Ketamine: The Glutamatergic Antidepressant and Its Efficacy

Abstract

Ketamine, an uncompetitive glutamatergic NMDA antagonist, was first synthesised as an anaesthetic agent, though its unwanted induction of post-operative ‘dissociative’ states led to its gradual withdrawal from mainstream use. It has remained a common drug of abuse ever since, in the same class as the more powerful phencyclidine (‘PCP’ or ‘angel-dust’). However, as well as subjectively pleasurable perceptual changes and alterations to consciousness, data began to emerge of a positive effect upon depressed mood states. Of particular interest, such effects, where they occurred, were seen to develop far more rapidly than with ‘traditional’ antidepressants. Scientific trials of effectiveness have included work exploring ketamine as the sole medication, co-prescribing studies, and work looking at augmentation of ECT. Overall these early data are showing some interesting and exciting results, with general support for efficacy in all settings tested. However, significant challenges remain. Firstly, benefits derived tend to be temporary, with rapid relapse after several weeks, and there is a need to find a mechanism to sustain the drug effects. Secondly, most studies utilised intravenous administration, which carries an obvious clinical burden. Finally, the risks of dependency and ketamine-induced psychosis remain as yet uncertain. Nevertheless the societal burden of depression mandates further work on this compound, not least to better understand the mechanism of action of any therapeutic changes.