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Ketamine’s mechanism of action still unclear, requires further investigation

SAN FRANCISCO — A panel of experts here agreed that while ketamine represents an effective therapy for patients with treatment-resistant depression and may have utility in other psychiatric conditions like OCD, there are still unanswered questions that require further study.

Jeff Newport, MD, of Dell Medical School at University of Texas at Austin, shared data from his meta-analysis published in 2015, that demonstrated the “rapid” and “robust” effects of ketamine in treatment-resistant depression.

“In patients with treatment-resistant depression, we’re seeing response rates — within an hour — of 50% or more. And remission rates of 20% or more, which is really remarkable when you’re looking at the patient population. ... [So] you see tremendous response rates but ... over the course of 2 weeks you begin to see those things return to baseline. So, you get this very rapid, robust therapeutic response but one that is transient, lasting a couple of weeks or so.”

This leaves researchers with questions regarding whether repeated administration is necessary, the safety of repeated use, as well as the efficacy of continued administration, he said.

During the session, Nolan Williams, MD, assistant professor of psychiatry and behavioral sciences at the Stanford University Medical Center, discussed findings from his 2018 study examining the role of the opioid system in ketamine’s antidepressant mechanism of action and echoed Newport’s concerns.

“We don’t know everything about this drug,” he said during his presentation. “... understanding the mechanism is really important to understanding the safety of this drug, who we should give it to and what sort of things we should look out for.”

Because it’s linked with glutamate levels, which are associated with OCD symptoms, ketamine could have utility in OCD. In her presentation, Carolyn Rodriguez, MD, PhD, associate professor of psychiatry at Stanford, explored the use of IV ketamine in refractory OCD.

According to the results of a proof-of-concept study she and colleagues published in 2013, ketamine infusion was associated with a decrease in intrusive obsessive thoughts among patients with OCD. The effects persisted for up to 1 week in 50% of patients, she said.

Despite these findings, Rodriguez also acknowledged that more work is needed to answer the questions Newport and Williams posed, like do we need repeated doses? And who would benefit most from treatment?

Rodriguez and Newport both highlighted future directions based on what’s been learned so far about ketamine. One direction is to look at other molecules to block NMDA antagonism, a search that Newport said is ongoing. He also referred to some small trials looking at alternate delivery methods, like oral administration as an augmentation strategy in treatment-resistant depression and another open-label trial looking at subcutaneous administration.

But the most work being done in this area is with intranasal esketamine. For OCD, Rodriguez and colleagues are looking at mechanisms of action of ketamine using MRI and fMRI as well as EEG via funding from the NIH. She has also partnered with Williams on a donor-funded study to explore the use of non-invasive transcranial magnetic stimulation.

“One of the problems in our field is that there is a vast underinvestment in psychiatry research,” Rodriguez said. “For every 11 compounds being studied in cancer and every 8 compounds being tested in neurology, only one is being tested in psychiatry. There’s a wonderful richness in the basic neurobiology of mechanism that we can use to translate into helping patients.” – by Stacey L. Adams

References:

Newport DJ, et al. Implications of understanding the mechanism of action of ketamine. Presented at: APA Annual Meeting; May 18-23, 2019; San Francisco.

Disclosures: Rodriguez reports consulting for Allergan, BlackThorn, Epiodyne and Rugen. Healio Psychiatry was unable to confirm any relevant financial disclosures for Newport and Williams at the time of publication.