Depression, suicidal behavior not observed with the naltrexone/bupropion combination in obesity

January 29, 2019

2 minute read

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According to a post hoc analysis of five placebo-controlled clinical trials, overweight or obese adults receiving naltrexone/bupropion combination therapy had fewer depression-related events than similar patients receiving placebo, with no suicidal behavior observed in patients treated.

Frank Greenway, MD

Safety concerns, including the increased risk of psychiatric adverse events such as depression, have hampered the development and approval of centrally acting obesity drugs, Frank Greenway, MD, medical director and professor at the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, and his colleagues wrote in the context of the study.

“Bupropion/naltrexone reduced depressive symptoms compared to placebo in clinical trials conducted to gain FDA approval as an obesity drug,” Greenway said. Endocrine today. “Obesity is associated with depression, so bupropion/naltrexone may be the drug of choice for patients with depressive symptoms who need obesity medication.”

Greenway and colleagues analyzed data from five placebo-controlled clinical trials, including one phase 2 trial and four phase 3 trials, all including overweight or obese adults without psychiatric disorders at baseline (>80% women; age average, 45 to 46 years; average BMI, 36.2 kg/m²). Researchers randomly assigned participants to 32 mg extended-release naltrexone plus 360 mg extended-release bupropion (Contrave, Nalpropion Pharmaceuticals; n=2,545) or placebo (n=1,515) given twice daily in divided doses. All studies were prospective and double-blind and included a 3 to 4 week dose escalation period; the duration of the studies was either 24 weeks (phase 2 study) or 56 weeks (phase 3 studies). Researchers assessed psychiatric adverse events via preferred terms at study visits, organized into major subthemes (anxiety, depression, and sleep disorders), which had incidence rates of at least 5%. The researchers used analysis of covariance to assess treatment-emergent depressive and anxiety symptoms via a change in the Inventory of Depressive Symptomatology, Self-Report (IDS-SR) total score (range of scores, 0-84) and the Columbia Classification Algorithm for Assessing Suicide.

Across all studies, 55% of participants assigned to naltrexone/bupropion and 54.7% of participants assigned to placebo completed treatment.

The most common psychiatric adverse events in the naltrexone/bupropion and placebo groups, respectively, were sleep disturbances (12.7% versus 7.9%; P 0.001), anxiety (5.4% versus 3.3%; P = 0.029) and depression, which occurred more frequently in the placebo group (1.8% versus 2.7%; P= .014). Psychiatric adverse events were most common with dose escalation and were generally mild or moderate, the researchers said.

Mean changes in the total IDS-SR score were low in both groups (0.13 for naltrexone/bupropion versus –0.45 for placebo). The researchers did not confirm any suicides, attempted suicides, or acts preparatory to imminent suicidal behavior.

“These data provide additional safety information and reassurance regarding the psychiatric effects of [naltrexone/bupropion]; however, under current etiquette, patients should be monitored for depression or suicidal thoughts,” the researchers wrote.

Greenway noted that clinical trials conducted for FDA approval excluded people with significant depression, and more research is needed to evaluate bupropion/naltrexone in people with more severe depression. – by Regina Schaffer

For more information:

Frank Greenway, MD, can be contacted at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808; email:

Disclosures: Greenway reports that he has received consulting fees from Ordemanden (acquired by Nalpropion Pharmaceuticals) and served on its advisory board, as well as grants from the company to his institution. Please see the study for relevant financial information from all other authors.