Simone Ciufolini

Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, Interleukin-6 and Tumour Necrosis Factor-α

Childhood trauma confers higher risk of adulthood physical and mental illness; however, the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis to establish whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta-analysis, including 18 studies encompassing a sample of 16 870 individuals for C-reactive protein (CRP), 15 studies including 3751 individuals for interleukin-6 (IL-6) and 10 studies including 881 individuals for tumour necrosis factor-α (TNF-α). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher’s z=0.10, 95% confidence interval (CI)=0.05–0.14), IL-6 (z=0.08, 95% CI=0.03–0.14) and TNF-α (z=0.23, 95% CI=0.14–0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta-regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-α. Age, body mass index (BMI) and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma.

Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First Episode Psychosis

Background: Cortisol and inflammatory markers have been increasingly reported as abnormal at psychosis onset. The main aim of our study was to investigate the ability of these biomarkers to predict treatment response at 12 weeks follow-up in first episode psychosis. Methods: In a longitudinal study, we collected saliva and blood samples in 68 first episode psychosis patients (and 57 controls) at baseline and assessed response to clinician-led antipsychotic treatment after 12 weeks. Moreover, we repeated biological measurements in 39 patients at the same time we assessed the response. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ (IFN-γ) levels were analyzed from serum samples. Patients were divided into Non-Responders (n = 38) and Responders (n = 30) according to the Remission symptom criteria of the Schizophrenia Working Group Consensus. Results: At first onset, Non-Responders had markedly lower CAR (d = 0.6, P = .03) and higher IL-6 and IFN-γ levels (respectively, d = 1.0, P = .003 and d = 0.9, P = .02) when compared with Responders. After 12 weeks, Non-Responders show persistent lower CAR (P = .01), and higher IL-6 (P = .04) and IFN-γ (P = .05) when compared with Responders. Comparison with controls show that these abnormalities are present in both patients groups, but are more evident in Non-Responders. Conclusions: Cortisol and inflammatory biomarkers at the onset of psychosis should be considered as possible predictors of treatment response, as well as potential targets for the development of novel therapeutic agents.

Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?

RationaleCurrent psychotropic medications have been shown to modulate immune activation. However, the effects of individual psychotropic agents on the immune system and how these might contribute to their efficacy remain largely unclear.ObjectiveThis paper aims to review previous literature on the effects of antidepressants and antipsychotics on the immune system, with a systematic review of in vitro findings, and discuss the relevance of these effects for the response to treatment and future drug development.ResultsInflammatory markers have been associated with fluctuations in clinical status and with treatment response both in depression and psychosis. The in vitro literature on antidepressants shows that some antidepressants, such as clomipramine and fluoxetine, more consistently decrease pro-inflammatory cytokines (interleukin (IL)-6, interferon (IFN)-γ, tumour necrosis factor (TNF)-α), whilst others (mirtazapine and venlafaxine) tend to increase their levels. However, any overall conclusion is challenged by several inconsistent findings, which appear partly dependent on different methodological approaches used. The in vitro studies on antipsychotics are even less clear-cut showing pro- and anti-inflammatory activity for the same antipsychotic agent (haloperidol, clozapine, risperidone) across different studies. We also noted inconsistencies between in vivo and in vitro literature, which could partly be attributed to the interaction in vivo with various biological systems or lifestyle factors that can modulate the immune system.ConclusionsInflammatory markers seem to hold potential for developing more individualised treatment strategies in the future. In this context, further research disentangling the differential immunomodulatory effects of different drugs could be used for tailoring treatment to specific individuals, according to their immune endophenotypes.

HPA axis response to social stress is attenuated in schizophrenia but normal in depression: Evidence from a meta-analysis of existing studies

We conducted a meta-analysis to investigate the HPA axis response to social stress in studies that used the Trier Social Stress Test (TSST), or comparable distressing paradigms, in individuals with either depression or schizophrenia. Sample size-adjusted effect sizes (Hedges g statistic) were calculated to estimate the HPA axis stress response to social stress. We used a meta-regression model to take into account the moderating effect of the baseline cortisol level. Participants with depression show an activation pattern to social stress similar to that of healthy controls. Despite a normal cortisol production rate, individuals with schizophrenia have lower cortisol levels than controls both in anticipation and after exposure to social stress. Participants with depression and higher cortisol levels before the task have an increased cortisol production and reached higher cortisol levels during the task. This may be explained by the presence of an impaired negative feedback. The activation pattern present in schizophrenia may explain the reduced ability to appropriately contextualize past experiences shown by individuals with psychosis in social stressful situation.

Inflammation and metabolic changes in first episode psychosis: Preliminary results from a longitudinal study

Metabolic abnormalities are commonly observed in patients with psychosis, and may confer greater risk of developing cardiovascular disease later in life. Such abnormalities are associated with inflammation in the general population, and there is increasing evidence for elevated inflammation in patients with first episode psychosis (FEP). The aim of this preliminary study is to examine the effect of changes in inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), on metabolic changes in a three-month longitudinal study in a FEP sample. Fifty-three FEP patients from in- and out-patient services in South London, England, were included in this longitudinal study. Social and clinical data were collected, and fasting blood samples and anthropometric measurements (weight, Body Mass Index (BMI), lipid profile and gluco-metabolic parameters) were obtained at baseline and at three-month follow-up. Correlation analyses showed that those with increases in hsCRP over the three-month period also had increases in triglyceride levels (r=0.49, p=0.02). No association was observed with other lipid profile, or gluco-metabolic parameters, across the whole sample. Increases in weight and BMI were also associated with increases in triglyceride levels (r=0.33, p=0.02; and r=0.31, p=0.03, respectively); however, a multiple linear regression analysis found that the effects of inflammation on triglycerides were independent from the effect of changes in weight, and from the baseline inflammatory state. Our preliminary findings suggest that those patients experiencing greater increases in inflammation early on in the course of their illness may be at greater risk of developing short-term metabolic abnormalities, in particular dyslipidaemia, independent of weight-gain. Future work should investigate the use of inflammatory markers to identify patients in greater need of physical health interventions.

Self esteem and self agency in first episode psychosis: Ethnic variation and relationship with clinical presentation

The impact of self esteem and Locus of Control (LoC) on clinical presentation across different ethnic groups of patients at their first psychotic episode (FEP) remains unknown. We explored these constructs in 257 FEP patients (Black n=95; White British n=119) and 341 controls (Black n=70; White British n=226), and examined their relationship with symptom dimensions and pathways to care. FEP patients presented lower self-esteem and a more external LoC than controls. Lower self esteem was associated with a specific symptoms profile (more manic and less negative symptoms), and with factors predictive of poorer outcome (longer duration of untreated psychosis (DUP) and compulsory mode of admission). A more external LoC was associated with more negative symptoms and an insidious onset. When we explored these constructs across different ethnic groups, we found that Black patients had significantly higher self esteem than White British. This was again associated with specific symptom profiles. While British patients with lower self esteem were more likely to report delusions, hallucinations and negative symptoms, Black patients with a lower self esteem showed less disorganization symptoms. These findings suggest that self esteem and LoC may represent one way in which social experiences and contexts differentially influence vulnerable individuals along the pathway to psychosis.

Cortical thickness correlates of minor neurological signs in patients with first episode psychosis

Neurological soft signs (NSS) are subtle abnormalities of motor and sensory function that are present in the absence of localized brain pathological lesions. In psychoses they have been consistently associated with a distinct pattern of cortical and subcortical brain structural alterations at the level of the heteromodal cortex and basal ganglia. However, a more specific and accurate evaluation of the cytoarchitecture of the cortical mantle could further advance our understanding of the neurobiological substrate of psychosis. We investigated the relationship between brain structure and NSS in a sample of 66 patients at their first episode of psychosis. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and Freesurfer to explore cortical thickness and surface area. Higher rates of NSS were associated with a reduction of cortical thickness in the precentral and postcentral gyri, inferior-parietal, superior temporal, and fusiform gyri. Higher rates of NSS were also associated with smaller surface areas of superior temporal gyrus and frontal regions (including middle frontal, superior and orbito-frontal gyri). Finally, more sensory integration signs were also associated with larger surface area of the latero-occipital region. We conclude that the presence of NSS in psychosis is associated with distinct but widespread changes in cortical thickness and surface area, in areas crucial for sensory-motor integration and for the fluid execution of movement. Studying these morphological correlates with advanced neuroimaging techniques can continue to improve our knowledge on the neurobiological substrate of these important functional correlates of psychosis.

Cortisol awakening response is decreased in patients with first-episode psychosis and increased in healthy controls with a history of severe childhood abuse

BACKGROUND Childhood abuse is highly prevalent in psychosis patients, but whether/how it affects hypothalamic-pituitary-adrenal (HPA) axis at the onset of psychosis remains unclear. We aimed to investigate the effects of severity of childhood abuse on HPA axis activity, in first-episode psychosis (FEP) and healthy controls. METHODS We recruited 169 FEP patients and 133 controls with different degrees of childhood physical and sexual abuse (i.e. no abuse exposure, non-severe abuse exposure, and severe abuse exposure). Saliva samples were collected to measure cortisol awakening response with respect to ground (CARg), increase (CARi) and diurnal (CDD) cortisol levels. Two-way ANOVA analyses were conducted to test the relationships between severity of childhood abuse and psychosis on cortisol levels in individuals with psychosis and healthy controls with and without childhood abuse history. RESULTS A statistically significant interaction between childhood abuse and psychosis on CARg was found (F(2,262) = 4.60, p = 0.011, ω2 = 0.42). Overall, controls showed a U-shaped relationship between abuse exposure and CARg, while patients showed an inverted U-shaped relationship. CARg values were markedly different between patients and controls with either no abuse history or exposure to severe childhood abuse. No significant differences were found when looking at CARi and CDD. CONCLUSIONS Our results show a divergent effect of severe childhood abuse on HPA axis activity in patients with first-episode psychosis and in controls. In the presence of exposure to severe childhood abuse, a blunted CARg and a less reactive HPA axis may represent one of the biological mechanisms involved in the development of psychosis.

O8.7. COGNITIVE SUBTYPES IN FIRST-EPISODE PSYCHOSIS AND ASSOCIATION TO TREATMENT RESPONSE

Abstract Background Psychotic disorders are characterized by large heterogeneity in clinical presentation, response to treatment and cognitive functioning. Indeed, there is evidence of the presence of cognitive subgroups of patients across affective and non-affective psychosis. However, very little is known about these subgroups in first episode psychosis (FEP) and whether they can be informative about course of illness, particularly response to treatment. The aim of this study is to investigate the number and the pattern of cognitive clusters in FEP, their external validity and association with treatment response at 12-week and 1-year follow up. Methods The sample was composed by a total of 212 participants including 105 FEP patients from the South London and Maudsley Foundation Trust and 107 Healthy Controls (HC). All participants underwent a comprehensive clinical and neurocognitive battery. Z-score [mean=0, and standard deviation (SD)=1] were created for the whole sample based on the neurocognitive performance of the HCs. Treatment response at 12-week and 1-year follow-up was used to explore potential utility of subtypes in predicting response to treatment. Hierarchical cluster analysis was carried out to determine the number of cognitive clusters in FEP patients. A series of analyses of variance were carried out to determine if FEP clusters differed among each other in relation to demographic and clinical characteristics, level of functioning and from the HC sample in term of cognitive performance. Logistic regression was used to explore whether cognitive clustering was predictive of treatment response at 12-week and 1-year FU. Results Four cognitive clusters emerged: one with near normal cognition (42.9% of the FEP patients) with a general cognitive score of z=-0.20, one with selected cognitive deficits (14.3%) in the domains of verbal memory, processing speed and executive functions (general cognitive score of z=-0.55); and two severe deficit clusters consisting in one cluster with severe deficits (33.3%; general score of z=-1.48) and the other with a deeply compromised cognitive ability (9.55%; general cognitive score of z=-2.34). There were no significant differences between clusters in terms of clinical features at baseline (including diagnosis, positive and negative symptoms, medication), apart from the level of functioning that was significantly lower in the severely compromised cluster compared to the near normal cognition cluster. It emerged that majority (about 68%) of the patients from the near normal cognition cluster were responsive to treatment, whilst the majority of the selective and severely impaired clusters did not respond to treatment at 12-week follow-up. There were no significant results with regard to treatment response at 1-year FU. Discussion Distinct patterns of cognitive impairments exist within FEP that might be characterized by different response to treatment. Clinical presentation at the onset of the illness is not useful in predicting response to treatment later on in the course of the illness, while cognitive functioning might be a more valid indicator. Cognitive stratification could represent a promising way forward to elucidate pathophysiology of psychosis and to provide tailored interventions.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project

BACKGROUND Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.