Explaining Naltrexone’s Interference With Ketamine’s Antidepressant Effect

To the Editor: In the December 2018 issue of the Journal, Williams and colleagues reported an unexpected attenuation of ketamine’s antidepressant effects by naltrexone (1). This finding represents an invaluable addition to our growing knowledge of ketamine’s therapeutic potential for depression; we would like to propose, however, that ketamine’s antidepressant effects are not mediated through direct opioid agonist activity. Neuromolecular data indicate that it may not be blockade of ketamine at the mu opioid receptor that stops the antidepressant effect, but rather that naltrexone at the mu opioid receptor enacts downstream signaling that interacts with the effects of ketamine.

It is recognized that N-methyl-d-aspartate (NMDA) receptors and mu opioid receptors are colocalized in many parts of the brain, serving as mutual regulators (2). This cross-regulation provides a parsimonious explanation for how naltrexone interferes with ketamine’s antidepressant activity: naltrexone antagonism of the mu opioid receptor increases cAMP, which interferes with ketamine’s activation of mammalian target of rapamycin (mTOR) (3, 4) (Figure 1). Numerous studies support mTOR activation as a crucial mediator of ketamine’s antidepressant effects (4–6) (Figure 2). Although ketamine ultimately leads to activation of mTOR through reduction of neuronal nitric oxide synthase (nNOS) activity, mu opioid receptor antagonism increases nNOS phosphorylation by cAMP, thus “hijacking” ketamine’s presumed antidepressant pathway. Naltrexone’s reversal of mu opioid receptors’ constitutive inhibition of cAMP subsequently leads to cAMP elevation and increases nNOS activity, ultimately preventing ketamine-induced formation of mTOR (Figure 3).

In summary, we present a mechanism, supported by two well-known pathways, through which naltrexone blocks ketamine’s antidepressant effect, and we add that this is possible without ketamine manifesting any opioid activity itself. Our conjecture further suggests that an adjunct cAMP or nNOS inhibitor, or an increase in neural mTOR signaling, might augment ketamine’s rapid and sustained antidepressant effect.