Targeting opioid dysregulation in depression for the development of novel therapeutics

Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD) have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4-6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development. For decades, no viable candidate target with a different mechanism of action to that of conventional therapies proved successful in clinical studies. Now several exciting avenues for drug development are under intense investigation. One of these emerging targets is modulation of endogenous opioid tone. This review will evaluate preclinical and clinical evidence pertaining to opioid dysregulation in depression, focusing on the role of the endogenous ligands endorphin, enkephalin, dynorphin, and nociceptin/orphanin FQ (N/OFQ) and their respective receptors, mu (MOR), delta (DOR), kappa (KOR), and the N/OFQ receptor (NOP) in mediating behaviors relevant to depression and anxiety. Finally, putative opioid based antidepressants that are under investigation in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501) and BTRX-246040 (formerly LY-2940094) will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for MDD.