What is ketamine, and how did an anaesthetic become a depression treatment (esketamine, Spravato)?

Ketamine is a medicine that was invented as an anaesthetic and is now also used, under medical supervision, against depression that has not responded to other treatments. It is a dissociative anaesthetic, which means it can leave a person feeling detached from their body and surroundings, and it blocks a brain receptor called NMDA.

It was first made in 1962, derived from phencyclidine in a search for a safer anaesthetic with fewer hallucinogenic effects, and was approved in the United States in 1970. Its great advantage was that, unlike many anaesthetics, breathing and airway reflexes are preserved and heart function is stimulated. After its approval it was first given to American soldiers during the Vietnam War. It is on the World Health Organization's List of Essential Medicines. The name "dissociative anesthesia" was even suggested by Toni Domino, the wife of one of its researchers, after hearing about the "disconnected" look of treated people; the researchers themselves had wanted to call the state "dreaming".

The surprise came in 2000, when ketamine's antidepressant action was discovered. It has been described as the single most important advance in the treatment of depression in more than 50 years. How it works against depression is not well understood and is under active investigation.

A version called esketamine, sold as Spravato, was introduced as an antidepressant in 2019 as a nasal spray for treatment-resistant depression. An advisory panel recommended it 14 to 2, on condition that it be given in a clinical setting and people stay on site for at least two hours. Yet the approval was controversial because evidence of efficacy and safety was limited and mixed, and in January 2020 Great Britain's NHS rejected it, questioning its benefits and cost.