The United States is in the midst of an epidemic of mental illness. Mental disorders, including depressive and anxiety disorders, were one of the leading causes of disability in the United States prior to 2020. The arrival and continuous spread of COVID-19 have been associated with further increasing the prevalence of major depressive disorder (MDD).1

The United States is also battling an obesity epidemic. Approximately 75% of Americans are at an unhealthy weight.2 In 2018, the incidence of obesity (body mass index [BMI] ≥30; ≥27 for people of Asian or Pacific Islander heritage) among adults living in the United States is 42.4%. An additional 33% of adults have a BMI of 25 to 29.9 (BMI of 23 to 26.9 for people of Asian or Pacific Islander heritage), which is characterized as preobesity.2

When counseling patients diagnosed with MDD, it is important to recognize the bidirectional nature of MDD and obesity — where the worsening of one condition contributes to the development or worsening of the other. In fact, obesity is 2- to 3-times more common in individuals with mental illness compared with the general population.3

The Paradox: MDD Treatment vs Weight Gain

Antidepressants remain the first-line treatment for individuals with MDD. However, weight gain and metabolic changes are major side effects of antidepressants and contribute to high rates of treatment discontinuation.4,5 In a study of patients on long-term antidepressant therapy, 65.3% experienced weight gain.6

Weight gain may occur during the acute and maintenance phases of MDD treatment, and early weight gain can predict future gains. In a study by Asmar et al, a 3% increase in weight after 1 month of therapy was the best predictor of long-term weight gain (>15%) after 3 to 6 months of therapy in patients with a normal weight at the start of the study.7

Weight gain is often an underrecognized trigger for treatment nonadherence in patients with depression. Weight gain associated with antidepressant therapy is a significant cause of treatment nonadherence and discontinuation within 2 months of starting therapy.8

Clinicians need to counsel patients with MDD about the potential side effect of weight gain when starting antidepressant treatment. Early intervention is paramount to preventing treatment-related weight gain. To mitigate weight gain, clinicians should suggest lifestyle modifications, monitor weight, prescribe weight-neutral medications when possible, and use antiobesity medications when appropriate.

The Choice: Comparing Antidepressant Classes

Understanding how antidepressants are likely to cause weight gain will help clinicians select the best agent for the patient. In general, the antidepressant’s mechanism of action and histamine (H1) receptor affinity are the best predictors of weight gain (Table 1).9-12 For example, drugs with a high affinity for H1-receptor blockade are associated with low satiety and increased carbohydrate craving.9 Antidepressants that target serotonin (5-HT2c) receptors, norepinephrine, and dopamine are associated with both weight gain and weight reduction. Acute serotonin reuptake inhibition, for example, helps to regulate appetite while decreased inhibition (which increases extracellular serotonin concentration) can result in weight gain. Dopamine plays a role in the reward system and eating behavior. Dopamine-receptor stimulation can produce weight reduction or weight gain depending on whether the agent increases or decreases dopaminergic neurotransmission.

The agents associated with the highest risk for weight gain include amitriptyline, citalopram, mirtazapine, nortriptyline, trimipramine, paroxetine, and phenelzine. Agents associated with a medium risk of weight gain include escitalopram, sertraline, and duloxetine. Those with the lowest risk include bupropion (associated with weight reduction), desvenlafaxine, fluoxetine, imipramine, levomilnacipran, moclobemide, tranylcypromine, venlafaxine, vilazodone, and vortioxetine.9

Preventing Weight Gain

Clinicians need to be proactive to prevent weight gain in patients with a BMI in the healthy range, to prevent the development of obesity in patients whose weight is in the preobesity category, and to prevent further weight gain in patients with obesity.

When prescribing antidepressants, it is important to discuss the benefits and risks of medications, including weight gain, with patients. For patients concerned about weight gain, consider prescribing a weight-neutral agent or transitioning to a medication that will have less effect on weight. Patients should be monitored for weight gain during the acute phase of treatment.

At the onset of treatment, strategies should be implemented to prevent or minimize weight gain. Patients should receive counseling about the importance of healthful nutrition, regular physical activity, stress reduction, and adequate sleep. Because weight gain can occur in the maintenance phase of treatment, continued weight gain monitoring is recommended. Referrals can be made to dietitians, health coaches, personal trainers, obesity specialists, and other health care professionals and/or community programs as needed.

Treating Weight Gain

An overall 10-lb weight gain is clinically significant in most patients and calls for a management plan.10 Because of the health risks of excess adiposity, a gain of 3% to 4% should prompt intervention.7 Outcomes are improved with earlier intervention. Lifestyle interventions are the foundation of obesity management and include a nutritional plan, a physical activity prescription, and behavioral counseling regarding stress reduction, the benefits of adequate sleep, and other behaviors that improve daily function and quality of life. The addition of antiobesity medications may be needed to reduce weight and/or prevent further gain. Clinicians can implement these interventions or refer the patient to other health care professionals, including obesity specialists.

Medication management for obesity includes US Food and Drug Administration (FDA)-approved agents as well as off-label use of agents that have been shown to reduce weight. On average, after 1 year, people who take prescription medications as part of a lifestyle program lose 3% to 12% more of their starting body weight compared with people in a lifestyle program alone.13 Research shows that some people taking prescription antiobesity medications lose 10% or more of their starting body weight.14,15

FDA-approved medications for obesity include orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, and semaglutide (Table 2).16,17 Agents used off label for obesity include metformin, topiramate, naltrexone, bupropion, zonisamide, and glucagon-like peptide-1 (GLP-1) agonists. These medications have varying effects on weight reduction, with some individuals having a greater response than others.18

Medication choice is based on the patient’s desired effect (eg, appetite suppression, craving suppression, increased satiety, and metabolic improvement), cost, and patient preference.16

  • Naltrexone/bupropion may be beneficial for those with mood disorders, as it has antidepressant benefits. It can be added to other compatible antidepressant medications or used as a stand-alone treatment. Both approaches require close monitoring, particularly at the onset of use and with dose increases.
  • Phentermine stimulates the release of norepinephrine, dopamine, and, to a lesser extent, serotonin and therefore has some antidepressant benefits. With close monitoring, it can be used with compatible antidepressant medications.
  • Topiramate should be used cautiously in those with depression due to the side effects of drowsiness, dizziness, confusion, and slowed thinking. However, the combination of phentermine/topiramate may be better tolerated.
  • Zonisamide can worsen depression and may not be appropriate for those with depression. This agent may be used with close monitoring.
  • Orlistat decreases the absorption of fat-soluble agents as well as metformin, levothyroxine, and antiepileptics; it therefore may not be an optimal choice for those with depression who are taking these agents.17


Weight gain is a common occurrence for those on antidepressant therapy, and it warrants effective prevention, mitigation, and treatment strategies. Given the bidirectional nature of MDD and obesity, improvement of one condition has the potential to improve the other. When considering antidepressant treatments, clinicians should choose agents that minimize weight gain and/or induce weight reduction when possible. When weight gain occurs, prompt intervention is needed as doing so will improve the physical health, mental health, and quality of life of patients living with depression.

Sandra M. Christensen, MSN, ARNP, FNP-BC, FOMA, is an obesity medicine specialist in Seattle Washington. She founded Integrative Medical Weight Management where she provides comprehensive evidence-based treatment. She is a Trustee of the Obesity Medicine Association and the Washington Obesity Society. Ms Christensen is an associate editor of Obesity Pillars and the author of A Clinician’s Guide to Discussing Obesity with Patients.


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