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What causes psychosis? An umbrella review of risk and protective factors
Open accessAbstract
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, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 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.
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“The CHR-P criteria are robustly associated with psychosis onset (Odds Ratio, OR=9.32) 44 within high-risk clinical samples (but not in the general population 84 )”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [44]
In the citing paper
“Transition to psychosis is associated with clinically meaningful real-world outcomes 89 and is modulated by baseline levels of attenuated positive psychotic (OR=2.56) and negative (OR=2.68) symptoms, while good functioning reduces the risk (OR=0.59) 44 .”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [44]
In the citing paper
“Psychotic disorders are infrequent before the age of 14 43 ; their risk peaks in the age group of 15-35 and declines after the age of 35 44 .”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [44]
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“Black - Caribbean ethnicity in England (OR=4.87) 44 ****”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [44]
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“We re-analyzed each metaanalysis using a random-effects model with a restricted maximum likelihood estimator which was consistent with methods in previous umbrella reviews [46, 47].”
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“CHR-P individuals are young and they accumulate risk factors such as living alone or being unemployed (Fusar-Poli et al., 2017e; Radua et al., 2018; Oliver et al., 2019) that enrich their level of risk for psychosis (Fusar-Poli et al.”
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“…participants have experienced discrimination in their lifetime; the Pubertal Development Scale 44 for determining the development of secondary sexual characteristics; and, lastly, the Psychosis Polyrisk Score 45 to capture exposure to a range of environmental risk factors associated with psychosis.”
BackgroundSelf-citationEstablishing a clinical service to prevent psychosis: What, how and when? Systematic review
de Pablo, G. S., Estradé, A., Cutroni, M., Andlauer, O., & Fusar‐Poli, P. (2021) · Translational Psychiatry · doi:10.1038/s41398-020-01165-x · Cited by 87
Self-citation‘At risk mental state’ clinics for psychosis – an idea whose time has come – and gone!
Ajnakina, O., David, A. S., & Murray, R. M. (2019) · Psychological Medicine · doi:10.1017/s0033291718003859 · Cited by 82
“These include obstetric events, childhood adversity, urban birth and upbringing and adverse life events (Stilo and Murray, 2010; Radua et al., 2018).”
Self-citationde Pablo, G. S., Woods, S. W., Drymonitou, G., de Diego, H., & Fusar‐Poli, P. (2021) · Brain Sciences · doi:10.3390/brainsci11111544 · Cited by 85
“At the same time, this finding contrasts with the epidemiological distribution of psychosis risk (at least for schizophrenia-spectrum psychoses), which is typically associated with a predominance in males [1,47].”
BackgroundResultSelf-citationSolmi, M., Cortese, S., Vita, G., Prisco, M. D., Raduà, J., Dragioti, E., Köhler‐Forsberg, O., Madsen, N. M., Rohde, C., Eudave, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02298-3 · Cited by 92
Self-citationD’Agostino, A., D’Angelo, S., Giordano, B., Cigognini, A. C., Chirico, M., Redaelli, C., & Gambini, O. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa112 · Cited by 77
Leaune, É., Dealberto, M.-J., Luck, D., Grot, S., Zeroug-Vial, H., Poulet, E., & Brunelin, J. (2018) · Psychological Medicine · doi:10.1017/s0033291718002271 · Cited by 80
“Moreover, a recent umbrella review demonstrated that EMP is among the most relevant environmental factors for clinical psychosis (Radua et al., 2018).”
BackgroundCOVID-19-associated psychosis: A systematic review of case reports
Smith, C. M., Gilbert, E. B., Riordan, P. A., Helmke, N., von Isenburg, M., Kincaid, B. R., & Shirey, K. (2021) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2021.10.003 · Cited by 75
“Understanding comorbid medical and substance use history in individuals presenting with psychosis is clinically important since such conditions can precipitate and lengthen duration of psychosis [5,67].”
Factors Moderating the Association between Cannabis Use and Psychosis Risk: A Systematic Review
van der Steur, S. J., Batalla, A., & Bossong, M. G. (2020) · Brain Sciences · doi:10.3390/brainsci10020097 · Cited by 78
“These controversial results probably reflect the limited value of the study of single genes for predicting mental health outcomes [106,107], since complex phenotypes like psychosis are associated with multiple genes [108].”
ResultSchizophrenia: A Narrative Review of Etiopathogenetic, Diagnostic and Treatment Aspects
Orsolini, L., Pompili, S., & Volpe, U. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11175040 · Cited by 89
Jahrami, H., AlKaabi, J., Trabelsi, K., Pandi-Perumal, S. R., Saif, Z., Seeman, M. V., & Vitiello, M. V. (2023) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2023.111479 · Cited by 72
Fullana, M. A., Tortella‐Feliu, M., de la Cruz, L. F., Chamorro, J., Pérez-Vigil, A., Ioannidis, J. P. A., Solanes, A., Guardiola-Ripoll, M., Almodóvar-Payá, C., Miranda‐Olivos, R., et al. (2019) · Psychological Medicine · doi:10.1017/s0033291719001247 · Cited by 80
Self-citationO’Connor, K., Wrigley, M., Jennings, R., Hill, M. B., & Niazi, A. (2020) · Irish Journal of Psychological Medicine · doi:10.1017/ipm.2020.64 · Cited by 69
“Trauma and social marginalisation are risk factors associated with longer term increased risk of psychosis (Radua et al. 2018).”
BackgroundOliver, D., Raduà, J., Reichenberg, A., Uher, R., & Fusar‐Poli, P. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00174 · Cited by 69
Self-citationForced normalization: A systematic review
Calle‐López, Y., Ladino, L. D., Benjumea‐Cuartas, V., Castrillón‐Velilla, D. M., Téllez‐Zenteno, J. F., & Wolf, P. (2019) · Epilepsia · doi:10.1111/epi.16276 · Cited by 66
Yıldız, E. (2020) · Perspectives in Psychiatric Care · doi:10.1111/ppc.12396 · Cited by 67
Mentis, A. A., Dardiotis, E., Efthymiou, V., & Chrousos, G. P. (2021) · BMC Medicine · doi:10.1186/s12916-020-01873-7 · Cited by 85
“In a way similar to umbrella reviews in other fields [34, 154], this metaumbrella study provides the opportunity to (a) stimulate more comprehensive, patient-centered approaches, allowing truly informed decisions during genetic counseling or/and coaching for lifestyle changes [154–156]; (b) enhance the accuracy of pre…”
BackgroundMethodResultInfluentialChemsex and Psychosis: A Systematic Review
Moreno-Gámez, L., Hernández-Huerta, D., & Lahera, G. (2022) · Behavioral Sciences · doi:10.3390/bs12120516 · Cited by 74
“Another factor that has been related to the occurrence of psychotic disorders is foreign/ethnic minority status, which generates a greater number of adverse circumstances and stressors that increase the risk of psychosis [42].”
BackgroundPries, L.-K., Ferro, G. A. D., van Os, J., Delespaul, P., Kenis, G., Lin, B. D., Luykx, J. J., Richards, A. L., Akdede, B. B., Binbay, T., et al. (2020) · Epidemiology and Psychiatric Sciences · doi:10.1017/s2045796020000943 · Cited by 60
“Similarly, several environmental exposures have been associated with a schizophrenia spectrum disorder, such as childhood adversities, cannabis use, urbanicity, migration, ethnic minorities, hearing impairment, and perinatal factors (Linszen et al., 2016; Radua et al., 2018; Stilo and Murray, 2019).”
BackgroundSelf-citationFusar-Poli, P., Spencer, T., De Micheli, A., Curzi, V., Nandha, S., & McGuire, P. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.08.002 · Cited by 57
Self-citationRaket, L. L., Jaskolowski, J., Kinon, B. J., Brasen, J. C., Jönsson, L., Wehnert, A., & Fusar-Poli, P. (2020) · The Lancet Digital Health · doi:10.1016/s2589-7500(20)30024-8 · Cited by 60
Self-citationAre climate change and mental health correlated?
Ramadan, A., & Ataallah, A. G. (2021) · General Psychiatry · doi:10.1136/gpsych-2021-100648 · Cited by 73
Bariatric surgery and health outcomes: An umbrella analysis
Liao, J., Yin, Y., Zhong, J., Chen, Y., Chen, Y., Wen, Y., & Cai, Z. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1016613 · Cited by 65
“When several meta-analyses investigated the same outcome, we selected the newest meta-analysis with the largest number of studies (21, 22).”
MethodSchizophrenia is Associated With an Aberrant Immune Response to Epstein–Barr Virus
Dickerson, F., Jones‐Brando, L. V., Ford, G. M., Genovese, G., Stallings, C. R., Origoni, A. E., O’Dushlaine, C. T., Katsafanas, E., Sweeney, K., Khushalani, S., et al. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby164 · Cited by 59
“[3] [4] [5] [6] The potential role of infections in the etiopathogenesis of schizophrenia is supported by the associations between schizophrenia risk and genes which encode HLA and other factors which control the immune response to infectious agents.”
BackgroundAlvarez-Mon, M. A., Llavero-Valero, M., Sánchez-Bayona, R., Pereira-Sanchez, V., Vallejo-Valdivielso, M., Monserrat, J., Lahera, G., Asunsolo del Barco, A., & Alvarez-Mon, M. (2019) · Journal of Medical Internet Research · doi:10.2196/14110 · Cited by 52
“Despite many decades of research, the treatment of psychotic disorders remains only partially effective, and their etiology is not fully understood [6,7].”
Brokmeier, L. L., Firth, J., Vancampfort, D., Smith, L., Deenik, J., Rosenbaum, S., Stubbs, B., & Schuch, F. B. (2020) · Psychiatry Research · doi:10.1016/j.psychres.2019.112675 · Cited by 56
de Pablo, G. S., Besana, F., Arienti, V., Catalán, A., Vaquerizo‐Serrano, J., Cabras, A., Pereira, J. F., Soardo, L., Coronelli, F., Kaur, S., et al. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100909 · Cited by 57
“CHR-P individuals are adolescents and young adults, and typically accumulate risk factors for psychotic disorders [5-7], present with subtle clinical symptoms [8] and suffer from functional impairment [9].”
BackgroundSelf-citationProgression from being at-risk to psychosis: next steps
Addington, J., Farris, M. S., Devoe, D. J. A., & Metzak, P. D. (2020) · Schizophrenia · doi:10.1038/s41537-020-00117-0 · Cited by 59
Travica, N., Lotfaliany, M., Marriott, A., Safavynia, S. A., Lane, M. M., Gray, L. J., Veronese, N., Berk, M., Skvarc, D., Aslam, H., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041610 · Cited by 54
“In line with previous umbrella reviews [26,27], the results of this umbrella review were classified as convincing, highly suggestive, suggestive, weak or no evidence, as defined using the following criteria:”
MethodResultAjnakina, O., Stubbs, B., Francis, E., Gaughran, F., David, A. S., Murray, R. M., & Lally, J. (2019) · Psychological Medicine · doi:10.1017/s0033291719000904 · Cited by 54
“Black ethnicity has consistently been highlighted as a risk factor for psychosis onset (Lally et al., 2016; Radua et al., 2018), and has been associated with the development of a treatment-resistant course of illness (Lally et al.”
BackgroundSelf-citationDiagnosis, prognosis, and treatment of brief psychotic episodes: a review and research agenda
Fusar‐Poli, P., de Pablo, G. S., Rajkumar, R. P., López‐Díaz, Á., Malhotra, S., Heckers, S., Lawrie, S. M., & Pillmann, F. (2021) · The Lancet Psychiatry · doi:10.1016/s2215-0366(21)00121-8 · Cited by 52
Self-citationVarchmin, L., Montag, C., Treusch, Y., Kaminski, J. A., & Heinz, A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.665957 · Cited by 57
“(11) examining the strength of evidence for risk and protective factors (socio-demographic, parental, perinatal, later factors, or antecedents) for psychosis, strong evidence was found for ultra-high risk states [a state operationalized with varying diagnostic tools (12), in which psychotic experiences occur, however,…”
BackgroundOliver, D., Spada, G., Colling, C., Broadbent, M., Baldwin, H., Patel, R., Stewart, R., Stahl, D., Dobson, R., McGuire, P., et al. (2021) · Schizophrenia Research · doi:10.1016/j.schres.2020.05.007 · Cited by 49
“5 because the risk calculator is lifespan-inclusive (although in this study only patients aged 14 or abovewere recruited) to capture psychosis onset across all ages, including the age band (15–35 (Radua et al., 2018)) with the highest risk of psychosis onset.”
Self-citationLalousis, P. A., Schmaal, L., Wood, S. J., Reniers, R. L. E. P., Barnes, N. M., Chisholm, K., Griffiths, S. L., Stainton, A., Wen, J., Hwang, G., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.03.021 · Cited by 48
Fusar‐Poli, P., Bauer, M., Borgwardt, S., Bechdolf, A., Correll, C. U., Kim, Q., Domschke, K., Galderisi, S., Kessing, L. V., Koutsouleris, N., et al. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2019.09.006 · Cited by 50
Self-citationAlbajes‐Eizagirre, A., Solanes, A., Fullana, M. A., Ioannidis, J. P. A., Fusar‐Poli, P., Torrent, C., Solé, B., Bonnín, C. D. M., Vieta, E., Mataix‐Cols, D., et al. (2019) · Journal of Visualized Experiments · doi:10.3791/59841-v · Cited by 48
Self-citationKinon, B. J. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00757 · Cited by 47
“Many genetic, developmental, behavioral, ethnocultural, and neurobiological factors have been associated with poor response or outcome in schizophrenia (11, 12) (Figure 2).”
BackgroundHypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia
Amato, D., Kruyer, A., Samaha, A., & Heinz, A. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00314 · Cited by 47
Fusar‐Poli, P., Micheli, A. D., Signorini, L., Baldwin, H., de Pablo, G. S., & McGuire, P. K. (2020) · EClinicalMedicine · doi:10.1016/j.eclinm.2020.100578 · Cited by 47
Self-citationNeed for Ethnic and Population Diversity in Psychosis Research
Burkhard, C., Çiçek, S., Barzilay, R., Radhakrishnan, R., & Gülöksüz, S. (2021) · Schizophrenia Bulletin · doi:10.1093/schbul/sbab048 · Cited by 50
Bündchen, D. C., Sousa, H., Afreixo, V. M. A., Frontini, R., Ribeiro, Ó. M., de Figueiredo, D. M. P., & Costa, E. M. (2021) · Clinical Rehabilitation · doi:10.1177/0269215520986784 · Cited by 44
Metadata
- Authors
- Radua, J., Ramella‐Cravaro, V., Ioannidis, J. P. A., Reichenberg, A., Phiphopthatsanee, N., Amir, T., Yenn Thoo, H., Oliver, D., Davies, C., Morgan, C., McGuire, P., Murray, R. M., & Fusar‐Poli, P.
- Affiliations
- Early Psychosis: Interventions & Clinical‐detection (EPIC) Lab, Department of Psychosis Studies Institute of Psychiatry, Psychology & Neuroscience, King's College London London UK
- King's College London (GB)
- Stanford Medicine (US)
- ORCID
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2018-01-19
- Volume
- 17
- Issue
- 1
- Pages
- 49-66
- ISSN
- 1723-8617 (ISSN-L)
- 2051-5545
- PMC
- PMC5775150
- OpenAlex
- W2768338105
- Cited by
- 553
- References
- 158
- Citations by year
- 2026: 33 · 2025: 55 · 2024: 67 · 2023: 70 · 2022: 73 · 2021: 92 · 2020: 82 · 2019: 66 · 2018: 15
- FWCI
- 49.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- World Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- Instituto de Salud Carlos III (CP14/00041 and PI14/00292)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- psychosis, risk factors, protective factors, ethnic minorities, urbanicity, immigrant status, childhood trauma, season of birth, Toxoplasma gondii, handedness, anhedonia, premorbid intelligence, birth order
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