Although research on levels of inflammatory plasma analytes in FEP subjects has been more prolific, it is also more inconsistent. A recent systematic review aggregated 59 studies of cytokine levels in early psychosis subjects, reporting evidence for significantly higher levels of circulating cytokines, IL-6, IL-1b, IL-2, IL-4, IL-10, TNF-α, and IL-8, in FEP as compared to HC groups. However, these results were not consistent across studies, with additional evidence from several studies demonstrating these findings only in drug naive subjects, no significant differences or suppression of analytes in FEP compared to HC subjects . As will be discussed, the effect of antipsychotic medication on inflammatory analytes is an important variable that has been inconsistently examined in current inflammatory research. Additionally, there have been few studies investigating levels of chemokines between FEP and HC subjects, with only one study examining MCP-1 in FEP subjects . Martínez-Cengotitabengoa et al. examined the association between MCP-1 and cognition in FEP subjects, reporting that MCP-1 was strongly associated with learning and memory, consistent with findings that MCP-1 is associated with cognitive deficits in Alzheimer disease and HIV dementia . More research is needed to explore the role of chemokines in early psychosis, particularly if these analytes are associated with cognitive decline and other relevant impairments in psychotic illness. More consistently, levels of BDNF have been reported to be significantly reduced in drug naïve FEP subjects, as compared to HC subjects . Importantly, Toll and Mane discuss that studies reporting reductions in FEP levels of BDNF compared to HC subjects have been predominantly conducted in drug-naïve FEP patients as compared to studies reporting no alterations in FEP levels of BDNF compared to HC subjects have been conducted in medicated patients. These results are consistent with previous meta-analyses in drug-naïve schizophrenia groups ,gardening rack as well as subsequent studies, which additionally report that levels of BDNF are generally reduced in drugnaïve FEP patients and appear to be associated with learning capacity and cognition ; however, reductions in BDNF have not been reported to be associated with psychotic symptom severity nor predictive of conversion to psychosis .
Despite inconsistent findings, several studies have demonstrated the clinical relevance of inflammatory plasma analytes in psychosis groups, through successful development of blood based protein biomarker multiplexed immuno assays that either discriminate individuals with a psychotic disorder from HC subjects or reliably predict which CHR individuals will go on to develop a psychotic disorder. In unmedicated FEP subjects, Schwarz et al. identified inflammatory, oxidative stress, and HPA signaling serum proteins that were uniquely altered in FEP subjects. Chan et al. established a biomarker panel with high discriminatory power to differentiate CHR individuals who would later be diagnosed with schizophrenia versus a diagnosis of bipolar disorder.Associations between inflammatory plasma analytes, psychotic symptoms severity, and functioning has been well studied in patients with chronic psychosis , but less extensively in FEP and CHR subjects. In schizophrenia groups, higher levels of pro-inflammatory cytokines TNF-α and IL-6 have been associated with higher levels of depressive symptoms, greater physical comorbidities, such as arthritis, reduced executive functioning, and lower self-rated mental well-being, suggesting that these markers are clinically relevant . Similarly, plasma levels of chemokines MCP-1, MIP-1β, Eotaxin-1, and MDC have been observed to not only be higher in patients with schizophrenia compared to healthy controls, but also significantly associated with increased levels of sub-clinical depressive symptoms, worse self-rated mental well-being, and greater overall severity of typically mild medical illnesses .In a sample of individuals with chronic schizophrenia subjects, Dennison, McKernan, Cryan, and Dinan provide evidence that individuals with a history of childhood trauma show significantly higher levels of TNF-a and IL-6 as compared to subjects without a history of trauma and healthy controls. In fact, both Dennison et al. and Di Nicola et al. demonstrated that levels of TNF-a were correlated with history of childhood trauma, specifically severity of the trauma in psychosis subjects.
Hepgul et al. , reports that levels of CRP were significantly higher in first episode psychosis subjects with a history of childhood trauma as compared to those without a history of childhood trauma and healthy controls. Chase et al. demonstrated that childhood trauma, through its effects on IL6, may be a risk factor for schizophrenia. This is consistent with the meta-analysis conducted by Baumeister, Akhtar, Ciufolini, Pariante, and Mondelli , demonstrating that CRP, IL-6, and TNF-a were markedly elevated in individuals with a history of childhood trauma versus those without. Finally, Mondelli et al. conducted research on cortisol awakening response in first episode psychosis and established that history of childhood sexual trauma is associated with blunted cortisol awakening response. Authors purport that this finding helps to explain the association between HPA-axis abnormalities and excess psychological stress in first episode psychosis subjects. Importantly, no studies to our knowledge have sought to examine the relationship between childhood trauma, inflammation, and clinical outcomes in CHR subjects. However, results from the North American Prodrome Longitudinal Study 2 have established several important findings regarding the relationship between childhood trauma and inflammation independently on clinical outcomes in CHR subjects. Firstly, Addington et al. evaluated the relationship between childhood trauma and clinical outcomes in CHR subjects. It was demonstrated that individuals at CHR report significantly more trauma and bullying than healthy controls. Further, those CHR subjects who experienced past trauma and bullying are more likely to have increased levels of depression and anxiety and a poorer sense of self. Importantly, higher levels of total childhood trauma were demonstrated to be associated with lower global role functioning . Second, Perkins et al. identified a multiplex blood assay that reliably distinguished participants at clinical high risk for psychosis from unaffected comparison subjects and predicted which CHR subjects are likely to transition to an acute psychotic disorder, confirming that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis .
The classifier included 15 analytes , demonstrating that unique profiles of inflammatory plasma analytes can be used to differentiate between patient and control groups. Finally, Walker et al. demonstrated evidence of heightened cortisol secretion in CHR individuals also indicating nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. Thus, adding to accumulating evidence regarding role of HPA activity in prediction of conversion to psychosis. However, despite these relevant discoveries, it has yet to be determined whether inflammation may serve as a biological mediator between childhood trauma and CHR clinical outcomes . A robust body of literature supports the hypothesis that exposure to early life stress, such as childhood trauma, may uncover genetic and epigenetic vulnerabilities that influence neurobiological responses to stress, including activation of the HPA-axis and associated immune system response. Further,vertical farming equipment individuals diagnosed with psychosis have a higher prevalence of exposure to childhood trauma, as well as evidence of inflammatory dysregulation. It is therefore reasonable to suggest that experience of maltreatment in childhood may lead to changes in neurobiological response to stress, as measured by markers of inflammation, and that this response is associated with the onset of various mental illnesses in adulthood, including psychosis. However, to our knowledge, no studies to date have evaluated the relationships between childhood trauma, inflammation, and clinical outcomes in individuals at clinical high risk for psychosis. Thus, the research question that guided this study is as follows: Is a history of childhood trauma linked to a pro-inflammatory phenotype in individuals at clinical high risk for psychosis?Exploratory Factor Analysis was used to explore whether highly correlated networks of inflammatory markers could be identified from the 117 analytes in the present study. EFA was chosen over Confirmatory Factor Analysis , as there is no defined theory regarding the number of factors or which factors theories might best fit an a-priori model of inflammatory networks. In order to limit the potential subjectiveness of EFA, we completed a systematic application of theoretical principles to latent variables, factor reduction, and construction . Firstly, the data was analyzed to determine suitability for factor analysis. A correlation matrix will be used to display the relationships between variables for inspection of correlation coefficients over 0.3. Hair J, Anderson RE, Tatham RL, and WC. categorized these loadings using another rule of thumb as ±0.30=minimal, ±0.40=important, and ±.50=practically significant. If no correlations go beyond 0.30, then factor analysis will be reconsidered, only inflammatory markers known to be associated with childhood trauma from existing research will be used in subsequent analyses. Kaiser-Meyer-Olkin Measure of Sampling Adequacy and Bartlett’s Test of Sphericity was used to assess the suitability of the respondent data for factor analysis. The KMO index is recommended when the cases to variable ratio is less than 1:5. The KMO index ranges from 0 to 1, with 0.50 considered suitable for factor analysis . Further, the Bartlett’s Test of Sphericity should be significant for factor analysis to be suitable to utilize .
If the data is not suitable for factorability analyses, EFA will stop after this step and apriori identified analytes, including Perkins et al. 15-Analyte Index will be used in subsequent correlation and mediation analyses. Otherwise, principal components analysis will be used to extract factors as no priori theory or model exists to guide this analysis . Thirdly, multiple extraction techniques will be used for factor extraction including: Kaiser’s criteria for eigenvalue’s > 1 , the Scree plot test , and parallel analysis . Each of these tests will be performed and extracted factors evaluated to determine the most consistent and parsimonious number of factors. Fourthly, factor rotation will be used in order to maximize high item loadings and minimize low item loadings, therefore producing a more interpretable and simplified solution . Although there are two common rotation techniques: orthogonal rotation and oblique rotation, oblique rotation will be used in order to account for factor correlations, which is more accurate for research involving human behaviors and preferred when data does not meet priori assumptions. Finally, factors will be labeled. The labelling of factors is a subjective, theoretical, and inductive process . Factors will be operationalized and descriptively labelled according to constructs that reflect theoretical concepts in inflammatory research.Mediators can be defined as mechanisms through which one variable might achieve its effects. The 3-step Baron and Kenny mediation analysis was conducted to determine if the mediator is caused by the initial IV and is a cause of the DV , the initial IV loses its significance once the mediator is included in the model. More explicitly, first, simple linear regression was used to confirm the relationship between the independent variable, total childhood trauma, and the dependent variable, psychosis risk symptom severity OR functioning. Second, simple linear regression was used to confirm the relationship of childhood trauma and inflammatory analytes defined in Hypothesis 2a and 3b. Third, a final linear regression was used to confirm the significance of the relationship between the inflammatory analytes and psychosis risk symptom severity, or functioning in the presence of childhood trauma, as well as confirm the insignificance or the relationship between the childhood trauma, psychosis risk symptom severity , in the presence of the mediator . Significant associations from hypotheses 3a and 3b will be used to determine the most reasonable clinical outcomes to be used as dependent variables and inflammatory analytes to be used as mediators in subsequent models.This study sought to examine the associations between childhood trauma, psychosis risk symptoms, functioning, and inflammatory analytes in a sample of 67 CHR subjects and 34 UCs, thus contributing to a growing body of literature examining the effect of early life adversity on later life outcomes in individuals at risk for psychosis and identifying associated biological mechanisms. More specifically, this study sought to examine whether inflammation mediates the relationship between childhood trauma and clinical outcomes in individuals at risk for psychosis. This is one of few studies to explore whether inflammatory analytes mediate the relationship between childhood trauma and psychosis risk symptoms or functioning in CHR subjects, providing important implications for clinical intervention in youth at risk for psychosis by helping to uncover biological mechanisms for therapeutic intervention. However, this is the first study to evaluate this hypothesis using an enhanced sample of CHR subjects.