Ketamine and Depression

Ketamine is a drug with a very wide range of uses. Developed in 1962 to be an alternative anesthetic to phencyclidine (PCP), it was first used as a battlefield anesthetic. It eventually became a popular veterinary medicine, used for anesthetic purposes with small animals (e.g. cats) and as an analgesic for larger animals like horses. It also became an established recreational drug, known for its psychedelic side effects and commonly referred to as “special K”.

Several years ago doctors noticed an unexpected behavioral effect while using ketamine to treat complex regional pain syndrome (CRPS) in human patients. It appeared to alleviate symptoms of depression associated with the CRPS. Further studies verified this therapeutic effect, while noting one advantage over other contemporary antidepressant medications: it began working within 24 hours of the dose.

This aroused great interest in understanding the mechanism of ketamine. Due to its side effects, most were unwilling to advocate the use of the drug itself. But if its method of action could be elucidated, then perhaps similar quick-acting antidepressant drugs (without psychedelic side effects) could be developed.

Research has indicated that the neuropharmacology of ketamine is complex. It is thought that it affects the glutamate system of the brain, a system that only recently has been implicated in depression. Ketamine is an antagonist (i.e. inhibits action) at a glutamate receptor called the NMDA receptor. The inhibition of this receptor seems to cause an increase in glutamatergic activity at another receptor, known as the AMPA receptor. It is thought this secondary activity may be integral to ketamine’s quick action.

Recently a neuroimaging experiment shed some more light on how ketamine exerts its effects regionally. Researchers at the University of Manchester found that almost immediately after injection of ketamine, high levels of activity in the orbitofrontal cortex (OFC) stopped.

The OFC is thought to be involved in the regulation of affective states, and abnormal activity has been found there in depressed patients. The researchers in this study suggest it is the quick action of ketamine to quiet overactivity in the OFC that may be responsible for its rapid antidepressant effects.

Watch for more research to focus on the glutamatergic system in relation to depression. The greatest downside of antidepressant drugs today is the long time a patient must wait for them to have an effect (up to 4 weeks in many cases). Manufacturing a quick-acting antidepressant would be a boon for any pharmaceutical company, so expect them to heavily investigate the potential of glutamate-influencing drugs.