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Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates
BACKGROUND: Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and sa...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764014/ https://www.ncbi.nlm.nih.gov/pubmed/31294646 http://dx.doi.org/10.1177/0269881119856850 |
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author | Cunningham, Jacobi I Eyerman, David J Todtenkopf, Mark S Dean, Reginald L Deaver, Daniel R Sanchez, Connie Namchuk, Mark |
author_facet | Cunningham, Jacobi I Eyerman, David J Todtenkopf, Mark S Dean, Reginald L Deaver, Daniel R Sanchez, Connie Namchuk, Mark |
author_sort | Cunningham, Jacobi I |
collection | PubMed |
description | BACKGROUND: Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine. METHODS: Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels. RESULTS: Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats. CONCLUSIONS: Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain. |
format | Online Article Text |
id | pubmed-6764014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-67640142019-10-22 Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates Cunningham, Jacobi I Eyerman, David J Todtenkopf, Mark S Dean, Reginald L Deaver, Daniel R Sanchez, Connie Namchuk, Mark J Psychopharmacol Original Papers BACKGROUND: Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine. METHODS: Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels. RESULTS: Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats. CONCLUSIONS: Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain. SAGE Publications 2019-07-11 2019-10 /pmc/articles/PMC6764014/ /pubmed/31294646 http://dx.doi.org/10.1177/0269881119856850 Text en © The Author(s) 2019 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Papers Cunningham, Jacobi I Eyerman, David J Todtenkopf, Mark S Dean, Reginald L Deaver, Daniel R Sanchez, Connie Namchuk, Mark Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates |
title | Samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
title_full | Samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
title_fullStr | Samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
title_full_unstemmed | Samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
title_short | Samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
title_sort | samidorphan mitigates olanzapine-induced weight gain and metabolic
dysfunction in rats and non-human primates |
topic | Original Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764014/ https://www.ncbi.nlm.nih.gov/pubmed/31294646 http://dx.doi.org/10.1177/0269881119856850 |
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