Hypothesis: social defeat is a risk factor for schizophrenia?

The increased schizophrenia risks for residents of cities withhigh levels of competition and for members of disadvantagedgroups (for example migrants from low- and middle-income countries,people with low IQ, hearing impairments or a history of abuse)suggest that social factors are important for aetiology. Dopaminergicdysfunctioning is a key mechanism in pathogenesis. This editorialisa selective literature review to delineate a mechanism wherebysocial factors can disturb dopamine function in the brain. Experiments with rodents have shown that social defeat leads to dopaminergichyperactivity and to behavioural sensitisation, whereby theanimal displays an enhanced behavioural and dopamine responseto dopamine agonists. Neuroreceptor imaging studies have demonstratedthe same phenomena in patients with schizophrenia who had neverreceived antipsychotics. In humans, the chronic experience of social defeat may lead to sensitisation (and/or increased baselineactivity) of the mesolimbic dopamine system and thereby increasethe risk for schizophrenia.

INTRODUCTION

TOP

INTRODUCTION

Current textbooks of psychiatry remain undecided about a causalrole for psychosocial stress in the aetiology of schizophrenia.Researchers who are opposed to this possibility often pointout that studies of life events occurring shortly before thefirst psychotic episode have yielded negative or inconclusiveresults. In actuality, we have no idea when a so-called schizophrenicdisorder really ‘begins’. Interestingly, a studyof discordant twins has shown that divergence in school performanceprecedes the onset of psychosis by an average of 10 years (van Oel et al, 2002).This suggests that certain causal factors may operate long beforethe emergence of psychotic symptoms and that the time frameof life-event studies is inadequate. The purpose of this paperis to present evidence in support of the hypothesis that achronic and long-term experience of social defeat may leadto sensitisation of the mesolimbic dopamine system (and/orto increased baseline activity of this system) and thereby increase the risk for schizophrenia. The hypothesis is based on epidemiological findings, studies of dopamine function in humans and animalexperiments.

EPIDEMIOLOGICAL FINDINGS

TOP

EPIDEMIOLOGICAL FINDINGS

Some established risk factors for schizophrenia, which are notpurely genetic, are the urban environment, migration, low IQ,hearing impairment and the use of illicit drugs.

Krabbendam & van Os (2005) performed a meta-analysis ofstudies that examined the rate of schizophrenia in urban as compared to rural areas, and obtained a mean weighted relativerisk (RR) of 1.72 (95% CI 1.53–1.92). The available evidencesuggests that causation (urban environment causes psychosis)is more important than selection (high-risk individuals moveinto urban areas) and that the effect of the environmentalfactors in the urban environment is conditional on genetic risk.

Considerable interest has been generated by studies of first-and second-generation migrants. A meta-analysis of incidencestudies found an even greater increase in psychosis risk forthe second generation (RR=4.5, 95% CI 1.5–13.1) thanfor the first (RR=2.7, 95% CI 2.3–3.2) (Cantor-Graae & Selten, 2005).Further subgroup comparisons showed greater effect sizes formigrants from lower and middle-income versus high income countriesand a remarkably high risk for migrants from countries wherethe majority of the population is Black (RR=4.8, 95% CI 3.7–6.2).It is important to note, however, that very high risks havealso been noted for non-Black immigrant groups. Denmark hasreceived many immigrants from its former colony Greenland andthe risk for second-generation Greenlanders, who are ethnicInuit, is 12.4 (95% CI 4.7–33.1) times the risk for ethnicDanes (Cantor-Graae & Pedersen, 2007). In the Netherlands,the risk for second-generation Moroccan males is 6.8 times(95% CI 3.3–14.1) the risk for Dutch males (Veling et al, 2006). Selective migration of genetically vulnerable individuals hasbeen ruled out as the sole explanation for the increased riskin migrants (Cantor-Graae & Selten, 2005).

A third risk factor for schizophrenia is low intelligence. Afollow-up study of Swedish conscripts, for instance, showedthat the risk for schizophrenia was strongly and linearly relatedto low IQ (Zammit et al, 2004). Subjects with an average IQ,for example, had a significantly greater risk of developingschizophrenia than those with an IQ of more than 126 (RR=1.3,95% CI 1.04–1.54).

It has been estimated that the use of cannabis and other dopamine-enhancing drugs approximately doubles the risk (Arseneault et al, 2004).Hearing impairment and deafness are well-established risk factorsfor psychosis, but the magnitude of the relative risk for narrow schizophrenia associated with these factors is not preciselyknown (Thewissen et al, 2005). Finally, accumulating evidenceindicates that a history of physical or sexual abuse duringupbringing is a risk factor for schizophrenia, but opinionsare still divided as to whether it is a causal risk factor (Read et al, 2005).

SOCIAL DEFEAT

TOP

SOCIAL DEFEAT

Previously, we have proposed that the long-term experience ofsocial defeat, defined as a subordinate position or as outsiderstatus, may well be the common denominator for these findings (Selten & Cantor-Graae, 2005). This interpretation iscompatible with the high levels of competition in urban areas,the fewer career opportunities for people with low IQ, thesocial exclusion experienced by immigrants and people with hearing impairments and the humiliation of being abused.

The pattern of findings among immigrants supports this idea.A greater effect size for the second generation than for thefirst can be expected, because it is more humiliating to feelunwelcome in the country that you are born in than to feelunwelcome because you are born abroad. Furthermore, the immigrantswith the highest risks (Moroccan males in the Netherlands, the Inuit in Denmark and African–Caribbeans in the UK) belongto the least successful and/or the most heavily discriminatedgroups. Moroccan males in the Netherlands are known for thehighest crime and unemployment rates and have reported thehighest frequency of the experience of discrimination. Remarkably,the schizophrenia risk for first- or second-generation Moroccan females is not increased (Veling et al, 2006). They have aninferior position in Moroccan society, but receive many opportunitiesfor education and career in the Netherlands. Since migrationhas conferred upon them a considerable rise in social status,their low risk accords with the hypothesis. (Moroccans of eithergender are exposed to the stress of acculturation and this typeof stressor is therefore unlikely to explain the pattern offindings.) In Denmark, first- and second-generation Greenlandershave higher rates of schizophrenia than most other ethnic groups.It should be noted that Greenlanders and citizens from otherNordic countries are granted automatic entry into Denmark byinter-Nordic agreement, yet the rates for schizophrenia amongGreenlanders are much higher than for persons from the otherNordic countries (Cantor-Graae et al, 2003). Rates of unemploymentand social welfare benefits are higher among Greenlanders thanamong nearly all other immigrant groups, suggesting that socialexclusion may play a key role in their increased risks forschizophrenia. Since the pain of social exclusion and humiliationmay be mitigated by social support, the social defeat hypothesisalso predicts a smaller risk increase in groups known for theirstrong social and family networks. Asian immigrants to theUK and Turkish immigrants to the Netherlands may serve as anexample. The observation that the incidence in minority ethnic groups is smaller when they comprise a greater proportion ofthe local population accords with this view (Boydell et al, 2001).

The experience of social defeat will lead to a greater needfor illicit drugs and to a greater susceptibility to thesesubstances (see below). Finally, since males may feel morepressed to achieve a social rank than females, the hypothesismay also explain the higher risk and earlier onset in males(Aleman et al, 2003), but this is uncertain.

CONCEPTUAL ISSUES

TOP

CONCEPTUAL ISSUES

The experience of defeat is in the eye of the beholder. Consequently,the absence of an association between socio-economic statusof the parents and risk for schizophrenia in the child doesnot necessarily argue against the hypothesis. Children of highsocio-economic status, who may feel pressured to meet the highexpectations of their parents, may feel more easily defeated than other children. Furthermore, social defeat is neithera necessary nor a sufficient condition for the developmentof schizophrenia, is not always followed by the developmentof a psychiatric disorder and is also a risk factor for depressionand addiction. Other factors, including those under a stronggenetic control, would determine the nature of the outcome ofexposure to social defeat. The important consideration hereis that the genetic vulnerability to schizophrenia may be presentin 10–20% of the population. Thus, the likelihood thatgene carriers may go on to develop the schizophrenia phenotypemay be strongly influenced by the experience of defeat. Theimportance of social defeat for the development of major psychiatricdisorders is not surprising, given the central role of social competition in the evolutionary process.

Finally, it is worthwhile to note that ‘social defeat’is also a consequence of a schizophrenic disorder, even beforethe emergence of psychotic symptoms. One may argue that itis difficult to distinguish between the episodes of defeatthat constitute causal risk factors for the disorder, and thesocial decline that has already been set in motion and is part-element of the schizophrenia prodrome. The fact remains, however, thatdefeated populations (i.e. certain immigrant groups) producemore cases than non-defeated populations. The question as towhether defeat in particular or stress in general contributesto the aetiology of schizophrenia is difficult to answer atthis point in time, because stressful experiences are also,to a varying degree, humiliating. The current hypothesis remainsthe most viable interpretation of the available epidemiologicaldata.

DOPAMINE FUNCTION IN SCHIZOPHRENIA

TOP

DOPAMINE FUNCTION IN...

Evidence for the role of dopamine in the development of schizophreniais provided by the increased occupancy of striatal D2 receptorsby dopamine in patients who have not received medication, thepsychotogenic effects of dopamine-enhancing drugs and the knownmode of action of antipsychotic drugs, i.e. blockade of dopamineD2 receptors (reviewed by Laruelle, 2003). Furthermore, currentevidence indicates that the mesolimbic dopamine system is sensitised in schizophrenia. Sensitisation is a process whereby exposureto a given stimulus results in an enhanced response at subsequentexposures, in this example excess release of dopamine or thedevelopment of psychotic symptoms. The notion that patientswith schizophrenia show dopamine sensitisation is supportedby neuroreceptor imaging studies which have shown that amphetamine-induceddopamine release is increased in neuroleptic-naive individualswith schizophrenia; and many patients display increased sensitivityto the psychotogenic effects of illicit drugs. This means that they develop psychotic symptoms after exposure to doses thatdo not induce psychosis in healthy subjects. However, dopamineonly mediates psychosis. Thus, important questions remain concerningthe nature of the earlier events that lead to dopaminergicdysregulation. That social defeat could well be one of theseearlier events is illustrated by a series of animal experiments.

ANIMAL STUDIES

TOP

ANIMAL STUDIES

In non-human primates dopamine function and social dominanceare related. A neuroreceptor imaging study, which examineddopamine function in individually and socially housed cynomolgusmacaques, yielded intriguing findings (Morgan et al, 2002). While the monkeys did not differ during individual housing,subsequent social housing increased the amount or availabilityof dopamine D2 receptors in the dominant monkeys and producedno change in the subordinate monkeys. Furthermore, the defeatedmonkeys consumed more cocaine than the dominant ones. The resultsindicated that individually housed monkeys and socially subordinateanimals had relatively high levels of synaptic dopamine (i.e. dopaminergic hyperactivity) and that the dominant animals,after social housing, returned to a ‘normal’ stateof dopamine function.

An even more interesting animal model for social defeat stressis the resident–intruder paradigm, whereby a male rodent(the intruder) is put into the cage of another male (the resident).Within a minute the resident attacks the intruder and promptshim to display submissive behaviour. The experiment showedthat social defeat stress leads to dopaminergic hyperactivityin the mesocorticolimbic system, not in the nigrostriatal system,and that the effects depended on the housing conditions afterdefeat (Tidey & Miczek, 1996). Lengthy isolation afterdefeat amplified the changes in the dopaminergic activity,whereas return to the group mitigated them (Isovich et al, 2001).(The reader may note a parallel with the protective effects of social cohesion and high ethnic density.) The researchersalso found that repeated experiences of defeat lead to a long-lastingbehavioural sensitisation, in which the animal displays anenhanced behavioural and dopamine response to dopamine agonists(e.g. Covington & Miczek, 2001). Several studies haveconfirmed this finding and shown that the endogenous kappaopioid system (McLaughlin et al, 2006) and the brain-derivedneurotrophic factor (BDNF) (Berton et al, 2006) contributeto the development of the response.

These observations lead to the important conclusion that patientswith schizophrenia who are antipsychotic-naive resemble insome aspects defeated animals and, subsequently, to the hypothesisthat the experience of social defeat is one of the factorsthat can lead to behavioural sensitisation in humans. Two otherschizophrenia risk factors that have been shown to produce behaviouralsensitisation in rats are repeated exposures to dopamine-enhancing drugs (Vanderschuren & Kalivas, 2000) and perinatal anoxia (Brake et al, 1997). Furthermore, an experimental lesion inthe ventral hippocampus, produced during the neonatal period,leads to dopamine sensitisation in the adult rat (Lipska et al, 1993). Thus, behavioural sensitisation seems a common pathogeneticmechanism for several schizophrenia risk factors.

It is important to note that social defeat is not the only socialstressor that can influence dopamine function in rats. Isolationrearing leads to elevated basal dopamine levels and to an enhancedamphetamine-evoked dopamine release (Hall et al, 1998). Maternaldeprivation, in contrast, leads to a diminished behaviouralresponse to amphetamine, despite apparent increases in presynaptic dopamine function in the nucleus accumbens (Hall et al, 1999).

Finally, since the gene for brain-derived neurotrophic factoris a candidate gene for schizophrenia, one can hypothesisethat variation in this gene contributes to variation in thegenetic vulnerability for schizophrenia by influencing theresponse to social defeat.

TESTING THE HYPOTHESIS

TOP

TESTING THE HYPOTHESIS

Thus, a major task for research in humans is to examine whethersocial defeat stress leads to sensitisation of the mesolimbicdopamine system. The results may have wide implications forour understanding of all major psychiatric disorders. Severalstrategies are possible; the most fruitful one for testingthe hypothesis would be a prospective, longitudinal study examiningdopamine function before and after a possible defeat. For example, one could compare healthy young adults who leave the same schooland start competing in the labour market and re-examine them2 years later. Since the experience of defeat is likely tolead to a decrease in self-esteem, one could conduct repeatedmeasurements of self-esteem. This type of research has been facilitated by major advances in the development of implicitassociation tests to measure self-esteem (e.g., Greenwald & Farnham, 2000;Greenwald et al, 2002). These tests assess automatic associations of self with positive or negative valence (by measuring differencesin reaction times) and are less biased by the need to representthe self in a socially acceptable manner.

A second possibility is to compare, again, ethnic groups. Itis likely that amphetamine-induced dopamine release is normallydistributed and that the distribution in defeated populationsis shifted towards the right. Consequently, one may compareimmigrants from a ‘super-high’ risk group (e.g.second-generation Moroccan males in the Netherlands) to natives (Fig. 1).

View larger version (14K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Fig. 1 Expected distribution of dopamine release, upon stimulation with amphetamine, in dominant and defeated population.

Although this type of research currently has limited feasibilityowing to the large numbers of participants that would be requiredto demonstrate a small- to medium-size difference in amphetamine-induceddopamine release between groups, developments in technologymay soon make this a more realistic undertaking.

Third, since the experience of social defeat is not only a riskfactor for schizophrenia, but also for addiction and depression,one can examine the risks for these disorders in defeated populations.A study conducted in the Netherlands showed that those immigrantgroups that are at increased risk of schizophrenia are alsoat an increased risk of drug use disorders, but not alcoholuse disorders (Selten et al, 2007).

Finally, history carries out natural experiments. The socialdefeat hypothesis predicts the highest risks of schizophreniafor minority ethnic groups who are lowest on the social scale:Albanians in Greece, North-Africans in France, African–Americansin the USA, Ethiopian Jews in Israel. Importantly, if thesegroups are successful in other host countries, their risksshould be not increased. Ethnic groups characterised by strongsocial and family networks (Cape Verdians in the Netherlands,for example) should have ‘normal’ risks or onlymildly increased risks.

REFERENCES

TOP