Semaglutide’s Weight-Loss Benefit Also Seen in Patients on Antidepressants

DALLAS — People taking antidepressants lost a similar amount of weight on semaglutide 2.4 mg (Wegovy) compared with those not taking antidepressants, according to a post-hoc analysis of four STEP trials.

Participants on antidepressants taking the GLP-1 receptor agonist lost an average 10.7% to 19% of their baseline body weight compared to a 9.5% to 15.9% loss in participants not taking antidepressants, reported Robert Kushner, MD, of Northwestern University Feinberg School of Medicine in Chicago, during the ObesityWeek annual meeting.

“In all trials in the semaglutide treatment arm, the change from baseline in percent body weight loss was greater in participants on antidepressants versus those who were not,” Kushner told attendees.”In the placebo arm of the trials, the opposite was observed.”

Total adverse events, as well as gastrointestinal and psychiatric adverse events, however, were also more common in patients taking antidepressants during the trials compared with those who were not.

Several antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), can lead to weight gain, but people with major depression are usually excluded from weight loss studies, leaving an evidence gap regarding the effectiveness of obesity medications in people taking antidepressants, Kushner noted.

“Emotional and psychological behaviors affecting control over eating and satiety are associated with obesity and depression and can contribute to metabolic dysfunction and weight gain in a mutually reinforcing cycle,” he explained.

Although the STEP trials also excluded patients with major depression, they did include patients taking antidepressants for other conditions, such as anxiety, obsessive compulsive disorder, sleep disturbances, neuropathy, panic disorder, post-traumatic stress disorder, and chronic pain.

In STEP 1, participants taking antidepressants lost an average 15.7% of body weight, while those not taking antidepressants lost 14.7% of body weight with semaglutide, compared with losses of 0.2% and 2.8% in the placebo groups with and without use of antidepressants, respectively. In STEP 2, participants taking semaglutide lost 10.7% and 9.5% of body weight with and without antidepressants compared with 3.3% and 3.4% losses, respectively, in the placebo groups.

In STEP 3, participants taking antidepressants lost 16.2% of body weight, while those not taking antidepressants lost 15.9% versus 5% and 5.9% in the placebo groups. Finally, in STEP 5, participants taking antidepressants lost 19% of body weight, while those not taking antidepressants lost 14.1%, and placebo participants gained 1.6% of body weight with antidepressants and lost 4% without antidepressants.

Kushner did not share P values or confidence intervals, but he noted that “significance for treatment by subgroup interactions between participants on antidepressants at baseline and those who were not was found in STEP 1 and STEP 5.”

In the STEP 1, 2, 3, and 5 trials, a combined 3,683 adults with overweight or obesity received either placebo or 2.4 mg of subcutaneous semaglutide once a week; 539 reported taking antidepressants at baseline. Only participants in STEP 2 had type 2 diabetes, and the 403 participants receiving 1-mg semaglutide (Ozempic) in this study were excluded from this analysis. STEP 1, 2, and 5 participants also received lifestyle intervention, and STEP 3 participants underwent intensive behavioral therapy.

All participants had a body mass index (BMI) of at least 30, or at least 27 with at least one weight-related complication (including type 2 diabetes for the STEP 2 participants). They also all had unsuccessfully attempted to lose weight at least once. No participants in any of the trials had major depressive disorder within 2 years before screening or a score of at least 15 or greater on the Patient Health Questionnaire-9 at screening.

STEP 1, 2, and 3 lasted for 68 weeks, and STEP 5 lasted 104 weeks.

Adverse event rates with semaglutide were higher in participants taking antidepressants at baseline. Across the four trials, 97.6% to 100% of participants taking antidepressants reported adverse events compared with 86.7% to 95.3% of participants not taking antidepressants. In the placebo groups, adverse event rates were also higher among those taking antidepressants (88.4% to 100%) than those not taking them (77.2% to 95.8%).

Gastrointestinal adverse events with semaglutide were also higher among those taking antidepressants across all four trials. Though rates of psychiatric adverse events were substantially lower than rates for gastrointestinal events, they were also more common among the participants taking antidepressants with the GLP-1 receptor agonist.

There were no significant differences in reports of suicidal ideation between those taking antidepressants and those not taking them in any of the trials. The questionnaire used for suicide assessment in the STEP trials asked whether participants intended to die by suicide, with or without a plan, or had nonspecific thoughts or wishes to be dead, Kushner said.

In STEP 2, 3, and 5, none of the patients taking antidepressants in the semaglutide or placebo groups reported suicidal ideation, though a few participants not taking antidepressants reported it. Among participants taking antidepressants in STEP 1, two patients in the placebo group and two patients in the semaglutide group had suicidal ideation.

Jack Yanovski, MD, PhD, chief of the section on growth and obesity at the NIH Intramural Research Program, noted that “it’s really important that we understand what goes on in patients with depression.”

Kushner pointed to the strict guidelines and use of the Columbia-Suicide Severity Rating Scale that were put in place after use of other weight-loss drugs appeared to increase risk of suicidal ideation.

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