Editorial

Is it time to trial vitamin D supplements forthe prevention of schizophrenia?

Migrant status and ethnicity as risk factors for psychosis

In this volume Dealberto reviews migrant statusand ethnicity as risk factors for schizophrenia (1).The evidence that certain migrant groups have an�epidemic� of psychosis is compelling (2, 3). Inparticular, dark-skinned migrants to European andScandinavian countries have a particularly highrelative risk of developing schizophrenia comparedto native-born (3). Kirkbride and Jones (4) esti-mate that if the causal factors underpinning themigrant risk could be identified and removed, thenit may be feasible to prevent 20.8% of first episodepsychosis in the population at-risk in England.Even more startling, within the Black Caribbeangroup, the proportion of cases attributable to theyet-to-be-identified risk factors is 82.5%.Migrant studies provide a natural experiment

that can help identify non-genetic risk factors fordisease. As Dealberto notes, incidence studies inthe countries of origin of these migrants do notindicate particularly high rates of schizophrenia inthese ethnic groups, thus the data strongly suggestthat the increased risk in the migrant groups isbecause of environmentally mediated exposures.To summarise: i) there is an epidemic of schizo-phrenia in certain subgroups of the population, ii)environmental factors seem to underlie this riskand iii) it is estimated that these exposures accountfor a staggering 82.5% of cases in certain sub-groups. In the field of public health, this scenariowould be triggering alarms bells and governmentswould be urgently co-ordinating research programsin order to generate treatment and preventioncampaigns (4). Morgan and Hutchinson (5) havelabelled the situation a �public health tragedy�,while Selten and Cantor-Graae note perceptivelythat any denial of this epidemic is an insidiousform of discrimination in itself (6).Being a migrant is stressful, but so too is

belonging to an easily identified minority group.One way to help generate more specific candidateexposures is to try to separate out ethnicity andmigrant status. Bresnahan et al. (7) had theopportunity to explore this issues in a well-

described US birth cohort. They found anincreased incidence of schizophrenia in AfricanAmericans, compared with white cohort members.They also noted that factors related to socio-economic status were not sufficient to explain thedifferential risk associated with ethnicity. Althoughit is difficult to fully disentangle the factorsunderlying this finding, this study has refocussedattention on a neglected issue – the risk ofschizophrenia in the US varies according toethnic status. Dealberto has identified severalolder studies that also suggested an increasedincidence of schizophrenia in African Americans.Thus, the problem is not only linked to recentmigrant status, but also it seems to include long-standing residents in some countries who belong tocertain ethnic groups.Why do dark-skinned ethnic groups living in

some countries have an increased risk of schizo-phrenia? For ethnic groups that have arrived in thehost nation recently, migration is clearly a majorstressor. For ethnic groups that have lived in thehost nation for several generations, belonging to anethnic minority (e.g. having dark-skin in an area ofpredominant white-skinned individuals) can alsobe associated with chronic social stress. It has beenproposed that �social defeat� may contribute tochronic psychosocial stress and that this processmay be the �toxic� exposure that contributes to theincreased risk of schizophrenia (8). There is nodoubt that stigma and racism can contribute toadverse health-, social-, educational- and crime-related outcomes. Factors related to stigma clearlywarrant more research and intervention. However,this commentary will focus on one of the maincandidate risk factor discussed in Dealberto�sreview – vitamin D deficiency.

Vitamin D deficiency as a risk-modifying factor forpsychosis

The production of vitamin D3 depends on theaction of sunlight on the skin. Vitamin D produc-tion is strongly and consistently associated with theduration of the photoperiod (which is influenced

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by latitude and season), and the prevalence ofhypovitaminosis D is particularly prominent indark-skinned people living in cold climates.The risk of schizophrenia varies according to

season of birth (highest in winter ⁄ spring births),thus vitamin D should be an obvious candidaterisk factor for schizophrenia. Indeed, the observa-tion was made over 50 years ago (9), but vitamin Dwas neglected in favour of other seasonally fluctu-ating exposures such as influenza. The link betweenvitamin D and season of birth resurfaced again inthe late 1970s (10), but once again failed to igniteresearch interest. At the time vitamin D was almostexclusively linked to bone health, and there wasscant evidence for or against a link betweenvitamin D and brain function.By the late 1990s, more epidemiological clues

implicated vitamin D as a candidate risk factor.We have already discussed the increased risk ofpsychosis in dark-skinned migrants (as reviewed byDealberto). In addition, those born in urban areashave an increased risk of schizophrenia comparedto those born in rural settings (11). Both dark skinand urban residence are associated with anincreased risk of hypovitaminosis D (12). Thus,low prenatal vitamin D could underlie the excess ofwinter ⁄ spring births, the urban vs. rural riskdifference, as well as the increased risk in dark-skinned second-generation migrants to coldclimates. Vitamin D seems an unusually parsimo-nious candidate risk factor because it couldpotentially underpin diverse epidemiological find-ings. Convergent epidemiological clues put vitaminD back on the agenda in 1999 (13), and since then,the data have steadily accumulated.With respect to basic science, there is now

substantial evidence that vitamin D plays animportant role in brain development and function(14). For example, the enzyme required for theconversion of vitamin D to the active seco-steroidhormone has now been identified in the humanbrain, and there is evidence from rodent modelsdemonstrating that transient prenatal vitamin Ddeficiency results in persistent changes in adultbrain structure, neurochemistry and behaviour(15).With respect to hypothesis-driven epidemiolog-

ical studies, the evidence remains scant. A smallpilot study examining the storage form of vitaminD in third trimester maternal sera (16) wasinconclusive. There is a need to test the hypothesisin well-powered samples of maternal banked seraor neonatal dried blood spots. Alas, these resourcesare rare. Recently, a sensitive assay for vitamin Dbased on archived dried blood spots has becomeavailable, and studies based on these samples are

underway (17). Based on the Northern Finnishbirth cohort study, a link between the absence ofvitamin D supplementation during the first year oflife and a significantly increased risk of schizo-phrenia in men was found (18). Thus, there is someindirect evidence suggesting that postnatal expo-sures might also be important.

Vitamin D and psychosis – gaps in the knowledge base

When is the critical window during which lowvitamin D impacts on brain development andfunction? Second generation dark-skinnedmigrants are exposed to low vitamin D prenatallyand after birth. However, the season of birth workand the current animal models of developmentalvitamin D deficiency suggest that (at least) prenataland early life exposures to hypovitaminosis D aredisruptive for brain development. Could cumula-tive prenatal and postnatal exposure be additivewith respect to subsequent risk of psychosis?We know even less about the critical window for

first generation migrants, who can arrive at variousages from neonates to adults. We lack high qualityresearch that has examined age-at-first-migrationand subsequent risk of psychosis. Brain growth isextremely rapid in the first few years of life –absence of vitamin D could disrupt cell cyclekinetics and a range of neurotrophic factors (15).However, puberty may also be a window ofvulnerability, as sex hormones and vitamin Dshare a broad range of downstream co-activatingagents. In summary, we need to keep an open mindabout the timing of the critical window – bothprenatal, early life and perhaps even adult hypo-vitaminosis D should be considered a candidaterisk factor for schizophrenia.

What mix of research do we need now?

How best can we move forward on these issues?Linking comprehensive mental health registers (19)with biobanks would be ideal, if such samples areavailable. However, samples with repeated mea-sures of vitamin D across the lifespan are rare.Traditionally, epidemiologists have recommendeda careful program of prospective observationalstudies in order to build the evidence base andallow for replications of early findings. Observa-tional studies are ideal for generating candidaterisk factors, but randomized controlled trials(RCTs) are the bench mark for evidence-basedmedicine. The importance of this type of experi-mental design has been brought into sharp relief inrecent years after large, well-conducted prospectiveobservational studies reported findings which were

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subsequently rejected when examined with ran-domized controlled trials (20).Should we adopt a more assertive strategy and

include RCTs alongside observational studies?Some would argue that it is too early to considerRCTs, because the current evidence is circumstan-tial and the evidence from analytic epidemiologyremains scant or inconclusive. Some would arguethat a more assertive approach is justifiable. Forexample, in the populations of interest to theschizophrenia research community, migrant status,ethnicity and low vitamin D are strongly corre-lated. An RCT would be able to sidestep the issueof confounding via the use of an experimentaldesign.Schizophrenia is a disorder associated with

substantial burden of disability and increasedmortality. Despite improvements in medications,service delivery and rehabilitation, outcomesremain suboptimal. Thus, there is a cogent argu-ment to fast track any type of safe intervention thatcould possibly result in the primary prevention ofschizophrenia. With respect to the potentialprimary prevention of schizophrenia, vitamin Dseems to be an attractive candidate from a publichealth perspective. It is a cheap, safe, and relativelysimple intervention that could potentially avert awide range of disorders other than schizophrenia(12).

Caveats and concerns

The literature is replete with nutritional interven-tions which promised great benefits and deliveredlittle, if anything. Even more concerning, somerandomized controls trials of nutritional agentshave resulted in unexpected adverse outcomes inthe active arm. In the absence of strong observa-tional data, premature trials may miscalculate theoptimal age ranges or doses required to avertschizophrenia in vulnerable groups.When case–control studies suggested that plac-

ing babies on their backs to sleep was associatedwith a reduced risk of Sudden Infant DeathSyndrome, the messaging was quickly translatedinto public health recommendation without ran-domized controlled trails (21). Reassuringly, theadoption of this practice was associated with asubstantial fall in deaths. The intervention wassimple and safe, and averted a catastrophic healthoutcome. In summary, just as there are circum-stances when researcher should �sit on theirhands� and collect more data prior to startingtrials, and there are also circumstances whenRCTs and public health interventions should befast-tracked.

Sartorius and Henderson (22) proposed threeoptions for the research community interested inthe primary prevention of mental illness. The firstoption was to forget about primary preventioncompletely and concentrate on better treatmentsand cures. The second option was to fund moreresearch in order to discover the causes of seriouspsychiatric illness and then commence primaryprevention when a thorough understanding ofpathogenesis is available. The final option was tostart primary prevention based on existing know-ledge, albeit imperfect. Based on the accumulatingevidence linking hypovitaminosis D and schizo-phrenia, and the potential that a simple, safe andcheap nutritional supplement could reduce theincidence of this disorder, I argue that we shouldmove to randomized controlled trials promptly. Inlight of the substantial burden of disability asso-ciated with schizophrenia, we should undertakethese studies with a sense of urgency.

Acta Psychiatrica ScandinavicaJohn McGrath

Invited Guest Editor

References

1. Dealberto MJ. Ethnic origin and increased risk forschizophrenia in immigrants to recent and traditionalcountries of immigration. Acta Psychiatr Scand 2010;121:325–339.

2. Mcgrath J, Saha S, Welham J, El Saadi O, MacCauley C,Chant D. A systematic review of the incidence of schizo-phrenia: the distribution of rates and the influence of sex,urbanicity, migrant status and methodology. BMC Med2004;2:13.

3. Cantor-Graae E, Selten JP. Schizophrenia and migration:a meta-analysis and review. Am J Psychiatry 2005;162:12–24.

4. Kirkbride JB, Jones PB. Putative prevention strategies toreduce serious Mental illness in migrant and black andminority ethnic groups. Foresight Mental Capital andWellbeing: Discussion Paper 12. In, London: HerMajesty�s Stationary Office, 2008.

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13. Mcgrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 1999;40:173–177.

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16. Mcgrath J, Eyles D, Mowry B et al. Low maternal vitaminD as a risk factor for schizophrenia: a pilot study usingbanked sera. Schizophr Res 2003;63:73–78.

17. Eyles D, Anderson C, Ko P et al. A sensitive LC ⁄MS ⁄MSassay of 25OH vitamin D3 and 25OH vitamin D2 in driedblood spots. Clin Chim Acta 2009;403:145–151.

18. Mcgrath J, Saari K, Hakko H et al. Vitamin D supple-mentation during the first year of life and risk of schizo-phrenia: a Finnish birth-cohort study. Schizophr Res2004;67:237–245.

19. Allebeck P. The use of population based registers inpsychiatric research. Acta Psychiatr Scand 2009;120:386–391.

20. Davey Smith G, Ebrahim S. Epidemiology – is it time to callit a day? Int J Epidemiol 2001;30:1–11.

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