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Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism

Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA.
Physiology & Behavior (Impact Factor: 3.03). 06/2011; 104(4):590-8. DOI: 10.1016/j.physbeh.2011.05.033
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ABSTRACT The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.

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    • "Hyperphagia is another major contributor to weight gain among SGAs users [1] [60]. The evidence suggest that the increase olanzapine-induced hyperphagia might be secondary to the activation of SREBP1c- controlled genes, like PPAR␥ [37] [2] [134] [117] [79], FASN [119] [134] and LDLR [134]. We believe that the overexpression of LDLR also results in an augmented capacity of adipocytes to accumulate cholesterol (Fig. 3). "
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    ABSTRACT: Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Pharmacological Research 07/2015; DOI:10.1016/j.phrs.2015.07.022 · 4.41 Impact Factor
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    • "There are interrelated hypotheses that have been proposed to explain antipsychotic-induced MetS. One hypothesis is that SGAs cause a dysregulation of hormones that control appetite and food intake such as insulin, leptin , adiponectin, and ghrelin (Sentissi et al., 2008; Teff and Kim, 2011; Stip et al., 2012). Most studies investigating this have focused on just a few metabolic mediators and Address for correspondence: C. "
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    ABSTRACT: Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia. However, SGAs cause metabolic disturbances that can manifest as metabolic syndrome (MetS) in a subset of patients. The causes for these metabolic disturbances remain unclear. We performed a comprehensive metabolomic profiling of 60 schizophrenia patients undergoing treatment with SGAs that puts them at high (clozapine, olanzapine), medium (quetiapine, risperidone), or low (ziprasidone, aripiprazole) risk for developing MetS, compared to a cohort of 20 healthy controls. Multiplex immunoassays were used to measure 13 metabolic hormones and adipokines in plasma. Mass spectrometry was used to determine levels of lipids and polar metabolites in 29 patients and 10 controls. We found that levels of insulin and tumor necrosis factor alpha (TNF-α) were significantly higher (p < 0.005) in patients at medium and high risk for MetS, compared to controls. These molecules are known to be increased in individuals with high body fat content and obesity. On the other hand, adiponectin, a molecule responsible for control of food intake and body weight, was significantly decreased in patients at medium and high risk for MetS (p < 0.005). Further, levels of dyacylglycerides (DG), tryacylglycerides (TG) and cholestenone were increased, whereas α-Ketoglutarate and malate, important mediators of the tricarboxylic acid (TCA) cycle, were significantly decreased in patients compared to controls. Our studies suggest that high- and medium-risk SGAs are associated with disruption of energy metabolism pathways. These findings may shed light on the molecular underpinnings of antipsychotic-induced MetS and aid in design of novel therapeutic approaches to reduce the side effects associated with these drugs.
    The International Journal of Neuropsychopharmacology 02/2014; 17(08):1-10. DOI:10.1017/S1461145714000157 · 5.26 Impact Factor
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    • "Olanzapine has been shown to be a high-affinity muscarinic receptor antagonist (40) and in vitro can block acetylcholine binding to muscarinic receptors on the pancreatic islet, thereby inhibiting insulin release (41). Based on these data and data from our own laboratory showing that vagally mediated, early phase insulin can be inhibited by muscarinic blockade (36), we (42) and others (40,43,44) speculated that olanzapine induces metabolic impairments by attenuating insulin release through muscarinic blockade. Surprisingly, we found significant increases in both early phase and postprandial insulin release after olanzapine. "
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    ABSTRACT: Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
    Diabetes 07/2013; 62(9). DOI:10.2337/db13-0430 · 8.47 Impact Factor
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