"Does the opioid system block or enhance the antidepressant effects of ketamine?"

Commentary on: Williams NR, Heifets BD, Blasey C, et al. Attenuation of antagonism effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205–1215; Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry. 2019;76(3):337–338. Despite tremendous growth in the off-label use of racemic ketamine for psychiatric indications and the recent U.S. Food and Drug Administration approval of esketamine nasal spray for treatment-resistant depression (TRD), neural mechanisms underlying the induction and maintenance of ketamine’s rapid but transient antidepressant effects remain obscure. Ketamine’s initial pharmacological target is not disputed: it acts as a nonselective, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. Converging preclinical evidence indicates that this NMDAR blockade inhibits (1) Gamma-aminobutyric acid (GABA) interneurons (resulting in enhanced presynaptic release of glutamate and stimulation of postsynaptic a-Amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptors), (2) extrasynaptic GluN2B-containing NMDARs (resulting in de-suppression of mTORC1 function), and (3) spontaneous neurotransmission (resulting in inhibition of eukaryotic elongation factor 2 kinase activity). A final common pathway for these effects involves activation of neurotrophic factor signaling pathways, increased synaptic protein synthesis, and dendritic spine formation and restoration of lost spines (‘‘spinogenesis’’). There is considerably less consensus in defining the role of non-NMDAR receptor activity in mediating the rapid (within several hours) and sustained (24 h to 7 days) antidepressant effects observed in numerous clinical trials. Indeed, the sustained antidepressant responses seen in some individuals are particularly puzzling, given the short elimination of half-life of ketamine and its primary metabolite norketamine. Recent preclinical experiments have shown that a different metabolite— hydroxynorketamine [(2R,6R)-HNK]—promotes AMPA-mediated synaptic potentiation via an entirely NMDAR independent pathway. Furthermore, ketamine has significant central antinociceptive effects, with activity at mu-, kappa-, and delta-opioid receptors. Inasmuch as the U.S. continues to face an alarming increase in the number of opioid-related overdose fatalities, some have urged more caution in the use of ketamine (and esketamine) for depression, particularly in the face of recent experimental evidence by Williams et al. that ketamine’s antidepressant effects may be mediated by mu-opioid receptor activity. In this Commentary, we evaluate the evidence presented in Williams’ et al. intriguing article as well as counterevidence. The study, a randomized, double-blind, placebo-controlled cross-over study in 12 participants with TRD, showed that pretreatment with the nonselective opioid antagonist naltrexone (50mg) resulted in marked attenuation of the rapid antidepressant effects of intravenous (IV) ketamine. There were marked differences in depression severity 24 hours and up to three days following the two ketamine infusions, which were administered at the conventional dose of 0.5mg/kg over 40min and separated by about 30 days. For the subgroup group of participants who met the prespecified ketamine response criteria (n1⁄4 7) at the 1 day end point, naltrexone pretreatment of ketamine resulted in a 5.6-point reduction in the 17-item Hamilton Depression Rating Scale (HAM-D), while the placebo pretreatment group had a 22.3-point improvement (effect size d1⁄4 2.5). Naltrexone pretreatment did not significantly attenuate ketamineinduced dissociative symptoms, although there was an approximate 6-point reduction in mean ClinicianAdministered Dissociative States Scale (CADSS). Overall, the between-group efficacy differences were robust, durable (lasting for up to three days, consistent with the known duration of naltrexone on opioid