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1.
Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics?
Munawar, N, Ahsan, K, Muhammad, K, Ahmad, A, Anwar, MA, Shah, I, Al Ameri, AK, Al Mughairbi, F
International journal of molecular sciences. 2021;(14)
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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2.
Different Immune Signature in Youths Experiencing Antipsychotic-Induced Weight Gain Compared to Untreated Obese Patients.
Pisano, S, Catone, G, Coppola, G, Carotenuto, M, Iuliano, R, Tiano, C, Montesanto, AR, D'Esposito, V, Miraglia Del Giudice, E, Formisano, P, et al
Journal of child and adolescent psychopharmacology. 2017;(9):844-848
Abstract
OBJECTIVES To assess cytokine and chemokine levels in youth experiencing antipsychotic-induced weight gain (AIWG) compared to obese patients, hypothesizing a different "immune signature" between the two kinds of obesity. METHODS We compared a group of youth experiencing AIWG (N 19, mean age 159 months, mean body mass index [BMI] z-score 1.81) and an age-, gender-, and BMI-matched group of untreated obese patients (N 19, mean age 147 months, mean BMI z-score 2) for a wide range of cytokines and chemokines by using a multiplex ELISA test. RESULTS Platelet-derived growth factor (PDGF), interleukin (IL)1-β, IL4, IL8, IL9, IL12, IL 17, eotaxin, FGF, GMCSF, IP10, MIP1b, and vascular-endothelial growth factor (VEGF) were significantly lower in the AIWG group, whereas IL13 and RANTES were significantly higher. Controlling for age, sex, and BMI, PDGF, IL4, IL8, IL13, IL17, eotaxin, fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GMCSF), IP10, MIP1b, and VEGF remain significantly different. CONCLUSION A clearly different pattern of cytokines distinguishes the two kinds of obesity, suggesting a different immune signature. Interestingly, most of the cytokines and chemokines bearing proinflammatory effects resulted decreased in the AIWG group, whereas IL-13, which holds an immune-modulatory effect, resulted increased.
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3.
Vitamin B12 in Association with Antipsychotic Drugs Can Modulate the Expression of Pro-/Anti-Inflammatory Cytokines in Alzheimer Disease Patients.
Vakilian, A, Razavi-Nasab, SM, Ravari, A, Mirzaei, T, Moghadam-Ahmadi, A, Jalali, N, Bahramabadi, R, Rezayati, M, Yazdanpanah-Ravari, A, Bahmaniar, F, et al
Neuroimmunomodulation. 2017;(6):310-319
Abstract
INTRODUCTION Patients with Alzheimer disease (AD) suffer from psychotic symptoms including pain. The current antipsychotic drugs confer limited effectiveness, and hence new strategies are being designed to decrease pain in order to increase antipsychological effectiveness. Vitamin B12 is a safe supplementary drug to decrease pain. Additionally, cytokines participate in the pathogenesis of immune-related diseases such as AD. Thus, the main aim of this clinical trial study was to determine the effects of treatment with risperidone and quetiapine, as antipsychotic drugs, with and without vitamin B12 on the psychotic symptoms of AD patients and the expression of IL-6, IL-8, tumor growth factor (TGF)-β, tumor necrosis factor (TNF)-α, and endothelin (ET)-1). MATERIAL AND METHODS Serum levels of IL-6, IL-8, TGF-β, TNF-α, and ET-1 were evaluated in the following groups: healthy controls, nonpsychotic AD patients, psychotic AD patients, psychotic AD patients under treatment with risperidone, psychotic AD patients under treatment with risperidone plus vitamin B12, psychotic AD patients under treatment with quetiapine, and psychotic AD patients under treatment with quetiapine plus vitamin B12. RESULTS Treatment with antipsychotic drugs plus vitamin B12 led to a decreased expression of IL-8 and TNF-α and an increased expression of TGF-β. Vitamin B12 in association with quetiapine reduced the pain in psychotic AD patients. DISCUSSION Proinflammatory cytokines play important roles in the pathogenesis of psychosis in AD patients. Antipsychotic drugs plus vitamin B12 can reduce and induce the expression of proinflammatory and anti-inflammatory cytokines to improve psychotic symptoms in AD patients.
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4.
C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications.
Fernandes, BS, Steiner, J, Bernstein, HG, Dodd, S, Pasco, JA, Dean, OM, Nardin, P, Gonçalves, CA, Berk, M
Molecular psychiatry. 2016;(4):554-64
Abstract
The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.
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5.
Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia.
Montejo, ÁL, Arango, C, Bernardo, M, Carrasco, JL, Crespo-Facorro, B, Cruz, JJ, Del Pino, J, García Escudero, MA, García Rizo, C, González-Pinto, A, et al
Revista de psiquiatria y salud mental. 2016;(3):158-73
Abstract
INTRODUCTION Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination. METHODOLOGY An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV). RESULTS Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk.
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6.
The influence of typical and atypical neuroleptic drugs in the production of interleukin-2 and interferon-gamma in vitro.
Rudolf, S, Peters, M, Rothermundt, M, Arolt, V, Kirchner, H
Neuropsychobiology. 2002;(4):180-5
Abstract
Alterations of cytokine levels represent the most consistent finding from studies concerning the involvement of the immune system in the etiology of schizophrenia. These results have been discussed controversially due to the potential influence of drug treatment on cytokine production and on the experimental procedures used for cytokine measurement. In the present study, the influences of typical and atypical neuroleptic drugs (haloperidol and clozapine) as well as a tricyclic antidepressive drug (amitriptyline) on cytokine levels (IL-2 and IFN-gamma) were examined in vitro in a whole blood assay under various conditions of phytohemagglutinin (PHA) stimulation and drug incubation. Stimulation was enhanced by haloperidol and clozapine, but not by the antidepressant, meaning that the results of decreased cytokine levels seen in earlier studies in schizophrenic patients cannot be explained through drug influences alone. Furthermore, our findings allow us to conclude that, in contrast to the antidepressant drug, the typical and atypical neuroleptic drugs seem to influence the examined cytokine levels.