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.; Sanchéz, Connie; Namchuk, Mark

doi:10.1177/0269881119856850

Cited by 25 publications

(33 citation statements)

References 60 publications

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“…The effects of OLZ/SAM on weight gain and body composition have been previously characterized in preclinical studies in rats and nonhuman primates. 63 In this narrative review, we summarize the clinical data for OLZ/SAM and describe its overall efficacy and safety profile.…”

Section: Overview Of Clinical Trialsmentioning

confidence: 99%

“… 80–82 In the periphery, blockade or genetic ablation of opioid receptors alters fat accumulation and glucose utilization, as well as glucose homeostasis. 63 , 83–85 Therefore, the weight-mitigating properties of samidorphan in combination with olanzapine may be mediated through opioid receptor blockade in both central and peripheral compartments.…”

Section: Pharmacology and Mode Of Action Of Samidorphanmentioning

confidence: 99%

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An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

Citrome¹,

Graham²,

Simmons³

et al. 2021

NDT

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Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥5 cm by half, compared with olanzapine at week 24. Based on openlabel extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.

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Section: Overview Of Clinical Trialsmentioning

confidence: 99%

Section: Pharmacology and Mode Of Action Of Samidorphanmentioning

confidence: 99%

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

Citrome¹,

Graham²,

Simmons³

et al. 2021

NDT

Self Cite

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show abstract

“…Previous studies have reported that induction of weight loss was observed in adolescent patients, obese mice, and male rats, 26–28 which, however, was inconsistent with previous studies reporting that olanzapine-induced weight gain is prevalent in a proportion of human patients and rodents over longer experimental periods. 29–32 Albaugh et al demonstrated that the drug effects plateaued within 7 to 10 days, and weight gain eventually plateaued under the same daily dose of olanzapine. 3 Similarly, our results showed that animals receiving olanzapine had an increased daily food intake within two weeks, accompanied by significant weight gain only observed in the first two weeks, which may be due to the olanzapine concentration reaching a plateau.…”

Section: Discussionmentioning

confidence: 99%

Early Lipid Metabolic Effects of the Anti-Psychotic Drug Olanzapine on Weight Gain and the Associated Gene Expression

Chen¹,

Nakano²,

Hsu³

et al. 2022

NDT

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Background Atypical antipsychotics such as olanzapine often cause metabolic side effects such as obesity and diabetes, leading to an increased risk of nonalcoholic fatty liver disease. The aim of the present study was to investigate the effects of olanzapine treatment on hepatic lipid metabolism and its possible relationship with adipose tissue status. Methods Using a female rat model, we investigated the effects of chronic olanzapine administration on the regulation of carbohydrate and lipid metabolism including lipid biosynthesis, oxidation, efflux, and lipolysis in liver and adipose tissue. Results The body weight, liver mass and visceral adiposity after olanzapine treatment (2 mg/kg) for five weeks were not significantly different compared with vehicle controls. The serum level of triglycerides was higher in the vehicle controls than in olanzapine-treated rats. Unexpectedly, olanzapine treatment did not reduce glucose tolerance in our model. The expression of functional thermogenic protein uncoupling protein 1 (UCP1) was increased in brown adipose tissue (BAT) of the olanzapine group. Additionally, olanzapine treatment also reduced adipose inflammation in white adipose tissue (WAT). The transcription factor sterol regulatory element-binding protein (SREBP)-1c, a key early regulator of lipogenesis, was downregulated following olanzapine treatment. The expression of genes related to the triglycerides synthesis apparatus in the liver was upregulated in the olanzapine group. Olanzapine treatment induced genes involved in PPAR-α signaling and mitochondrial fatty acid oxidation in response to increased ATGL-mediated lipolysis in the liver. Conclusion Together, our findings suggest a complicated link between olanzapine therapy and metabolic disturbance and may garner interest in assessing the action of antipsychotic-induced metabolic disturbances.

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“…91 Olanzapine is one of the most efficacious AAPs in the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects than with FGA treatment. 93,94 However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic abnormalities such as dyslipidemia, type II diabetes, and weight gain, limiting its clinical use and affecting treatment compliance. [93][94][95][96][97] In studies enrolling healthy adults and adults with schizophrenia, the combination of olanzapine with samidorphan, a μ-opioid receptor antagonist, mitigated weight gain associated with olanzapine monotherapy.…”

Section: Health Psychology Researchmentioning

confidence: 99%

“…93,94 However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic abnormalities such as dyslipidemia, type II diabetes, and weight gain, limiting its clinical use and affecting treatment compliance. [93][94][95][96][97] In studies enrolling healthy adults and adults with schizophrenia, the combination of olanzapine with samidorphan, a μ-opioid receptor antagonist, mitigated weight gain associated with olanzapine monotherapy. 94,98,99 The opioid system has been implicated in the role of mediating feeding behavior, food reward, and metabolism in many clinical and preclinical studies.…”

Section: Health Psychology Researchmentioning

confidence: 99%

Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review

Haddad

Boardman

Williams

et al. 2022

Health Psychology Research

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Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D.

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Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates

Cited by 25 publications

References 60 publications

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

Early Lipid Metabolic Effects of the Anti-Psychotic Drug Olanzapine on Weight Gain and the Associated Gene Expression

Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review

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