The extended-release combination of naltrexone and bupropion (NB-ER) may be used as safe and effective treatment for weight reduction among individuals with overweight/obesity and mild to moderate symptoms of depression, suggests a study.
“Treatment providers can be more confident that NB-ER is both safe and effective for weight loss when prescribed to patients presenting with overweight/obesity and mild to moderate symptoms of depression,” the investigators said.
Four double-blind, placebo-controlled trials were included in the pooled analysis involving 511 participants with baseline Inventory of Depressive Symptomatology—Self-Report scores ≥14, which indicated mild or greater depressive symptoms.
Percent weight loss at 56 weeks and changes in depression, as well as safety data for psychiatric adverse events (PAEs), depressive symptom increases, and suicidal ideation, were the primary outcomes. The investigators applied multiple imputation and compared outcomes in the intention-to-treat population.
Weight loss
At week 56, more participants who received NB-ER achieved weight loss than those on placebo (5.7 percent vs 2.7 percent; p=0.003). [Obesity 2026;34:1010-1019]
The use of NB-ER also resulted in clinically meaningful improvements in depression relative to placebo (‒7.1 vs ‒6.7), but no significant difference was noted between groups.
“The lack of significant differences between groups in reductions in depressive symptoms is not altogether surprising in view of other intervention studies that have targeted both depression and weight loss,” the investigators said.
“For example, a pilot study in patients with obesity and major depression found no differences in 46-week symptom improvement in participants who received intensive lifestyle intervention for weight loss, cognitive behavioral therapy (CBT) for depression, or a combined lifestyle plus CBT intervention,” they added. [Obesity 2018;26:1144-1152]
Likewise, another trial comparing lifestyle intervention alone to lifestyle plus CBT for depression in patients with both conditions observed no between-group differences in changes in depression at 52 weeks. [Ann Behav Med 2011;41:119-130]
Safety profile
NB-ER and placebo also showed no significant difference in safety signals, including PAE occurrence (27.5 percent vs 22.1 percent), depressive symptom increases (9.5 percent vs 8.8 percent), or suicidal ideation (1.8 percent vs 2.0 percent).
The most common PAE was insomnia, which occurred more frequently in the NB-ER group. Similarly, somnolence and abnormal dreams were numerically more frequent in participants treated with NB-ER, although the difference between groups were not significant.
Apart from the robust association between sleep disturbances and depression, the use of antidepressant medications, including bupropion, have been found to be associated with higher rates of short-term insomnia in placebo-controlled studies. [Neurosci Res 2025;221:57-64; J Clin Psychopharmacol 2015;35:296-303; J Clin Psychiatry 2005;66:1254-1269]
The findings of the current study “provide preliminary support for clinical guidelines recommending NB-ER for patients with overweight/obesity and depression,” the investigators said.
“A larger placebo-controlled trial in patients diagnosed with major depression and comparisons to other obesity medications are needed to fully establish evidence-based guidelines and ensure that these findings are generalizable,” they added.