A historical overview
11.5 Examples
Rethinking existing epidemiologic research and outstanding questions in the field of psychiatry within multilevel and longitudinal frameworks illustrates the relevance of this approaches when they are explicitly applied. Thinking about these issues in terms of levels of causation, and over time often adds intellectual interest and rigour, and opens new perspectives on intervention. The examples which follow, some drawn from our own research, show how multilevel reasoning and life course frame evolved from a research question or finding, and contributed to a new line of investigation.
11.5.1 Parental age
The archetypal parental-age related disorder is Down’s syndrome. Increased risk of Down’s syndrome in offspring among older mothers was noted in 1933 [70]. Whether paternal age is related to increased risk is debated. Recent analyses and reanalyses hoping to resolve the issue have supported a small to negligible effect of paternal age [71, 72].
The father’s age has, however, been related to a broad range of other outcomes including fetal death [73], congenital syndromes (Apert’s) [74] and neurocognitive deficits in childhood [75], and most relevant here autism [76] and schizophrenia [77, 78].
While the mechanism has not been established, the layering of risk across levels is elegantly illustrated in this example, and the direction of future research following up these findings brings us to the edge of current research technologies.
One hypothesis to explain the excess risk of schizophrenia associated with older fathers is muta- genesis. Mutations in the paternal germline increase with age [79, 80]. In genome-wide scans, copy num- ber variation in networks controlling neurodevelop- ment have been associated with schizophrenia [81].
Investigators have not yet established that these or similar mutations are more common in individu- als with schizophrenia whose fathers were relatively older when they were born.
Even if the causal process involves genetic muta- tions, the determinants of age at parenting arise in part from societal, family and partner relation- ships. Contextual influences on the distribution of age at child bearing are channelled through social norms for transitions into adult roles, educational and economic participation of women and economic conditions. When interventions are warranted, they may consist of policies that reinforce the value and feasibility of ‘on-time’ parenthood for both men and women (family policies, work policies, health care policies).
11.5.2 Neighbourhood and ethnic density
A rapidly growing body of work has demonstrated markedly elevated rates of schizophrenia in migrant and ethnic minority populations [82–84]. Such find- ings do not appear attributable to selective migration, nor to elevated background rates in countries of ori- gin. In particular, observed elevations in rates of schizophrenia in ethnic minority populations have catalysed a contemporary emphasis on the social patterning of schizophrenia, and of the risk and protective factors that influence it.
One especially compelling example is neighbour- hood ethnic density. In their classic analysis of schizophrenia in Chicago neighbourhoods, Faris and
Dunham found that rates of schizophrenia among blacks decreased as the percentage of black residents increased in neighbourhoods [40]. Recent studies in London [85] and The Hague [35], which mea- sured ethnic density around the time of illness onset, have reported similar results. In both studies, an interaction between individuals and neighbourhoods was found, and the protective effect of (own) ethnic density persisted even in the most deprived neigh- bourhoods.
The mechanism(s) by which ethnic density might operate to attenuate rates of schizophrenia remain elusive. Neighbourhood ethnic density also seems to be protective against other outcomes, such as psychological distress [86], admissions to psychiatric hospitals [87] and suicide [88]. Some have posited that ethnic minorities living in neighbourhoods with higher percentages of other ethnic minorities are subjected less to discrimination, which has been associated with rates of schizophrenia in ecological studies (e.g. [35]). Others have suggested that ethnic minority dense neighbourhoods are likely to have greater social cohesion than neighbourhoods in which majority ethnicity constitute the greatest proportion of residents.
Typically, ethnic density is measured using admin- istrative (e.g. census) data. Recent work in the United Kingdom indicates that perceived ethnic density and measured ethnic density are moderately correlated, and that the impact differs by ethnic group [34].
Further investigation at the neighbourhood and indi- vidual levels across a range of contexts and ethnic groups is required to better understand the protective properties of this social phenomenon, and perhaps to harness its salutary effects.
11.5.3 Alcohol: Genes, culture and health
The association between a genotype and disease can be modified by context. Genetic susceptibil- ity to alcohol dependence is associated with genes coding for enzymes involved in the metabolism of alcohol in the liver. In Asian populations, an allele coding for one of these enzymes, aldehyde dehydro- genase 2 (ALDH2*2), has repeatedly been shown to decrease alcohol consumption [89], and decrease the risk of alcohol dependence [90, 91]. The mechanism by which the allele reduces the risk of alcoholism
involves an aversive reaction to alcohol consump- tion caused by a high concentration of acetaldehyde in the blood following consumption. The aversive symptoms can be very unpleasant, including intense flushing, palpitations and headache.
Individuals who are homozygous for ALDH2 pro- tective alleles (ALDH2*2*2) have such a strong aversive reaction that they drink very little if at all [89]. This accounts for the fact that none were found in large samples of male alcoholics in Japan [90].
Individuals who are heterozygotes for this allele have a weaker and more variable aversive reaction.
Consequently the biological effects of homozygous ALDH2*2 are so strong that they are little affected by cultural factors, whereas the effects of being het- erozygous ALDH2*2 allow for an interaction of culture with the genotype. This was put forward as one possible explanation of observed changes in the proportion of ALDH2 heterozygotes in samples of male alcoholics in Japan [90]. The protective effect of the heterozygous genotype may have become weaker as the strength of the social pressures for heavy drinking increased.
The ALDH2 alleles have also been used to provide evidence on the health effects of alcohol consump- tion. A method referred to as ‘Mendelian randomi- sation’ is increasingly employed in epidemiology to provide complementary evidence as to whether an observed association between an environmen- tal exposure and a disease is causal (see [92–94]
for more detailed discussion). Often an exposure is associated with a cluster of potential confounders (e.g. high alcohol intake may be associated with cigarette smoking, poor diet and other unhealthy habits) and it is difficult to disentangle their effects.
This problem can be overcome to some degree by examining a genetic variant that is related to the exposure but not the confounders. This condition appeared to be met in a Japanese study in which ALDH2*2*2 was strongly related to (reduced) aco- hol intake but not to some potential confounders such as cigarette smoking [95]. ALDH2*2*2 was related to reduced levels of high-density lipoprotein cholesterol and increased risk of myocardial infarc- tion [95], providing some supportive evidence for a protective effect of alcohol use that has been reported from observational studies (e.g. [96–98]). Again, these relationships will vary across different contexts
according to the frequency of both the genetic vari- ant and of alcohol use. For instance, in many Asian societies, women consume much less alcohol than men and consequently the relation of ALDH2*2*2 to the health effects of alcohol is harder to detect among women.
11.5.4 Course and outcome of schizophrenia in developing and developed countries
In studies of schizophrenia in the twentieth century, the course and outcome were found to be on average more benign in developing than developed countries [99, 100]. Thinking only in terms of individual level influences on course and outcome, these findings were counterintuitive. It had been shown that within populations, modern treatments (e.g. medication, family interventions) reduce the risk of relapse in patients with schizophrenia [101].
And yet, in developed countries where individuals had greater access to those treatments, the mean outcome was comparatively worse.
To explain this difference in mean outcome across settings, researchers had to consider societal level pro- cesses. Speculation concentrated on three dimensions of context: family relationships, informal economies and segregation of the mentally ill. The overarching theme of most theories was that developing country settings offered more opportunities for individuals with mental illness to maintain family, work and community roles.
Recently some investigators have challenged whether this difference in course and outcome is valid [102]. Our view is that the original findings represent the best work on this topic in the twentieth century and were valid in that historical context.
Nonetheless, the world of today is dramatically different, and one should not expect therefore to see the same patterns of course and outcome today across these same countries. Massive urbanisation and the growth of megacities represent but one of the salient sociocultural changes that have taken hold in low- and middle-income countries. We do not know the implications of these sociocultural changes for either the incidence or the course of schizophrenia but this is surely an important topic for the future of psychiatric epidemiology.
11.5.5 BirthWeight and psychiatric outcomes
Relationships between birthweight and psychiatric outcomes have been postulated since the mid- twentieth century. Given the ready availability of birthweight data in many locales, this would seem to be one of the simplest relationships to establish (or refute), but in fact, has turned out to be among the most difficult. This question has still not been resolved, for example for schizophrenia and affective disorders, despite the availability of registries which link birthweight and psychiatric treatment outcomes for many millions of persons.
Therefore the experience may be instructive.
The central issues can be illustrated with the rela- tion of birthweight to IQ. Reports have suggested that birthweight may be related to IQ, well into the normal birth weight range [103, 104]. Studies of the relationship between birthweight and IQ are shadowed; however, by the powerful and potentially confounding influence of family social environment.
Removing the influence of family social environment is extremely difficult in individual level studies: con- trolling for parental attributes, and other measured family factors, does not fully capture the complex influence of family environment.
The aspects of family social environment that potentially confound these results are generally shared by siblings, and therefore, are better conceptualised as family level rather than individual level variables. So we are dealing with, a family level variable (social environment) as a potential confounder of an individual level association (of birth weight and IQ). Once the cross-level nature of the confounding is recognised, it becomes possible to design studies so as to tightly control it.
Sib-pair designs, examining individual level effects within families, offer a potential solution to this problem. Matte and colleagues used this strategy to examine the association of birthweight and IQ in a large cohort born 1959–1966 in the United States.
Comparing individuals within same-sex sibships, they demonstrated that for boys, the increase in childhood IQ with birthweight extends well into the normal birthweight range [105]. Under this design, the birthweight effect could not be confounded by family environment, as siblings within the same
family share this environment. Although the effect was modest, the ramifications on a population level were potentially important.
But this was not the end of the story. Some large contemporary studies of the birthweight-IQ relation- ship within sibling pairs have found minimal or no association (e.g. [106–108]). Although the most recent large study (probably the best study so far) did fine one, also there may be different causes of birth- weight variation within versus between families [109, 110]. The question remains open as to whether these conflicting findings reflect historical change or geo- graphic variation in the relationship. This example indicates still another way in which explicit thinking about multiple levels can be useful, that is in the control of confounding. Causal determinants at one level can be confounders of findings at another level.
Consequently, a clear conceptual framework that includes multiples levels of causation makes it much easier to find ways to control confounding, which is especially important for relatively small effects.
11.5.6 Violence and mental illness
There are many individual level risk factors for vio- lent behaviours and severe mental illness is one of them [111]. At the same time, it is clear that the soci- etal context exerts a powerful influence on violent behaviour. This was demonstrated, for example in an innovative study of Chicago neighbourhoods, where collective efficacy (similar to social cohesion) of the neighbourhood was inversely related to the rate of violent crime [24]. Consistent with this are findings from two studies by Link and colleagues, one in New York City and the other in Israel, using similar mea- sures of violence [112, 113]. They found modestly higher rates of violence among the mentally ill in both study populations; however, people with men- tal illness in Israel had rates of violence comparable to members of the public in New York City.
In light of these relationships, what do we do about higher rates of violence amongst people with schizophrenia and other severe mental illnesses? One answer is: we find out more about what predicts violence in samples of people who have been hos- pitalised for mental illnesses and we develop risk assessment tools to select out violent people for more thorough intervention and control. Individual risk
factors do seem to play a role in the increased rates of violence that people with mental illness exhibit.
Some investigators emphasise comorbid substance abuse [114], while others emphasise the nature of psychotic symptoms [113].
Such an approach is a reasonable and important one. But let us see how it can be enhanced by reasoning at a contextual level. Once we accept the possibility that context matters for violent behaviours we can begin to reason about the connec- tion between mental illnesses and violent behaviours with a different frame of reference. Our vision is then shifted to thinking about the policies we implement and the structural arrangements these impose on people who develop serious mental illnesses.
Currently, the most striking feature of policy towards individuals with schizophrenia in the United States is the scarcity of evidence-based treatments and the insufficient provision of even the most basic care such as shelter. Due in large part to the scarcity of supported housing, a very large number of mentally ill persons are presently residing in jails and pris- ons and municipal shelters. In these facilities, violent norms are well documented, and in such environ- ments, mentally ill men and women are likely to adopt more violent behaviours. Moreover, those who can obtain supported housing generally are located in neighbourhoods which have low social cohesion and high rates of violence; again these neighbour- hood characteristics can affect the behaviours of all residents including those who are mentally ill. To a large degree, these issues also pertain to individuals with other severe mental illnesses.
It may very well be, then, that policies shaped by irrational stigmatisation and fear of people with schizophrenia and other severe mental illnesses, have the ironic effect of contributing to high rates of violence in this group. The stigmatisation of men- tal illness no doubt contributes a great deal to the policy of scarce services and supported housing, as it would be inconceivable for a developed society to impose the appalling conditions of prisons and shelters on individuals with less stigmatised illnesses (e.g. diabetes). In addition, the strong societal fear that people with mental illnesses will be dangerous, a fear, that is entirely out of proportion to the real risk that people with these problems actually pose, breeds the ‘not in my back yard’ (NIMBY) syndrome,
ensuring that the available housing for people with mental illnesses will be mainly located in neighbour- hoods that do not have the clout to exclude this feared group from their midst.
Should these considerations change our viewpoint about policies to reduce violence among individuals with mental illness? Perhaps the most effective intervention of all would be to make adequate care available including supported housing in safe neighbourhoods. This policy would, at the same time, tend to reduce substance abuse and psychotic symptoms, which are among the important risk factors for violence that have been identified among mentally ill individuals. In addition, it might behoove us to address the antecedents of current policy, and advocate for change societal attitudes towards mental illness.