Depression: Ketamine steps out of the darkness

Abstract

The way in which ketamine exerts its antidepressant effects has been perplexing. Evidence that a metabolite of the drug is responsible, and acts on a different target from ketamine, might be the key to an answer.

Figure 1. Metabolite mediator of ketamine

How the drug ketamine exerts its antidepressant effects is unknown, although a common hypothesis states that it acts by binding to the receptor protein NMDAR on postsynaptic neurons, preventing neurotransmitter molecules released by presynaptic neurons from activating NMDAR and so inhibiting signalling processes triggered by the receptor. By contrast, Zanos et al. report that it is a metabolite of ketamine called hydroxynorketamine (HNK) that has antidepressant activity. They provide evidence that HNK, through unknown intermediates, increases the levels of another neuronal receptor protein, AMPAR, at synapses (dashed arrow), enhancing neural activity. But how this produces an antidepressant effect remains unclear.