While subtle MOR agonist effects of the BUP/SAM combination may be sufficient to modulate dysregulated opioidergic function, thereby improving symptoms in some individuals with depression, an alternative explanation is that antidepressant effects of the BUP/SAM combination may be driven by buprenorphine’s KOR antagonism (which is unaffected by samidorphan). Here, OPRK1 is linked to major depressive disorder.