The Gordian knot of the immune-redox systems' interactions in psychosis.

During the last decades the attempt to enlighten the pathobiological substrate of psychosis, from merely focusing on neurotransmitters, has expanded into new areas like the immune and redox systems. Indeed, the inflammatory hypothesis concerning psychosis etiopathology has exponentially grown with findings reflecting dysfunction/aberration of the immune/redox systems' effector components namely cytokines, chemokines, CRP, complement system, antibodies, pro-/anti-oxidants, oxidative stress byproducts just to name a few. Yet, we still lie far from comprehending the underlying cellular mechanisms, their causality directions, and the moderating/mediating parameters affecting these systems; let alone the inter-systemic (between immune and redox) interactions. Findings from preclinical studies on the stress field have provided evidence indicative of multifaceted interactions among the immune and redox components so tightly intertwined as a Gordian knot. Interestingly the literature concerning the interactions between these same systems in the context of psychosis appears minimal (if not absent) and ambiguous. This review attempts to draw a frame of the immune-redox systems' interactions starting from basic research on the stress field and expanding on clinical studies with cohorts with psychosis, hoping to instigate new avenues of research.

Neuropsychological Profile of Hospitalized Patients Due to COVID-19: Clinical and Inflammatory Correlates.

OBJECTIVES: In the present study, we investigated the pattern of cognitive difficulties in hospitalized patients due to COVID-19 and its relation with the clinical features of the disease. METHOD: Forty hospitalized patients with COVID-19 [mean age: 46.98 years (SD = 9.30); mean years of education: 13.65 (SD = 2.07) and 40 sex-, age- and education-matched healthy controls completed a set of neuropsychological measures administered by telephone. Participants' premorbid intellectual skills and patients' anxiety and depressive symptoms were also evaluated. The association of COVID-19-related biomarkers [oxygen saturation (SpO2), C-reactive protein (CRP), D-dimer and ferritin levels] with neuropsychological performances was examined with a series of hierarchical multiple linear regression analyses, after controlling for demographic and clinical characteristics, psychological distress and premorbid intellectual skills. RESULTS: Patients performed worse than healthy participants on measures of verbal memory, attention and working memory. SpO2 levels were associated with patients' performance on verbal and working memory, whereas CRP levels were associated with performance on verbal memory, abstract reasoning and verbal fluency, after controlling for demographic and clinical characteristics. Ferritin levels predicted performance on the verbal fluency test, whereas D-dimer levels did not predict any of the neuropsychological measures. CONCLUSIONS: Cognitive difficulties in verbal memory, attention and working memory were noted in patients with COVID-19. Markers of hyperinflammation predicted patients' performance above and beyond demographic characteristics, duration of symptoms, length of hospitalization and psychological distress.

The immune-stress/endocrine-redox-metabolic nature of psychosis' etiopathology; focus on the intersystemic pathways interactions.

The evidence supporting the involvement of a number of systems in the neurobiological etiopathology of psychosis has recently grown exponentially. Indeed, the focus of research has changed from measuring solely neurotransmitters to estimating parameters from fields like immunity, stress/endocrine, redox, and metabolism. Yet, little is known regarding the exact role of each one of these fields on the formation of not only the brain neuropathological substrate in psychosis but also the associated general systemic pathology, in terms of causality directions. Research has shown deviations in the levels and/or function of basic effector molecules of the aforementioned fields namely cytokines, pro-/anti- oxidants, glucocorticoids, catecholamines, glucose, and lipids metabolites as well as kynurenines, in psychosis. Yet the evidence regarding their impact on neurotransmitters is minimal and the findings concerning these systems' interactions in the psychotic context are even more dispersed. The present review aims to draw holistically the frame of the hitherto known "players" in the field of psychosis' cellular pathobiology, with a particular focus on their in-between interactions.

Psychologically Traumatic Oxidative Stress; A Comprehensive Review of Redox Mechanisms and Related Inflammatory Implications.

The organism's energy requirements for homeostatic balance are covered by the redox mechanisms. Yet in case of psychologically traumatic stress, allostatic regulations activate both pro-oxidant and antioxidant molecules as well as respective components of the inflammatory system. Thus a new setpoint of dynamic interactions among redox elements is reached. Similarly, a multifaceted interplay between redox and inflammatory fields is activated with the mediation of major effector systems such as the immune system, Hypothalamic-Pituitary-Adrenal axis, kynurenine, and the glycaemic regulatory one. In case of sustained and/or intense traumatic stress the prophylactic antioxidant components are inadequate to provide the organism with neuroprotection finally culminating in Oxidative Stress and subsequently to cellular apoptosis. In parallel multiple inflammatory systems trigger and/or are triggered by the redox systems in tight fashion so that the causation sequence appears obscure. This exhaustive review aims at the comprehension of the interaction among components of the redox system as well as to the collection of disperse findings relative to the redox-inflammatory interplay in the context of traumatic stress so that new research strategies could be developed.

Psychologically traumatic stress inducing redox - inflammation interplay; which comes first?

Evidence suggests the involvement of redox and inflammation fields under conditions of psychological trauma. Factors from immunity, Hypothalamic-Adrenal-Pituitary axis, Kynurenine pathway, Dysglycemia, Glutamatergic systems as well as elements from redox mechanisms participate in a highly complex neurobiological process. Yet, little is known about their interplay. There is evidence suggesting a psychologically traumatic stress induced redox-originated inflammatory activation and vice versa. A holistic approach would suggest a parallel activation of the involved mechanisms with highly tight interdependency. The present report aims at collecting the evidence supporting either directionality of the involved mechanisms, finally suggesting a diagram depicting a synthesis of this interplay.

Oxidative Dysregulation in Early Life Stress and Posttraumatic Stress Disorder: A Comprehensive Review.

Traumatic stress may chronically affect master homeostatic systems at the crossroads of peripheral and central susceptibility pathways and lead to the biological embedment of trauma-related allostatic trajectories through neurobiological alterations even decades later. Lately, there has been an exponential knowledge growth concerning the effect of traumatic stress on oxidative components and redox-state homeostasis. This extensive review encompasses a detailed description of the oxidative cascade components along with their physiological and pathophysiological functions and a systematic presentation of both preclinical and clinical, genetic and epigenetic human findings on trauma-related oxidative stress (OXS), followed by a substantial synthesis of the involved oxidative cascades into specific and functional, trauma-related pathways. The bulk of the evidence suggests an imbalance of pro-/anti-oxidative mechanisms under conditions of traumatic stress, respectively leading to a systemic oxidative dysregulation accompanied by toxic oxidation byproducts. Yet, there is substantial heterogeneity in findings probably relative to confounding, trauma-related parameters, as well as to the equivocal directionality of not only the involved oxidative mechanisms but other homeostatic ones. Accordingly, we also discuss the trauma-related OXS findings within the broader spectrum of systemic interactions with other major influencing systems, such as inflammation, the hypothalamic-pituitary-adrenal axis, and the circadian system. We intend to demonstrate the inherent complexity of all the systems involved, but also put forth associated caveats in the implementation and interpretation of OXS findings in trauma-related research and promote their comprehension within a broader context.

"Which baby?": a qualitative study exploring the fantasies about the unborn baby among women with hyperemesis gravidarum.

This study aims to explore the conscious fantasies about the unborn baby among women experiencing hyperemesis gravidarum and identify possible clinical implications. Fourteen inpatient women with moderate to severe symptoms of hyperemesis gravidarum and between the 12 and 14 weeks gestation participated in semi-structured interviews. Analysis of the transcripts revealed escape and aggression fantasies about the baby, denial of fantasies in the categories tested (name, sex, external and internal characteristics of the baby), freezing of the maternal-fetus bond, and ambivalence toward the continuation of the pregnancy. Neither the severity of symptoms nor the stated quality of life mediated the results. These findings suggest that the discussion and reframing of fantasies can be proven helpful and relieving for the women facing any pregnancy complication. Toward achieving a multidisciplinary approach, the variable of fantasy should be considered among others.

Social cognition in the course of psychosis and its correlation with biomarkers in a male cohort.

INTRODUCTION: Patients diagnosed with schizophrenia display deficits in Theory of Mind (ToM) and Emotion Perception (EP) even before the appearance of full-blown symptomatology. METHODS: We evaluated ToM and EP in a male cohort consisting of 25 First Episode Psychosis (FEP) and 16 relapsed schizophrenic patients (CHRON) compared to 12 subjects in Ultra-high Risk (UHR) and 23 healthy controls (CTR). Furthermore, we measured the levels of Cortisol, Insulin like Growth Factor (IGF-1), TNF-a, TNF-b and several interleukins as potential biomarkers. RESULTS: Deficits in EP and ToM were found in FEP, CHRON patients and UHR subjects compared to CTR. The impairments in these two domains seem to follow different patterns in the course of psychosis. EP was more impaired in subjects with a longer history of symptomatology whereas there was no statistically significant difference regarding ToM. On the other hand IL-4 was the only biomarker correlated to ToM and EP scores in two different samples of our study. CONCLUSION: Social Cognition (SC) domains are impaired in patients with psychosis as well as in UHR subjects compared to healthy controls. There are differences in the progress of ToM and EP deficits in the course of psychosis. Interleukins as IL-4 could correlate to SC.

Evidence for Hypothalamus-Pituitary-Adrenal Axis and Immune Alterations at Prodrome of Psychosis in Males.

We aimed to investigate the inflammatory substrate in psychosis by evaluating both the Hypothalamus-Pituitary-Adrenal axis function and immune state at prodrome. This involved the recruitment of Ultra High Risk (UHR) of Psychosis subjects, Healthy Controls (HC) and patients with established Schizophrenia (CHRON). Serum cortisol at 3 different times throughout the day was measured. The Dexamethasone Suppression Test was performed plus 12 circulating cytokines were measured. The UHR subjects presented increased IL-4 levels compared with both the HC and CHRON patients. In contrast the UHR differed only from the CHRON group regarding the endocrine parameters. In conclusion, IL-4 appears to play a key role at prodrome.

Cytokines, cortisol and IGF-1 in first episode psychosis and ultra high risk males. Evidence for TNF-α, IFN-γ, ΤNF-ß, IL-4 deviation.

The aim of the study was to determine circulating cytokines, cortisol and Insulin-like Growth Factor (IGF)-1, known for their involvement in inflammation, in male patients with First Episode Psychosis (FEP) and subjects at Ultra High Risk (UHR) for Psychosis. The FEP group presented increased pro-inflammatory cytokines (TNF-α, IFN-γ, ΤNF-ß) as well as increased anti-inflammatory cytokine (IL-4) compared with Healthy Controls (HC). The UHR group showed increased IL-4 against HC. In contrast, none of the groups did show deviation from normality in either cortisol or IGF-1 levels. These preliminary findings support the cytokines' role in the inflammatory hypothesis in psychosis.

Evidence for increased immune mobilization in First Episode Psychosis compared with the prodromal stage in males.

The aim of the study was to gauge both the immune and neuroendocrine function in Ultra High Risk for psychosis (UHR) subjects and compare them with a cohort presenting with First Episode Psychosis (FEP). We recruited two groups, the first group consisted of 12 UHR males and the second of 25 males with FEP. We measured serum cortisol levels at 08:00, 12:00, 18:00 with their Area Under Curve with respect to the ground (AUCg) and the increase (AUCi) and we measured serum cytokines levels, Interleukin-1a, IL-1a, IL-2, IL-4,IL-5,IL-6,IL-8, IL-10,IL-12, IL-17a, Tumor Necrosis Factor-a (TNF-a), Interferon-γ (IFN-γ). Dexamethasone Suppression Test (DST) was also performed . The results suggest higher levels of both pro-inflammatory (TNF-a, IL-2, IL-12, IFN-γ) and anti-inflammatory (IL-10) cytokines in the FEP group compared with the UHR counterparts. Regarding the HPA axis function, the prodromal subjects showed a trend for higher AUCg and AUCi change/decrease cortisol levels. On the contrary, the DST results did not differ between the groups. No significant associations were demonstrated within each group among cytokines, cortisol and psychopathology. The findings favor a hypothesis of a relatively increased mobilization of both the pro- and anti-inflammatory cytokine networks, in FEP compared with that of UHR subjects.

Role of cortisol in patients at risk for psychosis mental state and psychopathological correlates: A systematic review.

During recent decades, much evidence has been accumulated concerning the neuroendocrine basis of schizophrenia. Recently, research has focused on stress hormones, with cortisol being the most widely researched, during the prodromal phase of psychosis. Thus, the present study aims to systematically review the evidence concerning the role of cortisol in patients at risk for psychosis mental state and its associations with psychopathological correlates. We systematically reviewed the published reports referring to both 'at clinical risk for psychosis' and 'at genetic risk for psychosis' mental state. Sixteen studies were identified. A trend towards increased cortisol levels in saliva emerged. Findings concerning cortisol levels in the blood were minimal and less consistent. The longitudinal studies, though with divergent results, hinted towards upregulation of cortisol secretion prior to psychotic conversion. Regarding cortisol's reactivity, evaluated through neuroendocrine, psychosocial and naturalistic stressors, the findings were minimal and divergent. The hypothesized relation of psychotic symptomatology with cortisol in subjects at risk for psychosis was not confirmed by the majority of the studies. On the contrary, the anxiety parameter and stress-intolerance index were both positively associated with cortisol. In conclusion, the published reports related to the evaluation of cortisol levels/function at prodrome are hitherto minimal. Although the evidence favors cortisol's participation in the pathophysiology of psychosis, the exact cause-effect sequence and the intertwining of cortisol with psychopathology are still unclear.

The role of cortisol in first episode of psychosis: a systematic review.

The stress diathesis hypothesis is currently one of the prevailing models of etiology of psychotic disorders. Cortisol is the most researched stress hormone; yet its role in first episode psychosis (FEP) was only recently investigated. The aim of the present study is to systematically review the evidence on the potential role of cortisol in FEP. Higher cortisol levels in blood samples have been consistently replicated, whereas saliva studies measuring baseline cortisol levels have exhibited divergent results. Moreover, longitudinal studies have revealed a cortisol upregulation in FEP with a subsequent decrease induced by antipsychotic treatment. The evidence suggests a role for cortisol in psychosis, although the association of cortisol with psychopathological symptoms is currently non-specific. Future research should focus on more pure diagnostic entities, clearly defined stages of the disorder and refined methods of hormonal measurement.

Neuroendocrine stimulatory tests of hypothalamus-pituitary-adrenal axis in psoriasis and correlative implications with psychopathological and immune parameters.

Psoriasis constitutes one of the most representative examples of psychosomatic disorders. The published work investigating the psychological parameters and the way they interact during the course of the disease is extensive, whereas only a few studies have focused on the neuroendocrine framework of psoriasis. In the present study, the objective was to investigate the neuroendocrine parameters of psoriasis and the way they interact with psychopathological and immune variables. Patients with psoriasis (n=24) and the same number of matched healthy controls underwent psychiatric evaluation with interviews and psychometric questionnaires. Both of the groups underwent the corticotropin-releasing hormone (CRH) test and the dexamethasone suppression test (DST) to investigate functional parameters of the hypothalamus-pituitary-adrenal (HPA) axis. The evaluation of immune variables included the estimation of the distribution of T-cell and natural killer lymphocytes. Levels of depressive and anxiety features were increased within subjects with psoriasis and they were significantly correlated with stressful life events and the extent of the disease. The adrenocorticotrophic hormone and cortisol levels increased after CRH infusion without significant differences between the two groups and the psoriatic subjects' cortisol suppression after DST was within normal range, though relatively blunted. No significant correlations were identified among neuroendocrine, psychopathological and immune parameters. No particular neuroendocrine profile has been identified among psoriatic patients and the hypothesized interaction with psychopathological and immune parameters was not replicated. Nevertheless, it is still premature to exclude the possibility that a subtle latent alteration of the HPA axis function might exist, in psoriasis, either stemming from the psychopathology or from the disease per se.

Stimulation of the hypothalamic-pituitary-adrenal axis with corticotropin releasing hormone in patients with psoriasis.

OBJECTIVE: Psychocutaneous diseases constitute a large proportion of psychosomatic disorders, with psoriasis being one of the most typical cases. Though alteration of Hypothalamic-Pituitary-Adrenal (HPA) axis function has been suggested as underlying several psychiatric disorders and psychosomatic diseases, there is little evidence of reduced response of the HPA axis in psoriasis after psychosocially induced laboratory stress. The aim of the study was to investigate any alteration of the neuroendocrine profile of psoriatic patients. DESIGN: The psoriatic patients (n=24) and the same number of matched controls underwent a CRH test which consisted of 100 microg h-CRH IV infusion and drawing of blood samples at 0 min and at 15, 30 and 60 min post h-CRH for measurement of plasma ACTH and cortisol concentration. RESULTS: Mean plasma ACTH and cortisol levels in both groups increased during the 60-min CRH test without significant difference. The total secretion of plasma ACTH and serum cortisol estimated as Area Under the Curve did not show significant difference between the groups either. CONCLUSIONS: Contrary to previous studies no particular neuroendocrine profile of HPA axis responsiveness was identified in psoriatic patients.