Abstract
Globally, major depressive disorder, or MDD, is a leading cause of disability. It negatively impacts social interactions and significantly limits daily functioning, ultimately reducing life satisfaction. The prevalence rate is about twice as high in women as in males. It is believed that the genesis of major depressive disorder is complicated and includes biological, genetic, environmental, and psychological factors. Mental pain, although distinguishable, constitutes a crucial framework in major depressive disorder (MDD) as the pair may precipitate suicide risk. Mental pain, as conceptualized in Panksepp's emotional theory, is especially relevant when considering the key role of the opioid system, which can influence feelings tied to grief and separation. There has been a renewed interest in targeting the opioid system for antidepressant treatment in MDD and to soothe mental pain. Antidepressant drugs endowed with partial mu-opioid receptor (MOR) agonism and kappa-opioid receptor (KOR) antagonism might represent novel pharmacological tools to address unmet needs in MDD patients. The combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults affected by MDD. We hypothesized that dextromethorphan-bupropion could impact the reduction of mental pain in MDD patients by targeting the opioid system, as supported by Panksepp's theory. The combination of dextromethorphan with bupropion might deal with various aspects of mental pain, possibly improving treatment results.