5) Social Determinants of Paranoid Schizophrenia

Fig. 1- The Social Determinants of Health [2]
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Health is determined by individual and environmental factors.

The onset of Paranoid Schizophrenia is brought about through the interplay between genetic and environmental factors. The socio-environmental factors can be further subdivided into individual factors, such as low income, unemployment, low socio-economic status (SES) and community factors, such as urbanicity and social deprivation among many other factors[3]. The individual and community factors aforementioned are believed to induce epigenetic effects through mechanisms, which are still unknown.
When referring to schizophrenia in a social context, it is difficult to discern whether the disorder is a cause or a consequence of social paradigms; perhaps it is both. A social paradigm, such as social defeat, could increase the risk of schizophrenia or clinically diagnosed schizophrenia could induce the patient into contexts of social defeat. The fact that causality may operate in both directions makes studying schizophrenia from a social point of view very intricate. Over the course of the past several years, however, there has been increasing evidence that two social paradigms, primarily upbringing in urban settings and inequitable societies, explain the increased rates of schizophrenia in urban settings[3][13][19][21]. The evidence for social defeat supports its correlation with the disorder, with no indication of causality as of yet[20].

Increased Schizophrenia Rates in Urban Settings

Fig. 2- The Effect of Urbanity on the
Risk of Developing Schizophrenia [19]
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The relative risk of schizophrenia is highest in capital city areas
and is not significantly correlated with age

Certain psychiatric disorders like paranoid schizophrenia have continuously been observed to be most prevalent in urban settings[3][9][14][19][22]. Several hypotheses have surfaced over the years to explain this phenomena, however, none have been strongly conclusive.

Questioning the Social Drift Hypothesis

The social drift hypothesis is a well-established theory of mood disorder causation and is continuously referenced in the literature as a possible explanation for the observed increasing rates of psychiatric disorders in urban environments[14]. It argues that people who are genetically predisposed to developing mood disorders, such as paranoid schizophrenia, drift to lower socio-economic statuses and congregate in urban environments[14]. In recent years, this hypothesis has come under fire[14][19]because it fails to explain the reason why people with schizophrenia are drawn to urban as opposed to rural environments[9[11][19].
In recent years, however, a new theory has surfaced, which is called the social causation hypothesis[17]. This theory argues that individuals who find themselves in low socio-economic environments are confronted with social stressors that increase their risk of developing schizophrenia[17]. Several findings within the past decade strongly suggest that the social causation hypothesis may explain increased schizophrenia rates in urban environments[17][19]. Evidence by Pedersen et. al. supports a dose-response relationship between degree of urbanicity during upbringing and schizophrenia risk[19]. Pedersen et. al’s research entailed a longitudinal study in which they analyzed the effect of urbanicity at birth and during upbringing on schizophrenia risk for a cohort of 27.1 million people starting from 1971. Their research strongly indicates that people who moved to higher degrees of urbanicity-so from towns to cities for instance- over the span of five years had an almost 1.5-fold increase in their risk of developing schizophrenia. In contrary, those who moved to lower degrees of urbanicity, from cities to towns, over the span of five years had a 0.82-fold decrease in their risk of developing schizophrenia. These results suggest that urbanity during upbringing is a causal factor for developing schizophrenia[19].

See also the 'Urban upbringing' section of this wiki : causes-of-schizophrenia

Neural Basis: The Effect of a Life in an Urban Setting on Social Stress Processing

Urban environments are associated with stressful social conditions, which are implicated in mental disorders such as schizophrenia[13-14]. Some of the stressors include social defeat, discrimination, low socio-economic standing and low objective and perceived standing in society[14][20]. This presents a huge public health policy concern because as more of the world’s population urbanizes, more chronic diseases and mental disorders will arise[13].

In order to begin addressing this public health challenge, it is beneficial to first localize the effect of stress on brain activity so as to begin understanding the complexity of stress mechanisms on the brain.
Evidence put forth by Lederbogen et. al. strongly suggests that social stressful tasks increase activity in the perigenual anterior cingulate cortex (pACC) in people who have lived in cities in their youth[13]. This is in contrast to people who are currently living in cities, who show an increase in amygdala activity during social stressful tasks[2]. The amygdala is implicated in depression and anxiety disorders and the pACC is implicated in regulating stress in particular as it pertains to chronic social stress, such as social defeat[13]. Although the pACC and amygdala are localized in distinct regions in the brain, they function within the same corticolimbic pathway to regulate stress and emotion[15]. The pACC regulates the amgydala in the processing of negative emotion[15]. The results put forth by Lederbogen et. al. provide a neural premise for the difference in brain activity localization in stress paradigms for individuals who are brought up and are currently living in urban environments. This presents a great feat in understanding stress modification in humans.

Effect of Social Inequality and Stress on Schizophrenia Incidence Rates

Fig. 3- The Relationship between Countries’ Income Equalities as
defined by their Gini Coefficient and the Incidence of Schizophrenia [3]
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Higher Gini coefficients are positively correlated with
higher incidence rates of schizophrenia

The literature supporting the negative association between social inequality and health outcomes, particularly on mental disorders, is pervasive[3][9-10][12][21][23]. The social inequality paradigm to understanding health outcomes postulates that the social structure of societies is a good indicator of the health of a population. This means that the health outcomes of a population will suffer when there is a great disparity between the poorest and richest within a society[3]. This disparity is usually measured in the form of relative income[3][23] and is termed social inequality. Evidence supported by several bodies of research strongly suggests that low individual income and socio-economic status (SES) as well as community-level deprivation and inequality account for the increased rates of schizophrenia in urban environments[3][9][21]. Low SES is defined as having fewer resources such as education, job security and access to health care, which leads to a lower social standing[4].
Research by Kirkbride et. al. suggests that community-level deprivation, income inequality and population density are associated with increased schizophrenia rates[9]. Research by Tsai et. al. indicate that individuals who have low SES and live in deprived neighbourhoods have the highest risk of mortality associated with schizophrenia. This risk increases by 22% compared to those with high SES living in richer neighbourhoods[21]. A literature review conducted by Burns et. al. suggests that the same association between high income disparities and high rates of schizophrenia prevails at the level of countries. This means that the relative SES of countries with respect to one another has no bearing on the incidence rates of schizophrenia within each country, however, the social inequalities within each country does contribute to the incidence rates of the disorder[3].
The explanation for why social inequality leads to increased schizophrenia rates is only circumstantial, but scientists have postulated that social inequality may be the catalyst for several social stress markers such as the stress associated with work, low incomes and lower social standing in communities[21].

The Social Defeat Paradigm

The association between social defeat and schizophrenia is not simply causal in one direction[7]. This means that causality within this paradigm could operate in both directions. Animal models of chronic social defeat (CSD), however, have been paramount in understanding mental disorders like schizophrenia. Social defeat is a realistic social stressor that is also applicable to humans, so theoretically, results obtained in animal models should have some bearing in human models[20].

Perceived Social Standing Affects Perigenual Anterior Cingulate Cortex (pACC) Morphology

Fig. 4- The Associated Brain Morphology with Subjective Social Standing [4]
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A. Participants were asked to rate their subjective social standing based on a 10-point social ladder scale.
B. Saggital view showing the pACC area that is associated with lower subjective social status.
C. Lower subjective social standing is more closely associated with the peak pACC volume outlined in B.

One’s own subjective social standing is closely linked to individual socio-economic status (SES). The stress-induced mechanism by which low individual SES may increase rates of psychosis is postulated to be through the subjective perception of one’s own social standing[4]. Standard SES markers such as job security, income, education and access to health care are separate from social standing and may not fully encapsulate the extent of stress related to lower socio-economic standing[4]. Research by Gianoros et. al. strongly suggests that low subjective social standing, as measured by a lower social ladder ranking from participants, is correlated with reduced grey matter volume in the perigenual anterior cingulate cortex (pACC). This correlation was absent between object individual SES and pACC grey matter volume, which indicates that the brain processes subjective and objective SES differently[4].

Animal Models of Social Defeat

Effect of Social Isolation on Striatal Dopamine Transporter Binding (DAT)

Fig. 5- The Effect of Social Defeat and Isolation Housing versus
Group Housing Conditions on Striatal DAT Binding [8]
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The effect of social defeat on stratal DAT binding is most
pronounced in isolated housing and over time.

The mesolimbic dopamine response to stress has been implicated in various mental disorders such as paranoid schizophrenia[8][20]. Evidence of social defeat correlating with hyperactivity in the mesolimbic dopamine system has been well observed in animal models, however, the same has not been observed in human models due to the lack of studies[20]. Research by Isovich et. al. suggests, however, that the effect of social defeat on the dopamine system is dependent on environmental conditions[8]. Their results indicate that mice who endured social defeat and were later housed individually for varying lengths of time displayed a reduction in dopamine transporters (DAT) in the striatum. The effect was not observed for the mice who were placed in familiar cages after experiencing social defeat[8]. This suggests that social isolation for extended periods of time worsens the effects of social defeat in mice.

Effect of Social Defeat on Disc1 Mutated Mice

Fig. 6- Results from the FST, SC and EPM tests
on socially defeated mice [6]
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Socially defeated L100P+/- mice spent less time swimming in the FST and less time
in the open arm of the EPM test compared to the socially defeated Q31L +/- mice

The Disc1 gene has been implicated in several mental disorders such as schizophrenia[1]. The effect of environmental conditions of stress and its effects on the Disc1 gene have not been well elucidated. Research by Haque et. al. has begun unraveling the effects of chronic social defeat (CSD) as a model for chronic stress on two types of heterozygous mutations of the Disc1 gene; L100P+/- and Q31L +/-[6]. Homozygous L100P mutants show schizophrenic-type behaviours while homozygous Q31L mutants show depressive-type behaviours. The reason why the effects of CSD were measured on heterozygous Disc1 mutants is because their baseline behavioural phenotype is relatively normal, which allows the researchers to exclusively measure the effects of a stress paradigm on Disc1 gene mutant behavior[6]. The tasks used to measure CSD in the mutant mice included movement in a novel open field, latent inhibition, pre-pulse inhibition of the acoustic startle response, elevated plus maze (EPM), force swim test (FST), sucrose consumption (SC), and social interaction. The results of the study indicated that social defeat decreased horizontal motion as well as exploratory behaviours in the open field test, social interaction, preference for social novelty and the time spent in the open arms of the EPM test. A decrease in horizontal movement in the open field test, time in the open arms of the EPM and vertical activity associated with exploratory behaviours in the open field test are all animal models of anxiety. This is relevant because anxiety is often closely tied to mental disorders such as depression and schizophrenia[6]. While the paper by Haque et. al. did not look into a possible mechanism by which CSD might affect stress-related anxiety in Disc1 heterozygous mutants, they propose that the pathway could involve PDE4B, which is a protein that binds to Disc1 that regulates cAMP signaling[6][16]. Further research on the Disc1 gene could have potential long-run implications for understanding the mechanism by which social defeat effects stress modulation in humans.

Fig. 7- Summary of results from all nine tests for naive
and defeated L100P +/- and Q31L +/- mice [6]
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Social Deafferentation Hypothesis: A Coping Mechanism

The Social Deafferentation Hypothesis is based on literature, which characterizes the brain as a social brain in that it derives meaning by understanding other individuals’ emotions, actions, words, intentions or states of mind[7]. The hypothesis posits that individuals who experience high levels of social isolation will derive social meaning in their lives by conjuring auditory and visual hallucinations as a form of coping with their current condition[7]. Evidence for this hypothesis is reflected in first hand accounts of schizophrenic individuals who experience auditory hallucinations. Work by Nayani et. al. illustrate the intimacy that individuals experience with their “voices”[18]. In 40% of cases, individuals have indicated that their auditory hallucinations come from people whom they have previously known, and in those cases in which the auditory hallucinations are unfamiliar, they tend to become familiar over time[18]. In paranoid schizophrenia cases, individuals seek to derive meaning from other’s actions or intentions, which is usually interpreted as being threatening[5]. In both instances, individuals are seeking to socially connect with others in a deficient manner perhaps to make up for the loss of actual social contact due to social isolation

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