An Oral Ketamine Drug for Depression — Minus the Trip?

A novel oral ketamine drug was well tolerated and associated with reduced depressive symptoms in treatment-resistant depression (TRD) without significant dissociative effects, findings from two clinical trials showed.

In a phase 1 trial designed to measure dissociation, participants treated with a single dose of KET01, a prolonged-release racemic ketamine oral tablet, reported no significant dissociative symptoms, whereas those treated with the active comparator, esketamine, did show these effects.

In the phase 2 study, after 3 weeks of daily treatment with KET01 administered alongside standard antidepressant therapy, patients again reported no significant dissociation, with significant reductions in depressive symptoms at days 4 and 7 compared to placebo. However, the trial failed to meet its primary clinical efficacy endpoint at day 21 as the difference compared to placebo was no longer statistically significant.

A key issue with studies of psychedelics is functional unblinding, where participants can often distinguish drugs like ketamine from placebo, due to hallucinogenic or “trippy” effects, making it difficult to measure antidepressant effects.

In this trial, the investigators observed a clinical benefit in patients who did not report any dissociative side effects.

“In a nutshell, I think we can say it is not about the trip — at least not to a significant amount,” lead author Martin Walter, MD, PhD, told Medscape Medical News.

The findings add weight to a “true antidepressant mode of action” of the ketamine drug, Walter, chair in the Department of Psychiatry and Psychotherapy at University of Jena and director of the University Hospital of Psychiatry in Jena, Germany, added.

The study was published online on June 24 in JAMA Network Open.

A Novel Drug

Approximately one third of patients with major depressive disorder (MDD) will be diagnosed with TRD, for which limited treatment options are available. Over the past two decades, intravenous racemic ketamine and esketamine have emerged as efficacious for some patients with TRD, displaying rapid antidepressant benefits.

However, treatment with ketamine requires careful clinical monitoring due to cardiovascular fluctuations and dissociative effects. Interest in oral ketamine for TRD has grown in recent years, partly because it may be a noninvasive option that could potentially require less monitoring.

KET01 is an oral, prolonged-release ketamine hydrochloride formulation, designed as an adjunctive treatment for MDD and TRD that could potentially be taken at home and has been shown to have limited dissociative properties.

To study the drug’s efficacy, safety, and dissociative effects, researchers enrolled 26 healthy males (median age, 32 years) in a phase 1 trial and 122 outpatients with TRD (59% female; median age, 41 years) in a phase 2 trial. Both trials were double-blind.

In the phase 1 study, patients were randomized to receive a single dose of KET01 (240 mg) or an active comparator of intranasal esketamine (84 mg). Patients were monitored for 24 hours after each dose and blood samples were collected during and after treatment.

The primary endpoint was the difference in mean maximum change from baseline in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and esketamine within the first 24 hours. The key secondary endpoint was the incidence of dissociative symptoms.

In the phase 2 trial, patients were randomized to receive 120 or 240 mg of oral ketamine daily or placebo for 3 weeks, addition to standard antidepressant therapy.

The primary endpoint was least squares mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 21 for 240 mg of KET01 vs placebo. Secondary endpoints included the number of patients who achieved response or remission.

Less Dissociative Effects

In the phase 1 trial, intranasal esketamine was associated with significant dissociation at 24 hours, whereas KET01 was not (mean maximum CADSS score change, 29.6 vs 0.7 points; P < .001). In total, 96% of esketamine patients experienced dissociation vs just 4% of KET01 patients.

Treatment-emergent adverse events within the first 48 hours were reported in all of the esketamine group and in 62% of the KET01 group. In addition, blood pressure and pulse rapidly increased among esketamine patients but not in the KET01 group.

“Our findings indicate that oral prolonged-release ketamine is better tolerated than esketamine in terms of dissociation and offers a safer option for adjunctive treatment,” the investigators wrote.

In the phase 2 trial, there was no significant difference in mean CADSS total scores between KET01 and placebo groups.

The ketamine group reported statistically significant reductions in depression symptoms at day 4 (mean difference, -3.66; P = .02) and day 7 (-3.95; P = .04). 

However, the difference in MADRS score was not statistically significant at day 21, missing the primary efficacy endpoint (mean difference for 240 mg oral ketamine vs placebo, -1.82). In the KET01 240 mg group, 47.5% achieved a clinical response and 40% achieved remission at 21 days.

Peak ketamine plasma concentration was much lower with KET01 than with esketamine and occurred over a longer period. This lower and slower plasma peak might be the reason why oral ketamine does not lead to significant dissociation, the investigators hypothesized.

Concentrations of norketamine and hydroxynorketamine were higher with KET01 which, in combination with the signal of antidepressant efficacy, supports the “hypothesis that downstream metabolites may drive the antidepressant effect of ketamine,” the researchers wrote, although they cautioned more research is needed.

“The fact that we don’t see relevant cardiovascular defects neither in the blood pressure nor in the pulse is positive if you consider indications where we so far have been rather reluctant to opt for esketamine,” such as patients with cardiovascular risks, Walter said.

Limitations of the studies were the small sample sizes, short duration, and only male participants in the phase 1 trial.

‘Significant Contribution’

The findings are less robust than have been seen in studies of ketamine and esketamine, John Krystal, MD, who was not involved in the study, told Medscape Medical News.

The primary outcome was not met because the drug dosage was likely not high enough to yield significant effects, said Krystal, professor of translational research, psychiatry, neuroscience, and psychology at Yale University in New Haven, Connecticut.

Ketamine’s mechanism of action is still incompletely understood, and this study is a “significant contribution to the field of ketamine use for TRD,” Cristina Cusin, MD, wrote in an accompanying editorial.

“Despite the potential antidepressant effect of oral ketamine or esketamine, at this point, the evidence from controlled clinical trials is not sufficient to support their efficacy in TRD, in stark contrast with the widespread prescription of ketamine lozenges in the community,” Cusin, an associate professor of psychiatry and director of the Massachusetts General Hospital Ketamine Clinic, Harvard Medical School in Boston, wrote.

One possible explanation is that ketamine given orally undergoes extensive initial metabolic breakdown and oral doses used so far don’t reach a plasma level high enough to yield a significant antidepressant effect, she noted.

Clinical trials of psychedelics are also severely limited by requiring patients to taper off antidepressants, which is difficult to achieve in this population, she added.

“Because ketamine is prescribed in conjunction with antidepressant and augmenting agents, it represents a unique tool for the treatment of severe TRD, a tool we still need to understand better in order to help our sickest patients.”

Ketabon GmbH, a joint venture between HMNC Brain Health and Develco Pharma, is the manufacturer of the drug. Ketabon GmbH had an active role in the trial design and conduct. Walter reported having an institutional advisory role with HMNC Brain Health, receiving personal fees from Janssen, receiving speaker compensation from Heel, receiving advisor compensation from Boehringer Ingelheim, and participating in an institutional study with Perception Neuroscience during the conduct of the study. Cusin reported receiving personal fees from Janssen, Boehringer Ingelheim, and Compass Therapeutics and grants from LivaNova, Abbott, and AtaiBeckley outside the submitted work. Krystal disclosed involvement in Yale-held patents for Spravato development, co-founding Freedom Biosciences and consulting for several companies developing antidepressants.