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1.
Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia.
Al-Nema, MY, Gaurav, A
Current topics in medicinal chemistry. 2020;(26):2404-2421
Abstract
Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.
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2.
Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant.
Lin, CH, Chen, YM, Lane, HY
Current drug targets. 2020;(6):610-615
Abstract
Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as "clozapineresistant", "ultra-treatment-resistant", or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials. Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia. This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.
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3.
Effects of Transcranial Direct Current Stimulation (tDCS) and Approach Bias Modification (ABM) training on food cravings in people taking antipsychotic medication.
Grycuk, L, Gordon, G, Gaughran, F, Campbell, IC, Schmidt, U
Trials. 2020;(1):245
Abstract
BACKGROUND Antipsychotic drug-induced weight gain puts individuals with schizophrenia at increased cardiometabolic risk. As a potential intervention for this problem, we describe the theoretical background and a protocol for a feasibility randomised controlled trial (RCT) of approach bias modification (ABM) training combined with real versus sham (placebo) transcranial direct current stimulation (tDCS). The primary aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of ABM and tDCS in this group of participants. Second, the study will assess the preliminary efficacy of ABM + tDCS in reducing food cravings in people who take antipsychotic medication. METHODS Thirty adults with a DSM-V diagnosis of schizophrenia or schizoaffective disorder treated with anti-psychotic medication will be randomly allocated to receive five sessions that will combine ABM and real or sham tDCS, in a parallel group design. In this feasibility study, a broad range of outcome variables will be examined. Measures will include food craving, psychopathology (e.g. symptoms of schizophrenia and depression), neuropsychological processes (such as attentional bias and impulsiveness), and the tolerability and acceptability of tDCS. The feasibility of conducting a large-scale RCT of ABM + tDCS and appropriateness of tDCS as a treatment for antipsychotic drug-induced weight gain will be evaluated by assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up). DISCUSSION The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. In addition, results from this study will provide a preliminary indication of the efficacy of ABM + tDCS treatment for antipsychotic drug-induced weight gain. TRIAL REGISTRATION ISRCTN Registry, ISRCTN13280178. Registered on 16 October 2018.
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4.
Nonmedical Interventions for Schizophrenia: A Review of Diet, Exercise, and Social Roles.
Helman, DS
Holistic nursing practice. 2020;(2):73-82
Abstract
Schizophrenia is a major mental illness with a disease course that is influenced by lifestyle. The risk-benefit ratio for alternative interventions is more favorable than for antipsychotics in long-term treatment. Dietary interventions may target autoimmune features, vitamin or mineral deficiencies, abnormal lipid metabolism, gluten sensitivity, or others. Examples of interventions involving diet, physical activity, or physical processes or social interventions including talk therapy exist in the literature. Notwithstanding, the general utility of these types of interventions remains inconclusive, awaiting long-term randomized trials. A perspective that separates the cause of the disease from its symptoms may be helpful in treatment planning and is warranted to distinguish between short-term and long-term recovery goals.
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5.
Trace elements in schizophrenia: a systematic review and meta-analysis of 39 studies (N = 5151 participants).
Saghazadeh, A, Mahmoudi, M, Shahrokhi, S, Mojarrad, M, Dastmardi, M, Mirbeyk, M, Rezaei, N
Nutrition reviews. 2020;(4):278-303
Abstract
CONTEXT The pathogenesis of schizophrenia appears to be multifaceted. OBJECTIVE The aim of this meta-analysis of studies that investigated blood and hair concentrations of trace elements in people diagnosed with schizophrenia was to determine whether levels of trace elements in patients with schizophrenia differ from those in healthy individuals. DATA SOURCES The PubMed, Scopus, and Web of Science databases were searched to January 2018. STUDY SELECTION Studies that compared concentrations of trace elements in patients with schizophrenia with those in healthy controls, in patients with schizophrenia under different treatment regimens, or in patients with schizophrenia at different stages of disease were included. DATA EXTRACTION Data on study and sample characteristics and measures of trace elements were extracted. RESULTS Thirty-nine studies with a total of 5151 participants were included. Meta-analysis of combined plasma and serum data showed higher levels of copper, lower levels of iron, and lower levels of zinc among patients with schizophrenia vs controls without schizophrenia. Subgroup analyses confirmed the following: higher levels of copper in plasma, in users of typical antipsychotic drugs, and in males; lower levels of zinc in serum, in patients in Asia, in drug-naive/drug-free patients, and in inpatients; lower levels of iron in serum, in patients in Asia, in drug-naive/drug-free patients, in patients on antipsychotic drugs, in inpatients, in patients with acute or newly diagnosed schizophrenia, in patients with chronic or previously diagnosed schizophrenia, and in males; and lower levels of manganese in plasma and in patients with chronic or previously diagnosed schizophrenia. CONCLUSIONS This meta-analysis provides evidence of an excess of copper, along with deficiencies of zinc, iron, and manganese, in patients with schizophrenia.
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6.
Review of Standard Laboratory Blood Parameters in Patients with Schizophrenia and Bipolar Disorder.
Memic-Serdarevic, A, Burnazovic-Ristic, L, Sulejmanpasic, G, Tahirovic, A, Valjevac, A, Lazovic, E
Medical archives (Sarajevo, Bosnia and Herzegovina). 2020;(5):374-380
Abstract
INTRODUCTION Symptomatic and etiopathologic heterogeneity of schizophrenia (SCH) and bipolar disorder (BD) can be adequately addressed using a dimensional approach to psychopathology, as well as interpreting physiological properties and markers as predictors of disease onset and relapse. Risk factors, genetic and environmental, are likely to modify the neurobiological processes characteristic of certain physiological processes that manifest to a greater degree of overlapping symptoms. One of the most common laboratory tests in psychiatric patients is a standard laboratory blood test. It gives us an insight into the general somatic condition of the patient. It assesses the ability to transport oxygen to tissues and carbon dioxide back to the lungs via erythrocytes (RBC) and hemoglobin (HGB) as their most important constituents, and is also an indicator of iron status and blood oxygenation. AIM: Schizophrenia (SCH) and bipolar disorder (BD) are psychiatric disorders whose complex etiology and pathogenesis are still far from known. A correlation between red blood cell abnormalities and these diseases has been recognized in some studies. One of the most common laboratory tests in psychiatric patients is a standard laboratory blood test. However, so far there is a small number of published papers that relate to the relationship between laboratory parameters of blood and the aim of this paper is to reveal more light in this subject. METHODS The research was done as an observational prospective clinical study that has evaluated different physiological and pathological parameters in patients with BD and SCH over a two-year period. A total of 159 patients with schizophrenia, 61 patients diagnosed with bipolar disorder and 82 healthy subjects participated in this study. RESULTS At baseline, BD compared to SCH patients had higher mean lymphocyte count (2,6±0,7 vs. 2,0±0,6x109; p=0,006) and haemoglobin concentration (146,8±12,2 vs. 140,2±14,7 g/L; p=0,03), and significantly lower red cell distribution width (13,6±2,2 vs. 14,7±1,8%; p=0,008). In both BD and SCH patients there was a significant number of patients with low red blood cells count and low haemoglobin concentration, and high MCH and MCHC at baseline and at 3 and 6 months of follow up. CONCLUSIONS The finding that SCH as well as BD differed from controls with respect to red blood cells, hemoglobin, lymphocytes, and average platelet count was consistent with previous findings and could be understood as a qualitative measure in the evaluation of this sample. The fact that no association with other parameters was found, as well as an association with the diagnosis, does not exclude that these associations can be found in larger samples.
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7.
From probiotics to psychobiotics - the gut-brain axis in psychiatric disorders.
Zagórska, A, Marcinkowska, M, Jamrozik, M, Wiśniowska, B, Paśko, P
Beneficial microbes. 2020;(8):717-732
Abstract
This review aims to present a comprehensive state-of-the-art analysis of the bidirectional crosstalk between gut microbiota and the central nervous system (CNS). The literature concerning the potential effects of gut microbiota on psychiatric disorders through neural pathways comprising the 'gut-brain axis' were gathered. In addition, the influence of probiotics and prebiotics and dairy-rich diets combined with the intake of probiotics and prebiotics on gut microbiota and the subsequent relationship with brain function was reviewed. However, a meta-analysis on the effectiveness of probiotic supplementation in psychiatric disorders is lacking. Therefore, a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from January 1969 to December 2019 was conducted. It led to the identification of a total of 844 research articles. Of these, a total of 23 studies met the meta-analysis criteria. Statistical analysis revealed that there was no significant difference in the symptoms of schizophrenia, stress, and anxiety between probiotic and placebo groups, post-intervention. Probiotic administration reduced depressive symptoms among patients with depression in a statistically significant manner (standardised mean difference (SMD) = -0.87; 95% confidence interval (95% confidence interval): -1.66, -0.99; P=0.03). Further evidence from larger and more rigorous studies with longer duration of probiotic administration, as well as well-defined populations, homogenous probiotic intervention and outcome measures, are needed to clarify the potential therapeutic effects of probiotics on psychiatric symptoms. Based on the current literature, it seems that not all probiotic-/prebiotic-/dairy-rich diet-based treatments exhibited a psychobiotic effect on the CNS. Among the parameters determining the success of the given treatment, the most significant were probiotic composition (multi-strain formulation), the quantity of ingested psychobiotics and the duration of the study.
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8.
Genetic polymorphisms of PIP5K2A and course of schizophrenia.
Poltavskaya, EG, Fedorenko, OY, Vyalova, NM, Kornetova, EG, Bokhan, NA, Loonen, AJM, Ivanova, SA
BMC medical genetics. 2020;(Suppl 1):171
Abstract
BACKGROUND Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia. METHODS In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). RESULTS PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04-2.54) and rs946961*CC (OR = 5.17, 95% CI: 1.20-22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR = 0.53, 95% CI: 0.29-0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one. CONCLUSIONS Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia.
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9.
Beneficial effects of konjac powder on lipid profile in schizophrenia with dyslipidemia: A randomized controlled trial.
Zhang, L, Han, Y, Zhao, Z, Liu, X, Xu, Y, Cui, G, Zhang, X, Zhang, R
Asia Pacific journal of clinical nutrition. 2020;(3):505-512
Abstract
BACKGROUND AND OBJECTIVES Konjac powder has the effect of improving blood lipids in the general population, but there is no research on schizophrenic patients who are susceptible to dyslipidemia. The aim of our study is to evaluate the effects of konjac powder on blood lipid, glucose levels, body weight, and blood pressure in schizophrenia inpatients with dyslipidemia. METHODS AND STUDY DESIGN After a two-week adaptation period, 76 people with schizophrenia were enrolled in a 30-day double-blind randomized controlled trial. The subjects in the experimental group were given a beverage containing konjac powder 30 minutes before each meal, whereas those in the control group were given a beverage containing resistant maltodextrin. RESULTS The lipid profile, plasma glucose, blood pressure, and body weight were measured at baseline and at the end of 30-day treatment. Fiftynine subjects completed the study. There was a substantial decrease in total serum cholesterol in the experimental group, but an increase in the control group. Likewise, apolipoprotein B decreased in the experimental group but increased in the control group. CONCLUSIONS We concluded that a diet supplemented with konjac powder may prevent the deterioration of dyslipidemia in people with schizophrenia, demonstrating its potential value in the treatment of metabolic disorders in schizophrenia as a new therapeutic method.
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10.
Altered Signaling in CB1R-5-HT2AR Heteromers in Olfactory Neuroepithelium Cells of Schizophrenia Patients is Modulated by Cannabis Use.
Guinart, D, Moreno, E, Galindo, L, Cuenca-Royo, A, Barrera-Conde, M, Pérez, EJ, Fernández-Avilés, C, Correll, CU, Canela, EI, Casadó, V, et al
Schizophrenia bulletin. 2020;(6):1547-1557
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Abstract
Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.