Weight gain is a common and often concerning side effect of psychotropic medications, including antidepressants, antipsychotics, lithium, and anticonvulsants. A systematic review by Sepulvida-Lizcano et al. found that 89% of frequently prescribed psychotropic medications are associated with metabolic alterations. This is particularly concerning for children and adolescents, who are at heightened risk of weight gain due to these drugs.
Psychotropic drug-related weight gain can lead to non-initiation, discontinuation, or dissatisfaction with treatment. Moreover, it contributes to obesity, which is linked to an increased risk of sleep apnea, type 2 diabetes, dyslipidemia, nonalcoholic fatty liver disease, and cardiovascular disease. Therefore, healthcare providers must be aware of the differential risks associated with psychotropic medications in order to evaluate these risks against the potential therapeutic benefits.
ANTIDEPRESSANTS
The risk of weight gain varies significantly across different antidepressants. Those associated with a high risk of weight gain include:
- Amitriptyline
- Citalopram
- Clomipramine
- Fluvoxamine
- Mirtazapine
- Nortriptyline
- Paroxetine
- Phenelzine
Moderate-risk antidepressants include:
- Desipramine
- Duloxetine
- Escitalopram
- Sertraline
- Venlafaxine
Low-risk antidepressants include:
- Agomelatine
- Desvenlafaxine
- Gepirone
- Levomilnacipran
- Moclobemide
- Selegiline
- Tranylcypromine
- Vilazodone
- Vortioxetine
Antidepressants with a neutral or weight-loss effect include:
- Bupropion
- Dextromethorphan-bupropion
- Esketamine
- Fluoxetine
- Zuranolone
Antidepressants are thought to stimulate appetite and caloric intake due to their effects on cholinergic, histaminergic (H1), and serotonergic receptors.
ANTIPSYCHOTICS
Antipsychotics, particularly second-generation antipsychotics, are strongly associated with weight gain. The medications most likely to cause significant weight gain include:
- Clozapine
- Olanzapine
Moderate-risk antipsychotics include:
- Chlorpromazine
- Olanzapine/samidorphan
- Paliperidone
- Quetiapine
- Risperidone
Low-risk antipsychotics include:
- Amisulpride
- Aripiprazole
- Asenapine
- Brexpiprazole
- Cariprazine
- Haloperidol
- Iloperidone
- Ziprasidone
Antipsychotics with a neutral risk for weight gain include:
- Lumateperone
- Lurasidone
Risk factors for weight gain with antipsychotics include younger age, early stages of illness, antipsychotic-naïve status, lower pretreatment weight, and weight gain soon after starting treatment. Weight gain is dose-dependent with certain antipsychotics, such as olanzapine, and tends to increase with longer exposure. It is thought to result from a combination of factors, including high affinity and antagonism at histamine (H1), alpha-1 adrenergic, and 5-HT2C receptors; the absence of specific genetic variants (i.e., 5-HT2C receptor variant); and interactions between central dopamine and insulin signaling.
Lithium and Anticonvulsants. Among anticonvulsants, valproic acid carries the highest risk for weight gain. Lithium can also lead to weight gain, though the risk is generally considered lower than thought previously. Anticonvulsants with a low risk of weight gain include carbamazepine, gabapentin, oxcarbazepine, and pregabalin, while lamotrigine and topiramate have the lowest risk.
Preventing and managing psychotropic drug-related weight gain involves several strategies. These include encouraging lifestyle and behavioral modifications, prioritizing medications with a lower risk of weight gain, and adhering to metabolic monitoring guidelines. Additionally, providers can consider medications to promote weight gain.
For both adults and youth, metformin can be prescribed to prevent or treat weight gain related to antipsychotics. There is also some preliminary evidence suggesting that glucagon-like peptide-1 (GLP-1) agonists may help manage psychotropic-drug related weight gain, perhaps even more effectively than metformin; however, further research is needed.
References
Mansuri Z, Makani R, Trivedi C, et a. The role of metformin in treatment of weight gain associated with atypical antipsychotic treatment in children and adolescents: A systematic review and meta-analysis of randomized controlled trials. Frontiers in Psychiatry. 2022;13. doi:10.3389/fpsyt.2022.933570
McIntyre RS, Kwan ATH, Rosenblat JD, Teopiz KM, Mansur RB. Psychotropic Drug–Related Weight Gain and Its Treatment. American Journal of Psychiatry. 2024;181(1):26-38. doi:10.1176/appi.ajp.20230922
Sepúlveda-Lizcano L, Arenas-Villamizar VV, Jaimes-Duarte EB, et al. Metabolic Adverse Effects of Psychotropic Drug Therapy: A Systematic Review. European journal of investigation in health, psychology and education. 2023;13(8):1505-1520. doi:10.3390/ejihpe13080110
AUTHOR:
Dr. Kristen Kim, MD
Child, Adolescent and Adult Psychiatrist
Vista Hill Foundation