Only five risk factors for schizophrenia held up under rigorous review, and cannabis was one of them
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Cannabis was one of only 5 risk factors (out of 98 tested) with robust evidence for schizophrenia
- Evidence Grade:
- This is an umbrella review of meta-analyses, representing the highest level of evidence synthesis, with rigorous quality assessment of underlying studies.
- Study Age:
- Published in 2018. The five identified risk factors continue to be validated in subsequent research.
- Original Title:
- Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.
- Published In:
- Acta psychiatrica Scandinavica, 137(2), 88-97 (2018)
- Authors:
- Belbasis, L, Köhler, C A, Stefanis, N, Stubbs, B, van Os, J, Vieta, E, Seeman, M V, Arango, C, Carvalho, A F, Evangelou, E
- Database ID:
- RTHC-01588
Evidence Hierarchy
Analyzes all available research on a topic using a structured method.
What do these levels mean? →Frequently Asked Questions
Is cannabis really a risk factor for schizophrenia?
According to this umbrella review, yes. After examining 98 proposed risk factors and subjecting each to rigorous quality tests, cannabis was one of only five that showed truly robust evidence. This does not mean cannabis always causes schizophrenia, but the statistical association is among the strongest and most reliable of all non-genetic risk factors.
What other risk factors are as well-established as cannabis?
Only four others met the same rigorous evidence criteria: childhood adversities, history of obstetric complications, stressful events during adulthood, and low serum folate levels. Many other commonly cited risk factors did not hold up under strict scrutiny.
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Cite This Study
https://rethinkthc.com/research/RTHC-01588APA
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
MLA
Belbasis, L, et al. "Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.." Acta psychiatrica Scandinavica, 2018. https://doi.org/10.1111/acps.12847
RethinkTHC
RethinkTHC Research Database. "Risk factors and peripheral biomarkers for schizophrenia spe..." RTHC-01588. Retrieved from https://rethinkthc.com/research/belbasis-2018-risk-factors-and-peripheral
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.