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The Role of the Social Environment in Psychiatric Research: Outstanding Challenges and Future Directions

Posted on 16 Mar 2009
Dana March James Kirkbride Wim Veling

On 17 March 2009, we hosted a live discussion of fresh new ideas in the epidemiology of schizophrenia. Discussion leaders Dana March of Columbia University, James Kirkbride of the University of Cambridge, and Wim Veling of Parnassia Psychiatric Institute delivered a wide-ranging discussion of social factors such as migration, ethnicity, and urbanicity, but also asked how this research could benefit from genetic insights. Finally, they discussed possible biological mechanisms that might transduce social factors into psychosis.



I. Background

1. Elucidation of several factors well established: migration, ethnicity, urbanicity
The study of social causes of schizophrenia, once a dominant focus of attention, has been reinvigorated in the current era. This growing area of study draws on evidence from analyses of migration, ethnicity, and urbanicity. Recent and ongoing work grows out of interest in work linking migration and schizophrenia. Evidence indicates that migration itself is not the important exposure, since second-generation migrants appear more at risk (Cantor-Graae and Selten, 2005).

Studies of ethnicity and race, stimulated by the migration work, show that racial and ethnic minorities are at markedly increased risk of schizophrenia, compared to their majority native-born counterparts (Fearon et al., 2006; Veling et al., 2006; Bresnahan et al., 2007). Interestingly, ethnic minorities who live in areas with greater concentrations of other ethnic minorities are less at risk than ethnic minorities who live in areas with few ethnic minorities (Boydell et al., 2001; Veling et al., 2007). One possible explanation is the lack of discrimination, which has been associated with increased risk (Veling et al., 2007). Still, these findings leave many questions unanswered, and evidence is lacking across settings.

Finally, studies of urbanicity indicate that people born in urban areas are about two times more likely to develop schizophrenia than those born in less densely populated areas (e.g., Mortensen and Pedersen, 1999). However, what it is about being born in an urban area remains elusive—the relevant exposures may be physical (e.g., infection, toxins, nutrition) or social (e.g., crowding, adversity) in nature. Moreover, it is unclear whether this finding holds across a range of settings, since the bulk of evidence comes from Western Europe (March et al., 2008).

Together, studies of migration, ethnicity, and urbanicity frame a set of compelling questions that are being taken up by a new wave of research. Here we address the conceptual and methodological aspects of this work that currently make it one of the most interesting frontiers of schizophrenia research.

2. From risk indicators to causes
One of the central paradoxes in the social epidemiology of schizophrenia and other psychoses is that while urbanicity and black and minority ethnic status are associated with increased rates of disorder, they are ubiquitous “exposures” with little specificity. Many millions of people are exposed to these factors, but roughly only 50 per 100,000 people per year will go on to develop the disorder (Kirkbride et al., 2006). These factors may be better described as risk indicators—associated with an increased risk of psychoses, but not of themselves etiologically relevant. Rather, they lie on the causal pathway and present markers of risk for factors which lie closer to the causal genetic, individual, and environmental effects we will need to elicit before it will be possible to think about identifying environmental factors which offer potentially tangible public health prevention targets. Current research should focus on identifying risk factors for psychoses with greater specificity to allow us to resolve this paradox. So far, there have been important contributions from two streams of research, elucidating distinct genetic and environmental risks for psychotic disorders (McGrath et al., 2004; International Scizophrenia Consortium, 2008). To understand the likely complexity in the etiology of psychosis, we now need to move toward investigating how social factors interact with underlying genetic vulnerability to increase the risk of psychosis for some, but not all, individuals. Important contributions in this regard are beginning to emerge (Caspi et al., 2005), but we will need to develop a better understanding of the likely multifactorial, multilevel structure of exposures which increase and protect against the onset of psychosis across the life course, elucidating the critical time periods where these factors have the greatest effect (March and Susser, 2006).

3. Possible biological mechanisms
There is general consensus that heightened dopaminergic transmission plays a central role in schizophrenia. Several studies demonstrated that (untreated) schizophrenia patients have an increased mesolimbic dopamine release after acute amphetamine challenge (Laruelle et al., 1996; Abi-Dargham et al., 1998), suggesting an abnormal responsiveness of dopaminergic neurons. The question remains as to what causes this hypersensitivity to dopamine. It has been speculated that dopamine dysregulation arises from genetic factors, such as the valine-to-methionine (Val/Met) polymorphism in the catechol-O-methyl transferase (COMT) gene, which is involved in dopamine metabolism (Williams et al., 2007). Dopamine dysregulation might also be caused by early environmental insults such as prenatal infections, malnutrition, or obstetric complications, and by social stress in adolescence or early adult life (Howes et al., 2004). Several neurobiological models suggest links among stress, the hypothalamic-pituitary-adrenal (HPA) axis, and dopamine activity (Corcoran et al., 2003). Animal experiments have shown that exposure to stress as well as the biological induction of HPA activation enhance the behavioral response of rats to dopamine agonists (Covington and Miczek, 2001), and lead to mesolimbic dopaminergic hyperactivity (Tidey and Miczek, 1996). Thus, social stress may lead to (further) dysregulation of the dopamine system through an augmenting effect of the HPA axis on dopamine synthesis and release (Walker and Diforio, 1997). At the same time, it is likely that there is a reciprocal effect such that heightened sensitivity to dopamine influences HPA activation and thus renders the individual hyper-responsive to stress, consistent with recent human studies that found that individuals who are genetically vulnerable to psychosis are more emotionally and behaviorally sensitive to daily life stress than are healthy controls (Myin-Germeys et al., 2001). Consequently, if the results of the animal experiments can be extended to humans, it is possible that chronic exposure to social stress leads to disturbances in dopamine function and further to the development of psychosis.

But several challenges remain

1. Understanding the broader social processes which underpin social epidemiology.
2. Understanding historical timing of social events and historical changes in social factors.
3. Understanding critical timing of exposures across the life course.
4. Understanding interactions (interplay) between genes and environment to increased risk of schizophrenia.
5. Elucidating biological processes which link social factors to onset of schizophrenia—dopamine pathways, hippocampus changes, epigenetics, etc.
6. Understanding the contextual nature of risk factors—different factors in different populations (both genetic and environmental variation).
7. Construct refinement in gXe interactions—types of interactions.

II. Questions for Discussion

We need a better understanding of the phenotype, genotype, and envirome (greater specificity). What to target first? Candidate genes? What putative mechanisms are worth pursuing?

How do we design studies to deal with the complexities in etiology, and the particular complexities in social etiology?

How do we integrate systematically the individual life course?

How do we reconcile different contextual mechanisms in different settings to have meaningful public health implications?

1. Construct refinement/meaning
What are we actually capturing when we measure urbanicity or ethnic density? Examining critically the constructs of interest is a key step in understanding mechanisms. Part of this is trying to understand the broader social processes that create the conditions we ultimately measure as exposures of interest (e.g., population density, percent minority composition). With urbanicity, for instance, how do areas become densely populated? What are the patterns of urbanization and suburbanization in a given geographic location?

2. Study designs
We propose that it is necessary to design studies that investigate multiple levels of causation, because the complex etiology of schizophrenia involves factors acting at the level of genes, individuals, ethnic/racial groups, and neighborhoods. It is likely that higher-order interactions between genes and environment, and/or genes and genes, and/or environment and environment, determine the development of schizophrenia. Many different pathways are conceivable. This complexity requires research with carefully specified hypotheses and large samples in varying social contexts. But how can we accomplish that?

3. Time
Both historical time and timing of exposure during the life course are critical to understanding contextual effects. Indeed, period and cohort effects may exist with contextual exposures; beyond that, to understand better broader social processes, a historical view is beneficial. For example, in the work being conducted in Oakland, urbanization and suburbanization during the 1940s and 1950s created particular and identifiable patterns of urbanicity by race (hence “ethnic” density) and SES. Different patterns may be observed in other locations at other times. Understanding particulars may just help us wrap our minds around the generalizable; they are not mutually exclusive.

With respect to timing of exposure, we know population density has the greatest effect at birth. Ethnic density seems to operate around the time of illness onset—or does it? We need to examine these contextual exposures systematically across the life course in order to understand potential mechanisms.

Construct refinement by understanding broader social processes with a historical perspective and consideration of the individual life course will also inform the potential confounds we measure and include in our models.

If further studies would find more (specific) evidence for a social etiology of schizophrenia, public health interventions might be developed to prevent psychosis. These interventions may include strategies to diminish social isolation, increase social capital, and facilitate access to this capital. It may be feasible to strengthen social structures within social groups and within neighborhoods.

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