02. Which Antidepressants Cause the Most Weight Gain?

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Weight Gain: A Key Antidepressant Concern

I often encounter patients who are deeply concerned about potential weight gain when starting antidepressant medication. This concern is valid, given the metabolic risk factors associated with weight gain. However, providing accurate information about weight changes can be challenging, due to the complex relationship between depression and weight.

Untreated depression can affect appetite and psychomotor activity in various ways, making it difficult to isolate the direct effects of antidepressants on weight.

Fortunately, a new study published in the Annals of Internal Medicine aims to address this issue by comparing weight changes across different antidepressants.

Study Design Mimics Clinical Trials

This study employed a target trial emulation design, which attempts to replicate the procedures and criteria of a randomized trial through retrospective chart review.

The researchers analyzed data from over a million patients who started antidepressants during the 2010s, ultimately including 183,000 patients who met specific criteria:

• Monotherapy with one of eight commonly prescribed antidepressants
• Age between 20 and 80 year
• Baseline weight measurement within three months of medication initiation

Exclusion criteria included conditions significantly affecting weight, such as cancer, pregnancy, or recent bariatric surgery.

While not truly randomized, this approach provides valuable insights into antidepressant-related weight changes.

Escitalopram Leads in Weight Gain

After adjusting for various factors, the study found that:

• Escitalopram users gained the most weight: 1.03 kg more than sertraline users after six months
• Bupropion users lost 0.8 kg relative to sertraline users
• Other antidepressants showed no significant difference compared to sertraline

Intent-to-Treat Analysis Reveals Nuances

Considering medication adherence varied from 28% to 41%, the researchers conducted an intent-to-treat analysis. This approach revealed:

• Escitalopram still led in weight gain: 0.41 kg more than sertraline
• Paroxetine, duloxetine, venlafaxine, and citalopram also showed slightly more weight gain than sertraline
• Fluoxetine showed no significant difference from sertraline
• Bupropion users gained 0.22 kg less than sertraline users

Clinically Significant Weight Gain

The study also examined the risk of gaining more than 5% of body weight:

• Escitalopram, paroxetine, and duloxetine showed a 10-15% greater risk
• Bupropion demonstrated a 15% reduced risk

Surprising Findings and Limitations

I found it intriguing that escitalopram users gained significantly more weight than citalopram users, despite citalopram being half escitalopram. This raises questions about potential confounding factors or unexpected properties of the R-enantiomer.

While this large-scale observational study provides valuable insights, it’s worth noting that mirtazapine, often associated with weight gain, was not included due to its limited use in the sample.

Clinical Implications

We should consider weight gain potential when selecting antidepressants, but remember it’s just one factor among many. For patients with major depression concerned about sexual side effects and seeking improved attention, bupropion’s reduced risk of weight gain adds to its potential benefits.

Ultimately, this study provides a useful guide for clinical practice, helping us better inform our patients about potential weight changes associated with different antidepressants.

Abstract

Medication-Induced Weight Change Across Common Antidepressant Treatments: A Target Trial Emulation Study

Joshua Petimar, ScD, Jessica G. Young, Ph.D., Han Yu, Ph.D., Sheryl L. Rifas-Shiman, MPH, Matthew F. Daley, M.D., William J. Heerman, M.D., MPH, David M. Janicke, Ph.D., and Jason P. Block, M.D, MPH.

Background:

Antidepressants are among the most commonly prescribed medications, but evidence on comparative weight change for specific first-line treatments is limited.

Objective:

To compare weight change across common first-line antidepressant treatments by emulating a target trial.

Design:

Observational cohort study over 24 months.

Setting:

Electronic health record (EHR) data from 2010 to 2019 across 8 U.S. health systems.

Participants:

183 118 patients.

Measurements:

Prescription data determined initiation of treatment with sertraline, citalopram, escitalopram, fluoxetine, paroxetine, bupropion, duloxetine, or venlafaxine. The investigators estimated the population-level effects of initiating each treatment, relative to sertraline, on mean weight change (primary) and the probability of gaining at least 5% of baseline weight (secondary) 6 months after initiation. Inverse probability weighting of repeated outcome marginal structural models was used to account for baseline confounding and informative outcome measurement. In secondary analyses, the effects of initiating and adhering to each treatment protocol were estimated.

Results:

Compared with that for sertraline, estimated 6-month weight gain was higher for escitalopram (difference, 0.41 kg [95% CI, 0.31 to 0.52 kg]), paroxetine (difference, 0.37 kg [CI, 0.20 to 0.54 kg]), duloxetine (difference, 0.34 kg [CI, 0.22 to 0.44 kg]), venlafaxine (difference, 0.17 kg [CI, 0.03 to 0.31 kg]), and citalopram (difference, 0.12 kg [CI, 0.02 to 0.23 kg]); similar for fluoxetine (difference, −0.07 kg [CI, −0.19 to 0.04 kg]); and lower for bupropion (difference, −0.22 kg [CI, −0.33 to −0.12 kg]). Escitalopram, paroxetine, and duloxetine were associated with 10% to 15% higher risk for gaining at least 5% of baseline weight, whereas bupropion was associated with 15% reduced risk. When the effects of initiation and adherence were estimated, associations were stronger but had wider CIs. Six-month adherence ranged from 28% (duloxetine) to 41% (bupropion).

Limitation:

No data on medication dispensing, low medication adherence, incomplete data on adherence, and incomplete data on weight measures across time points.

Conclusion:

Small differences in mean weight change were found between 8 first-line antidepressants, with bupropion consistently showing the least weight gain, although adherence to medications over follow-up was low. Clinicians could consider potential weight gain when initiating antidepressant treatment.

Primary Funding Source:

National Institutes of Health.

Reference

Petimar, J. ScD, Young, J. Ph.D., Yu, H. Ph.D., Rifas-Shiman, S. MPH, Daley, M. M.D., Heerman, W. M.D., MPH, Janicke, D. Ph.D., & Block, J. M.D, MPH. (2024). Medication-Induced Weight Change Across Common Antidepressant Treatments: A Target Trial Emulation Study. Annals of Internal Medicine. Volume 177, Number 8.