Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

Yoon, Sehyoun; Noh, Jai Sung; Choi, Se‐Young; Baik, Ja Hyun

doi:10.1016/j.bbrc.2010.01.108

Cited by 15 publications

(8 citation statements)

References 37 publications

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“…Several studies suggest that weight reduction may be associated with decreased activity but depending on the doses administered. Some authors have shown a relationship of the neuroleptic effects of olanzapine, ziprasidone, and risperidone with the decrease in food intake, the reduction of body mass, and motor activity since these changes are only present in wild-type mice but not in D2R knockout mice (Yoon et al, 2010). However, treatment with risperidone 4 mg/kg p.o.…”

Section: Discussionmentioning

confidence: 99%

Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer’s Disease and Mice With Normal Aging

2019

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Psychosis and/or aggression are common problems in dementia, and when severe or persistent, cause considerable patient distress and disability, caregiver stress, and early institutionalization. In 2005, the Food and Drug Administration (FDA) determined that atypical antipsychotics were associated with a significantly greater mortality risk compared to placebo, which prompted the addition of an FDA black-box warning. The American College of Neuropsychopharmacology (ACNP) White Paper, 2008, reviewed this issue and made clinical and research recommendations regarding the use of antipsychotics in dementia patients with psychosis and/or agitation. Increased mortality risk has also been described in cerebrovascular adverse events in elderly users of antipsychotics. In the present work, at the translational level, we used male 3xTg-AD mice (PS1M146V, APPSwe, tauP301L) at advanced stages of the disease reported to have worse survival than females, to study the behavioral effects of a low chronic dose of risperidone (0.1 mg/kg, s.c., 90 days, from 13 to 16 months of age) and its impact on long-term survival, as compared to mice with normal aging. Animals were behaviorally assessed for cognitive and BPSD (behavioral and psychological symptoms of dementia)-like symptoms in naturalistic and experimental conditions (open-field test, T-maze, social interaction, Morris water maze, and marble test) before and after treatment. Weight, basal glucose levels, and IPGTT (i.p. glucose tolerance test) were also recorded. Neophobia in the corner test was used for behavioral monitoring. Survival curves were recorded throughout the experiment until natural death. The benefits of risperidone were limited, both at cognitive and BPSD-like level, and mostly restricted to burying, agitation/vibrating tail, and other social behaviors. However, the work warns about a clear early mortality risk window during the treatment and long-lasting impact on survival. Reduced life expectancy and life span were observed in the 3xTg-AD mice, but total lifespan (36 months) recorded in C57BL/6 × 129Sv counterparts with normal aging was also truncated to 28 months in those with treatment. Sarcopenia at time of death was found in all groups, but was more severe in wild-type animals treated with risperidone. Therefore, the 3xTg-AD mice and their non-transgenic counterparts can be useful to delimitate critical time windows and for studying the physio-pathogenic factors and underlying causal events involved in this topic of considerable public health significance.

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Section: Discussionmentioning

confidence: 99%

Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer’s Disease and Mice With Normal Aging

2019

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“…Several reports suggest that drug-induced changes in appetite and food intake are involved in these adverse effects (Cooper et al 2005;Coccurello et al 2006;Davoodi et al 2009). Among many in vivo and in vitro studies on this mechanism, some authors have suggested that antagonism of the receptors for monoamine neurotransmitters, including dopamine, histamine, and serotonin, contributes to druginduced weight gain (Kirk et al 2009;Yoon et al 2010;Deng et al 2010). However, other mechanisms also have been proposed in the mediation of olanzapine-induced weight gain (Starrenburg and Bogers 2009).…”

Section: Introductionmentioning

confidence: 95%

A Role for Hypothalamic AMP-Activated Protein Kinase in the Mediation of Hyperphagia and Weight Gain Induced by Chronic Treatment with Olanzapine in Female Rats

et al. 2011

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Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.

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“…The effect of olanzapine, and not ziprasidone or risperidone, on rodent weight change in general appeared to be mediated at least in part by D2. 29 In D2-deficient mice, weight loss has been observed, along with increased oxygen consumption, decreased food intake and decreased plasma levels of leptin, an adipose hormone implicated in growth, glucose metabolism and reproduction. 30 An enhanced response to leptin, indicated by STAT3 phosphorylation, was observed.…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of dopamine receptor genes (DRD1–DRD5) in antipsychotic-induced weight gain

et al. 2010

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Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

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Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

Cited by 15 publications

References 37 publications

Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer’s Disease and Mice With Normal Aging

Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer’s Disease and Mice With Normal Aging

A Role for Hypothalamic AMP-Activated Protein Kinase in the Mediation of Hyperphagia and Weight Gain Induced by Chronic Treatment with Olanzapine in Female Rats

Systematic analysis of dopamine receptor genes (DRD1–DRD5) in antipsychotic-induced weight gain

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