Emerging research generally supportive of ketamine’s rapid antidepressant effects has encouraged a few clinicians to prescribe the drug for their severely depressed, suicidal, and hospice-care patients, with reportedly good results.
“For the most part, the ketamine story and the excitement surrounding it is derived from research studies at the NIMH and Mount Sinai School of Medicine,” said David Feifel, MD, PhD, Professor of Psychiatry at the University of California, San Diego (UCSD) and Director of the Neuropsychiatry and Behavioral Medicine Program.
Ketamine is an FDA-approved anesthetic used in human and veterinary medicine. It is a high-affinity, noncompetitive NMDA-glutamate receptor antagonist that may also stimulate other receptors. It is classified as a Schedule III non-narcotic controlled substance and, at higher doses, is sometimes abused as a street drug called “Special K.”
In a recent article, Murrough and Charney1 wrote that ketamine “appears to be effective at reducing the range of depressive symptoms, including sadness, anhedonia, low energy, impaired concentration, negative cognitions, and suicidal ideation.”
Carlos Zarate Jr, MD, and his team from the NIMH’s Experimental Therapeutics and Pathophysiology Branch, along with NIMH-sponsored researchers, have conducted studies exploring ketamine’s rapid antidepressant effects among treatment-resistant depressed patients with either MDD or bipolar disorder.2,3 The drug might work, in part, they suggest, by strengthening neural connections.4
Recently, Zarate and colleagues reported that ketamine produced the fastest, strongest, and longest-lasting anti-suicidal intervention ever demonstrated in a controlled trial. In a replication of an earlier study, the researchers confirmed that ketamine not only lifts depression but also reduces suicidal thoughts in bipolar patients.5 Intravenous ketamine may prove useful for acutely suicidal patients receiving treatment in hospital emergency departments. A clinical trial sponsored by the Mount Sinai School of Medicine is investigating ketamine’s anti-suicidal ideation effects in patients admitted to a psychiatric hospital with prominent suicidal ideation and elevated risk of suicide.
A recent review of published literature on intravenous ketamine for depressive symptoms in patients with treatment-resistant depression (TRD) included 3 case series, 1 case report, 3 open-label trials, and 1 randomized crossover trial.6
The findings from the analysis indicate that intravenous infusion of ketamine 0.5 mg/kg has rapid effects on reducing depression symptom scores in patients with treatment-resistant MDD, although the effects are generally not long-lasting (hours to days). In 2 of the small studies, the ketamine effect size was considered large or moderate to large. Regarding adverse effects, the authors noted that ketamine “is generally well tolerated, with adverse effects including transient changes in vital signs, mild dissociative effects that rapidly regress, and other relatively benign symptoms, such as headache and dizziness.”
The researchers concluded that there is insufficient evidence to recommend ketamine as a viable treatment option for TRD because the sustainability of ketamine efficacy across all patient populations remains to be seen and because the long-term adverse effects in the TRD patient population are unknown.
“People are of differing opinions,” Feifel acknowledged. “Some doctors are uncomfortable using it, both because it is a controlled substance that has psychotogenic properties and also because they believe it has not been researched enough in the arena of depression.”
Conversely, he added, there are other physicians (himself included) who feel it is warranted to use ketamine as an off-label treatment under certain circumstances. He pointed to ketamine’s well-established safety record and the use of a dose much lower than that used for anesthesia. Equally important, he said, “there are patients with severe treatment-refractory depression who are absolutely despondent and hopeless and are at risk for suicide.”
While extensive research is needed to understand how to optimally use ketamine, Feifel said, “I do believe it is reasonable and appropriate for clinicians who want to do so, to start using the medication for their patients. There are people who are going to die every day from lack of something that will help their depression. I don’t think we should sit by when we have something that could potentially make a difference.”
1. Murrough JW, Charney DS. Is there anything really novel on the antidepressant horizon? Curr Psychiatry Rep. 2012;14:643-649.
2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
3. Luckenbaugh DA, Ibrahim L, Brutsche N, et al. Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression. Bipolar Disord. 2012;14:880-887.
4. Duncan WC, Sarasso S, Ferrarelli F, et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2012 Jun 7:1-11; [Epub ahead of print].
5. Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939-946.
6. Covvey JR, Crawford AN, Lowe DK. Intravenous ketamine for treatment-resistant major depressive disorder. Ann Pharmacother. 2012;46:117-123.
7. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2012 Jul 26; [Epub ahead of print].
8. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med.