Potential mechanism of atypical antipsychotic-induced metabolic derangement: Clues for understanding obesity and novel drug design

Institute of Neuroscience, National Research Council (C.N.R.), Via del Fosso di Fiorano, 64-00143 Roma, Italy.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 09/2010; 127(3):210-51. DOI: 10.1016/j.pharmthera.2010.04.008
Source: PubMed


Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescription of atypical agents is also associated to the emergence of severe metabolic derangement in patients is not a mystery anymore. Body weight gain, dyslipidemia, adiposity, impaired glucose homeostasis, insulin and leptin resistance and new-onset type II diabetes are all part of a syndromic cluster of vast medical concern. Thus, clinical reports and rodent models of atypical antipsychotic-associated metabolic impairment have growth in parallel as separate territories. This review focuses on the attempt to take a snapshot of the present developing moment and to describe to what extent clinical data are reflected by the findings derived from animal studies. This aim is pursued through different steps that, starting from the criteria necessary to characterize the "atypicality" of atypical drugs, then explore the consistency among clinical and animal-based data. The endpoint of this survey consists in the analysis of the potential mechanisms underlying the metabolic derangement induced by this class of drugs. It is, indeed, our opinion that some atypical antipsychotics should be viewed as potent obesogenic factors that can be exploited as valuable tools to shed light into the elusive dilemma of obesity. For this reason, recently identified obesogenic and diabetogenic mechanisms are the background on which the present work is built and some novel forthcoming lines of investigation suggested.

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Available from: Roberto Coccurello, Mar 13, 2015
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    • "Antagonism of histamine H 1 receptors may impair metabolic function of leptin, leading to insulin resistance and impaired glucose tolerance (Coccurello and Moles, 2010). "
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    ABSTRACT: Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase(®), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase(®) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase(®). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase(®) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Jul 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "In conclusion, antipsychotics-induced weight gain develops as consequence of a disconnection in the brain–adipose tissue axis (Coccurello and Moles, 2010). As a whole, these studies suggest that the mechanisms by which atypical antipsychotics increase the risk of overweight and obesity might be explained, at least in part, by their ability to increase lipogenesis, decrease lipolysis and stimulate adipocyte differentiation in white adipose tissue, particularly the visceral one. "
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    ABSTRACT: The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Dec 2014 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "All of these neurotransmitters have been directly or indirectly involved in the pathways associated with the regulation of food intake [58], metabolism [59] [60], and weight balance [61] [62]. Blockades of dopamine (D2 and D3), serotonin (5HT2c), histamine (H1) [63], and muscarinic (M2 and M3) receptors have all been shown to increase appetite [64] [65]. Additionally, by endocrine/metabolic mechanisms, antipsychotics can directly induce the activation of the hypothalamus-pituitary-adrenal axis [66], deficits in insulin secretion [67], and changes in gastrointestinal hormones [68]. "
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    ABSTRACT: Objective. Despite evidence from case series, the comorbidity of eating disorders (EDs) with schizophrenia is poorly understood. This review aimed to assess the epidemiological and clinical characteristics of EDs in schizophrenia patients and to examine whether the management of EDs can be improved. Methods. A qualitative review of the published literature was performed using the following terms: "schizophrenia" in association with "eating disorders, " "anorexia nervosa, " "bulimia nervosa, " "binge eating disorder, " or "night eating syndrome. " Results. According to our literature review, there is a high prevalence of comorbidity between schizophrenia and EDs. EDs may occur together with or independent of psychotic symptoms in these patients. Binge eating disorders and night eating syndromes are frequently found in patients with schizophrenia, with a prevalence of approximately 10%. Anorexia nervosa seems to affect between 1 and 4% of schizophrenia patients. Psychopathological and neurobiological mechanisms, including effects of antipsychotic drugs, should be more extensively explored. Conclusions. The comorbidity of EDs in schizophrenia remains relatively unexplored. The clearest message of this review is the importance of screening for and assessment of comorbid EDs in schizophrenia patients. The management of EDs in schizophrenia requires a multidisciplinary approach to attain maximized health outcomes. For clinical practice, we propose some recommendations regarding patient-centered care.
    Full-text · Article · Nov 2014
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