Atypical antipsychotics and effects on feeding: from mice to men

Benarroch, Louise; Kowalchuk, Chantel; Wilson, Virginia; Teo, Celine; Guenette, Melanie; Chintoh, Araba; Nesarajah, Yasika; Taylor, Valerie H.; Selby, Peter; Fletcher, Paul; Remington, Gary; Hahn, Margaret

doi:10.1007/s00213-016-4324-8

Cited by 31 publications

(20 citation statements)

References 140 publications

(250 reference statements)

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“…Despite the associated cardio-metabolic morbidity, the underlying causes of AIWG and other metabolic changes remain largely elusive. Increased food intake appears to be a component (Benarroch et al, 2016 ), although it is less clear if AIWG is also attributable to reductions in resting energy expenditure (Cuerda et al, 2013 ). Animal and some human studies show that the various areas of neurotransmission altered by antipsychotics may affect energy and glucose regulation (Hahn et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment

et al. 2018

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Background: Antipsychotic-induced weight gain (AIWG) and other adverse metabolic effects represent serious side effects faced by many patients with psychosis that can lead to numerous comorbidities and which reduce the lifespan. While the pathophysiology of AIWG remains poorly understood, numerous studies have reported a positive association between AIWG and the therapeutic benefit of antipsychotic medications.Objectives: To review the literature to (1) determine if AIWG is consistently associated with therapeutic benefit and (2) investigate which variables may mediate such an association.Data Sources: MEDLINE, Google Scholar, Cochrane Database and PsycINFO databases were searched for articles containing all the following exploded MESH terms: schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles.Results: Our literature search uncovered 31 independent studies which investigated an AIWG-therapeutic benefit association with a total of 6063 enrolled individuals diagnosed with schizophrenia or another serious mental illness receiving antipsychotic medications. Twenty-two studies found a positive association while, 10 studies found no association and one study reported a negative association. Study variables including medication compliance, sex, ethnicity, or prior antipsychotic exposure did not appear to consistently affect the AIWG-therapeutic benefit relationship. In contrast, there was some evidence that controlling for baseline BMI/psychopathology, duration of treatment and specific agent studied [i.e., olanzapine (OLZ) or clozapine (CLZ)] strengthened the relationship between AIWG and therapeutic benefit.Limitations: There were limitations of the reviewed studies in that many had small sample sizes, and/or were retrospective. The heterogeneity of the studies also made comparisons difficult and publication bias was not controlled for.Conclusions: An AIWG-therapeutic benefit association may exist and is most likely to be observed in OLZ and CLZ-treated patients. The clinical meaningfulness of this association remains unclear and weight gain and other metabolic comorbidities should be identified and treated to the same targets as the general population. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG.

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Section: Introductionmentioning

confidence: 99%

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment

et al. 2018

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“…Preclinical studies, which can be performed in a controlled environment and also grant access to biological samples not available in clinical studies, are valuable in this context. In the female rat, antipsychotic-induced metabolic adverse effects such as hyperphagia, weight gain, increased serum lipids, and glucose dysregulation have been extensively reproduced (Boyda et al, 2010; Benarroch et al, 2016). For some dysmetabolic features, molecular mechanisms have been suggested.…”

Section: Introductionmentioning

confidence: 99%

One-Year Treatment with Olanzapine Depot in Female Rats: Metabolic Effects

Ersland

Myrmel

Fjære

et al. 2019

International Journal of Neuropsychopharmacology

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Background Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time. Methods To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months. Results Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months. Conclusion Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.

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“…AP-induced hyperphagia is a complex behavior involving both physiological and behavioral changes that cannot be replicated in cell culture systems and require a whole animal model. Pre-clinical rodent models have been established that replicate the weight gain effects of AP-treated human patients but are not suited for a screening based approach 21 .…”

Section: Introductionmentioning

confidence: 99%

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

et al. 2018

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Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

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Atypical antipsychotics and effects on feeding: from mice to men

Cited by 31 publications

References 140 publications

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment

One-Year Treatment with Olanzapine Depot in Female Rats: Metabolic Effects

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

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