How does ketamine alleviate depression?

Ketamine, which was initially evaluated on prisoners in 1965 (see here) was introduced in the 1960s as a dissociative aesthetic that was preferable to phencyclidine (PCP). It is also widely used in veterinary medicine as a horse tranquiliser and is used non-medically as a psychoactive drug that has earned the moniker Special K. The effects of ketamine are widely attributed to its antagonism of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, which are well-known to perform a number of critical functions within the central nervous system. When Berman and colleagues initially reported in 2000 that single i.v. infusions of subanaesthetic doses of ketamine produced rapid antidepressant effects in depressed patients (see here), there was surprise and amazement in equal measure. The surprise was that a field that had previously been dominated by the hypothesis that depression is caused by an imbalance in monoamine neurotransmitters now had to incorporate a completely novel mechanism, namely hyperfunction of NMDA receptors. The amazement was derived from the size and speed of onset of the antidepressant effect, which was in the region of tens of minutes rather than the weeks required to manifest the effects of “traditional” antidepressants. Initially, these data appeared to be too good to be true and were greeted with a healthy degree of scepticism. Accordingly, the scientific community set about trying to reproduce these data and sure enough, carefully controlled studies replicated these initial observations (see here and here) to the point that the antidepressant effects of ketamine are now generally accepted.

Ketamine is a mixture of two mirror-image molecules (enantiomers); (R)- and (S)-ketamine and Janssen, the pharmaceutical arm of the global healthcare giant Johnson & Johnson, recently reported that (S)-ketamine (esketamine) was able to produce antidepressant effects (see here). The collective data for ketamine and the presumed NMDA receptor antagonism mechanism of action have resulted in a number of NMDA-related drugs being pursued as novel antidepressants (Table 1, see also here) with the commercial interest in this area being reflected by the $560 million that Allergan paid to acquire Naurex and their GLYX-13 (Rapastinel) and NRX-1074 assets (see here).


However, as with all good scientific stories, recent data has provided a surprising twist. Hence, recent data from Zanos and colleagues (see here) suggests that not only might (R)-ketamine be more biologically active that (S)-ketamine, but that the biological activity may actually be associated with the active metabolite (2R,6R)-hydroxynorketamine (HKN) with effects being mediated via AMPA rather than NMDA receptors.



Figure showing the metabolism of racemic (R,S)-ketamine into corresponding (R) and (S) enantiomers of norketamine (norKET) and the (2S,6S) and (2R,6R) enantiomers of hydroxyketamine (HK) and hydroxynorketamine (HNK).

For example, ketamine produced a greater antidepressant-like effect in female mice compared to male mice which corresponded to higher levels of the (2S,6S;2R,6R)-HNK in female compared to male mouse brains. In addition, deuteration of (R,S)-ketamine not only reduced the production of 2S,6S;2R,6R)-HNK but also prevented deuterated ketamine having any antidepressant-like effects in either the mouse forced-swim or learned helplessness tests. More detailed analysis of 2R,6R-HNK showed that this metabolite produced a much greater antidepressant-like effect in mouse models of depression relative to the 2S,6S metabolite.


Left hand panel shows that (2R,6R)-hydroxynorketamine (HNK) has greater efficacy than (2S,6S)-HNK in the mouse learned helplessness test. Right-hand panel shows that (2R,6R)-HNK is not self-administered in mice whereas racemic ketamine is, indicating that compared to the parent, the metabolite has no rewarding properties and is therefore unlikely to be a drug of abuse.

More remarkable, however, were the observations that (2R,6R)-HNK (and also (2S,6S)-HNK) did not affect NMDA-induced currents in a rat hippocampal slice model but rather increased AMPA-mediated excitatory postsynaptic currents. The in vivo antidepressant like effects of (2R,6R)-HNK could be blocked by prior treatment of mice with the AMPA receptor blocker NBQX and the longer-lasting (i.e., 24-h postdose) antidepressant effects of (2R,6R)-HNK were associated with an increased expression of the GluA1 and GluA2 subunits of the AMPA receptor.

Is it actually important that we understand the mechanism of ketamine’s antidepressant effects? Well, the simple answer is no and yes; no from the patient’s point of view since he/or she is not too concerned about how they have got better, only that they have got better; and yes, because despite ketamine’s remarkable effects, the therapeutic use of ketamine (or esketamine) is associated with significant issues related to its mechanism-related dissociative side-effects and its route of administration (intravenous or possibly intranasal). Accordingly, we need to understand the mechanism of action to develop new and improved drugs that retain the antidepressant effects but are devoid of the issues associated with ketamine itself. Irrespective of what the actual mechanism of action of ketamine turns out to be, there is little doubt that we are on the verge of a major breakthrough in the treatment of treatment-resistant depression, and possibly the broader population of depressed patients. This in turn could not only revolutionise the treatment of depression but could reenergise the whole field of psychiatric drug discovery that has become a backwater of pharmaceutical company drug discovery over the last decade or so.

Blog written by John Atack


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