The Hospice Clinician Blog

In our previous blog post regarding the rapid treatment of depression in hospice patients (5/2/12), we discussed the use of methylphenidate, which has been shown to improve depression in a matter of days, instead of weeks like traditional antidepressants. Now, we turn to a discussion of ketamine, which in some patients, can improve symptoms in a matter of hours, with the effect lasting for weeks.

Ketamine is an NMDA-receptor antagonist that has been used as an anesthetic drug for decades. There is also good evidence for the use of ketamine in the treatment of cancer-related pain. The use of ketamine for depression is a relatively new area of investigation. One of the first studies of ketamine for this use was published in 2006 by a group of researchers from the National Institute of Mental Health. In this study, 17 patients were treated with a single intravenous ketamine infusion (0.5 mg/kg given over 40 minutes), resulting in robust and rapid antidepressant effects. Onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. This same group of investigators has also studied ketamine for treatment-resistant bipolar depression and for emergent treatment of suicidal ideation in depressed patients, with similar findings.

At San Diego Hospice and the Institute for Palliative Medicine, Scott Irwin, MD, PhD and his team have also been conducting clinical trials using ketamine for depression for several years. Whereas previous research has exclusively used intravenous ketamine infusions, Dr. Irwin is currently conducting an open label pilot study to evaluate the efficacy and tolerability of oral ketamine for the treatment of major depression in hospice patients. Fourteen of a planned 20 patients have completed the 28-day study. The dose is 0.5 mg/kg by mouth once daily, which is prepared by mixing the intravenous ketamine solution with cherry syrup to mask the taste. The therapeutic efficacy has been impressive, as reflected in a drop in average scores on the Hospital Anxiety and Depression Scale from about 20 to 5. "Interestingly, several patients had diagnosable severe anxiety disorders that went away completely. We’re finding that anxiety may be even more affected by ketamine than depression," Dr. Irwin said. The high burden of somatic symptoms present in these patients also lightened significantly, with scores on the Adverse Symptom Checklist falling from about 28 to 5. This doesn’t appear to be a result of the drug’s analgesic effect, because some patients didn’t have significant pain, while in others the somatic symptoms improved while pain scores remained unchanged. Another 30 or so San Diego Hospice patients have received oral ketamine outside of the pilot study, with similar benefits.

The dose used for depression is much lower than the dose typically used for anesthesia (anesthesia doses are generally > 2 mg/kg), but dissociative symptoms (such as hallucinations and euphoria) may still occur. Increases in blood pressure and heart rate may also occur. However, these side effects should be very short-lived. In studies using a single intravenous infusion, side effects dissipated after just a few minutes. The severity and duration of side effects when ketamine is given orally are still under investigation.

Perhaps the most important development that has occurred as a result of this growing body of research is additional insight into the mechanisms underlying depression, with the efficacy of ketamine serving as a “proof of concept” that alterations in the regulation of glutamatergic neurotransmission contribute to the pathophysiology of depression. Ketamine does have limitations in the treatment of depression, including side effects and relatively short duration of action, but an understanding of its mechanism of action may be key to developing a new generation of improved treatments for this devastating illness.

References
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.
DiazGranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67: 793-802.
DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71: 1605-1611.

Photo Credit