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1.
Targeting the microbiome-gut-brain axis for improving cognition in schizophrenia and major mood disorders: A narrative review.
Bioque, M, González-Rodríguez, A, Garcia-Rizo, C, Cobo, J, Monreal, JA, Usall, J, Soria, V, , , Labad, J
Progress in neuro-psychopharmacology & biological psychiatry. 2021;:110130
Abstract
Cognitive impairment has been consistently found to be a core feature of serious mental illnesses such as schizophrenia and major mood disorders (major depression and bipolar disorder). In recent years, a great effort has been made in elucidating the biological causes of cognitive deficits and the search for new biomarkers of cognition. Microbiome and gut-brain axis (MGB) hormones have been postulated to be potential biomarkers of cognition in serious mental illnesses. The main aim of this review was to synthesize current evidence on the association of microbiome and gut-brain hormones on cognitive processes in schizophrenia and major mood disorders and the association of MGB hormones with stress and the immune system. Our review underscores the role of the MGB axis on cognitive aspects of serious mental illnesses with the potential use of agents targeting the gut microbiota as cognitive enhancers. However, the current evidence for clinical trials focused on the MGB axis as cognitive enhancers in these clinical populations is scarce. Future clinical trials using probiotics, prebiotics, antibiotics, or faecal microbiota transplantation need to consider potential mechanistic pathways such as the HPA axis, the immune system, or gut-brain axis hormones involved in appetite control and energy homeostasis.
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2.
Antipsychotic-Induced Constipation: A Review of the Pathogenesis, Clinical Diagnosis, and Treatment.
Xu, Y, Amdanee, N, Zhang, X
CNS drugs. 2021;(12):1265-1274
Abstract
Antipsychotic-induced gastrointestinal hypomotility and, in particular, its manifestation of constipation are common adverse effects in patients with schizophrenia in clinical practice. Serious complications of antipsychotic-induced constipation include ileus, ischaemic bowel disease, colon perforation, aspiration pneumonia, and bacterial septicaemia, which can be life threatening if left untreated, especially in patients prescribed clozapine. The aim of this paper is to review the latest research on the epidemiology, clinical examination methods, pathophysiology, and treatment options and preventive measures for antipsychotic-induced constipation. While clinicians are normally aware of the overall side effects caused by antipsychotics, constipation is often an under-recognized condition despite its relatively high incidence and its impact on daily living. The incidence of constipation differs among individual antipsychotics, but more than 50% of patients prescribed antipsychotics suffer from constipation. Limited fluid intake, poor dietary habits, and a sedentary lifestyle can also worsen constipation. The mechanisms of antipsychotic-induced constipation may be antagonism of cholinergic, histaminergic, and serotonergic receptors, with both parent drug and metabolite(s) contributing to the effects on gastrointestinal motility. Numerous methods, mainly divided into scale evaluations and objective examinations, are applied to evaluate antipsychotic-induced constipation; however, objective examinations have a greater ability to identify cases of gastrointestinal hypomotility since there is often an under-reporting of symptoms in subjective reporting and scale evaluation due to a higher pain threshold, an inability to express pain sensations, and a lack of symptom awareness in these patients. Antipsychotic drug-induced constipation should be closely monitored in patients receiving these medications, with timely intervention to avoid serious gastrointestinal consequences. There is currently no consensus on the efficacy of laxatives in these patients. Further in-depth studies should explore the underlying mechanisms and devise optimal therapeutic approaches to minimize constipation during antipsychotic treatment.
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3.
Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options.
Correll, CU, Howes, OD
The Journal of clinical psychiatry. 2021;(5)
Abstract
Treatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.
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4.
Memantine in neurological disorders - schizophrenia and depression.
Czarnecka, K, Chuchmacz, J, Wójtowicz, P, Szymański, P
Journal of molecular medicine (Berlin, Germany). 2021;(3):327-334
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Abstract
Memantine is used in Alzheimer's disease treatment as a non-competitive modern-affinity strong voltage-dependent N-methyl-D-aspartate receptor antagonist. The fundamental role of these receptors is to bind glutamate: the main excitatory neurotransmitter in the brain, believed to play a crucial role in neuronal plasticity and learning mechanisms. Glutamate transmission plays an important role in all internal CNS structures and maintains the physiological state of the brain. Excessive glutamate transmission can lead to enlarged calcium ion current which may cause neurotoxicity; however, insufficient transmission can drastically alter the information flow in neurons and the brain, potentially causing schizophrenia-like symptoms by replacing lost information with completely new stimuli. Hence, it is possible that the modulation of NMDA activity may give rise to pathophysiological states. Available literature and clinical trials indicate that memantine is well tolerated by patients, with very few and light side effects. There is a belief that memantine may also benefit other conditions such as schizophrenia and depression.
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5.
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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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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7.
Therapeutic Potential of Carnosine and Its Derivatives in the Treatment of Human Diseases.
Chmielewska, K, Dzierzbicka, K, Inkielewicz-Stępniak, I, Przybyłowska, M
Chemical research in toxicology. 2020;(7):1561-1578
Abstract
Despite significant progress in the pathogenesis, diagnosis, treatment, and prevention of cancer and neurodegenerative diseases, their occurrence and mortality are still high around the world. The resistance of cancer cells to the drugs remains a significant problem in oncology today, while in the case of neuro-degenerative diseases, therapies reversing the process are still yet to be found. Furthermore, it is important to seek new chemotherapeutics reversing side effects of currently used drugs or helping them perform their function to inhibit progression of the disease. Carnosine, a dipeptide constisting of β-alanine and l-histidine, has a variety of functions to mention: antioxidant, antiglycation, and reducing the toxicity of metal ions. It has therefore been proposed to act as a therapeutic agent for many pathological states. The aim of this paper was to find if carnosine and its derivatives can be helpful in treating various diseases. Literature search presented in this review includes review and original papers found in SciFinder, PubMed, and Google Scholar. Searches were based on substantial keywords concerning therapeutic usage of carnosine and its derivatives in several diseases including neurodegenerative disorders and cancer. In this paper, we review articles and find that carnosine and its derivatives are potential therapeutic agents in many diseases including cancer, neurodegenerative diseases, diabetes, and schizophrenia. Carnosine and its derivatives can be used in treating neurodegenerative diseases, cancer, diabetes, or schizophrenia, although their usage is limited. Therefore, there's an urge to synthesize and analyze new substances, overcoming the limitation of carnosine itself.
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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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9.
Association between Serum Lipids and Antipsychotic Response in Schizophrenia.
Kim, DD, Barr, AM, Fredrikson, DH, Honer, WG, Procyshyn, RM
Current neuropharmacology. 2019;(9):852-860
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Abstract
Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled trials, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.
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10.
Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome.
Postolache, TT, Del Bosque-Plata, L, Jabbour, S, Vergare, M, Wu, R, Gragnoli, C
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2019;(3):186-203
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Abstract
Schizophrenia (SCZ) and major depressive disorder (MDD) in treatment-naive patients are associated with increased risk for type 2 diabetes (T2D) and metabolic syndrome (MetS). SCZ, MDD, T2D, and MetS are often comorbid and their comorbidity increases cardiovascular risk: Some risk genes are likely co-shared by them. For instance, transcription factor 7-like 2 (TCF7L2) and proteasome 26S subunit, non-ATPase 9 (PSMD9) are two genes independently reported as contributing to T2D and SCZ, and PSMD9 to MDD as well. However, there are scarce data on the shared genetic risk among SCZ, MDD, T2D, and/or MetS. Here, we briefly describe T2D, MetS, SCZ, and MDD and their genetic architecture. Next, we report separately about the comorbidity of SCZ and MDD with T2D and MetS, and their respective genetic overlap. We propose a novel hypothesis that genes of the prolactin (PRL)-pathway may be implicated in the comorbidity of these disorders. The inherited predisposition of patients with SCZ and MDD to psychoneuroendocrine dysfunction may confer increased risk of T2D and MetS. We illustrate a strategy to identify risk variants in each disorder and in their comorbid psychoneuroendocrine and mental-metabolic dysfunctions, advocating for studies of genetically homogeneous and phenotype-rich families. The results will guide future studies of the shared predisposition and molecular genetics of new homogeneous endophenotypes of SCZ, MDD, and metabolic impairment.