BRITISH JOURNAL OF PSYCHIATRY (2007), 191 (suppl. 51), s9^s12. doi: 10.1192/bjp.191.51.s9 EDITORIAL

Hypothesis: social defeat is a risk factor for migrants from lower and middle- income versus high income countries and for ? a remarkably high risk for migrants from countries where the majority of the population is Black (RR¼4.8, 95% CI JEAN-PAUL SELTENand ELIZABETH CANTOR-GRAAE 3.7–6.2). It is important to note, however, that very high risks have also been noted for non-Black immigrant groups. Denmark has received many immigrants from its former colony Greenland and the risk for second-generation Greenlanders, who are ethnic Inuit, is 12.4 (95% CI 4.7–33.1) Summary The increased really ‘begins’. Interestingly, a study of dis- times the risk for ethnic Danes (Cantor- schizophrenia risks for residents of cities cordant twins has shown that divergence in Graae & Pedersen, 2007). In the Nether- school performance precedes the onset of lands, the risk for second-generation with high levels of competition and for psychosis by an average of 10 years (van Moroccan males is 6.8 times (95% CI members of disadvantaged groups (for OelOel et aletal, 2002). This suggests that certain 3.3–14.1) the risk for Dutch males (Veling example migrants fromlow- and middle- causal factors may operate long before the et aletal, 2006). Selective migration of geneti- income countries, people with low IQ, emergence of psychotic symptoms and that cally vulnerable individuals has been ruled hearingimpairments or a history of abuse) the time frame of life-event studies is inade- out as the sole explanation for the increased quate. The purpose of this paper is to pre- risk in migrants (Cantor-Graae & Selten, suggestthat social factors are important sent evidence in support of the hypothesis 2005).2005). for aetiology.Dopaminergic that a chronic andlong-term experience of A third risk factor for schizophrenia is dysfunctioning is a key mechanism in social defeat may lead to sensitisation of low intelligence. A follow-up study of pathogenesis.This editorialis a selective the mesolimbic system (and/or to Swedish conscripts, for instance, showed increased baseline activity of this system) that the risk for schizophrenia was strongly literature review to delineate a and thereby increase the risk for schizo- and linearly related to low IQ (Zammit etet mechanism whereby social factors can phrenia. The hypothesis is based on epidemi- alal, 2004). Subjects with an average IQ, for disturbdisturbdopaminefunctioninthebrain. dopamine function in the . ological findings, studies of dopamine example, had a significantly greater risk of Experiments withwithrodents rodents have shown function in and animal experiments. developing schizophrenia than those with that social defeat leads to dopaminergic an IQ of more than 126 (RR¼1.3, 95%1.3,95% CI 1.04–1.54). hyperactivity and to behavioural EPIDEMIOLOGICAL FINDINGS It has been estimated that the use ofuseof sensitisation, whereby the animal displays cannabis and other dopamine-enhancing an enhanced behavioural and dopamine Some established risk factors for schizo- drugs approximately doubles the risk (Ar- response to dopamine agonists. phrenia, which are not purely genetic, are seneaultseneault et aletal, 2004). Hearing impairment Neuroreceptor imaging studies have the urban environment, migration, low and deafness are well-established risk fac- IQ, hearing impairment and the use of illicit tors for psychosis, but the magnitude of demonstrated the same phenomena in drugs.drugs. the relative risk for narrow schizophrenia patientswith schizophreniawhohadneverschizophreniawho hadnever Krabbendam & van Os (2005) per- associated with these factors is not precisely received antipsychotics.In humans, the formed a meta-analysis of studies that ex- known (Thewissen et aletal, 2005). Finally, ac- chronic experience of social defeat may amined the rate of schizophrenia in urban cumulating evidence indicates that a history as compared to rural areas, and obtained of physical or sexual abuse during upbring- lead to sensitisation (and/or increased a mean weighted relative risk (RR) of ing is a risk factor for schizophrenia, but baseline activity) ofthe mesolimbic 1.72 (95% CI 1.53–1.92). The available opinions are still divided as to whether it dopamine system and thereby increase evidence suggests that causation (urban is a causal risk factor (Read et aletal, 2005).,2005). the risk for schizophrenia. environment causes psychosis) is more im- portant than selection (high-risk individuals Declaration of interest None. move into urban areas) and that the effect SOCIAL DEFEAT of the environmental factors in the urban environment is conditional on genetic risk. Previously, we have proposed that the long- Current textbooks of psychiatry remain un- Considerable interest has been gener- term experience of social defeat, defined as decided about a causal role for psychosocial ated by studies of first- and second-genera- a subordinate position or as outsider status, in the aetiology of schizophrenia. Re- tion migrants. A meta-analysis of incidence may well be the common denominator for searchers who are opposed to this possibil- studies found an even greater increase in these findings (Selten & Cantor-Graae, ity often point out that studies of life events psychosis risk for the second generation 2005). This interpretation is compatible occurring shortly before the first psychotic (RR(RR¼4.5, 95% CI 1.5–13.1) than for the with the high levels of competition in urban episode have yielded negative or inconclu- first (RRfirst(RR¼2.7, 95% CI 2.3–3.2) (Cantor- areas, the fewer career opportunities for sive results. In actuality, we have no idea Graae & Selten, 2005). Further subgroup people with low IQ, the social exclusion ex- when a so-called schizophrenic disorder comparisons showed greater effect sizes perienced by immigrants and people with

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hearing impairments and the of The experience of social defeat will lead the most viable interpretation of the avail- being abused. to a greater need for illicit drugs and to a able epidemiological data. The pattern of findings among immi- greater susceptibility to these substances grants supports this idea. A greater effect (see below). Finally, since males may feel DOPAMINE FUNCTION size for the second generation than for the more pressed to achieve a social rank than IN SCHIZOPHRENIA first can be expected, because it is more hu- females, the hypothesis may also explain miliating to feel unwelcome in the country the higher risk and earlier onset in males Evidence for the role of dopamine in the de- that you are born in than to feel unwelcome (Aleman(Aleman et aletal, 2003), but this is uncertain. velopment of schizophrenia is provided by because you are born abroad. Furthermore, the increased occupancy of striatal D2 re- the immigrants with the highest risks ceptors by dopamine in patients who have (Moroccan males in the Netherlands, the CONCEPTUAL ISSUES not received medication, the psychotogenic Inuit in Denmark and African–Caribbeans effects of dopamine-enhancing drugs and in the UK) belong to the least successful The experience of defeat is in the eye of the the known mode of action of antipsychotic and/or the most heavily discriminated beholder. Consequently, the absence of an drugs, i.e. blockade of dopamine D2 recep- groups. Moroccan males in the Netherlands association between socio-economic status tors (reviewed by Laruelle, 2003). Further- are known for the highest crime and of the parents and risk for schizophrenia more, current evidence indicates that the unemployment rates and have reported in the child does not necessarily argue mesolimbic dopamine system is sensitised the highest frequency of the experience of against the hypothesis. Children of high so- in schizophrenia. Sensitisation is a process discrimination. Remarkably, the schizo- cio-economic status, who may feel pres- whereby exposure to a given stimulus re- phrenia risk for first- or second-generation sured to meet the high expectations of sults in an enhanced response at subsequent Moroccan females is not increased (Veling their parents, may feel more easily defeated exposures, in this example excess release of et aletal, 2006). They have an inferior position than other children. Furthermore, social de- dopamine or the development of psychotic in Moroccan society, but receive many feat is neither a necessary nor a sufficient symptoms. The notion that patients with opportunities for education and career in condition for the development of schizo- schizophrenia show dopamine sensitisation the Netherlands. Since migration has con- phrenia, is not always followed by the de- is supported by neuroreceptor imaging stu- ferred upon them a considerable rise in so- velopment of a psychiatric disorder and is dies which have shown that amphetamine- cial status, their low risk accords with the also a risk factor for depression and addic- induced dopamine release is increased in hypothesis. (Moroccans of either gender tion. Other factors, including those under a neuroleptic-naive individuals with schizo- are exposed to the stress of acculturation strong genetic control, would determine the phrenia; and many patients display in- and this type of stressor is therefore un- nature of the outcome of exposure to social creased sensitivity to the psychotogenic likely to explain the pattern of findings.) defeat. The important consideration here is effects of illicit drugs. This means that they In Denmark, first- and second-generation that the genetic vulnerability to schizo- develop psychotic symptoms after exposure Greenlanders have higher rates of schizo- phrenia may be present in 10–20% of the to doses that do not induce psychosis in phrenia than most other ethnic groups. It population. Thus, the likelihood that gene healthy subjects. However, dopamine only should be noted that Greenlanders and citi- carriers may go on to develop the schizo- mediates psychosis. Thus, important ques- zens from other Nordic countries are phrenia phenotype may be strongly influ- tions remain concerning the nature of the granted automatic entry into Denmark by enced by the experience of defeat. The earlier events that lead to dopaminergic inter-Nordic agreement, yet the rates for importance of social defeat for the develop- dysregulation. That social defeat could well schizophrenia among Greenlanders are ment of major psychiatric disorders is not be one of these earlier events is illustrated much higher than for persons from the surprising, given the central role of social by a series of animal experiments. other Nordic countries (Cantor-Graae etet competition in the evolutionary process. alal, 2003). Rates of unemployment and so- Finally, it is worthwhile to note that cial welfare benefits are higher among ‘social defeat’ is also a consequence of a ANIMAL STUDIES Greenlanders than among nearly all other schizophrenic disorder, even before the immigrant groups, suggesting that social emergence of psychotic symptoms. One In non- primates dopamine function exclusion may play a key role in their may argue that it is difficult to distinguish and social dominance are related. A neuro- increased risks for schizophrenia. Since the between the episodes of defeat that consti- receptor imaging study, which examined pain of social exclusion and humiliation tute causal risk factors for the disorder, dopamine function in individually and may be mitigated by , the and the social decline that has already been socially housed cynomolgus macaques, social defeat hypothesis also predicts a set in motion and is part-element of the yielded intriguing findings (Morgan et aletal,, smaller risk increase in groups known schizophrenia prodrome. The fact remains, 2002). While the monkeys did not differ for their strong social and family net- however, that defeated populations (i.e. during individual housing, subsequent works. Asian immigrants to the UK and certain immigrant groups) produce more social housing increased the amount or Turkish immigrants to the Netherlands cases than non-defeated populations. The availability of dopamine D2 receptors in may serve as an example. The observation question as to whether defeat in particular the dominant monkeys and produced no that the incidence in minority ethnic or stress in general contributes to the aeti- change in the subordinate monkeys. groups is smaller when they comprise a ology of schizophrenia is difficult to answer Furthermore, the defeated monkeys con- greater proportion of the local population at this point in time, because stressful ex- sumed more cocaine than the dominant accords with this view (Boydell et aletal,, periences are also, to a varying degree, hu- ones.ones.TheThe results indicated that individually 2001).2001). miliating. The current hypothesis remains housed monkeys and socially subordinate

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animals had relatively high levels of synap- levels and to an enhanced amphetamine- tic dopamine (i.e. dopaminergic hyperactiv- evoked dopamine release (Hall et aletal,, ity) and that the dominant animals, after 1998). Maternal deprivation, in contrast, social housing, returned to a ‘normal’ state leads to a diminished behavioural response of dopamine function. to amphetamine, despite apparent increases An even more interesting animal model in presynaptic dopamine function in the nu- for social defeat stress is the resident– cleus accumbens (Hall et aletal, 1999).,1999). intruder paradigm, whereby a male rodent Finally, since the gene for brain-derived (the intruder) is put into the cage of another neurotrophic factor is a candidate gene for male (the resident). Within a minute the re- schizophrenia, one can hypothesise that sident attacks the intruder and prompts him variation in this gene contributes to varia- Fig. 11Fig. Expected distribution of dopamine release, to display submissive behaviour. The ex- tion in the genetic vulnerability for schizo- upon stimulation with amphetamine, in dominant periment showed that social defeat stress phrenia by influencing the response to and defeated population. leads to dopaminergic hyperactivity in the social defeat. mesocorticolimbic system, not in the nigrostriatal system, and that the effects depended on the housing conditions after TESTING THE HYPOTHESIS developments in technology may soon defeat (Tidey & Miczek, 1996). Lengthy make this a more realistic undertaking. isolation after defeat amplified the changes Thus, a major task for research in humans Third, since the experience of social de- in the dopaminergic activity, whereas re- is to examine whether social defeat stress feat is not only a risk factor for schizo- turn to the group mitigated them (Isovich leads to sensitisation of the mesolimbic do- phrenia, but also for addiction and et aletal, 2001). (The reader may note a parallel pamine system. The results may have wide depression, one can examine the risks for with the protective effects of social cohe- implications for our understanding of all these disorders in defeated populations. A sion and high ethnic density.) The research- major psychiatric disorders. Several strat- study conducted in the Netherlands showed ers also found that repeated experiences of egies are possible; the most fruitful one that those immigrant groups that are at in- defeat lead to a long-lasting behavioural for testing the hypothesis would be a pros- creased risk of schizophrenia are also at an sensitisation, in which the animal displays pective, longitudinal study examining increased risk of drug use disorders, but not an enhanced behavioural and dopamine dopamine function before and after a poss- alcohol use disorders (Selten et aletal, 2007).,2007). response to dopamine agonists (e.g. ible defeat. For example, one could com- Finally, history carries out natural experi- Covington & Miczek, 2001). Several pare healthy young adults who leave the ments. The social defeat hypothesis predicts studies have confirmed this finding and same school and start competing in the the highest risks of schizophrenia for minor- shown that the endogenous kappa opioid labour market and re-examine them 2 years ity ethnic groups who are lowest on the social system (McLaughlin et aletal, 2006) and the later. Since the experience of defeat is likely scale: Albanians in Greece, North-Africans brain-derived neurotrophic factor (BDNF) to lead to a decrease in self-esteem, one in France, African–Americans in the USA, (Berton(Berton et aletal, 2006) contribute to the devel- could conduct repeated measurements of Ethiopian Jews in Israel. Importantly, if opment of the response. self-esteem. This type of research has been these groups are successful in other host These observations lead to the import- facilitated by major advances in the devel- countries, their risks should be not in- ant conclusion that patients with schizo- opment of implicit association tests to creased. Ethnic groups characterised by phrenia who are antipsychotic-naive measure self-esteem (e.g., Greenwald & strong social and family networks (Cape resemble in some aspects defeated animals Farnham, 2000; Greenwald et aletal, 2002).,2002). Verdians in the Netherlands, for example) and, subsequently, to the hypothesis that These tests assess automatic associations should have ‘normal’ risks or only mildly the experience of social defeat is one of of self with positive or negative valence increased risks. the factors that can lead to behavioural (by measuring differences in reaction times) sensitisation in humans. 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