For me, the most exciting part of the ketamine story is a growing literature of neuroimaging studies looking at brain structural and functional changes (especially the hippocampus and prefrontal cortex) and increased global brain connectivity, which are observed in human studies to occur within hours and days of a single treatment dose of ketamine. As we untangle the mosaic of research data, it appears that ketamine ultimately improves brain connectivity with an associated rapid decrease in depressive symptoms that seems to result from a range of downstream cascades that culminates in the activation of mTOR, which plays a primary role in synaptogenesis. Remarkably, the brain’s structure appears to rewire in hours after a single dose of ketamine—wrap your brain around that!
I would be remiss not to mention a study published in 2018 that hypothesized opioid receptors played a primary role in ketamine’s antidepressant action.3 Williams and colleagues looked at pretreatment with naltrexone, followed by the IV administration of ketamine. Their study had a small number of participants. Of the 30 adults who were initially enrolled in this study, 12 completed the protocol to allow an interim analysis fraught with limitations. Two subsequent studies in 2019 demonstrated no interplay between the mu opioid receptor and ketamine’s rapidly acting antidepressant effect.4,5
So, psychiatry has finally crossed into a new paradigm in the treatment of TRD, bringing the glutamate system on board to join the modulation of the monoamine systems. Esketamine is the first in what we hope will be a long list of non-monoamine-based treatments to help improve the lives and functioning of the many individuals suffering from TRD.
Dr Miller reports that he is on Janssen’s Advisory Board and on the Speaker’s Bureau for Spravato.
1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
2. Wilkinson ST, Katz RB, Toprak M, et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry. 2018;79:pii:17m11731.
3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215.
4. 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; 76:337-338.
5. Marton T, Barnes DE, Wallace A, et al. Concurrent use of buprenorphine, methadone, or naltrexone does not inhibit ketamine’s antidepressant activity. Biol Psychiatry. March 26, 2019; Epub ahead of print. ❒