H1-histamine Receptor Affinity Predicts Short-term Weight Gain for Typical and Atypical Antipsychotic Drugs

Goudie, Andrew J.; Halford, Jason C.G.; Dovey, Terence M.; Cooper, Gail; Neill, Joanna C.

doi:10.1038/sj.npp.1300291

Cited by 23 publications

(12 citation statements)

References 3 publications

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“…These represent functional evidence of the central role of histamine in mediating feeding, as well as of the consequences of a serious depletion of central hypothalamic histamine. Drawing on the above discussion and considering the high positive correlation between H1 affinity and propensity to elicit weight gain, we agree with the suggestions (i.e., Wirshing et al 1999;Goudie et al 2003;Kroeze et al 2003) that in developing new AAPs, special attention should be paid to the extent these compounds can selectively bind H 1 receptors.…”

Section: Aaps and Metabolic Dysregulation: Insulin Resistance On Metasupporting

confidence: 89%

Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects

et al. 2006

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Section: Aaps and Metabolic Dysregulation: Insulin Resistance On Metasupporting

confidence: 89%

Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects

et al. 2006

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“…16 H1-histamine receptors have been linked to some of the metabolic side effects of atypical antipsychotics. 5,[34][35][36] However, 2 example antihistamines tested here, astemizole and terfenadine, did not cause any effects on RER or VO 2 . It seems unlikely, therefore, that histamine receptors are involved in these responses.…”

Section: Cpt-1 Inhibitors and Sgasmentioning

confidence: 61%

Second-Generation Antipsychotics Cause a Rapid Switch to Fat Oxidation That Is Required for Survival in C57BL/6J Mice

Klingerman

Stipanovic

Bader

et al. 2013

Schizophrenia Bulletin

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Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO 2 ), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10 mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO 2 , and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO 2 , in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO 2 , or physical activity. The VO 2 and RER effects appear independent of sedation/ physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO 2 by itself caused precipitous drops in VO 2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO 2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.

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“…Many atypical antipsychotics are H 1 antagonists [126,127] and H 1 receptor affinity is the most reliable predictor of antipsychotic weight gain [128–132]. A role of the H 1 receptor is supported further by a pilot study that showed that treatment with β‐histine, a H 1 agonist but H 3 antagonist, attenuated olanzapine‐induced weight gain [133].…”

mentioning

confidence: 96%

Obesity, serious mental illness and antipsychotic drugs

Holt

Peveler

2009

Diabetes Obesity Metabolism

135

103

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The prevalence of overweight and obesity is higher in people with mental illness than in the general population. Body weight is tightly regulated by a complex system involving the cortex and limbic system, the hypothalamus and the gastrointestinal tract. While there are justifiable concerns about the weight gain associated with antipsychotic medication, it is too simplistic to ascribe all obesity in people with serious mental illness (SMI) to their drug treatment. The development of obesity in SMI results from the complex interaction of the genotype and environment of the person with mental illness, the mental illness itself and antipsychotic medication. There are dysfunctional reward mechanisms in SMI that may contribute to poor food choices and overeating. While it is clear that antipsychotics have profound effects to stimulate appetite, no one receptor interaction provides an adequate explanation for this effect, and many mechanisms are likely to be involved. The complexity of the system regulating body weight allows us to start to understand why some individuals appear much more prone to weight gain and obesity than others.

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H1-histamine Receptor Affinity Predicts Short-term Weight Gain for Typical and Atypical Antipsychotic Drugs

Cited by 23 publications

References 3 publications

Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects

Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects

Second-Generation Antipsychotics Cause a Rapid Switch to Fat Oxidation That Is Required for Survival in C57BL/6J Mice

Obesity, serious mental illness and antipsychotic drugs

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