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1.
The phenolic interactome and gut microbiota: opportunities and challenges in developing applications for schizophrenia and autism.
Jaskiw, GE, Obrenovich, ME, Donskey, CJ
Psychopharmacology. 2019;(5):1471-1489
Abstract
Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges. Some SPMs have multiple structural isomers and most have conjugates. Without specialized approaches, SPMs can be incorrectly assigned or inaccurately quantified. In addition, SPM levels can be affected by dietary polyphenol or protein consumption and by various medications and diseases. Nonetheless, heterotypical excretion of various SPMs in association with schizophrenia or autism continues to be reported in independent samples. Recent studies in human cerebrospinal fluid demonstrate the presence of many SPMs A large number of these are bioactive in experimental models. Whether such mechanisms are relevant to the human brain in health or disease is not known. Systematic metabolomic and microbiome studies of well-characterized populations, an appreciation of multiple confounds, and implementation of standardized approaches across platforms and sites are needed to delineate the potential utility of the phenolic interactome in neuropsychiatry.
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2.
Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities.
Krogmann, A, Peters, L, von Hardenberg, L, Bödeker, K, Nöhles, VB, Correll, CU
CNS spectrums. 2019;(S1):38-69
Abstract
Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine's efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.
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3.
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.
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4.
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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Principi di farmacodinamica e farmacocinetica nello switch tra antipsicotici: focus su cariprazina.
Fagiolini, A, Bolognesi, S, Goracci, A, Beccarini Crescenzi, B, Cuomo, A
Rivista di psichiatria. 2019;(6):1-6
Abstract
Cariprazina {RGH-188; trans-N- [4- [2- [4- (2,3-diclorofenil) piperazin-1-il] etil] cicloesil] -N_, N_-dimetilurea cloridrato} è un antipsicotico atipico di nuova generazione, con un originale profilo farmacodinamico e farmacocinetico. Cariprazina ha due metaboliti attivi, uno dei quali ha un'emivita di 1-3 settimane, che è la più lunga di qualsiasi antipsicotico atipico, con emivita effettiva funzionale totale (cariprazina più due metaboliti) di 7 giorni. Il farmaco mostra un'affinità che è circa 10 volte più alta per i recettori D3 che per D2 (rispettivamente pKi 10,07 e 9,31). L'affinità per D3 è superiore all'affinità della stessa dopamina. Cariprazina mostra inoltre un'elevata affinità per i recettori 5-HT2B (pKi 9,24), con antagonismo puro. Cariprazina è un agonista parziale e ha un'affinità significativa, ma inferiore all'affinità per D3, sui recettori 5-HT1A (pKi 8,59). Agendo su D3 e 5-HT1, cariprazina migliora i sintomi negativi, l'anedonia e i deficit cognitivi. L'affinità per i recettori 5-HT2A (pKi 7,73), H1 (pKi 7,63) e 5-HT2C (pKi 6,87) è inferiore, così come minori sono le affinità per i recettori adrenergici, istaminergici e colinergici, recettori che sono spesso responsabili di effetti collaterali. Grazie al profilo di tollerabilità (sicurezza cardiovascolare, bassa probabilità di dare sedazione e iperprolattinemia, basso rischio metabolico), insieme alla sua peculiare efficacia sui sintomi negativi e alla sua lunga emivita, che spesso migliora la scarsa aderenza, cariprazina è un candidato valido per il passaggio da un antipsicotico inefficace (o parzialmente efficace, con particolare riferimento ai sintomi negativi), poco tollerato, o assunto con una scarsa aderenza. Questo articolo esamina le caratteristiche farmacocinetiche e farmacodinamiche di cariprazina e discute le loro implicazioni in termini di identificazione dei pazienti che possano beneficiare di un passaggio a cariprazina, e della migliore strategia per completare lo switch con successo.
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An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis.
Çakici, N, van Beveren, NJM, Judge-Hundal, G, Koola, MM, Sommer, IEC
Psychological medicine. 2019;(14):2307-2319
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Abstract
BACKGROUND Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). METHODS PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. RESULTS Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. CONCLUSIONS Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.
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Pharmacotherapy for schizophrenia in postmenopausal women.
González-Rodríguez, A, Seeman, MV
Expert opinion on pharmacotherapy. 2018;(8):809-821
Abstract
INTRODUCTION Reduced estrogen levels at menopause mean a loss of the neuroprotection that is conferred, from puberty until menopause, on women with schizophrenia. The postmenopausal stage of schizophrenia requires therapeutic attention because women with this diagnosis almost invariably experience increased symptoms and increased side effects at this time. So far, few targeted therapies have been successfully developed. AREAS COVERED This non-systematic, narrative review is based on the relevant published literature indexed in PubMed. A digital search was combined with a manual check of references from studies in the field of gender differences, menopause and schizophrenia. Aside from the inclusion of a few early classic papers, the review focuses on 21st century basic, psychopharmacologic, and clinical literature on the treatment of women with schizophrenia after menopause. EXPERT OPINION Beyond a relatively low dose threshold, all antipsychotic medications have adverse effects, which become more prominent for women at the time of menopause. Estrogen modulators may not help all symptoms of schizophrenia but are, nevertheless, relatively safe and, when used as adjuncts, help to keep antipsychotic doses low, thus reducing the side effect burden. The field is currently moving towards precision medicine and individual genetic profiles will help to determine the efficacy of available treatments in the future.
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Mini-review: Update on the genetics of schizophrenia.
Coelewij, L, Curtis, D
Annals of human genetics. 2018;(5):239-243
Abstract
A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk. Other rare, damaging variants are enriched in genes that are loss of function intolerant and/or whose products localise to the synapse. These and particular copy number variants can result in increased risk of schizophrenia but also of other neurodevelopmental disorders. The findings for C4 and NRXN1 may be especially helpful for elucidating the biological mechanisms that can lead to disease.
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Inborn errors of metabolism associated with psychosis: literature review and case-control study using exome data from 5090 adult individuals.
Trakadis, YJ, Fulginiti, V, Walterfang, M
Journal of inherited metabolic disease. 2018;(4):613-621
Abstract
A literature review was conducted, using the computerized "Online Mendelian Inheritance in Man" (OMIM) and PubMed, to identify inborn errors of metabolism (IEM) in which psychosis may be a predominant feature or the initial presenting symptom. Different combinations of the following keywords were searched using OMIM "psychosis", "schizophrenia", or "hallucinations" and "metabolic", "inborn error of metabolism", "inborn errors of metabolism", "biochemical genetics", or "metabolic genetics". The OMIM search generated 126 OMIM entries, 40 of which were well known IEM. After removing IEM lacking evidence in PubMed for an association with psychosis, 29 OMIM entries were identified. Several of these IEM are treatable. They involve different small organelles (lysosomes, peroxisomes, mitochondria), iron or copper accumulation, as well as defects in other met-abolic pathways (e.g., defects leading to hyperammonemia or homocystinemia). A clinical checklist summarizing the key features of these conditions and a guide to clinical approach are provided. The genes corresponding to each of these con-ditions were identified. Whole exome data from 2545 adult cases with schizophrenia and 2545 unrelated controls, accessed via the Database of Genotypes and Phenotypes (dbGaP), were analyzed for rare functional variants in these genes. The odds ratio of having a rare functional variant in cases versus controls was calculated for each gene. Eight genes are significantly associated with schizophrenia (p < 0.05, OR >1) using an unselected group of adult patients with schizophrenia. Increased awareness of clinical clues for these IEM will optimize referrals and timely metabolic interventions.
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A review of the safety of clozapine during pregnancy and lactation.
Mehta, TM, Van Lieshout, RJ
Archives of women's mental health. 2017;(1):1-9
Abstract
Clozapine is an antipsychotic used in the management of treatment-resistant schizophrenia. However, little is known about clozapine use during pregnancy and lactation, or its impact on the mother, foetus, and infant. This review aims to summarize the available literature on the safety of clozapine use during the perinatal period. EMBASE, PsycINFO, and MEDLINE were searched from their inceptions through June 2016. The review encompasses 21 studies that have examined clozapine use during pregnancy and lactation. The limited available data do not support an increased risk of congenital malformations in foetuses exposed to clozapine during pregnancy, though rates of gestational diabetes are twice as high in pregnant women using clozapine. Clozapine accumulation in foetal serum possibly contributes to increased rates of floppy infant syndrome at delivery, decreased foetal heart rate variability, and seizures in infancy. Clozapine crosses the placenta and also accumulates in breast milk, which may increase the risk of agranulocytosis in infants and may necessitate infant testing. The majority of these data come from case reports and case series, making it unclear if the published risks associated with clozapine are due to mental illness, lifestyle factors, or co-treatment with other psychotropic medications. While the available literature on clozapine use during the perinatal period is very limited, the risks of clozapine use during pregnancy and the postpartum period should be discussed with women and weighed against those associated with other treatments and partially or untreated schizophrenia.