Pharmacogenetics of antipsychotic-induced weight gain: Review and clinical implications

Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Molecular Psychiatry (Impact Factor: 14.5). 09/2011; 17(3):242-66. DOI: 10.1038/mp.2011.109
Source: PubMed


Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.

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    • "Antipsychotic drugs can affect multiple neurotransmitter systems and exert antagonistic actions on dopamine receptors , serotonergics, histamine, muscarinics, and adrenergics [57]. 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]. "
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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.
    11/2014; 2014. DOI:10.1155/2014/791573
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    • "Together, these changes could cause a critical level of inhibition of insulin activity, leading to insulin resistance and metabolic disorders [22] [23] [24] [25]. Clozapine treatment has been associated with elevated weight gain and TNF-a plasma levels [26] [27] [28]. "
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    ABSTRACT: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices < 25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state.
    Biochemical and Biophysical Research Communications 08/2014; 450(4). DOI:10.1016/j.bbrc.2014.07.005 · 2.30 Impact Factor
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    • "With respect to side effects, efforts have been made toward identifying patients with increased propensity for antipsychotic-induced weight gain (Lett et al., 2012; Malhotra et al., 2012). A genetic test that investigates genetic variants in the drug metabolizing enzymes CYP2D6 and CYP2C19 (Vetti et al., 2010), which are two major mechanisms impacting on inter-individual variability in response and side effects is commercially available with Food and Drug Administration approval (AmpliChip® CYP450 Test; Table 1). "
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    ABSTRACT: Introduction Pharmacogenetics attempts to identify inter-individual genetic differences that are predictive of variable drug response and propensity to side effects, with the prospect of assisting physicians to select the most appropriate drug and dosage for treatment. However, many concerns regarding genetic tests exist. We sought to test the opinions of undergraduate science and medical students in southern Ontario universities toward pharmacogenetic testing. Methods and Results Questionnaires were completed by 910 undergraduate medicine and science students from 2005 to 2007. Despite students' concerns that the results of genetic tests may be used for other purposes without consent (71%) or lead to discrimination (78%), an overwhelming number of students were in favor of pharmacogenetic testing (90%). Discussion To our knowledge, this study is the first to survey a large sample for their attitude toward pharmacogenetic testing for psychotropic medications. Our results indicate that, although concerns remain and scientific advancements are required, respondents were in support of pharmacogenetic testing for medications used to treat schizophrenia. © 2014 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 05/2014; 29(3). DOI:10.1002/hup.2383 · 2.19 Impact Factor
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