Harvard University Ketamine Research
Ketamine for major depression: New tool, new questions
May 22, 2019
By Robert C. Meisner, MD, Contributor
First things first:
You may be asking yourself, "What is ketamine?"
Well, it was once used mainly as an anesthetic on battlefields and in operating rooms. Now this medication is gaining ground as a promising treatment for some cases of major depression, which is the leading cause of disability worldwide. In the US, recent estimates show 16 million adults had an episode of major depression in the course of a year. Suicide rates rose substantially between 1999 and 2016, increasing by more than 30% in 25 states. Because of its rapid action, ketamine could have a role to play in helping to prevent suicide.
Why is ketamine exciting for treating depression?
If a person responds to ketamine, it can rapidly reduce suicidality (life-threatening thoughts and acts) and relieve other serious symptoms of depression. Ketamine also can be effective for treating depression combined with anxiety.
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Other treatments for suicidal thoughts and depression often take weeks or even months to take effect, and some people need to try several medications or approaches to gain relief. This is true for talk therapies, antidepressant medicines, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT), which is currently the most effective treatment for major depression that fails to respond to other therapies.
Are there different types of ketamine?
Two main types of ketamine are used to treat major depression that hasn’t responded to two or more medications (treatment-resistant depression).
Intravenous ketamine, which is most often given as an infusion into the bloodstream. This is sometimes called IV, ketamine. It is a mixture of two mirror-image molecules: "R" and "S" ketamine. While it was approved decades ago as an anesthetic by the FDA, it is used off-label to treat depression.
Sublingual Tablets or Troches
Tablets or troches (pronounced “tro-keys”) are compounded tablets from a pharmacy that are absorbed into the brain/bloodstream sublingually, or held in the mouth. Dosing can vary from 10-200 milligrams (mg) per tablet on average, depending on the compounding pharmacy and the order from the clinician.
Tablets are the method utilized by clinicians, allowing for a greater flexibility in treatment based on the client’s response to the medication. Tablets also provide an identical delivery mechanism as IV/IM, but without the risk of infections or introducing harmful agents into the bloodstream — contributing to an increased safety profile.
A secondary benefit is there is a ceiling, an upper limit, to how much medicine an individual can absorb sublingually, making it nearly impossible to take larger doses than necessary.
How does ketamine work?
It’s not entirely clear how ketamine works. Because it exerts an antidepressant effect through a new mechanism, ketamine may be able to help people successfully manage depression when other treatments have not worked.
One likely target for ketamine is NMDA receptors in the brain. By binding to these receptors, ketamine appears to increase the amount of a neurotransmitter called glutamate in the spaces between neurons. Glutamate then activates connections in another receptor, called the AMPA receptor. Together, the initial blockade of NMDA receptors and activation of AMPA receptors lead to the release of other molecules that help neurons communicate with each other along new pathways. Known as synaptogenesis, this process likely affects mood, thought patterns, and cognition.
Ketamine also may influence depression in other ways. For example, it might reduce signals involved in inflammation, which has been linked to mood disorders, or facilitate communication within specific areas in the brain. Most likely, ketamine works in several ways at the same time, many of which are being studied.
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