Depression Risk Unchanged in Patients with Obesity Taking Semaglutide

Thomas A. Wadden, PhD

Credit: Perelman School of Medicine

A post hoc analysis of the STEP 1, 2, 3 and 5 trials showed no clinically significant differences in depression symptoms or suicidal ideation/behavior between the semaglutide and placebo groups. Depression scores remained similar throughout the trials, and less than 1% of participants reported suicidal thoughts or behavior in either group.

The drug was also linked to a small but statistically significant reduction in depressive symptoms, though it was not deemed clinically meaningful. Findings suggest that semaglutide 2.4 mg does not increase the risk of psychiatric issues compared with placebo. However, investigators encourage providers to monitor patients with obesity for mental health concerns so they can receive the appropriate care and support.

Obesity has been linked to a number of psychosocial complications, such as an increased risk of depressive disorders and other psychiatric illnesses. This is particularly noticeable among those with a body mass index of ≥ 40. This may be due in part to the stigma of obesity, although depression can also increase the risk of weight gain.

Therefore, psychiatric safety is considered an important factor when treating patients with obesity. However, few studies have evaluated the psychiatric safety of newly available medications for weight loss.

The analysis assessed the psychiatric safety of once weekly subcutaneous semaglutide 2.4 mg in people with overweight or obesity without known major psychopathology. Investigators used pooled data from the randomized, double-blind, placebo-controlled, multicenter STEP 1, 2 and 3 trials—conducted over 68 weeks—and STEP 5, which was performed over 104 weeks.

“Randomized clinical trials are critical for understanding post-marketing reports of depression and suicidality in the general population prescribed glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes (T2D) or weight management,” wrote lead investigator Thomas A. Wadden, PhD, professor of Psychology in Psychiatry at the Perelman School of Medicine at the University of Pennsylvania.

Differences in Patient Health Questionnaire 9 (PHQ-9) scores were evaluated between patients receiving semaglutide 2.4 mg and placebo groups. The proportion of patients reporting any suicidal ideation or behavior was determined by the Columbia-Suicide Severity Rating Scale. Psychiatric and nervous system disorder-related adverse events were also monitored.

A total of 3,377 patients were included from the STEP 1, 2 and 3 trials and 304 patients from the STEP 5 trial. Most patients were women (69.6% and 77.6%, respectively) and the mean age was 49 years and 47 years, respectively.

At baseline, In STEP 1, 2 and 3, the mean PHQ-9 scores for the semaglutide and control groups were 2.0 and 1.8, respectively, which suggested no or minimal symptoms of depression. At the conclusion of the studies, the mean scores were 2.0 and 2.4, respectively. Additionally, those receiving semaglutide were less likely to move to a more severe category of depression.

Suicidal ideation/behavior was also comparable between groups, with 1% or fewer reporting suicidal ideation or behavior during treatment with semaglutide. Adverse events related to psychiatric disorders were generally balanced between cohorts, and similar results were reported for the STEP 5 trial analysis.

Strengths of the analysis included the large sample size, inclusion of well-validated measures of depressive symptoms and the use of randomized clinical trials. Bias was mitigated due to the high retention rates in both groups. However, excluding patients with previous suicide attempts, those and high risk of suicidal ideation and those recently diagnosed with major depressive disorder limited the study as they may be more vulnerable to psychiatric adverse events while taking the medication compared with the general population.

“A small number of patients taking semaglutide, 2.4 mg, may experience depression or suicidal ideation, which may be related to psychosocial complications of obesity or other factors, including life stressors,” investigators noted.