Ketamine was initially developed as an anesthetic, but today it is also used as an analgesic and an antidepressant. It has been used as a recreational drug since the 1970s. After administration, ketamine is rapidly and extensively metabolized into an active metabolite called norketamine, which is thought to play an important role in ketamine’s anesthetic and analgesic effects.
Ketamine and norketamine both act at a receptor for the neurotransmitter glutamate called the NMDA receptor. Glutamate is the primary excitatory neurotransmitter in the brain, and ketamine and norketamine act as antagonists at the NMDA receptor, which means that they block the receptor and inhibit activity there. Inhibition of NMDA receptors can substantially affect neurotransmission, and is thought to be critical to the anesthetic and analgesic effects of ketamine.
While most other antidepressants take several weeks to achieve a therapeutic effect, ketamine can begin to improve depressive symptoms within hours and last for up to 2 weeks after a single administration. The mechanisms underlying ketamine’s antidepressant action are not fully understood, but it’s thought that it cannot be explained by NMDA antagonism alone. One hypothesis is that another glutamate receptor known as an AMPA receptor may play a key role.
AMPA receptors may be stimulated indirectly by ketamine or directly by other ketamine metabolites such as hydroxynorketamine. Stimulation of AMPA receptors may lead to the activation of multiple signaling pathways. and downstream effects such as new synapse formation in areas of the brain like the prefrontal cortex and hippocampus.
These synaptic connections may bolster neural circuits involved with regulating stress and mood. Ketamine also acts on a number of other receptors, however, and there is still much more to learn about ketamine’s antidepressant mechanism of action. Additionally, more evidence about the safety and effectiveness of ketamine needs to be collected for more physicians to support the use of ketamine as an antidepressant.
