Can Ketamine Help Us Understand Depression?
For most of us, the word ketamine calls to mind cheap highs and horse tranquilizers. In 2000, however, a pilot study by John Krystal and colleagues from Yale provided evidence that this dissociative anesthetic agent is capable of producing rapid antidepressant effects in patients with difficult-to-treat depression. Compared to first-line medications, which require two weeks for therapeutically relevant results, a sub-anesthetic dose of ketamine (roughly a quarter of the anesthetic dose), generates a similar effect within just 24 hours.
In 2015, the World Health Organization reported that an estimated 322 million people are currently diagnosed with depression — almost exactly the population of the United States — representing an increase of nearly 20% over 10 years. The issue is further complicated by a low remission rate amongst responders (35%), as well as a time lag of up to two weeks necessary to achieve remission in most patients. Add to this the finding that 60% of people who die by suicide have been diagnosed with depression, and a bleak picture begins to emerge of a disorder in urgent need of relief.
Most medications used in the treatment of depression target one or more of the monoamine systems in the brain, comprised of the ubiquitous neurotransmitters serotonin, dopamine, and norepinephrine. While increase in the activity of these brain chemicals has been shown to alleviate depressive symptoms, the inconsistency in remission and response to medications suggests there is more than one face to this disorder. For some time now, researchers have known that a combination of genetics and life experiences put some people at greater risk of experiencing a depressive episode than others. The question is: What don’t genetics and life experiences account for?
Unlike the vast majority of available medications used to treat depression, ketamine doesn’t target any of the monoamine systems directly. It acts instead via glutamate — the most abundant excitatory neurotransmitter in the brain. But binding of the drug to one of the glutamate receptors is only the beginning. Research has shown that it also decreases the activity of the major inhibitory neurotransmitter in the brain, γ-amino butyric acid (GABA).
Additionally, there is a decrease in the activity of the lateral habenula (LHb), a region of the brain that is activated in response to negative events, within 30 minutes of administration. Decrease in this region’s brain activity results in an increase in dopamine. Put simply, the drug appears to decrease inhibition and increase excitation in specific regions of the brain that are dysregulated during a depressive episode.
The antidepressant activities of the drug do not stop there. There is also a rapid increase in proteins and molecules involved in brain cell growth. And emerging evidence suggests that in a brief time-span, ketamine is able to reverse some of the neural depletion caused by repeated exposure to stressful life events.
After nearly two decades of research, the Food and Drug Administration (FDA) approved ketamine for the treatment of depression in 2019. This means a larger population of individuals diagnosed with depression will have access to the drug, seeking relief from a haze of depressive symptoms. It is still unclear whether or not this re-purposed drug will help us understand depression, but it’s a flicker of light in a field once shrouded in darkness.
