An umbrella review of 98 associations found only five risk factors with robust evidence for schizophrenia: childhood adversity, cannabis use, obstetric complications, adult stressful events, and low serum folate.
Read this if you want to understand which risk factors for schizophrenia have the strongest scientific evidence.
Cannabis was one of only 5 risk factors (out of 98 tested) with robust evidence for schizophrenia
What the researchers found
Researchers conducted an umbrella review, a review of reviews, to systematically evaluate all published meta-analyses of non-genetic risk factors and biomarkers for schizophrenia spectrum disorders. They identified 98 associations across 41 eligible papers.
Of these 98 associations, 62 showed nominally significant effects. However, when subjected to rigorous quality assessment including tests for publication bias, small-study effects, and excess significance bias, only five risk factors showed truly robust evidence: childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level.
The vast majority of associations (72 of 98) exhibited large between-study heterogeneity, 13 showed evidence of small-study effects (suggesting publication bias), and 18 showed excess significance bias. This means that many commonly cited risk factors and biomarkers for schizophrenia may be less reliable than individual studies suggest.
Why it matters
With hundreds of studies claiming various risk factors for schizophrenia, it is difficult for clinicians, patients, and policymakers to know which ones truly matter. This umbrella review cuts through the noise and identifies the factors with the most reliable evidence. Cannabis being one of only five robust risk factors underscores its significance in psychosis research.
The numbers in context
41 eligible papers reviewed containing 98 associations. 62 associations nominally significant. 72 had large between-study heterogeneity. 13 showed small-study effects. 18 showed excess significance bias. Only 5 factors met robust evidence criteria: childhood adversities, cannabis use, obstetric complications, adult stressful events, low serum folate.
How the study worked
This was an umbrella review capturing all meta-analyses and Mendelian randomization studies examining non-genetic risk factors and schizophrenia spectrum disorders. For each meta-analysis, the researchers calculated summary effect sizes, confidence and prediction intervals, heterogeneity (I-squared), and tested for small-study effects and excess significance bias.
What this study cannot tell us
The umbrella review is limited by the quality of the underlying meta-analyses. Some risk factors may have insufficient meta-analytic coverage rather than genuinely weak evidence. The review focused on non-genetic factors and did not integrate gene-environment interactions. The criteria for "robust" evidence may be conservative, potentially excluding legitimate associations.
How to read the evidence
This is an umbrella review of meta-analyses, representing the highest level of evidence synthesis, with rigorous quality assessment of underlying studies.
When this study was published
Published in 2018. The five identified risk factors continue to be validated in subsequent research.
The bigger picture
This study is a reality check for schizophrenia risk factor research. It demonstrates that most claimed associations do not hold up under rigorous scrutiny, while cannabis use stands out as one of the few that does. This places cannabis alongside early life experiences and prenatal complications as a genuinely important modifiable risk factor.
Questions still open
- Can the five robust risk factors be integrated into a practical screening tool for psychosis risk? How do these non-genetic factors interact with genetic vulnerability? Could addressing modifiable factors like cannabis use meaningfully reduce psychosis incidence at the population level?
Common questions
Is cannabis really a risk factor for schizophrenia?
What other risk factors are as well-established as cannabis?
Read the original research
Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.
Acta psychiatrica Scandinavica, 137(2), 88-97
Citation
Belbasis, L; Köhler, C A; Stefanis, N; Stubbs, B; van Os, J; Vieta, E; Seeman, M V; Arango, C; Carvalho, A F; Evangelou, E. (2018). Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.. Acta psychiatrica Scandinavica, 137(2), 88-97. https://doi.org/10.1111/acps.12847
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