Drug Induced Weight Gain, an Impediment to Successful Pharmacotherapy: Focus on Antipsychotics

Abstract

The antipsychotic drugs (APDs) are fundamental tools in current psychiatric practice. A new generation of agents, the atypical APDs, represents an important progress in the treatment of psychotic disorders. Unfortunately, some of them induce excessive body weight gain (BWG), obesity, hyperglycemia and dyslipidemia in the following order: clozapine approximately equal to olanzapine > quetiapine > risperidone > ziprasidone = aripiprazole. Appetite stimulation is probably the main mechanism of BWG and this is strongly correlated with the APD affinity for H1 (histaminergic) and alpha1 (adrenergic) receptors. A composed ratio of the APD affinity for diverse neurotransmitters involved in food intake (FI) regulation correlates with BWG as well. Endocrine/metabolic mechanisms, such as the activation of the hypothalamus-pituitary-adrenal axis, changes in insulin sensitivity (by conventional and atypical agents), hyperprolactinemia and gonadal dysfunction (by conventional APDs and risperidone) may also be involved. Importantly, patients with schizophrenia may have a genetically-based predisposition to appetite dysregulation, insulin resistance and endocrine imbalance involving gonadal steroids. Excessive BWG must be prevented or attenuated by proper drug selection, combining or switching agents, nutritional assistance and physical exercise. Amantadine. metformin and reboxetine proved to significantly lessen APD-induced BWG. Notwithstanding this, novel strategies are necessary to treat this side effect in a clinical population particularly prone to poor compliance and under a high risk of negative drug interaction.

No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs

“…Overall, appetite stimulation seems to be an important mechanism for BW gain induced by AAD. 40 In the current study, we found that food intake was increased by all AAD tested, suggesting that hyperphagia is indeed a cause of the increased weight gain. However, our analysis of FE (weight gain/kcal consumed) would suggest that hyperphagia is not the only mechanism responsible for the weight gain.…”

Ziprasidone versus Olanzapine in the weight gain associated with the treatment of schizophrenia: A six-month double-blind randomized parallel group study

“…In this study, appetite decreased significantly in ziprasidone treated patients while no significant change in olanzapine treated patients was reported. Appetite stimulation is strongly correlated with antipsychotic drug affinity for H1 and alpha1 adrenergic receptors 35 and appetite decrease in ziprasidone treated patients is probably associated to the drug's low affinity for H1 re- ceptor. The olanzapine treated patients did not show a significant increase in appetite, but still showed a significant increase in body weight, suggesting that other mechanisms may be involved in olanzapine-induced weight gain.…”

Food and Drug Administration's Obesity Drug Guidance Document

“…[52][53][54] The 2007 draft guidance recommends that subjects eligible for participation in trials examining the efficacy and safety of obesity drugs for the treatment of medication-induced weight gain have a documented increase in body weight of at least 5% within 6 months of starting a drug known to cause weight gain. Furthermore, subjects should have BMIs Ն30 kg/m 2 or Ն27 kg/m 2 with comorbidities at the time of study screening.…”