57 58 59 60 9 https://mc.manuscriptcentral.com/bmj BMJ Page 10 of 26
1 2 3 4 5 Sensitivity analyses, excluding potentially prevalent cases amongst immigrants, did not appreciably 6 alter estimates of associations for our main exposures (Supplemental Tables 3 and 4). The 7 8 Confidential:assumption of proportional hazards was not For violated (p=0.84 Review and p=0.13 for analyses Only of refugee 9 status and region of origin, respectively). 10 11 12 13 Discussion 14 In this cohort study, we have found that refugees granted asylum in a high income setting were, on 15 16 average, 66% more likely to develop schizophrenia or another non-affective psychotic disorder than 17 18 migrants from the same regions of origin, and up to 3.6 times more likely to do so than the Swedish- 19 born population. 20 21 22 Strengths and weaknesses 23 24 This study has several methodological strengths. It was based on a large, national population-based 25 26 cohort of over 1.3m people, followed for more than 8.9m person-years using linked Swedish register 27 data. This research has not previously been possible due to a lack of information on the reason for 28 29 migration in official Swedish registers; one earlier attempt to investigate this issue in Sweden could 30 not distinguish between refugee and non-refugee from the same region. 21 Swedish register data is 31 32 known to be reliable for research purposes, 22 23 and diagnosis of psychotic disorders recorded in the 33 24-26 34 National Patient Register has good validity and positive predictive value. This register is highly 35 complete, recording all psychiatric contacts from in-patient settings from 1988 onwards, and from 36 37 out-patient settings since 2001. While this may have led to slight under-ascertainment from out- 38 39 patient settings between 1998 and 2000, we have no reason to believe this would have introduced 40 differential bias by refugee status or region of origin. We cannot exclude the possibility that we 41 42 under-estimated the true incidence of non-affective psychoses in Sweden, particularly for certain 43 groups, such as recent immigrants or refugees, who may have been unfamiliar with the Swedish 44 45 healthcare system, faced greater language barriers or who had poor health literacy. 27 If these 46 47 accessibility issues differed according to gender, the true incidence amongst migrant and refugee 48 women may have been underestimated in the Swedish patient register, making our hazard ratios 49 50 conservative. 51 52 53 Sensitivity analyses suggested that our results were not attributable to prevalent cases amongst 54 55 refugees and migrants. Although diagnostic bias has been proposed to explain excess rates of 56 psychotic disorders observed in immigrant groups, 8 there is little evidence to support this 57 58 59 60 10
https://mc.manuscriptcentral.com/bmj Page 11 of 26 BMJ
1 2 3 possibility. 28 Studies where participant ethnicity was blinded during the diagnostic process have
4 29 5 confirmed rates of psychotic disorders in ethnic minority groups. In our study, any diagnostic bias is 6 unlikely to have accounted for observed differences in risk between refugees and migrants from the 7 8 Confidential:same regions of origin. Furthermore, by law, For interpreters Review have to aid clinical consultations Only when 9 13 necessary in Sweden. Refugees are also at elevated risk of PTSD, which can present with psychotic 10 11 features; however, our findings are unlikely to be attributable to misdiagnosed cases of PTSD 12 13 amongst refugees, since these disorders often present comorbidly in people exposed to 14 psychologically traumatic expderiences.30 15 16 17 18 We were unable to include immigrants who arrived in Sweden before 1998 in our study, because 19 data on refugee status was unavailable before that year. These groups were more likely to come 20 21 from the former Yugoslavia, reflecting geopolitical conflicts of the time. This may have reduced our 22 power to detect differences between refugees and other migrants from Eastern Europe, but we 23 24 have no reason to believe their exclusion would have otherwise biased our estimates; the crude 25 26 incidence in this group was comparable with that for included immigrants, despite their higher post- 27 migratory disposable income. Finally, notwithstanding our large cohort size, the number of cases in 28 29 refugees was small, which limited our power to detect effects in certain groups, most notably 30 women, for whom risk of non-affective psychotic disorders is, on average, half that of men. 31 31 32 33 34 As our study was based on routine register data, information on potentially aetiologically relevant 35 experiences prior to migration was unavailable. Such pre-migratory experiences remain an 36 37 important area for future research. Our cohort includes migrants and refugees exposed to various 38 39 humanitarian crises resulting from conflict (i.e. Iraq, Iran, Afghanistan, the Balkans, Central Africa) as 40 well as famine (i.e. East Africa). Whilst it is too early to determine whether people currently seeking 41 42 refuge in Europe following contemporary humanitarian crises (i.e. in Syria, Iraq, Afghanistan, parts of 43 North Africa, Kosovo, Albania) would also be at greater risk of psychotic disorder, we assume our 44 45 findings will generalise to these groups for two reasons. First, there is a degree of geographical 46 32 47 overlap between the regions we included and those generating current humanitarian crises. 48 Second, we presume that exposure to war, famine and persecution would have a universal effect on 49 50 individual psychosis risk, all other risk and protective factors being equal. 51 52 53 We adjusted for possible differences between refugees, migrants and the Swedish-born population 54 55 with regard to age, sex, disposable income and population density at cohort entry. We did not 56 include other post-migratory markers of potential social disadvantage; such factors may lie on the 57 58 59 60 11
https://mc.manuscriptcentral.com/bmj BMJ Page 12 of 26
1 2 3 causal pathway between immigration and psychosis risk, thus making adjustment difficult to 4 5 interpret. We were unable to examine psychosis risk in so-called second generation refugees or 6 migrants, because our study population was born after 1984, making their children too young to 7 8 Confidential:have entered the risk period for psychosis beforeFor the end Review of our follow-up period inOnly 2011. 9
10 11 Clinical and public health implications of the study 12 13 Contemporary humanitarian crises in Europe, the Middle East, North Africa and Central Asia have 14 contributed to more displaced persons, asylum seekers and refugees worldwide than at any time 15 16 since World War II. 33 The severe social, economic and health inequalities faced by displaced 17 18 populations arising from these crises are often compounded by national immigration policies and 19 structural constraints in receiving countries. In turn, exposure to these ongoing adversities appears 20 11-13 21 likely to contribute to the increased risk of PTSD and common mental disorders among refugees. 22 Our data highlight further mental health inequalities facing such groups. 34 Clinicians and service 23 24 planners in high income settings should be aware of the early signs of psychosis in refugees, for 25 26 whom median presentation to services after arrival to Sweden was over a year sooner than for other 27 migrant groups. Just as for the general population, refugees and their families will benefit from 28 29 timely and early interventions and care, particularly in those exposed to severe psychosocial 30 adversity. Our findings are consistent with the hypothesis that increased risk of non-affective 31 32 psychotic disorders among immigrants is due to exposure to psychologically traumatic experiences 33 35 34 prior to migration, including the effects of war, violence, famine or persecution. Further studies will 35 be required to confirm this possibility. Violence experienced by children 36 and adults 11 who flee 36 37 persecution has been linked to worse subsequent mental health in general. Intriguingly, there was 38 39 some evidence to suggest that psychosis risk in refugees relative to other migrants varied by region 40 of origin in our data. While this finding requires replication in larger samples, it suggests that in 41 42 addition to refugee status, context matters. For example, we observed no differences in psychosis 43 risk between refugees and non-refugee migrants amongst immigrants from Sub-Saharan Africa; 44 45 perhaps because both groups experienced highly increased rates of disorder (over 165 new cases 46 47 per 100 000 person-years) . One parsimonious explanation for this finding is that a larger proportion 48 of Sub-Saharan Africa immigrants will have been exposed to deleterious psychosocial adversities 49 50 prior to emigration, irrespective of refugee status. By contrast, pre-migratory psychosocial 51 52 adversities experienced by refugees from Eastern Europe and Russia vis-à-vis non-refugee migrants 53 from these countries, may differ substantially, thus confining excess psychosis risk to the refugee 54 55 group from such regions. 56
57 58 59 60 12
https://mc.manuscriptcentral.com/bmj Page 13 of 26 BMJ
1 2 3 Other issues, including difficulties in the asylum process, also warrant further investigation. For 4 5 example, women seeking asylum are less likely to be granted refugee status than men, given greater 6 structural and cultural barriers in the asylum process. 37 In our study, such an effect would have led 7 8 Confidential:to a higher proportion of women being classified For as migrants, Review which may have partially Only explained 9 why differences in incidence between female refugees and non-refugees were less pronounced than 10 11 for their male counterparts. A recent study by Oram et al has further highlighted high levels of 12 13 severe mental illness faced by trafficked migrants, who represent another vulnerable group of 14 migrants. 38 Another important avenue will be to investigate whether post-migratory risk and 15 16 protective factors affect the risk and course of disorder in refugees and other migrants following 17 18 resettlement. In general population samples, there is some evidence to suggest that perceived 19 discrimination 39 and ethnic density 40 (proximity to one’s own ethnic group) are, respectively, risk and 20 21 protective factors for psychosis. Issues including cultural distance, social network size, employment 22 opportunities and the host population’s perceptions about immigration may also influence exposure 23 24 to ongoing social adversity experienced by different immigrant populations. 25 26 27 Conclusion 28 29 Our study shows that, on average, refugees in a high income setting face substantially elevated rates 30 of schizophrenia and other non-affective psychoses, in addition to the array of other mental, 31 32 physical and social inequalities which already disproportionately affect these vulnerable populations. 33 34 This risk exceeded the well-established excess burden of psychosis experienced in immigrant and 35 ethnic minority groups more generally, and thus emphasises the need to take the early signs and 36 37 symptoms of psychosis into account in refugee populations, as part of any clinical mental health 38 39 service responses to current global humanitarian crises. More broadly, our findings support the 40 possibility that exposure to psychosocial adversity increases the risk of psychosis. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13
https://mc.manuscriptcentral.com/bmj BMJ Page 14 of 26
1 2 3 Details of contributors 4 5 A-CH and JK had full access to the final data, performed statistical analyses, drafted the tables of the 6 data, co-wrote the manuscript, had final responsibility for content, and the decision to submit for 7 8 Confidential:publication. A-CH, JK and HD prepared the Fordata. A-CH and Review CD conceived of the study. Only A-CH, JK and 9 CD designed the study. CD and HD acquired all other cohort data. A-CH, CD and, HD acquisitioned 10 11 the migration data. A-CH, JK and CD obtained funding for the study. A-CH, JK, CD, CM, GL interpreted 12 13 statistical analyses. HD coordinated the data management and A-CH wrote the study protocol. All 14 authors critically revised the paper for important intellectual content and approved the final version. 15 16 17 18 Declaration of interests 19 All authors have completed the Unified Competing Interest form at 20 21 www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare 22 that (1) A-CH, JK, HD, CD, CM and GL have no support from any company for the submitted work; (2) 23 24 A-CH, JK, HD, CD, CM and GL have no relationships with any companies that might have an interest 25 26 in the submitted work in the previous 3 years; (3) their spouses, partners, or children have no 27 financial relationships that may be relevant to the submitted work; and (4) A-CH, JK, HD, CD, CM and 28 29 GL have no non-financial interests that may be relevant to the submitted work. 30
31 32 Funding and role of funder 33 34 The work for this paper was supported by FORTE (dnr 2014-1430) and FORTE (dnr 2014-2678). Dr 35 Kirkbride is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the 36 37 Royal Society (Grant number: 101272/Z/13/Z). 38 39 40 Ethics approval 41 42 This research has ethical approval as part of Psychiatry Sweden “Psykisk ohälsa, psykiatrisk sjukdom: 43 förekomst och etiologi”, approved by the Stockholm Regional Ethical Review Board Dnr 2010/1185- 44 45 31/5. The funders had no involvement in any aspect of the design of this study, preparation of 46 47 results, or decision to submit for publication. 48 49 50 Access to data 51 52 All authors had full access to all of the data (including statistical reports and tables) in the study and 53 can take responsibility for the integrity of the data and the accuracy of the data analysis. 54 55 56 Data sharing 57 58 59 60 14
https://mc.manuscriptcentral.com/bmj Page 15 of 26 BMJ
1 2 3 Statistical code is available from the corresponding author. Under Swedish law and ethical approval, 4 5 patient-level data cannot be made available. 6 7 8 Confidential:Transparency declaration For Review Only 9 Anna-Clara Hollander (the manuscript's guarantor) affirms that the manuscript is an honest, 10 11 accurate, and transparent account of the study being reported; that no important aspects of the 12 13 study have been omitted; and that any discrepancies from the study as planned (and, if relevant, 14 registered) have been explained. 15 16 17 18 Copyright for authors 19 The Corresponding Author, Anna-Clara Hollander, has the right to grant on behalf of all authors and 20 21 does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in 22 perpetuity, in all forms, formats and media (whether known now or created in the future), to i) 23 24 publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into 25 26 other languages, create adaptations, reprints, include within collections and create summaries, 27 extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the 28 29 Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links 30 from the Contribution to third party material where-ever it may be located; and, vi) licence any third 31 32 party to do any or all of the above 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15
https://mc.manuscriptcentral.com/bmj BMJ Page 16 of 26
1 2 3 References 4 5 1. Laursen TM, Munk-Olsen T, Vestergaard M. Life expectancy and cardiovascular mortality in 6 persons with schizophrenia. Curr Opin Psychiatry 2012;25(2):83-8. 7 2. Bourque F, van der Ven E, Malla A. A meta-analysis of the risk for psychotic disorders among first- 8 Confidential:and second-generation immigrants. For Psychological Review Medicine 2011;41(5):897-910. Only 9 3. Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J 10 Psychiatry 2005;162(1):12-24. 11 4. Kirkbride JB, Errazuriz A, Croudace TJ, Morgan C, Jackson D, Boydell J, et al. Incidence of 12 schizophrenia and other psychoses in England, 1950-2009: a systematic review and meta- 13 analyses. PLoS One 2012;7(3):e31660. 14 5. Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB, et al. Psychoses, ethnicity and 15 socio-economic status. Br J Psychiatry 2008;193(1):18-24. 16 6. Mahy GE, Mallett R, Leff J, Bhugra D. First-contact incidence rate of schizophrenia on Barbados. Br 17 18 J Psychiatry 1999;175:28-33. 19 7. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, et al. Schizophrenia: 20 manifestations, incidence and course in different cultures. A World Health Organization ten- 21 country study. Psychol Med Monogr Suppl 1992;20:1-97. 22 8. Selten JP, Hoek H. Does misdiagnosis explain the schizophrenia epidemic among immigrants from 23 developing countries to Western Europe? Social Psychiatry and Psychiatric Epidemiology 24 2008;43(12):937-39. 25 9. van der Ven E, Dalman C, Wicks S, Allebeck P, Magnusson C, van Os J, et al. Testing Odegaard's 26 selective migration hypothesis: a longitudinal cohort study of risk factors for non-affective 27 psychotic disorders among prospective emigrants. Psychological Medicine 2015;45(4):727- 28 34. 29 10. Steel Z, Chey T, Silove D, Marnane C, Bryant RA, van Ommeren M. Association of torture and 30 other potentially traumatic events with mental health outcomes among populations 31 32 exposed to mass conflict and displacement: a systematic review and meta-analysis. JAMA 33 2009;302(5):537-49. 34 11. Porter M, Haslam N. Predisplacement and postdisplacement factors associated with mental 35 health of refugees and internally displaced persons: a meta-analysis. JAMA 2005;294(5):602- 36 12. 37 12. Hollander AC, Bruce D, Burstrom B, Ekblad S. The association between immigrant subgroup and 38 poor mental health: a population-based register study. J Nerv Ment Dis 2013;201(8):645-52. 39 13. Fazel M, Wheeler J, Danesh J. Prevalence of serious mental disorder in 7000 refugees resettled in 40 western countries: a systematic review. Lancet 2005;365(9467):1309-14. 41 14. Hollander AC. Social inequalities in mental health and mortality among refugees and other 42 immigrants to Sweden - epidemiological studies of register data. Glob Health Action 43 2013;6:21059. 44 45 15. Norredam M, Garcia-Lopez A, Keiding N, Krasnik A. Risk of mental disorders in refugees and 46 native Danes: a register-based retrospective cohort study. Soc Psychiatry Psychiatr Epidemiol 47 2009;44(12):1023-9. 48 16. Cantor-Graae E, Pedersen CB, McNeil TF, Mortensen PB. Migration as a risk factor for 49 schizophrenia: a Danish population-based cohort study. Br J Psychiatry 2003;182:117-22. 50 17. Anderson K, Cheng J, Susser E, McKenzie K, Kurdyak P. The incidence of psychotic disorders 51 among first generation immigrants and refugees to Ontario. Canadian Medical Association 52 Journal 2015. 53 18. Swedish Migration Agency. http://www.migrationsverket.se/english, 2015. Retrived December 1, 54 2015 55 19. The World Bank. http://databank.worldbank.org/data/home.aspx. 2015 ed, 2015. Retrived 56 December 1, 2015 57 58 59 60 16
https://mc.manuscriptcentral.com/bmj Page 17 of 26 BMJ
1 2 3 20. United Nations High Commissioner for Refugees (UNHCR). Convention and protocol relating to 4 the status of refugees, 1951, 1967. Retrived December 1, 2015 5 21. Leao TS, Sundquist J, Frank G, Johansson LM, Johansson SE, Sundquist K. Incidence of 6 schizophrenia or other psychoses in first- and second-generation immigrants: a national 7 cohort study. J Nerv Ment Dis 2006;194(1):27-33. 8 Confidential:22. Abel KM, Heuvelman HP, Jorgensen L, MagnussonFor C , ReviewWicks S, Susser E, et al. Severe Only 9 bereavement stress during the prenatal and childhood periods and risk of psychosis in later 10 life: population based cohort study. BMJ 2014;348:f7679. 11 12 23. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal 13 antidepressant use during pregnancy, and risk of autism spectrum disorders: population 14 based case-control study. BMJ 2013;346:f2059. 15 24. Dalman C, Broms J, Cullberg J, Allebeck P. Young cases of schizophrenia identified in a national 16 inpatient register--are the diagnoses valid? Soc Psychiatry Psychiatr Epidemiol 17 2002;37(11):527-31. 18 25. Jorgensen L, Allebeck P, Dalman C. Prevalence of psychoses in Stockholm County-A population- 19 based study using comprehensive healthcare registers. Nord J Psychiatry 2013. 20 26. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review 21 and validation of the Swedish national inpatient register. BMC Public Health 2011;11:450. 22 27. Wangdahl J, Lytsy P, Martensson L, Westerling R. Health literacy among refugees in Sweden - a 23 cross-sectional study. Bmc Public Health 2014;14. 24 25 28. Myers NL. Update: schizophrenia across cultures. Curr Psychiatry Rep 2011;13(4):305-11. 26 29. Fearon P, Kirkbride JB, Morgan C, Dazzan P, Morgan K, Lloyd T, et al. Incidence of schizophrenia 27 and other psychoses in ethnic minority groups: results from the MRC AESOP Study. Psychol 28 Med 2006;36(11):1541-50. 29 30. O’Conghaile A, DeLisi LE. Distinguishing schizophrenia from posttraumatic stress disorder with 30 psychosis. Curr Opin Psychiatry 2015;28(3):249-55. 31 31. Kirkbride JB, Fearon P, Morgan C, Dazzan P, Morgan K, Tarrant J, et al. Heterogeneity in incidence 32 rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP 33 study. Arch Gen Psychiatry 2006;63(3):250-8. 34 32. European Commission, Eurostat. http://ec.europa.eu/eurostat/estat-navtree-portlet- 35 prod/BulkDownloadListing?file=data/migr_asyappctzm.tsv.gz. 2015 ed, 2015. 36 33. United Nations High Commissioner for Refugees (UNHCR). Global Appeal 2015 Update, 2015. 37 38 34. Hjern A, Wicks S, Dalman C. Social adversity contributes to high morbidity in psychoses in 39 immigrants--a national cohort study in two generations of Swedish residents. Psychol Med 40 2004;34(6):1025-33. 41 35. Kirkbride JB, Jones PB. Epidemiological aspects of migration and mental illness. In: Bhugra D, 42 Gupta S, editors. Migration and mental health . Cambridge: Cambridge University Press, 43 2011:xv, 350 p. 44 36. Fazel M, Reed RV, Panter-Brick C, Stein A. Mental health of displaced and refugee children 45 resettled in high-income countries: risk and protective factors. Lancet 2012;379(9812):266- 46 82. 47 37. United Nations High Commissioner for Refugees (UNHCR). Beyond Proof, Credibility Assessment 48 in EU Asylum Systems. http://www.unhcr.org/51a8a08a9.html, 2013. Retrived December 1, 49 2015 50 51 38. Domoney J, Howard LM, Abas M, Broadbent M, Oram S. Mental health service responses to 52 human trafficking: a qualitative study of professionals' experiences of providing care. BMC 53 Psychiatry 2015;15(1):289. 54 39. Veling W, Selten JP, Susser E, Laan W, Mackenbach JP, Hoek HW. Discrimination and the 55 incidence of psychotic disorders among ethnic minorities in The Netherlands. International 56 Journal of Epidemiology 2007;36(4):761-68. 57 58 59 60 17
https://mc.manuscriptcentral.com/bmj BMJ Page 18 of 26
1 2 3 40. Shaw RJ, Atkin K, Becares L, Albor CB, Stafford M, Kiernan KE, et al. Impact of ethnic density on 4 adult mental disorders: narrative review. Br J Psychiatry 2012;201(1):11-9. 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 18
https://mc.manuscriptcentral.com/bmj Page 19 of 26 BMJ
1 2 3 4 5 Table 1: CohortConfidential: characteristics by migrant status; refugees, non-refugee For migrants andReview the Swedish-born population Only 6 7 Refugee status 8 9 Swedish -born population Non -refugee migrants Refugee migrants 1 1 1 10 Category Case (%) Person -years (%) Case (%) Person -years (%) Case (%) Person -years (%) 11 Total 3 232 (100.0) 8 38 4 891 (100.0) 379 (100.0) 471 308 (100.0) 93 (100.0) 73 6 04 (100.0) 12 13 Sex Men 1 778 (55.0) 4 31 0 99 0 (51.4) 234 (61.7) 232 118 (49. 2) 66 (71.0) 41 0 69 (55.8) 14 Women 1 454 (45.0) 4 073 90 1 (48.6) 145 (38.3) 239 190 (50. 8) 27 (29.0) 32 535 (44.2) 15 16 Birth year 1984 -86 1 279 (39.5) 2 928 40 1 (34.9) 175 (46.2) 185 05 2 (39.3) 35 (37.6) 23 82 0 (32.4) 17 1987 -89 1 111 (34.4) 2 510 8 35 (29.9) 107 (28.2) 125 7 70 (26.7) 28 (30.1) 19 093 (25.9) 18 1990 -92 649 (20.1) 1 896 9 03 (22.6) 74 (19.5) 91 965 (19.5) 22 (23.7) 16 837 (22.9) 19 1993 -95 174 (5.4) 903 84 0 (10.8) 19 (5.0) 56 2 37 (11.9) 8 (8.6) 11 728 (15.9) 20 21 1996 -97 19 (0.6) 144 91 1 (1.7) 4 (1.1) 12 28 3 (2.6) 0 (0.0) 2 127 (2.9) 22 Region of origin Sweden 3 232 (100.0) 8 3 45 891 (100.0) - - - - 23 24 Sub -Saharan Africa - - 111 (29.3) 59 4 47 (12.6) 31 (33.3) 18 67 0 (25. 4) 25 Asia - - 66 (17.4) 105 64 7 (22.4) 15 (16.1) 12 929 (17.6) 26 Eastern Europe - - 80 (21.1) 134 09 4 (28.5) 7 (7.5) 6 54 6 (8.9) 27 Middle East - - 122 (32.2) 172 120 (36.5) 40 (43.0) 35 4 59 (48.2) 28 29 Income 1. Lowest quartile 1 156 (35.8) 2 161 330 (25.8) 264 (69.7) 339 062 (7 1.9) 63 (67.7) 51 9 53 (70.6) 30 2. Second quartile 830 (25.7) 2 185 386 (26.1) 52 (13.7) 63 153 (13.4) 12 (12.9) 10 486 (14.2) 31 3. Third quartile 679 (21.0) 2 073 84 1 (24.7) 45 (11.9) 35 919 (7.6) 13 (14.0) 6 768 (9.2) 32 33 4. Highest quartile 567 (17.5) 1 964 334 ( 23.4 ) 18 (4.8 ) 33 174 (7.0 ) 5 (5.4 ) 4 398 (6.0 ) 34 Population density 0-26.2 ppkm 2 875 (27.1) 2 303 728 (27.5) 50 (13.2) 55 129 (11.7) 25 (26.9) 21 746 (29.5) 35 26.3 -260 ppkm 2 1698 (52.5) 4 472 698 (53.3) 168 (44.3) 216 155 (45.9) 49 (52.7) 35 031 (47.6) 36 2 37 260.1 -4617.2 ppkm 659 (20.4) 1 608 466 (19.2) 161 (42.5) 200 024 (42.4) 19 (20.4) 16 827 (22.9) 38 1Rounded to nearest integer. ppkm 2: people per km 2 39 40 41 42 19 43 44 45 46 https://mc.manuscriptcentral.com/bmj 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 20 of 26
1 2 3 4 5 Table 2: RiskConfidential: of non-affective psychoses by migrant status after adjustment For for confounders Review Only 6 7 8 All Men Women 9 10 Category Model 1 Model 2 Model 1 Model 2 Model 1 Model 2
11 HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 12 Swedish -born 1 1 1 1 1 1 13 Non -refugee migrant 2.28 (1.99 -2.62) 1. 75 (1.5 1-2. 02 ) 2.61 ( 2.22 -3.07 ) 2.0 1 (1.7 0-2. 38) 1.91 (1.58 -2.31) 1. 44 (1. 19 -1. 76 ) 14 Refugee migrant 3.61 (2.87 -4.53) 2.9 0 (2.3 1-3.6 4) 4.28 (3.28 -5.58) 3. 49 (2.6 7-4.5 5) 2.6 5 (1.80 -3.92) 2.0 7 (1.4 0-3.0 6) 15 16 17 Non -refugee migrant 1 1 1 1 1 1 18 Refugee migrant 1.58 (1.26 -1.99) 1.6 6 (1. 32-2.0 9) 1.64 (1.25 -2.15 ) 1.7 4 (1. 32-2.2 8) 1.39 (0.92 -2.10) 1. 43 (0.9 5-2. 16 ) 19 20 21 Legend: HR: Hazard Ratio; 95% CI: 95% confidence interval. Model 1 is adjusted for age-at-risk, sex and their interaction. Model 2 is also adjusted for disposable income and 2 22 population density. A likelihood ratio test on four degrees of freedom confirmed statistical interaction between sex and age-at-risk in Model 1 ( χ : 71.5; p<0.001) and 23 Model 2 ( χ2: 73.0; p<0.001). A LRT, on two degrees of freedom, also confirmed statistical interaction between sex and refugee status in Model 1 ( χ2: 11.7; p=0.003) and 24 Model 2 ( χ2: 13.5; p=0.001). Hazard ratios by refugee status are therefore presented separately for men and women. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 20 43 44 45 46 https://mc.manuscriptcentral.com/bmj 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 26 BMJ
1 2 3 Table 3: Risk of non-affective psychoses in refugees relative to non-refugees, by region of origin 4 5 6 All Men 7 Crude incidence Model 2 Crude incidence Model 2 8 Confidential:rate per 100,000 ForHR (95% CI)Review rate per 100,000 Only HR (95% CI) 9 PYAR (95% CI) PYAR (95% CI) 10 Swedish -born 38.5 (37.2 -39.9) - 41.2 (39.4 -43.2) - 11 12 13 Eastern Europe 14 Non -refugees 59. 7 (47.9 -74. 3) 1 62.5 (45. 9-85.2) 1 15 Refugees 106.9 (51.0 -224.3) 1.7 6 (0.8 1-3.8 2) 184.1 (82.7 -409. 8) 2. 88 (1.2 2-6.8 2) 16
17 18 Asia 19 Non -refugees 62. 5 (49. 1-79.5) 1 67.0 (48.3 -92. 9) 1 20 Refugees 116.0 (69.9 -192.4) 1. 78 (1.0 1-3.1 4) 146.1 (83.0 -257.3) 2.2 0 (1.1 3-4. 25 ) 21 22 23 Middle East & North Africa 24 Non -refugees 70. 9 (59. 4-84.6) 1 94.4 (75.9 -117. 4) 1 25 Refugees 112.8 (82.7 -153.8) 1.5 6 (1.0 8-2.2 3) 143. 5 (100.3 -205.2) 1.5 5 (1.0 1-2.3 6) 26 27 Sub -Saharan Africa 28 29 Non -refugees 186. 7 (15 5.0-224. 9) 1 26 9.0 (21 5.1-336. 3) 1 30 Refugees 166.0 (116.8 -236.1) 0.8 1 (0.5 4-1.2 3) 207.1 (130.5 -328.8) 0. 68 (0.4 0-1.1 6) 31 32 33 Legend: HR: Hazard Ratio; 95% CI: 95% confidence interval. PYAR: Person-years at-risk. Estimates from Model 34 1 and Model 2 were similar, and only data from Model 2, adjusted for age-at-risk, sex, their interaction (for 2 35 both sexes combined), disposable income and population density is reported. LRT χ p-values, on 3 degrees of 36 freedom, for statistical interaction between refugee status and region of origin were χ2: 8.0; p=0.05 for the full 37 sample, and χ2: 12.0; p=0.007 in an analysis restricted to men. Given the small number of refugee women with 38 the outcome (N=27) no attempt was made to inspect risk by region of origin separately for women. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21
https://mc.manuscriptcentral.com/bmj BMJ Page 22 of 26
1 2 3 Figure 1: Hazard ratios for schizophrenia and other non-affective psychotic disorders by refugee 4 status and sex 5 6 7 6 8 Confidential: For Review Only 9 10 11 5 12 13 14 4 15 16 17 3 18 19 20 2 21
22 CI) (95% ratio Hazard 23 1 24 25 26 0 27 All Men Women All Men Women 28 29 Model 1 Model 2 30 31 Swedish-born Non-refugee migrant 32 Refugee migrant Refugee vs non-refugee migrant 33 34 35 Legend: Model 1 is adjusted for age-at-risk, sex and their interaction (where appropriate). Model 2 is 36 additionally adjusted for disposable income and population density. The Swedish-born group provide 37 the reference category, except for the hashed columns, which show hazard ratios for refugees 38 relative to non-refugee migrants. Error bars represent 95% confidence intervals. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 22
https://mc.manuscriptcentral.com/bmj Page 23 of 26 BMJ
1 2 3 Supplementary Table 1: Region of origin classification and basic sample characteristics 4 Region of SMA Cohort characteristics Countries 3 5 1 2 6 origin classification Cases (%) PYAR (%) 7 Sweden Sweden 3 233 (87.3) 8 385 059 (93.9) Sweden 8 Confidential:Sub -Saharan West Africa 20 (0.5) For10 261 (0.1)Review Benin, Burkina Faso, Only Cape Verde, Gambia, 9 Africa Ghana, Guinea, Guinea Bissau, Ivory Coast, 10 Liberia, Mali, Mauritania, Niger, Nigeria, 11 Senegal, Sierra Leone, Togo 12 East Africa 93 (2.5) 50 562 (0.6) Djibouti, Eritrea, Ethiopia ,Somalia 13 Africa, other 29 (0.8) 17 333 (0.2) Angola, Botswana, Burundi, Cameroon, Central 14 African Republic, Chad, Comoros, Congo, 15 Democratic Republic of Congo, Equatorial 16 Guinea, Gabon, Kenya, Lesotho, Madagascar, 17 Malawi, Mauritius, Mozambique, Namibia, 18 Rwanda, Sao Tome and Principe, Seychelles, 19 South Africa, Swaziland, Tanzania, Uganda, 20 Zambia, Zanzibar 21 Asia Central Asia 42 (1.1) 57 020 (0.6) Afghanistan, Armenia, Azerbaijan, Bangladesh, 22 Bhutan, Georgia, India, Kazakhstan, Kyrgyzstan, 23 Maldives, Nepal, Pakistan, Sri Lanka, Tajikistan, 24 Turkmenistan 25 Northeast 14 (0.4) 22 714 (0.3) China, Japan, Mongolia, People’s Republic of 26 Asia Korea, South Korea, Taiwan 27 Southeast 25 (0.7) 36 946 (0.4) Brunei, Cambodia, East Timor, Hong Kong, 28 Asia Indonesia, Laos, Malaysia, Myanmar, 29 Philippines, Singapore, Thailand, Vietnam 30 Eastern Eastern 36 (1.0) 52 957 (0.6) Albania, Belarus, Bulgaria, Czech Republic, 31 Europe & Europe Hungary, Moldova, Poland, Romania, Slovakia, 32 Russia Ukraine 33 Former 36 (1.0) 58 534 (0.7) Bosnia Herzegovina, Croatia, Kosovo, 34 Yugoslavia Macedonia, Montenegro, Serbia, Slovenia 35 Russia & the 15 (0.4) 29 297 (0.3) Estonia, Latvia, Lithuania, Russia 36 Baltic States 37 Middle East Iran 105 (2.8) 138 638 (1.6) Iran 38 39 & North Iraq 21 (0.6) 20 057 (0.2) Iraq 40 African Middle East, 30 (0.8) 42 253 (0.5) Bahrain, Cyprus, Israel, Jordan, Kuwait, 41 other Lebanon, Oman, Palestine, Qatar, Saudi Arabia, 42 Syria, United Arab Emirates, Yemen, Turkey 43 North Africa 6 (0.2) 6 752 (0.1) Algeria, Egypt, Libya, Morocco, Tunisia 44 SMA: Swedish Migration Agency; PYAR: Person-years at-risk 45 1Predefined by authors for analysis, based on SMA classification 46 2 47 Categories provided by the Swedish Migration Agency for research purposes, reflecting major migrant and 48 refugee flows to Sweden 49 3Countries of origin, as defined by the Swedish Migration Agency, in each SMA category. Country-level data is 50 not made available by the SMA/Statistics Sweden for research purposes. 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 24 of 26
1 2 3 4 5 SupplementaryConfidential: Table 2: Risk of non-affective psychoses by region ofFor origin for all immigrantReview groups Only 6 7 All Men Women 8 Category Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 9 HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 10 Sweden 1 1 1 1 1 1 11 12 Sub -Saharan Africa 5.2 4 (4.3 2-6.3 4) 4. 10 (3. 38 -4.98 ) 6. 68 (5. 33-8. 37) 5.25 (4.18 -6. 59 ) 3. 64 (2. 68 -4. 94 ) 2. 82 (2.07 -3.83 ) 13 Asia 1.9 6 (1.54 -2.51) 1. 50 (1.17-1.93 ) 2.0 4 (1.5 0-2. 77 ) 1.55 (1.1 3-2. 12) 1.8 8 (1. 31 -2. 69 ) 1. 43 (1.0 0-2. 06 ) 14 Eastern Europe 1.74 (1.38 -2. 20 ) 1. 41 (1.11-1. 78) 1.7 4 (1. 28 -2. 37 ) 1. 42 (1.0 4-1. 93) 1. 75 (1. 26 -2. 41 ) 1. 38 (1.0 0-1. 92) 15 Middle East & North Africa 2.16 (1.81 -2.58) 1. 62 (1. 35 -1.94 ) 2.6 4 (2.1 5-3. 25 ) 2.0 1 (1. 63 -2. 48) 1. 55 (1.1 6-2.0 7) 1.1 3 (0. 84-1. 52)
16 17 18 19 20 21 Legend: HR: Hazard Ratio; 95% CI: 95% confidence interval. Model 1 was adjusted for age-at-risk, sex and their interaction (where appropriate). Model 2 was additionally 22 adjusted for disposable income and population density. Likelihood ratio tests, on four degrees of freedom, confirmed statistical interaction between age-at-risk and sex on 2 2 23 the risk of non-affective psychotic disorder in Model 1 ( χ : 72.2; p<0.001) and Model 2 ( χ : 73.6; p<0.001). LRTs, on four degrees of freedom, also confirmed statistical 2 2 24 interaction between sex and region of origin on psychosis risk in Model 1 ( χ : 20.7; p<0.001) and Model 2 ( χ : 22.9; p<0.001). 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 https://mc.manuscriptcentral.com/bmj 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 26 BMJ
1 2 3 4 5 SupplementaryConfidential: Table 3: Sensitivity analysis of psychosis risk by exposure For status, excluding Review refugee and other migrants Only who were diagnosed with a non- 6 affective psychotic disorder within 12 months of arrival in Sweden 7 8 All Men Women 9 Category N (excluded N, Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 10 11 %) 12 HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 13 Refugee status Swedish -born 3 232 (0, 0 .0) 1 1 1 1 1 1 14 Non -refugee 288 (91, 24 .0) 2.0 8 (1.79 -2.41) 1. 57 (1. 34 -1. 83 ) 2.32 (1.94-2.77 ) 1.75 (1 .46 -2.1 1) 1.81 (1 .47-2.24 ) 1. 35 (1.09 -1.67 ) 15 Refugee 63 (30, 32 .2) 3.1 0 (2. 38 -4.0 5) 2.4 4 (1. 87-3.19 ) 3.74 (2 .73-5.12) 2.98 (2.18 -4. 08 ) 2.21 (1 .38-3.54 ) 1.69 (1.05-2.71) 16 17 Non -refugee 288 (91, 24 .0) 1 1 1 1 1 1 18 Refugee 63 (30, 32 .2) 1. 49 (1.1 4-1.9 6) 1. 56 (1.1 9-2.05 ) 1.61 (1.16 -2.24) 1. 70 (1. 22 -2. 36 ) 1.2 2 (0.7 4-2.00 ) 1. 25 (0. 76 -2.06 ) 19
20 21 Region of origin Sweden 3 232 (0, 0 .0) 1 1 1 1 1 1 22 Sub -Saharan 104 (38, 26 .8) 4.7 9 (3.8 7-5.9 5) 3. 67 (2.95 -4. 56 ) 6.10 (4 .72 -7.87 ) 4. 69 (3. 62 -6. 06 ) 3.32 (2 .34 -4.72 ) 2.5 1 (1.76-3. 58 ) 23 Africa 24 Asia 59 (22, 27 .2) 1.8 3 (1.39 -2.4 3) 1. 39 (1.0 5-1. 84 ) 1.71 (1 .18 -2.48 ) 1.29 (0 .88 -1.88 ) 2.00 (1 .36 -2.95) 1.51 (1.02-2. 23) 25 Eastern Europe 67 (20, 23 .0) 1.6 3 (1.2 6-2.1 1) 1. 30 (1.0 0-1. 69 ) 1.73 (1 .24-2.42) 1.39 (1.0 0-1.95 ) 1.51 (1.03 -2.20 ) 1.18 (0 .81-1.74 ) 26 Middle East & 85 (41, 32 .5) 1.89 (1.55 -2.30) 1. 38 (1.1 3-1. 69 ) 2.21 (1 .74-2.81) 1.64 (1. 29 -2. 09) 1.47 (1 .07-2.02 ) 1.0 5 (0 .76 -1.45) 27 North Africa 28 Legend: HR: Hazard Ratio; 95% CI: 95% confidence interval. Model 1 was adjusted for age-at-risk, sex and their interaction (where appropriate). Model 2 was additionally 29 adjusted for disposable income and population density. LRT χ2 p-values, on two degrees of freedom, for interaction between sex and refugee status, were χ2: 7.2; p=0.03 30 2 2 2 31 (Model 1) and χ : 8.4; p=0.02 (Model 2) and, on four degrees of freedom, between sex and region of origin, were χ : 13.5; p=0.01 (Model 1) and χ : 14.9; p=0.005 (Model 32 2). 33 34 35 36 37 38 39 40 41 42 43 44 45 46 https://mc.manuscriptcentral.com/bmj 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 26 of 26
1 2 3 Supplemental Table 4: Sensitivity analysis of risk of non-affective psychoses in refugees relative to 4 non-refugees for men by region of origin, excluding immigrants who were diagnosed within 12 5 months of arrival in Sweden 6 7 8 Confidential: All ( Model 2)For MenReview ( Model 2 ) Only 9 Refugee vs non -refugee HR ( 95% CI) HR ( 95% CI) 10 Sub -Saharan Africa 0.93 (0 .5 5-1.5 9) 0.9 1 (0 .46-1.8 2) 11 Asia 1.8 7 (0.96 -3. 63 ) 2.53 (1.1 2-5.7 1) 12 13 Eastern Europe 1.69 (0 .73 -3.9 3) 2.46 (0 .96-6.3 3) 14 Middle East & North Africa 1.58 (1 .04-2.41 ) 1.73 (1 .06-2.8 5) 15 16 17 Legend: HR: Hazard Ratio; 95% CI: 95% confidence interval. All models were conducted on a restricted cohort, 18 excluding the Swedish-born population and refugee or migrant cases presenting within 12 months of arrival in 19 Sweden. Baseline groups are non-refugees from each country of origin. For all people, Model 2 was adjusted 20 for age-at-risk, sex, their interaction, disposable income and population density. For men, it was adjusted for 21 2 22 age-at-risk, disposable income and population density. LRT χ p-values, on three degrees of freedom, for 2 2 23 interaction between refugee status and region of origin, were χ : 3.7; p=0.29 (all people) and χ : 4.9; p=0.18 24 (men). Given the small sample size for women, no attempt to analyse whether hazard ratios by refugee status 25 differed by region of origin. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj
