Results from a newly published study indicate that intranasal ketamine spray can produce a rapid and sustained antidepressant effect within 24 hours, and was well tolerated in a small group of patients with treatment-resistant major depressive disorder.
This is the first study to show benefits with an intranasal formulation of ketamine. Previous research has indicated that intravenous ketamine may have a role in helping patients with major depressive disorder and suicidal ideation.
The study was published online in the Biological Psychiatry on April 2.
In a double-blind, crossover study, the researchers randomized 20 patients with major depressive disorder to ketamine (a single 50 mg dose) or saline. Change in depression severity was measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included changes in self-reports of depression, anxiety, the durability of response, as well as the proportion of responders. Eight patients met response criteria to ketamine within 24 hours versus one on saline, out of 18 patients completing two treatment days with ketamine or saline.
In the study, ketamine was found to be safe with minimal dissociative effects or changes noted in blood pressure or heart rate. The intranasal route for drug delivery has been of interest to investigators because it is non-invasive, and may offer rapid absorption and delivery. In addition, the ease of administration may potentially improve compliance.
"We found intranasal ketamine to be well tolerated with few side effects," said Kyle Lapidus, MD, PhD, Assistant Professor of Psychiatry, at the Icahn School of Medicine at Mount Sinai.
Ketamine, an FDA-approved anesthetic which is an NMDA receptor antagonist, has been used in animals and humans for many decades. Ketamine has also been a drug of abuse and can lead to adverse psychiatric or cognitive problems when abused. In low doses, ketamine has already shown promise in providing rapid relief of depression, with tolerable side effects.
"One of the primary effects of ketamine in the brain is to block the NMDA [N-methyl-d-aspartate] glutamate receptor," said James W. Murrough, MD, principal investigator of the study, and Assistant Professor of Psychiatry and Neuroscience, and Associate Director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai. "There is an urgent clinical need for new treatments for depression with novel mechanisms of action. With further research and development, this could lay the groundwork for using NMDA targeted treatments for major depressive disorder."
"What we have here is a proof of concept study,” stated co-author Dr. Dennis S. Charney, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and President for Academic Affairs for the Mount Sinai Health System, and a world expert on the neurobiology and treatment of mood disorders, “and we consider the results very promising. We hope to see this line of research further developed so that we have more treatments to offer patients with severe, difficult-to-treat major depressive disorder."
Ketamine, which acts by blocking the NMDA receptor, has a more rapid effect in alleviating symptoms of depression (within hours) compared to more standard medications such as SSRIs which take many weeks to months to begin to have effects. In fact, serial ketamine infusions have shown promise compared to the effect of a single dose of ketamine for treatment-resistant depression. Overall, medications such as SSRIs may only be moderately effective, leaving up to a third of depressed patients resistant to medical therapy.
“Currently, there is an important unmet need for additional antidepressant options,” Lapidus explained. “Many patients fail to respond to many medication treatments and even if response is achieved, there often is a long delay in treatment efficacy."
“Although more research is needed to confirm the antidepressant effects and to determine how to extend this potential benefit, our findings suggest that intranasal ketamine can have antidepressant properties and limited side effects even when given in addition to other ongoing antidepressant medications," added Lapidus.
Lapidus explained that they noted these effects in both a highly treatment-resistant population and in subjects with fewer antidepressant failures.
Whether ketamine holds promise for use in the emergency department as a “rescue medication” to alleviate the symptoms of depression has intrigued both researchers and the public.
“Our research provides a proof of concept for intranasal ketamine in depression. In this context, it remains too early to advocate treatment clinically in any setting.” said Lapidus.
Lapidus believes that additional research is required before clear clinical recommendations can be formulated. But he also felt that there was clear promise for the utility of the approach in the near future.
“Our findings suggest that intranasal ketamine may be easily and rapidly administered and previous studies have included administration of ketamine in emergency rooms as well as other contexts," explained Lapidus. “Providing medication via an intranasal route could also reduce the level of support services needed relative to an intravenous infusion.”
Whether intranasal ketamine can be a game change in the management of depression as rescue or even longer term therapy will likely be debated from this study.
"A growing body of evidence continues to support a possible role for ketamine as a rapid-acting antidepressant. A specific role in acute symptom exacerbations has not been directly addressed in our study, but rapid-action could potentially have increased utility in such situations,” said Lapidus.
“It is difficult to completely predict the long-term implications of our research. Our recent study of intranasal ketamine in depression builds on previous findings with intravenous ketamine from our group at Mount Sinai and others including work by Drs. Dennis Charney, James Murrough, Dan Iosifescu, Sanjay Mathew, and Carlos Zarate”.
