By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
SYNOPSIS: This observational study finds that, compared to sertraline, six-month weight gain is higher in patients prescribed other antidepressants in the same category (paroxetine, citalopram, escitalopram) as well as in patients prescribed duloxetine and venlafaxine, similar in patients prescribed fluoxetine, and lower in patients prescribed bupropion.
SOURCE: Petimar J, Young JG, Yu H, et al. Medication-induced weight change across common antidepressant treatments: A target trial emulation study. Ann Intern Med 2024; July 2. doi: 10.7326/M23-2742. [Online ahead of print.]
Antidepressants, a cornerstone in treating various disorders of mental health, such as depression, anxiety, and other conditions, are the most prescribed medication for adults aged 20-59 years in the United States. They also are widely used by older adults.1 In clinical practice, selecting the appropriate antidepressant for a patient is challenging and may be influenced by a host of factors, including patient preference, side-effect profile, and efficacy.
Weight gain is a prevalent and often problematic side effect of antidepressant use, potentially impacting overall health, compliance, and treatment outcomes.2,3 Recognizing the variability of weight gain potential among different antidepressants and the existing knowledge gap regarding the relative weight gain associated with each of these specific medications, Petimar et al designed an extensive observational cohort study leveraging electronic health system data from more than 183,000 patients to emulate the rigor of randomized controlled trials (RCTs).
This innovative target trial emulation approach compared weight changes across eight first-line antidepressants. The resulting comprehensive analysis provides robust evidence on the weight gain profiles of these medications, ultimately attempting to guide clinicians in making more personalized and effective treatment choices.
In essence, this emulation approach entailed designing an RCT and applying the conditions and key features of such an approach to observational data. In this way, the expense and time, as well as other challenges in conducting a large-scale RCT, are bypassed.
Sertraline, a selective serotonin reuptake inhibitor (SSRI) and the most prescribed antidepressant in the United States, was selected as the reference antidepressant. The other studied antidepressants were fluoxetine, citalopram, escitalopram, and paroxetine (all SSRIs); venlafaxine (a serotonin-norepinephrine reuptake inhibitor [SNRI]); duloxetine (a selective serotonin and norepinephrine reuptake inhibitor [SSNRI]); and bupropion (a norepinephrine and dopamine reuptake inhibitor [NDRI]).
While pre-existing evidence suggests that bupropion often is associated with weight loss and SSRIs with weight gain, there is limited information on the specifics of these associations in real-world settings and among first-time antidepressant users.3 This study attempts to fill this gap by providing detailed comparative data. Data regarding weight were analyzed for up to 24 months from onset of antidepressant use, with weight measurements taken at six-, 12-, and 24-month intervals. The primary outcome was mean weight change at month 6, while the secondary outcomes were the probability of gaining at least 5% of baseline weight and adherence probabilities.
Note that no baseline cognitive scores were available. All results are based on shifts in the mean global cognitive score for each category:
- Bupropion: At six months, compared with sertraline, bupropion was associated with 0.22 kg (approx. 0.5 lb) less weight gain and patients being 15% less likely to gain at least 5% of baseline weight.
- Escitalopram: At six months, compared with sertraline, escitalopram was associated with 0.41 kg (approx. 0.9 lb) more weight gain and patients being 10% to 15% more likely to gain at least 5% of baseline weight.
- Paroxetine: At six months, compared with sertraline, paroxetine was associated with 0.37 kg (approx. 0.8 lb) more weight gain and patients being 10% to 15% more likely to gain at least 5% of baseline weight.
- Duloxetine: At six months, compared with sertraline, duloxetine was associated with 0.34 kg (approx. 0.7 lb) weight gain and patients being 10% to 15% more likely to gain at least 5% of baseline weight.
- Venlafaxine: At six months, compared with sertraline, venlafaxine was associated with 0.17 kg (approx. 0.37 lb) weight gain and patients being 10% to 15% more likely to gain at least 5% of baseline weight.
- Citalopram: At six months, compared with sertraline, citalopram was associated with 0.32 kg (approx. 0.26 lb) weight gain and patients being 10% to 15% more likely to gain at least 5% of baseline weight.
- Fluoxetine: At six months, compared with sertraline, fluoxetine was associated with no significant difference in weight change.
Notably, six-month adherence rates estimated by pharmacy records and chart review were low for all these medications, ranging from 28% for duloxetine to 41% for bupropion.
Commentary
This comprehensive analysis reveals small but potentially clinically significant differences in weight change profiles among common antidepressants. Bupropion consistently showed the least weight gain and higher adherence rates, making it a top consideration for patients where weight gain is a concern.
On the other hand, SSRIs, such as paroxetine and escitalopram, were associated with higher weight gain, potentially affecting long-term adherence and patient health outcomes.
However, it is essential to consider factors beyond weight when choosing an antidepressant. For example, bupropion can lower seizure threshold (especially in immediate release form) and is associated with sleep difficulties and worsening of tics.4 Duloxetine is helpful for chronic pain, and both venlafaxine and paroxetine can have significant adverse effects when abruptly discontinued.5,6 Additionally, fluoxetine, while mimicking the weight change profile of sertraline, can have a long half-life that might affect its discontinuation profile.6 The Petimar et al study focused on weight gain as one factor among many to consider when selecting an appropriate antidepressant.
Several limitations should be noted. The study sought to select only first-time antidepressant users but relied on electronic chart records, which may not be as reliable as pharmacy data or direct interviews. There also was no direct means to assure daily medication compliance. Finally, although robust efforts were made to emulate an RCT, the results are from an observational study, so a causal relationship cannot be established.
It also should be noted that many patients taking antidepressants also take other medications, and many have had multiple trials of different antidepressants. The results of this study cannot be generalized to include these scenarios, highlighting an area for further investigation.
Furthermore, factors such as patient comorbidities, lifestyle, and other individual characteristics can influence both weight gain and treatment adherence, suggesting a need for more personalized research approaches.
When prescribing an antidepressant, clinicians incorporate individual patient needs and preferences into prescribing decisions to optimize treatment adherence and outcomes. Information on the likelihood of weight gain from each of the specified agents has direct clinical impact and can be incorporated into the overall decision.
This study accentuates the importance of personalized medicine, where understanding the side effect profiles of medications can significantly enhance patient care. Given the potential implications of weight gain on cardiovascular and metabolic health, this information is essential for guiding both initial treatment choices and long-term management strategies.
References
- National Center for Health Statistics. Prescription drug use in the United States, 2015-2016. Centers for Disease Control and Prevention. Published May 2019. https://www.cdc.gov/nchs/products/databriefs/db334.htm
- Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up: Population based cohort study. BMJ 2018;361:k1951.
- Ghusn W, Bouchard C, Frye MA, Acosta A. Weight-centric treatment of depression and chronic pain. Obes Pillars 2022;3:100025.
- Patel K, Allen S, Haque MN, et al. Bupropion: A systematic review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol 2016;6:99-144.
- Birkinshaw H, Friedrich CM, Cole P, et al. Antidepressants for pain management in adults with chronic pain: A network meta-analysis. Cochrane Database Syst Rev 2023;5:CD014682.
- Zwiebel SJ, Viguera AC. Discontinuing antidepressants: Pearls and pitfalls. Cleve Clin J Med 2022;89:18-26.
This observational study finds that, compared to sertraline, six-month weight gain is higher in patients prescribed other antidepressants in the same category (paroxetine, citalopram, escitalopram) as well as in patients prescribed duloxetine and venlafaxine, similar in patients prescribed fluoxetine, and lower in patients prescribed bupropion.
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