In the Journals

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

Adults with overweight or obesity assigned to combination naltrexone/bupropion therapy experienced fewer depression-related events vs. similar patients assigned to placebo, with no suicidal behaviors observed among treated patients, according to a post hoc analysis of five placebo-controlled clinical trials.

Frank Greenway, MD

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

“Bupropion/naltrexone reduced depressive symptoms compared to placebo in the clinical trials done to win FDA approval as an obesity drug,” Greenway told Endocrine Today. “Obesity is associated with depression, so bupropion/naltrexone may be the drug of choice in patients who have depressive symptoms and need an 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 adults with overweight or obesity without psychiatric conditions at baseline (> 80% women; mean age, 45 to 46 years; mean BMI, 36.2 kg/m²). Researchers randomly assigned participants to 32 mg naltrexone prolonged release plus 360 mg bupropion prolonged release (Contrave, Nalpropion Pharmaceuticals; n = 2,545) or placebo (n = 1,515) administered twice daily in divided doses. All studies were prospective and double-blind and included a dose escalation period of 3 to 4 weeks; study durations were 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 subtopics (anxiety, depression and sleep disturbances), which had incidence rates of at least 5%. Researchers used analysis of covariance to assess treatment-emergent depressive and anxiety symptoms via change in the Inventory of Depressive Symptomatology, Self-Report (IDS-SR) total score (score range, 0-84) and the Columbia Classification Algorithm of Suicide Assessment.

Across 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 disorders (12.7% vs. 7.9%; P < .001), anxiety (5.4% vs. 3.3%; P = .029) and depression, which occurred more frequently in the placebo group (1.8% vs. 2.7%; P = .014). Psychiatric adverse events were most common during dose escalation and were generally mild or moderate, according to researchers.

Mean changes in the IDS-SR total score were small in both groups (0.13 for naltrexone/bupropion vs. –0.45 for placebo). Researchers did not confirm any completed suicides, suicide attempts or preparatory acts toward imminent suicidal behavior.

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

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

For more information:

Frank Greenway, MD, can be reached at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808; email: frank.greenway@pbrc.edu.

Disclosures: Greenway reports he has received consultant fees from Orexigen (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 all other authors’ relevant financial disclosures.

Adults with overweight or obesity assigned to combination naltrexone/bupropion therapy experienced fewer depression-related events vs. similar patients assigned to placebo, with no suicidal behaviors observed among treated patients, according to a post hoc analysis of five placebo-controlled clinical trials.

Frank Greenway, MD

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

“Bupropion/naltrexone reduced depressive symptoms compared to placebo in the clinical trials done to win FDA approval as an obesity drug,” Greenway told Endocrine Today. “Obesity is associated with depression, so bupropion/naltrexone may be the drug of choice in patients who have depressive symptoms and need an 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 adults with overweight or obesity without psychiatric conditions at baseline (> 80% women; mean age, 45 to 46 years; mean BMI, 36.2 kg/m²). Researchers randomly assigned participants to 32 mg naltrexone prolonged release plus 360 mg bupropion prolonged release (Contrave, Nalpropion Pharmaceuticals; n = 2,545) or placebo (n = 1,515) administered twice daily in divided doses. All studies were prospective and double-blind and included a dose escalation period of 3 to 4 weeks; study durations were 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 subtopics (anxiety, depression and sleep disturbances), which had incidence rates of at least 5%. Researchers used analysis of covariance to assess treatment-emergent depressive and anxiety symptoms via change in the Inventory of Depressive Symptomatology, Self-Report (IDS-SR) total score (score range, 0-84) and the Columbia Classification Algorithm of Suicide Assessment.

Across 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 disorders (12.7% vs. 7.9%; P < .001), anxiety (5.4% vs. 3.3%; P = .029) and depression, which occurred more frequently in the placebo group (1.8% vs. 2.7%; P = .014). Psychiatric adverse events were most common during dose escalation and were generally mild or moderate, according to researchers.

Mean changes in the IDS-SR total score were small in both groups (0.13 for naltrexone/bupropion vs. –0.45 for placebo). Researchers did not confirm any completed suicides, suicide attempts or preparatory acts toward imminent suicidal behavior.

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

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

For more information:

Frank Greenway, MD, can be reached at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808; email: frank.greenway@pbrc.edu.

Disclosures: Greenway reports he has received consultant fees from Orexigen (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 all other authors’ relevant financial disclosures.