Bodyweight Gain with Atypical Antipsychotics

Wetterling, Tilman

doi:10.2165/00002018-200124010-00005

Cited by 222 publications

(142 citation statements)

References 77 publications

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“…Drugs with high H 1 -receptor affinity also have sedative effects, leading some investigators to speculate that sedation may induce weight gain because of reduced mobility. 59 Genetic variation may also influence antipsychotic drug-induced weight gain. For example, treatmentnaive patients with a variant of the 5-HT 2C receptor gene are less likely to experience significant weight gain following olanzapine or risperidone therapy than those with the wild-type polymorphism.…”

Section: Weight Gainmentioning

confidence: 99%

“…71 Moreover, diabetes is frequently undiagnosed and undertreated in patients with schizophrenia, and screening methods vary significantly among different clinical studies. 71,72 Consequently, it is difficult to gauge the extent to which diabetes and other abnormalities in glucose metabolism result from Serotonin 5-HT 1A Weight gain 55 Histamine H 1 antagonism Weight gain, diabetes, sedation [51][52][53][54][55]59 Dopamine D 2 antagonism EPS, weight gain, endocrine effects [59][60][61] Muscarinic M 1 antagonism Anticholinergic (dry mouth, blurred vision, constipation) [12][13][14] Muscarinic M 3 antagonism…”

Section: Glucose Dysregulationmentioning

confidence: 99%

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Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

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Section: Weight Gainmentioning

confidence: 99%

Section: Glucose Dysregulationmentioning

confidence: 99%

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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“…For instance, an SGA that does not appear to produce BWG, ziprasidone, also binds with substantial affinity to the 5-HT 2C and H 1 receptors (Richelson, 1999;Richelson and Souder, 2000;Pouzet et al, 2003;Kirk et al, 2004). Hence, it is possible that simultaneous blockade of several (rather than single) receptor, for example, H 1 , 5-HT 2 , D 2 , and acetylcholine receptors may have a synergistic effect on increased appetite and food intake (Masand, 1999;Wetterling, 2001;Hartfield et al, 2003b).…”

Section: Effects Of Sgas On Food Intakementioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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“…Several studies have now demonstrated that a number of typical and atypical antipsychotic drugs may induce both short-and long-term weight gain (Taylor and McAskill, 2000;McIntyre et al, 2001;Wetterling, 2001). Recently, the related side effects of hyperlipidemia, hyperglycemia, and hypertension have attracted considerable attention.…”

Section: Introductionmentioning

confidence: 99%

“…The results with 5-HT 2C receptor and m3-muscarinic receptor knockout mice imply that the interactions of antipsychotic drugs with these receptors may be responsible for weight gain. Others have suggested that interactions of typical and atypical antipsychotic drugs with H 1 -histamine receptors, or their relative affinities for the D 2 and 5-HT 2A receptors, may be responsible for antipsychotic-drug-induced weight gain (eg see Wetterling, 2001).…”

Section: Introductionmentioning

confidence: 99%

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

705

494

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As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT 2A and 5-HT 2C serotonin receptors, H 1 -histamine receptors, a 1 -and a 2 -adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H 1 -histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman r ¼ À0.72; po0.01), as were affinities for a 1A adrenergic (r ¼ À0.54; po0.05), 5-HT 2C (r ¼ À0.49; po0.05) and 5-HT 6 receptors (r ¼ À0.54; po0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H 1 , a 2A , a 2B , 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors were most highly correlated with the first principal component, and affinities for the D 2 , 5-HT 1A , and 5-HT 7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H 1 and a 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H 1 -histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H 1 -histamine receptor antagonists are known to induce weight gain with chronic use, and because H 1 -histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H 1 -histamine receptors.

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Bodyweight Gain with Atypical Antipsychotics

Cited by 222 publications

References 77 publications

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

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