The Potential of Ketamine: Public Workshop and New Research Explores Uses

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In collaboration with the US Food and Drug Administration (FDA), the Reagan-Udall Foundation for the FDA, is today hosting a hybrid public workshop on "Understanding Current Use of Ketamine for Emerging Areas of Therapeutic Interest." While ketamine is a not approved for the treatment of depression or chronic pain, clinicians have shown increased interest in using it for these conditions.

To explore its potential, varied clinicians, researchers, and federal partners are set to present on topics such as the scope of ketamine use, including approved products and compounded products, for these emerging areas of therapeutic interest; potential safety concerns; and online promotion of and access to ketamine.

“This workshop is an important opportunity for us to expand our knowledge about the current use of ketamine products. What evidence do we have? What are the gaps? What else do we need to address? Today, I look forward to this discussion from a variety of stakeholders who are committed to advancing the science of understanding in this emerging space,” said Marta Sokolowska, PhD, deputy center director for Substance Use and Behavioral Health at the FDA Center for Drug Evaluation and Research in her opening remarks.

In looking at the history of ketamine, Gerard Sanacora, MD, PhD, the George D. Gross and Esther S. Gross Professor of Psychiatry at Yale University School of Medicine, the director of the Yale Depression Research Program, and codirector of the Yale New Haven Hospital Interventional Psychiatry Service, said, “The landscape is changing so rapidly. It has changed how people are using ketamine, so where do we stand today?”

Most of the published research on ketamine has been with off-label use of racemic ketamine, specifically intravenous ketamine,¹ or in the more recent FDA-approved intranasal esketamine for treatment-resistant depression (TRD).² The interest in studying ketamine can be seen in 2 important pieces of recent research that Sanacora called out.

Jha et al, in evaluating 365 adults with nonpsychotic TRD, found that patients may want to consider ketamine over electroconvulsive therapy (ECT) for TRD.³ Participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. There were 195 participants randomized to the ketamine group (53.4%) and 170 to the ECT group (46.6%). Participants randomized to ketamine received twice-weekly infusions over 3 weeks. Each infusion contained a subanesthetic dose of 0.5 mg/kg of body weight and was administered for over 40 minutes with allowance for dose modification. Meanwhile, participants randomized to ECT received 3 treatments per week, with the recommended starting procedure as a right unilateral ultrabrief pulse width at 6 times the seizure threshold determined during the titration at the first visit, with subsequent modifications of settings and electrode placements permitted if clinically indicated. In a secondary analysis, greater reductions in depression severity were observed with ketamine among outpatients and in those with moderately severe or severe depression.

Glue et al found that ketamine has rapid-onset antidepressant activity in patients with TRD.⁴ Investigators realized the safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107). In this phase 2 multicenter clinical trial, adult patients with TRD and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8. On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized (1:1:1:1:1) to receive double-blind R-107 doses of 30, 60, 120, or 180 mg, or placebo, twice weekly for 12 additional weeks. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. The twice-weekly 180 mg dose showed statistically significant and clinically meaningful improvement in depressive symptoms based on MADRS score compared with placebo, with a group-treatment difference of 6.1. Common adverse effects of injected or intranasal ketamine such as dissociation, sedation, and increased blood pressure, were minimal.

“Use of an extended-release oral dosage ketamine formulation may be advantageous compared with intranasal or intravenous dosing, in terms of reduced intensity of dissociation, lower risk of abuse, reduced frequency and intensity of sedative and cardiovascular side effects, and improved convenience for administration in the community,” wrote the study authors.⁴

Psychiatric Times will provide further updates as the workshop progresses. Do you have interest in using ketamine for your patients? Let us know at PTEditor@MMHGroup.com!

References

1. Nikolin S, Rodgers A, Schwaab A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023;62:102127.

2. Kim J, Farchione T, Potter A, et al. Esketamine for treatment-resistant depression—first FDA-approved antidepressant in a new class. N Engl J Med. 2019;381(1):1-4.

3. Jha MK, Wilkinson ST, Krishnan K, et al. Ketamine vs electroconvulsive therapy for treatment-resistant depression: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024;7(6):e2417786.

4. Glue P, Loo C, Fam J, et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nat Med. 2024 Jun 24. Online ahead of print.