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Structural imaging studies have consistently found reduced gray matter thickness of the cerebral cortex in schizophrenia, a finding that is evident in first episode psychosis and may be progressive in some cases. Although genetic predisposition and medication effects may contribute to cortical thinning, we hypothesize that the cumulative effects of stress may represent an environmental factor impacting brain morphology in schizophrenia. We examined the relationship between allostatic load, an index of peripheral biomarkers representing the cumulative effects of stress, and cortical thickness. Allostatic load was calculated for 44 patients with schizophrenia spectrum disorders (SSD) and 33 normal controls (NC) based on 13 cardiovascular, neuroendocrine, immune, and metabolic measurements. Controlling for age, SSD had significantly elevated allostatic load as compared with NC (p=0.008). Controlling for age, whole brain average cortical thickness was lower in SSD patients compared to NC (p=0.008). However, once allostatic load was accounted for, the group difference in cortical thickness became marginal (p=0.058). Exploratory analyses on subcomponents of allostatic load suggested that elevated immune marker C-reactive protein, stress hormones, and cardiovascular indices within allostatic load were more strongly associated with reduced cortical thickness in SSD. In NC, only the association between immune marker C-reactive protein and cortical thickness was replicated. These results support the hypothesis that allostatic load may account for some of the gray matter deficits observed in schizophrenia. Among the allostatic indices, the inflammatory mechanism appears particularly relevant to cortical thickness in both schizophrenia patients and normal controls., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid-immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both p<.05). In controls, the rise in cortisol following the challenge was negatively correlated to the subsequent changes in IL-6 (r=-.461, p=.003), such that rise of cortisol immediately after stress predicts subsequently lower IL-6 levels. In contrast, this relationship was positive in schizophrenia patients (r=.379, p=.027). The trends were significantly different (Z=3.7, p=.0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Summary Background The etiopathophysiology of schizophrenia has long been linked to stress and the influence of stress is important in all stages of the illness. Previous examinations of perceived stress and acute stress responses may not capture this longitudinal stress pathophysiology. We hypothesized that the cumulative negative effects of stress, indexed by allostatic load (AL), would be elevated in schizophrenia, and that the AL paradigm would be relevant to our understanding of pathophysiology in schizophrenia. Methods We assessed allostatic load in 30 patients with schizophrenia (SZ; mean age = 33; 17 males) and 20 healthy controls (HC; mean age = 35; 12 males) using 13 cardiovascular, metabolic, neuroendocrine and immune biomarkers. Participants’ perceived stress over the past month, functional capacity and psychiatric symptoms were also measured. Results Controlling for age, SZ had significantly higher AL as compared to HC ( p = 0.007). Greater AL was present in both early course and chronic SZ, and was associated with reduced functional capacity ( p = 0.006) and more psychotic symptoms ( p = 0.048) in SZ. Current level of perceived stress was not significantly elevated in SZ or associated with AL in either group. Conclusions The higher AL found in SZ may reflect increased bodily “wear and tear”, possibly caused by more chronic stress exposure or maladaptive responses to stress over time, although additional research is required to differentiate these causes. The higher AL is similarly present in early and chronic SZ, suggesting primary maladaptive stress physiology rather than secondary effects from medications or chronic illness. [ABSTRACT FROM AUTHOR]