While there are a number of treatments for major depressive disorder, or MDD, these often need weeks to take effect and for some people with "treatment resistant depression," or TRD, they may not work at all. This has led to efforts to find other drugs that can help people with TRD, one of which is ketamine.
Ketamine, Glutamate and Treatment Resistant Depression
Ketamine is widely used in anesthesia because of its sedative effects. It works by blocking some of the actions of a brain chemical called glutamate. Glutamate is involved in processes such as learning, memory and cell signaling, but excess glutamate can damage cells, causing malfunction. Increases in glutamate levels have been found in the plasma, cerebrospinal fluid and some brain areas of people with MDD.
Glutamate works by activating two types of receptors on the surface of brain cells, called the NMDA and the AMPA receptors, which is the mechanism behind cell signaling. The damaging effects of glutamate may be due to increased actions at NMDA receptors and one of the effects of antidepressants is to decrease NMDA receptor function. Antidepressants can also increase levels of AMPA receptors and these two actions are thought to stabilize glutamate levels, thus relieving depression.
The Advantages of Ketamine
Ketamine works by blocking NMDA receptors and increasing glutamate throughput at AMPA receptors. A number of studies show that ketamine can produce rapid relief from depression in some people with TRD, including one led by Carlos Zarate and published in the August 2006 edition of "Archives of General Psychiatry." They gave a single low dose of ketamine to 17 subjects with TRD and found that 12 of them had notable depression relief within an hour that lasted through the following day. For six of the subjects, the dose's effects lasted for the following week.
Although this treatment brought only short-term relief, one of the main uses for ketamine may be for those who are suicidal and need immediate care. In another study, reported in the September 2009 edition of "Biological Psychiatry," Rebecca Price and colleagues reported that of 26 patients with TRD, 21 of them had no thoughts or intentions of suicide when tested the day following ketamine administration. In a follow-up study on ten subjects who received a further five treatments over 12 days, nine of them reported no thoughts or intentions of suicide throughout the treatment and decreased depression levels.
The Disadvantages of Ketamine
Ketamine has some side effects, such as the depersonalization, euphoria, dizziness, motor retardation, gastrointestinal symptoms and increased blood-pressure reported by Zarate. However, these are very short-term.
Long-term studies have only been carried out with people who already use ketamine as a recreational drug. One led by Celia Morgan, and reported in the January 2010 edition of "Addiction," found that people who used ketamine at least four times a week for a year had problems with memory, verbal fluency, delusions, depression, dissociation and psychosis. However, these subjects took ketamine at far higher doses than used in the antidepressant studies. It does have implications as to whether repeated administration similar to that in the study by Price would have long-term effects. Further studies are being carried out on this matter with both ketamine and other similar acting drugs.
References
- "Pharmacology & Therapeutics;" Ketamine and the Next Generation of Antidepressants with a Rapid Onset of Action; Rodrigo Machado-Vieira et al; August 2009
- "Brain Research Reviews;" Emerging Role of Glutamate in the Pathophysiology of Major Depressive Disorder; Kenji Hashimoto; October 2009
- "Archives of General Psychiatry;" A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression; Carlos Zarate et al; August 2006
- "Biological Psychiatry;" Effects of Intravenous Ketamine on Explicit and Implicit measures of Suicidality in Treatment-Resistant Depression; Rebecca Price et al; September 2009
- "Addiction;" Consequences of Chronic Ketamine Self-Administration Upon Neurocognitive Function and Psychological Wellbeing: a 1-Year Longitudinal Study; Celia Morgan et al; January 2010
