What causes psychosis? An umbrella review of risk and protective factors

Abstract

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR59.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR54.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.

Ten simple rules for conducting umbrella reviews

“…For example, in our review we found that childhood trauma was considered as a common risk factor for psychosis,13 but available literature lacked standard operationalisation. Our pragmatic approach was to define the factors as each meta-analysis or systematic review had defined them.…”

“…Second, a clear link between the need to address uncertainty and advancing clinical knowledge should be identified a priori, and acknowledged as the strong rationale for conducting an umbrella review. For example, in our previous work we speculated that by clarifying the evidence for an association between risk or protective factors and psychotic disorders we could improve our ability to identify those individuals at risk of developing psychosis 13. Clearly, improving the detection of individuals at risk is the first step towards the implementation of preventive approaches, which are becoming a cornerstone of medicine 14–16.…”

“…Importantly, specific inclusion and exclusion criteria should be prespecified. For example, inclusion criteria from our umbrella review13 were: (a) systematic reviews or meta-analyses of individual observational studies (case-control, cohort, cross-sectional and ecological studies) that examined the association between risk or protective factors and psychotic disorders; (b) studies considering any established diagnosis of non-organic psychotic disorders defined by the International Classification of Disease (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM); (c) inclusion of a comparison group of non-psychotic healthy controls, as defined by each study and (d) studies reporting enough data to perform the analyses. Similarly, the reporting of the literature search should adhere to the Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations19 and additional specific guidelines depending on the nature of the studies included (eg, in case of observational studies, the Meta-analysis of Observational Studies in Epidemiology guidelines20).…”

“…Another issue relates to whether and how analysts should group similar factors. For example, in our umbrella review13 we wondered whether to merge the first-generation immigrant and second-generation immigrant risk factors for psychosis in a unique category of ‘immigrants’. However, this would have introduced newly defined categories of risk factors that were not available in the underlying literature.…”

“…Rather than being an exhaustive primer on the methodological underpinning of umbrella reviews, we only highlight 10 key points that to our opinion are essential for conducting robust umbrella reviews. As reference example, we will use an umbrella review on risk and protective factors for psychotic disorders recently completed by our group 13. However, we generalise the considerations presented in this manuscript and the relative recommendations to any other area of medical knowledge.…”