Ketamine/esketamine: Putative mechanisms of action

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Mathew and Rivas-Grajales17 recently published a thoughtful critique and analysis of the study design and conclusions of the original Williams paper.15 They concluded that insufficient evidence exists to answer the question of how ketamine may interface with the opioid system, and they encourage further research into this important topic.

Two additional recent publications18,19 reported that naltrexone pretreatment did not attenuate the antidepressant effects of ketamine in their participants. Additionally, a recent publication in the anesthesiology literature20 concluded that esketamine reversed respiratory depression that was induced by remifentanil. From a clinical perspective, the most compelling argument against a direct mu opioid receptor mechanism for K/ESK is the lack of any craving, tolerance, or withdrawal in patients with TRD treated with K/ESK in numerous clinical publications comparing K/ESK with placebo. In the case of esketamine, during the 5 phase III clinical trials—including both short- and long-term studies—there was no signal for an opioid-like pharmacology. Significantly, both K/ESK are rapidly metabolized by the human body, and the typical dosing is 2 doses/week for the first month, then 1 dose/week for the next month, then 1 dose every week or less for the remainder of treatment.

Curiously, in the May 2019 issue of the American Journal of Psychiatry, Schatzberg21 (one of the co-authors of the prior 2 studies opining that ketamine has direct opioid system activation) wrote a “Reviews and Overviews” article in which he misrepresents the conclusions of an elegant study by Abdallah et al22 published in December 2018.

Abdallah et al22 added rapamycin, an immunosuppressant and a known inhibitor of mTOR, as a pretreatment to patients in a major depressive episode prior to infusion with IV ketamine. Their hypothesis was to see if the rapamycin decreased ketamine’s rapid antidepressant response—putatively by inhibiting the effect of mTOR. Rather than decreasing ketamine’s antidepressant effect, and in contrast to the placebo pretreatment group, at 2 weeks post IV ketamine infusion, patients treated with rapamycin-ketamine had a longer duration/greater improvement in their depressive symptoms compared with the patients receiving placebo-ketamine (improvement of 41% vs 13%, respectively, P = .04). Abdallah et al22 hypothesized that the pretreatment with rapamycin provides anti-inflammatory benefits to the synaptogenesis resulting from ketamine, which protects the newly formed synapses and prolongs ketamine’s antidepressant effect. Schatzberg21 came to a different conclusion than Abdallah et al,22 opining that because the rapamycin “failed to decrease ketamine response,” this result debunks the role of mTOR as a mediator in the antidepressant effect of ketamine through synaptogenesis.

Much more to learn

We still have a great deal to learn about the mechanism of action of K/ESK. However, clinics that are augmenting antidepressants with K/ESK in patients with TRD report significant and rapid symptom improvement in some patients (personal communications). We still do not understand the actual mechanisms of action of antidepressants and antipsychotics, but this does not curtail their use and clinical benefits to our patients. Ketamine has been extensively studied. In the current appropriate climate of concern about the pervasive and lethal opioid epidemic in the United States, we must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our most depressed and refractory patients.

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