Semaglutide induces weight loss despite antidepressant use

Treatment with semaglutide 2.4 mg results in clinically meaningful weight loss, irrespective of baseline antidepressant (AD) use, among adults with overweight/obesity, reports a post hoc study of the Semaglutide Treatment Effect for People with obesity (STEP).

“In this population, semaglutide demonstrated weight loss efficacy comparable to that in people with overweight/obesity who did not take ADs,” the investigators said. “Adverse events (AEs) for semaglutide were consistent with the glucagon-like peptide-1 receptor agonist drug class.”

The STEP 1‒3 and 5 trials enrolled adults with overweight/obesity and type 2 diabetes (STEP 2 only). Participants with severe major depressive disorder (MDD) within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded.

The investigators categorized participants into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials.

A total of 3,683 overweight/obese adults were included, of whom 539 were using ADs at baseline. Mean body weight change from baseline to week 68 was greater in participants treated with semaglutide than those on placebo, regardless of baseline AD use. [Obesity 2024;32:273-280]

In STEP 1, mean change from baseline was ‒15.7 percent with semaglutide versus ‒0.2 percent with placebo among participants on ADs at baseline and ‒17.7 percent versus ‒2.8 percent, respectively, for those not on ADs at baseline. Similar patterns were observed in STEP 2, 3, and 5.

AE prevalence was comparable between the two treatment groups in participants on ADs at baseline.

“Permanent discontinuation rates varied across the trials, and there were generally more AEs in participants on ADs at baseline versus those who were not,” the investigators said.

“A potential explanation for this could be that symptoms of depression can manifest as gastrointestinal complications (eg, nausea or stomach pain); therefore, people suffering from depression or anxiety who are on ADs may already be monitoring and/or experiencing these symptoms, thus lowering the threshold for detecting these AEs,” they added.

Semaglutide 2.4 mg was not known to have any direct interaction with ADs, but some ADs may cause gastrointestinal side effects, thus compounding an overlapping AE profile. [Cleve Clin J Med 2006;73:351-361; https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215256s005lbl.pdf; https://www.ema.europa.eu/en/documents/product-information/wegovy-epar-product-information_en.pdf;

The results of the present study were in line with those of a previous analysis on liraglutide 3.0 mg, wherein a secondary endpoint assessed weight loss in people with obesity who also had underlying psychiatric disorders such as depression, anxiety, schizophrenia, and bipolar disorder. [Endocr Pract 2020;26:235-240]

“The results from this study support future trials examining the impact of weight-management medications in individuals with MDD and other psychiatric disorders and will be of interest to practitioners and patients when considering an optimal treatment plan for such individuals,” according to the investigators.