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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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Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial.
Lin, CH, Lin, CH, Chang, YC, Huang, YJ, Chen, PW, Yang, HT, Lane, HY
Biological psychiatry. 2018;(6):422-432
Abstract
BACKGROUND Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine. METHODS We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks' add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured. RESULTS Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group. CONCLUSIONS Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.
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Effects of nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan: A randomized controlled trial.
Sugawara, N, Sagae, T, Yasui-Furukori, N, Yamazaki, M, Shimoda, K, Mori, T, Sugai, T, Matsuda, H, Suzuki, Y, Ozeki, Y, et al
Journal of psychiatric research. 2018;:77-83
Abstract
OBJECTIVE Patients with schizophrenia have a higher prevalence of metabolic syndrome (MetS) than the general population. Minimizing weight gain and metabolic abnormalities in a population with an already high prevalence of obesity is of clinical and social importance. This randomized controlled trial investigated the effect of monthly nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan. METHODS From July 2014 to December 2014, we recruited 265 obese patients who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Participants were randomly assigned to a standard care (A), doctor's weight loss advice (B), or an individual nutritional education group (C) for 12 months. The prevalence of MetS and body weight were measured at baseline and 12 months. RESULTS After the 12-month treatment, 189 patients were evaluated, and the prevalence of MetS based on the ATP III-A definition in groups A, B, and C was 68.9%, 67.2%, and 47.5%, respectively. Group C showed increased weight loss (3.2 ± 4.5 kg) over the 12-month study period, and the change in weight differed significantly from that of group A; additionally, 26.2% of the participants in group C lost 7% or more of their initial weight, compared with 8.2% of those in group A. CONCLUSION Individual nutrition education provided by a dietitian was highly successful in reducing obesity in patients with schizophrenia and could be the first choice to address both weight gain and metabolic abnormalities induced by antipsychotic medications.
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CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.
Siskind, D, Friend, N, Russell, A, McGrath, JJ, Lim, C, Patterson, S, Flaws, D, Stedman, T, Moudgil, V, Sardinha, S, et al
BMJ open. 2018;(3):e021000
Abstract
INTRODUCTION Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation. METHODS AND ANALYSIS A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants. ETHICS AND DISSEMINATION Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER ACTRN12617001547336; Pre-results.
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Exercise, diet and educational interventions for metabolic syndrome in persons with schizophrenia: A systematic review.
Gurusamy, J, Gandhi, S, Damodharan, D, Ganesan, V, Palaniappan, M
Asian journal of psychiatry. 2018;:73-85
Abstract
INTRODUCTION Individuals with major psychotic disorders such as schizophrenia are at increased risk for developing metabolic syndrome due to lifestyle- and treatment-related factors. Numerous interventions have been tested in inpatient and outpatient mental health settings to decrease risk factors. Diet and exercise represent the mainstay of weight loss treatment. With this background the review aimed to evaluate the effects of psychoeducation, diet and physical activity interventions on reduction of metabolic syndrome risk factors such as BMI, Body weight, biochemical profiles in schizophrenia. METHODS The authors conducted database searches of PsychINFO, MEDLINE, Pubmed, Proquest, EBSCO and the Cochrane Database of Systematic Reviews, and manual searches from 1968 to 2017. Search indentified 11 studies that met the inclusion criteria. Study quality was critically appraised by 2 reviewers using established criteria. The outcome measures were body mass index, body weight, waist circumference, lipid profile, fasting glucose. RESULTS Interventions led to significant weight reduction (8 studies), reduced body mass index (5 studies), decreased waist circumference (4 studies) and lower blood glucose levels (5 studies). Dietician and nurse led interventions (6 studies). The studies showed non pharmacological interventions were effective in reducing risk factors. CONCLUSION This review was able to demonstrate effectiveness of peychoeducation, diet and physical activity interventions were helpful to decrease and manage antipsychotic-induced weight gain. Results showed lifestyle interventions are safer and effective for promoting decrease or maintenance of weight and it can be delivered at low cost, safe and improves quality of life.
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Psychotic and Bipolar Disorders: Antipsychotic Drugs.
Holder, SD, Edmunds, AL, Morgan, S
FP essentials. 2017;:23-29
Abstract
Antipsychotic drugs block dopamine receptors and are used to manage psychosis as well as other mental illnesses that may or may not have psychotic features, such as bipolar disorders and major depressive disorder. First-generation antipsychotic drugs are more likely to cause adverse effects such as extrapyramidal symptoms and tardive dyskinesia. Adverse effects of second-generation antipsychotic drugs typically are related to metabolic abnormalities such as weight gain, abnormal blood glucose levels, and elevated lipid levels. Neuroleptic malignant syndrome is a rare but serious adverse effect of antipsychotic drugs that causes mental status changes, hyperthermia, and generalized rigidity. Timely diagnosis is essential due to a high risk of related morbidities if the syndrome remains untreated. Some adverse effects of antipsychotics can be identified and managed so that patients can continue beneficial therapy while minimizing the physiologic consequences. Patients taking antipsychotic drugs should be monitored regularly for adverse effects. Antipsychotics are also associated with potential drug interactions, the most lethal being prolongation of the QT interval, which can lead to fatal arrhythmias. Antipsychotic drugs can be used in special populations, such as pregnant women, children, and elderly patients, per recommendation from a mental health subspecialist.
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[Hypokalemic rhabdomyolisis and schizophrenia].
Fantacone, N, Carísimo, E, Landi, P, Del Mar Walsöe, E, Fadel, D
Vertex (Buenos Aires, Argentina). 2017;(134):271-279
Abstract
The purpose of this report is to emphasize the necessity to periodically explore internal environment variables, as certain metabolic alterations often go unnoticed during antipsychotic treatment. Early detection of such alterations may prevent catastrophic syndromes. We will also stress the clinical relevance of cognitive perseverations in schizophrenic patients, as these often condition habits of consumption which can alter the internal environment. In this clinical case of a schizophrenic patient, a chain of events led to a catastrophic syndrome: a trivial home accident (fall from own height) developed into a condition characterized by oligoanuria, hypokalemia, creatine phosphokinase (CPK) elevation (125,000 IU / L) and acute renal failure with dialysis requirement. This episode was non lethal due to the early implementation of support measures. We performed a revision of the available literature in order to discern the cause of the elevation of CPK. Here we aim to highlight the importance of 1) careful clinical and laboratory monitoring of psychopharmacological treatment, 2) interactions resulting from consumption habits capable of generating unforeseen consequences, 3) the role of the psychiatrist in the context of multidisciplinary work.
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ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial.
Lieberman, JA, Davis, RE, Correll, CU, Goff, DC, Kane, JM, Tamminga, CA, Mates, S, Vanover, KE
Biological psychiatry. 2016;(12):952-61
Abstract
BACKGROUND An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins. METHODS A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales. RESULTS ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone. CONCLUSIONS The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.
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Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses.
Henderson, DC, Vincenzi, B, Andrea, NV, Ulloa, M, Copeland, PM
The lancet. Psychiatry. 2015;(5):452-464
Abstract
Patients with schizophrenia have increased mortality and morbidity compared with the general population. These patients have a 20-year shorter lifespan than peers without schizophrenia, mainly due to premature cardiovascular disease, suicide, and cancer. Patients with severe mental illness are at increased risk for cardiovascular disease related to increased incidence of diabetes, hypertension, smoking, poor diet, obesity, dyslipidaemia, metabolic syndrome, low physical activity, and side-effects of antipsychotic drugs. Some second-generation antipsychotics (eg, clozapine, olanzapine, quetiapine, and risperidone) are associated with an increased risk of weight gain and obesity, impaired glucose tolerance and new-onset diabetes, hyperlipidaemia, and cardiovascular disease. The mechanisms by which schizophrenia and patients with severe mental illness are susceptible to cardiometabolic disorders are complex and include lifestyle risks and direct and indirect effects of antipsychotic drugs. An understanding of these risks might lead to effective interventions for prevention and treatment of cardiometabolic disorders in schizophrenia and severe mental illness.
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The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia.
Bonaccorso, S, Sodhi, M, Li, J, Bobo, WV, Chen, Y, Tumuklu, M, Theleritis, C, Jayathilake, K, Meltzer, HY
Bipolar disorders. 2015;(5):528-35
Abstract
OBJECTIVES We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. METHODS This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). RESULTS BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). CONCLUSIONS The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.