Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine

Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30-50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.

Automated summary

Major depressive disorder (MDD) affects approximately 5% of the world population, and a significant percentage of patients do not achieve complete remission with classical antidepressant medications. Recent evidence suggests that targeting opioid receptors may offer effective therapeutics for stress-related psychiatric disorders. The dysregulation of opioid signaling in depression and the success of opioid modulation in preclinical studies and clinical trials highlight the potential of opioids as adjuvant or alternative treatments for depression. However, further research is needed to fully understand the benefits and weaknesses of opioid system modulation in depression.