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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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Adjunctive Aripiprazole Treatment for Risperidone-Induced Hyperprolactinemia: An 8-Week Randomized, Open-Label, Comparative Clinical Trial.
Zhao, J, Song, X, Ai, X, Gu, X, Huang, G, Li, X, Pang, L, Ding, M, Ding, S, Lv, L
PloS one. 2015;(10):e0139717
Abstract
OBJECTIVE The present study aimed to evaluate the efficacy and safety of adjunctive aripiprazole treatment in schizophrenia patients with risperidone-induced hyperprolactinemia. METHODS One hundred and thirteen patients who were receiving a stable dose of risperidone were randomly assigned to either adjunctive aripiprazole treatment (10 mg/day) (aripiprazole group) or no additional treatment (control group) at a 1:1 ratio for 8 weeks. Schizophrenia symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Rating scales and safety assessments (RSESE, BARS, UKU) were performed at baseline and at weeks 4 and 8. Serum levels of prolactin were determined at baseline and at weeks 2, 4, 6 and 8. Metabolic parameters were determined at baseline and again at weeks 4 and 8. RESULTS One hundred and thirteen patients were enrolled in this study, and 107 patients completed the study (54 in the aripiprazole group, and 53 in the control group). PANSS-total scores in the aripiprazole group decreased significantly at week 4 (P = 0.003) and week 8 (P = 0.007) compared with the control group. PANSS-negative scores in the aripiprazole group also decreased significantly at week 4 (P = 0.005) and week 8 (P< 0.001) compared with the control group. Serum levels of prolactin in the aripiprazole group decreased significantly at week 2 (P< 0.001), week 4 (P< 0.001), week 6 (P< 0.001) and week 8 (P< 0.001) compared with the control group. There were no significant differences in changes of Fasting Plasma Glucose, Total cholesterol, Triglycerides and High Density Lipoprotein within each group at week 4 and 8 execpt low density lipoproteins. There was no significant difference in the incidence of adverse reactions between the two groups. CONCLUSIONS Adjunctive aripiprazole treatment may be beneficial in reducing serum levels of prolactin and improving negative symptoms in schizophrenia patients with risperidone-induced hyperprolactinemia. TRIAL REGISTRATION chictr.org ChiCTR-IOR-15006278.
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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.
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Supplementation of antipsychotic treatment with sarcosine – GlyT1 inhibitor – causes changes of glutamatergic (1)NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia.
Strzelecki, D, Podgórski, M, Kałużyńska, O, Gawlik-Kotelnicka, O, Stefańczyk, L, Kotlicka-Antczak, M, Gmitrowicz, A, Grzelak, P
Neuroscience letters. 2015;:7-12
Abstract
Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance ((1)H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.
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Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study.
Modabbernia, A, Heidari, P, Soleimani, R, Sobhani, A, Roshan, ZA, Taslimi, S, Ashrafi, M, Modabbernia, MJ
Journal of psychiatric research. 2014;:133-40
Abstract
UNLABELLED We aimed to determine the efficacy of melatonin 3 mg/day in prevention of olanzapine-induced metabolic side-effects. In a randomized double-blind placebo-controlled study, 48 patients with first-episode schizophrenia who were eligible for olanzapine treatment, were randomly assigned to olanzapine plus either melatonin 3 mg/day or matched placebo for eight weeks. Anthropometric and metabolic parameters as well as psychiatric symptoms using The Positive and Negative Syndrome Scale (PANSS) were assessed at baseline, week 4, and 8. Primary outcome measure was the change from baseline in weight at week 8. Data were analyzed using t-test, Mann-Whitney U test, and mixed-effects model. Thirty-six patients had at least one post-baseline measurement. At week eight, melatonin was associated with significantly less weight gain [mean difference (MD) = 3.2 kg, P = 0.023], increase in waist circumference [MD = 2.83 cm, P = 0.041] and triglyceride concentration [MD = 62 mg/dl, P = 0.090 (nearly significant)] than the placebo. Changes in cholesterol, insulin, and blood sugar concentrations did not differ significantly between the two groups. Patients in the melatonin group experienced significantly more reduction in their PANSS scores [MD = 12.9 points, P = 0.014] than the placebo group. No serious adverse events were reported. To summarize, in patients treated with olanzapine, short-term melatonin treatment attenuates weight gain, abdominal obesity, and hypertriglyceridemia. It might also provide additional benefit for treatment of psychosis. The study was registered in the ClinicalTrials.gov ( REGISTRATION NUMBER NCT01593774).
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Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from a randomized controlled trial.
Stroup, TS, Byerly, MJ, Nasrallah, HA, Ray, N, Khan, AY, Lamberti, JS, Glick, ID, Steinbook, RM, McEvoy, JP, Hamer, RM
Schizophrenia research. 2013;(1-3):190-5
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Abstract
PURPOSE This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. METHOD Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. RESULTS The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885). CONCLUSION Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.
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A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia.
Bentsen, H, Osnes, K, Refsum, H, Solberg, DK, Bøhmer, T
Translational psychiatry. 2013;(12):e335
Abstract
Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo-controlled 2 × 2 factorial design. Patients aged 18-39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day⁻¹ and active or placebo vitamin E 364 mg day⁻¹+vitamin C 1000 mg day⁻¹ (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop-out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe.
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Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor.
Lane, HY, Lin, CH, Green, MF, Hellemann, G, Huang, CC, Chen, PW, Tun, R, Chang, YC, Tsai, GE
JAMA psychiatry. 2013;(12):1267-75
Abstract
IMPORTANCE In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of d-amino acids by blocking their metabolism. Sodium benzoate is a d-amino acid oxidase inhibitor. OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer. INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment. RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for d-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.
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A randomized controlled trial undertaken to test a nurse-led weight management and exercise intervention designed for people with serious mental illness who take second generation antipsychotics.
Usher, K, Park, T, Foster, K, Buettner, P
Journal of advanced nursing. 2013;(7):1539-48
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AIM: To test the effect of a nurse-led intervention on weight gain in people with serious mental illness prescribed and taking second generation antipsychotic medication. BACKGROUND Weight gain and obesity has reached epidemic proportions in the general population with the prevalence of Metabolic Syndrome reaching 20-25% of the global population. People with serious mental illness are at even higher risk, particularly those taking second generation antipsychotic medication. DESIGN An experimental randomized controlled trial was undertaken. METHOD The control group received a 12-week healthy lifestyle booklet. In addition to the booklet, the intervention group received weekly nutrition and exercise education, exercise sessions, and nurse support. Participants (n = 101) were assessed at baseline and 12 weeks. Data were collected between March 2008-December 2010. Seven outcome measures were used: body measurements included girth (cm), weight (kg), height (cm), and body mass index (kg/m(2) ); questionnaires included the medication compliance questionnaire, the Drug Attitude Inventory, the Liverpool University Neuroleptic Side Effect Rating Scale, and the Medical Outcomes Study Short Form 36. Differences in primary outcome measures between baseline and 12 weeks follow-up were compared between intervention and control groups using standard bi-variate statistical tests. The study was conducted between 2008-2010. RESULTS The analysis of outcome measures for the control group (n = 50) and intervention group (n = 51) was not statistically significant. There was a mean weight change of -0·74 kg at 12 weeks for the intervention group (n = 51), while the control group (n = 50) had a mean weight change of -0·17 kg at 12 weeks. CONCLUSION The results were not statistically significant.
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Comparison of fasting blood sugar and serum lipid profile changes after treatment with atypical antipsychotics olanzapine and risperidone.
Kaushal, J, Bhutani, G, Gupta, R
Singapore medical journal. 2012;(7):488-92
Abstract
INTRODUCTION This study aimed to compare the effects of the two most commonly prescribed atypical antipsychotics, olanzapine and risperidone, on fasting blood sugar and serum lipid profile of the recipients. METHODS A randomised, comparative, open clinical study was conducted on 60 schizophrenic patients. The patients were divided into two groups, one receiving olanzapine and the other receiving risperidone. The patients were assessed for changes in fasting blood sugar and serum lipid profile (triglycerides [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very-low-density lipoprotein [VLDL] and total cholesterol) eight weeks after starting treatment. The number of patients positive for fasting blood sugar and lipid profile criteria of metabolic syndrome was calculated by applying the modified National Cholesterol Education Programme Adult Treatment Panel III guidelines (NCEP ATP III) criteria at eight weeks. RESULTS Patients treated with olanzapine showed a highly significant increase in the observed parameters, whereas those treated with risperidone showed a significant increase in fasting blood sugar, HDL and LDL levels, and a highly significant increase in other parameters. Intergroup comparison was insignificant except for TG, VLDL and total cholesterol levels. More men as compared to women fulfilled the NCEP ATP III criteria for metabolic syndrome in both groups. CONCLUSION Olanzapine has a higher propensity to cause derangement of some parameters of lipid profile than risperidone. These parameters include TG, VLDL and total cholesterol levels.