Ketamine: A Breakthrough Therapy for Treatment-resistant Depression?

The drug, an anesthetic, has banished depression for days, weeks, or months in individuals who did not respond to other therapies.

Ketamine, a drug long used as a general anesthetic, is getting new attention these days as a medication for treatment-resistant depression (TRD) and pointing the way to new approaches to depression treatment. Currently, as many as 33 percent of people with major depressive disorder fail to respond to antidepressant drugs despite multiple medication attempts.

Rapid effects

A number of recent studies have looked at the effects of a single dose of ketamine in TRD patients, either in combination with other drugs or alone, and found rapid and meaningful antidepressant benefits for a significant percentage of study participants. Since these one-dose studies involved a number of unpleasant side effects, and benefits lasted only about one week, re-searchers in the United Kingdom set out to determine whether a series of smaller infusions spread out over several weeks would deliver the same benefits with fewer side effects. The study involved individuals with TRD who continued using their prescribed antidepressant medications while undergoing a series of intravenous infusions of low-dose ketamine either once or twice a week for three weeks. Eight of the 28 participants responded to the treatment, with depression remission that lasted from 25 days to 24 weeks. In most participants, side effects were short-lived, and included nausea, confusion, anxiety, and changes in perception, the researchers reported in the April 3, 2014 online issue of the Journal of Psychopharmacology. No problems with memory or cognition were observed.

“What is exciting about the ketamine research is that it appears to be the first step in the development of a completely new type of antidepressant that taps into wholly new mechanisms involved in depression,” says Cristina Cusin, MD, a staff psychiatrist at MGH’s Depression Clinical and Research Program and a TRD researcher. “It represents a profound innovation in the treatment and understanding of depression.”


Dr. Cusin urges individuals with TRD to consider participating in research trials. To find out about studies enrolling in your area, she suggests that you:

  • Ask your medical care professional for information on research organizations and studies on de-pression
  • Contact the National Institute of Mental Health at the National Institutes of Health at for general information, and look for lists of research studies nationwide on
  • Contact a major academic center in your region for information about enrolling in research trials there.

A different pathway

Antidepressants in common use today—selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants—target the monoamine system with its chemicals called neurotransmitters that are involved in communication between brain cells, and with emotion and cognition. By raising levels of the neurotransmitters serotonin, norepinephrine, and dopa-mine, the drugs have been found to improve mood in a substantial portion of people with depression. These drugs require several weeks of treatment before symptoms improve, and have been found to be ineffective in many patients.

In contrast, ketamine has a completely different mechanism of action. The drug targets the glutamate system, dysfunction in which has been linked to certain psychiatric disorders. Glutamate is an abundant neurotransmitter that plays an important role in memory, learning, and cognition. Ketamine is thought to lift mood either by blocking certain glutamate receptors in the brain, or by stimulating growth factors that promote the production of new brain cells. Ketamine is fast-acting, and has been compared to electroconvulsive therapy (ECT) in its ability to transform mood in some patients within hours.

Because it may trigger undesirable side effects—such as hallucinations, changes in blood pressure, respiration, and heart rate, problems with memory and cognition, and dependence—treatment with ketamine requires careful supervision and is currently restricted to a medical setting, such as a hospital or clinic. However, researchers are working to develop antidepressant medications that target the glutamate system, as ketamine does, but are safer, longer-lasting, and suitable for use on an outpatient basis.

“We still have a great deal to learn about ketamine, and we will need to do many more studies before we fully understand this type of medication and find ways to eliminate or decrease some of its side effects,” says Dr. Cusin.

“We need the help of people with depression who are willing to participate in trials,” she says (see What You Can Do). “These altruistic individuals are not guinea pigs—they’re patients who are very carefully monitored and treated by experts in the field. They’re acting as valuable contributors to the process of finding therapies that work for depression and will one day help others as well as themselves.”


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