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      Adjunctive Lurasidone Suppresses Food Intake and Weight Gain Associated with Olanzapine Administration in Rats

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          Abstract

          Objective

          Lurasidone is an antipsychotic drug that shows a relative lack of weight gain common to many antipsychotics. Aripiprazole and ziprasidone also show little weight gain and can reduce olanzapine-induced food intake and weight gain in animals, paralleling some clinical findings. We hypothesized that lurasidone would have similar actions.

          Methods

          Female Lister-hooded rats received intraperitoneal injection either 2× vehicle (saline), lurasidone (3 mg/kg) and vehicle, olanzapine (1 mg/kg) and vehicle, or olanzapine and lurasidone. Following drug administration food intake was measured for 60min. A further series of rats underwent a seven-day regime of once-daily administration of the above doses and free access to food and water. Weight gain over the course of the study was monitored.

          Results

          Olanzapine induced a significant increase in food intake while lurasidone showed no significant effect. Co-administration of lurasidone with olanzapine suppressed the increase in food intake. Repeated dosing showed an increase in body weight after seven days with olanzapine, and no significant effect observed with lurasidone, while repeated administration of lurasidone with olanzapine reduced the effect of olanzapine on the increase in body weight.

          Conclusion

          These findings support our hypotheses in that lurasidone, in addition to a lack of effect on acute food intake and short term weight gain, can reduce olanzapine-induced food intake and weight gain in rats. This indicates the drug to have an active anti-hyperphagic mechanism, rather than solely the absence of a drug-induced weight gain that is such a severe limitation of drugs such as olanzapine.

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          Most cited references9

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          Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis.

          Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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            Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial.

            Clozapine is associated with significant weight gain and metabolic disturbances. This multicentre, randomized study comprised a double-blind, placebo-controlled treatment phase of 16 wk, and an open-label extension phase of 12 wk. Outpatients who met DSM-IV-TR criteria for schizophrenia, who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or =2.5 kg while taking clozapine, were randomized (n=207) to aripiprazole at 5-15 mg/d or placebo, in addition to a stable dose of clozapine. The primary endpoint was mean change from baseline in body weight at week 16 (last observation carried forward). Secondary endpoints included clinical efficacy, body mass index (BMI) and waist circumference. A statistically significant difference in weight loss was reported for aripiprazole vs. placebo (-2.53 kg vs. -0.38 kg, respectively, difference=-2.15 kg, p<0.001). Aripiprazole-treated patients also showed BMI (median reduction 0.8 kg/m(2)) and waist circumference reduction (median reduction 2.0 cm) vs. placebo (no change in either parameter, p<0.001 and p=0.001, respectively). Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein (LDL) cholesterol. There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator's Assessment Questionnaire scores favoured aripiprazole over placebo. Safety and tolerability were generally comparable between groups. Combining aripiprazole and clozapine resulted in significant weight, BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine. Improvements may reduce metabolic risk factors associated with clozapine treatment.
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              Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia.

              Weight gain is a common consequence of antipsychotic drug treatment and can lead to further morbidity. To assess the effects of antipsychotic drug therapy on abdominal fat deposition, on insulin and leptin secretion, and on circulating glucose and lipids. Abdominal body fat was determined by magnetic resonance imaging in a group of previously untreated patients with schizophrenia, before and after 10 weeks' antipsychotic drug treatment. Body mass and blood concentrations of glucose, insulin, leptin and lipids were also measured. Significant increases in both subcutaneous and intra-abdominal fat were identified after antipsychotic drug treatment. A three-fold increase in leptin secretion as well as significant increases in levels of circulating lipids and non-fasting glucose were also identified. Patients first receiving antipsychotic drugs experience substantial deposition of both subcutaneous and intra-abdominal fat, reflecting a loss of the normal inhibitory control of leptin on body mass. Along with fat deposition, the increase in levels of fasting lipids and in non-fasting glucose may provide early signs of drug-induced progression towards the metabolic syndrome.
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                Author and article information

                Journal
                Clin Psychopharmacol Neurosci
                Clin Psychopharmacol Neurosci
                Clinical Psychopharmacology and Neuroscience
                Korean College of Neuropsychopharmacology
                1738-1088
                2093-4327
                March 2019
                30 April 2019
                : 17
                : 2
                : 314-317
                Affiliations
                [1 ]Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK
                [2 ]Division of Pharmacy and Optometry, School of Health Sciences, Manchester, UK
                Author notes
                Address for correspondence: Gavin P. Reynolds, PhD, Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard St, Sheffield S1 1WB., UK, Tel: +44-114-225-5555, Fax: +44-114-225-4449, E-mail: gavin.reynolds@ 123456hotmail.com , ORCID: https://orcid.org/0000-0001-9026-7726
                Article
                cpn-17-314
                10.9758/cpn.2019.17.2.314
                6478088
                30905132
                d9f7e0e9-dd8d-4bae-a227-b2d3c544956c
                Copyright © 2019, Korean College of Neuropsychopharmacology

                This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 February 2018
                : 02 April 2018
                : 03 April 2018
                Categories
                Brief Report

                antipsychotic agents,eating,weight gain,lurasidone hydrochloride,olanzapine

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