- •
Although some atypical antipsychotic drugs, particularly olanzapine and clozapine, have more severe weight-gain side effects, all antipsychotics, including typical antipsychotics currently used clinically, may cause some degree of weight gain.
- •
There are time-dependent changes in weight gain associated with antipsychotic medication, with development of a 3-stage time course; in particular, rapid weight gain in the initial stage is a good indicator for a long-term outcome of weight gain and
Endocrinology and Metabolism Clinics of North America
Effects of Antipsychotic Medications on Appetite, Weight, and Insulin Resistance
Section snippets
Key points
Weight-Gain/Obesity Side Effects: Typical Versus Atypical APDs
It had been reported since the 1950s that treatment with some typical APDs (such as chlorpromazine) is associated with weight gain; however, many psychiatrists still hold believe that atypical APDs are associated with significant weight gain and obesity side effects, whereas typical APDs are not.14 For example, the commonly used typical APD, haloperidol, was once believed to have a minimal weight-gain side effect.14 However, a recent report on the European First-Episode Schizophrenia Trial
Effects of antipsychotic medication on appetite and food intake
Theoretically, gain in body weight results from an imbalance between energy intake and energy expenditure, whereby overeating and/or less energy expenditure (such as decreasing resting metabolism and activity) may contribute to overweight and obesity. Over the past 15 years, accumulated data from both clinical and animal studies suggest that increasing appetite and food intake, as well as delayed satiety signaling, are key behavioral changes related to APD-induced weight gain/obesity.32, 33, 34
Effects of Atypical APDs
Validated evidence over the past 20 years has indicated that APD medication significantly increases the risk of insulin resistance, glucose dysregulation, and the development of T2DM.5, 48, 49 Although patients with psychiatric disorders such as schizophrenia have been observed to have an increased risk of developing diabetes regardless of antipsychotics, suggesting that the disease itself may be a predisposing risk factor,50, 51, 52 APD medication has been widely recognized as a main
Neuropharmacologic mechanisms for APD-induced weight gain and glucometabolic side effects
In contrast to typical APDs (such as haloperidol) that are largely potent and selective D2 antagonists, atypical APDs have binding affinities for various neurotransmitter receptors, such as dopamine D2, serotonin 5-HT2A and 5-HT2C, adrenergic α1-2, muscarinic M1 and M3, and histamine H1 receptors.98 Among these receptors, dopamine D2 and 5-HT2 receptors play critical roles in the therapeutic effects of atypical APDs.99, 100 Accumulated evidence has revealed that the antagonistic properties of
Summary
Over the past 20 years it has been established that treatment with atypical APDs is associated with serious weight gain, obesity, and other metabolic side effects such as insulin resistance, glucose dysregulation, and T2DM; however, the metabolic side effects associated with some typical APDs are possibly underestimated. Emerging evidence over the past 5 to 6 years from the studies in first-episode psychotic and drug-naïve patients show that some commonly used typical APDs (such as haloperidol)
References (136)
- et al.
Treatment of first-episode schizophrenia: pharmacological and neurobiological aspects
Drug Discov Today
(2011) - et al.
New-onset type-2 diabetes associated with atypical antipsychotic medications
Prog Neuropsychopharmacol Biol Psychiatry
(2006) - et al.
Antipsychotic drugs and obesity
Trends Mol Med
(2011) - et al.
Obesity as a risk factor for antipsychotic noncompliance
Schizophr Res
(2004) - et al.
Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial
Lancet
(2008) - et al.
Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study
Schizophr Res
(2009) - et al.
Are there different neural mechanisms responsible for three stages of weight gain development in anti-psychotic therapy: temporally based hypothesis
Asian J Psychiatr
(2012) - et al.
Olanzapine differentially affects 5-HT2A and 2C receptor mRNA expression in the rat brain
Behav Brain Res
(2006) - et al.
Short- and long-term effects of antipsychotic drug treatment on weight gain and H1 receptor expression
Psychoneuroendocrinology
(2008) - et al.
The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain?
Prog Neuropsychopharmacol Biol Psychiatry
(2010)
Influence of resting energy expenditure on weight gain in adolescents taking second-generation antipsychotics
Clin Nutr
Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design
Pharmacol Ther
Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection
Behav Brain Res
Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats
Behav Brain Res
Obesity among those with mental disorders: a National Institute of Mental Health meeting report
Am J Prev Med
Insulin resistance following continuous, chronic olanzapine treatment: an animal model
Schizophr Res
Intermittent treatment with olanzapine causes sensitization of the metabolic side-effects in rats
Neuropharmacology
Preclinical models of antipsychotic drug-induced metabolic side effects
Trends Pharmacol Sci
Chlorpromazine exacerbates hepatic insulin sensitivity via attenuating insulin and leptin signaling pathway, while exercise partially reverses the adverse effects
Life Sci
The elucidation of the mechanism of weight gain and glucose tolerance abnormalities induced by chlorpromazine
J Pharm Sci
Clozapine-induced weight gain predicts improvement in psychopathology
Schizophr Res
Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naive population
Schizophr Res
Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents
J Psychiatr Res
Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model
Schizophr Res
Insulin resistance and secretion in vivo: effects of different antipsychotics in an animal model
Schizophr Res
A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model
Prog Neuropsychopharmacol Biol Psychiatry
The time-dependent change of insulin secretion in schizophrenic patients treated with olanzapine
Prog Neuropsychopharmacol Biol Psychiatry
The role of serotonin receptors in the action of atypical antipsychotic drugs
Curr Opin Pharmacol
Half a century of antipsychotics and still a central role for dopamine D2 receptors
Prog Neuropsychopharmacol Biol Psychiatry
The Global Burden of Disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020
Managing the metabolic adverse effects of antipsychotic drugs in patients with psychosis
Australian Prescriber
Second-generation atypical antipsychotics and metabolic effects. a comprehensive literature review
CNS Drugs
Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia
Curr Opin Investig Drugs
Clozapine versus other atypical antipsychotics for schizophrenia
Cochrane Database Syst Rev
Which comes first: atypical antipsychotic treatment or cardiometabolic risk?
Acta Psychiatr Scand
Antipsychotic-induced weight gain: a comprehensive research synthesis
Am J Psychiatry
Metabolic considerations in the use of antipsychotic medications: a review of recent evidence
J Clin Psychiatry
Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder
Arch Gen Psychiatry
Folie en masse! It's so tempting to drink the Kool-Aid
Curr Psychiatr
Effect of antipsychotics on peptides involved in energy balance in drug-naive psychotic patients after 1 year of treatment
J Clin Psychopharmacol
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia
N Engl J Med
Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol
Br J Psychiatry
Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study
Am J Psychiatry
Long-term treatment with atypical antipsychotics and the risk of weight gain: a literature analysis
Drug Saf
Association of initial antipsychotic response to clozapine and long-term weight gain
Am J Psychiatry
Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders
J Clin Psychopharmacol
The potential role of appetite in predicting weight changes during treatment with olanzapine
BMC Psychiatry
Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review
J Clin Psychiatry
The association of weight gain and olanzapine plasma concentrations
J Clin Psychopharmacol
Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration
J Clin Psychopharmacol
Cited by (140)
Salsalate and/or metformin therapy confer beneficial metabolic effects in olanzapine treated female mice
2023, Biomedicine and PharmacotherapyDiabetes and Mental Health
2023, Canadian Journal of DiabetesEating cognitions, emotions and behaviour under treatment with second generation antipsychotics: A systematic review and meta-analysis
2023, Journal of Psychiatric ResearchDrug-induced hyperglycemia and diabetes
2023, TherapiesAntipsychotic Use in Early Pregnancy and the Risk of Maternal and Neonatal Complications
2022, Mayo Clinic Proceedings
Funding Sources: This study was supported by a Project grant (APP1044624) from the National Health and Medical Research Council (NHMRC), Australia.
Conflicts of Interest: None.