors using the delta method. We evaluated the performance of this approach in simulations and applied it to assess the mediating roles of positive symptoms of schizophrenia and weight gain in the treatment effect of paliperidone ER on negative symptoms across four efficacy trials. Results: Both simulations and the application showed that the meta-analytic approaches increased statistical power. In the application, we observed substantial mediating effects of positive symptoms (proportions mediated from fixed-effects meta-analysis:). Weight gain may have beneficial mediating effects; however, such benefit may disappear at high doses when metabolic side effects were excessive. Conclusions: Meta-analyzing causal mediation analysis combines evidence from multiple sources and improves power. Targeting positive symptoms may be an effective way to reduce negative symptoms that are challenging to treat. Future work should focus on extending the existing methods to allow for more flexible modeling of mediation.

Original languageEnglish (US)
Pages (from-to)120-130
Number of pages11
StateAccepted/In press - 2020


  • Antipsychotics
  • Interaction
  • Mediation
  • Meta-analysis
  • Schizophrenia
  • Weight gain

ASJC Scopus subject areas

  • Epidemiology


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