Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Weston–Green, Katrina; Huang, Xu‐Feng; Deng, Chao

doi:10.1371/journal.pone.0033548

Cited by 84 publications

(67 citation statements)

References 141 publications

(151 reference statements)

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“…This is also consistent with previous reports in female rat models for olanzapine-induced weight gain with a significant increase of NPY mRNA expression [25,[27][28][29]70]. In addition, it has previously been found that acute ICV olanzapine treatment led to an upregulated AgRP level in male adult rats [17].…”

Section: Mrna Expressions Of Hypothalamic Neuropeptidessupporting

confidence: 93%

“…Using the adult female rat model for antipsychotic-induced weight gain, it has been repeatedly revealed that olanzapine elevated the expression of appetite stimulating neuropeptides in the hypothalamus, including neuropeptide Y (NPY) and agouti-related peptide (AgRP), while decreasing appetite inhibiting neuropeptides such as proopiomelanocortin (POMC) [25,[27][28][29]. On the other hand, H 1 R is independent of POMC regulation [30], but links to NPY expression [31].…”

Section: Introductionmentioning

confidence: 99%

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Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Lian

Santis

et al. 2015

Pharmacological Research

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. (2015). Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways. Pharmacological Research,[95][96] Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways AbstractSecond generation antipsychotic drugs (SGAs) such as risperidone are increasingly prescribed (mostly for offlabel use) to children and adolescents for treating various mental disorders. SGAs cause serious weight gain/ obesity and other metabolic side-effects. This study aimed to establish an animal model of risperidoneinduced weight gain in female juvenile rats, and to investigate the effects of risperidone on the expression of hypothalamic histaminergic H1 receptors (H1R) and neuropeptides, and their association with weight gain. Female Sprague Dawley rats were treated orally with risperidone (0.3 mg/kg, 3 times/day) or vehicle (control) starting from postnatal day (PD) 23 (±1 day) for 3 weeks (a period corresponding to the childhoodadolescent period in humans). In the female juvenile rats, risperidone treatment increased food intake and body weight gain, which started to appear after 12 days' treatment. Risperidone also significantly decreased the locomotor activity of the female rats. Consistently, risperidone significantly elevated mRNA expression of hypothalamic H1R, neuropeptide Y (NPY), and agouti-related peptide (AgRP) compared to controls, and H1R and NPY levels were correlated with risperidone enhanced weight gain and food intake in the female juvenile rats. However, risperidone did not affect hypothalamic proopiomelanocortin (POMC) and cocaineand amphetamine-regulated transcript (CART) mRNA expression. Therefore, these results suggested that risperidone elevated appetite and body weight gain in juveniles via regulation of the hypothalamic H1R, NPY and AgRP pathways, as well as by reducing activity.

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Section: Mrna Expressions Of Hypothalamic Neuropeptidessupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Lian

Santis

et al. 2015

Pharmacological Research

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“…Fernø and colleagues demonstrated that short-term exposure to olanzapine (6 days) resulted in upregulated NPY and AgRP expressions in the Arc of both rats fed ad libitum and pair-fed rats [98]. Olanzapine upregulated NPY mRNA expression in a dosage dependent manner in the hypothalamic Arc [128]. Furthermore, increased hypothalamic NPY and AgRP expression were also observed by the study using ICV administration of olanzapine [98,99].…”

Section: The Role Of Npy and Agrp In Sga-induced Weight Gainmentioning

confidence: 98%

“…In terms of the effect of SGAs on expression of POMC and CART, it was shown that olanzapine treatment resulted in attenuation of POMC but not CART expression in the hypothalamus of rats [98,65,160,128,129]. Ak and colleagues also reported that the plasma POMC level was elevated in first attack psychotic male patients treated with olanzapine, but no changes in plasma CART level were observed [100].…”

Section: The Role Of Pomc and Cart In Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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“…24 Weight gain due to atypical antipsychotics correlates to an extent with affinity for the H 1 , 5-HT 2C , melanocortinergic, GABAergic, cannabinoid and M 3 receptors. [25][26][27] Higher number of olanzapine treated patients developed weight gain in present study suggesting implication of olanzapine to a greater extent than zotepine for these receptors. Weight gain was the major cause for dropout in olanzapine treated patients in present study.…”

Section: Discussionmentioning

confidence: 45%

Efficacy, tolerability and cost effectiveness of zotepine versus olanzapine in patients of acute schizophrenia

Kothari¹,

Patel²,

Changulai³

et al. 2013

Int J Basic Clin Pharmacol

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Background: Schizophrenia is a functional psychosis with severe personality changes and thought disorders without cerebral damage. No reports are available in literature regarding efficacy and tolerability of atypical antipsychotic drug zotepine over olanzapine a preferred drug worldwide for the treatment of schizophrenia. Therefore, present study is undertaken to evaluate efficacy, tolerability and cost effectiveness of zotepine over olanzapine in patients suffering from schizophrenia. Methods: A prospective, randomized, single blind, parallel, 6 weeks clinical study was conducted on a total of 112 patients, of schizophrenia attending psychiatry outpatient department at G. R. Medical College, Gwalior, India randomized into two groups (56 in each). Patients received either olanzapine (10-20mg) or zotepine (75-150mg) per day for a period of 6 week. Efficacy was measured by Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scale whereas tolerability was measured by dropout rate and frequency of adverse effects. Cost effectiveness was calculated in terms of cost incurred for improvement at the end of treatment period. Results: Both the drugs showed significant (P<0.05) improvement in PANSS total score as compared to their respective baseline scores however, there was no significant difference between the two groups (P>.0.05). Olanzapine showed significantly better (P<0.05) positive subscale and CGI scale score improvement as well as response rate when compared to zotepine. Incidences of adverse effects like weight gain, somnolence and hyperglycemia were 42, 32 and12 % respectively with olanzapine and 39, 30 and 9% respectively with zotepine with no significant difference (P>0.05) between the two groups. Incidence of akathisia and drop out (16% and 23%) with zotepine were significant (P<0.05) as compared to olanzapine (2% and 11%) respectively. Conclusions: Though the efficacy of both the drugs is comparable, olanzapine appears to have better tolerability and cost effectiveness than zotepine in patients of schizophrenia. [Int J Basic Clin Pharmacol 2013; 2(5.000): 577-582

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Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Cited by 84 publications

References 141 publications

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Efficacy, tolerability and cost effectiveness of zotepine versus olanzapine in patients of acute schizophrenia

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