Debate Continues on Esketamine Efficacy and Safety for Depression Treatment

Abuse Potential

Ketamine has been abused as a party drug for decades for its hallucinatory and dissociative effects.

Schatzberg and his colleagues have reported that oral naltrexone blocks the antidepressant effects of ketamine, indicating the drug’s effect arises in part either through a release of endogenous opioids or binding to the mu opioid receptor.⁶

“The opioid properties may explain the drug’s abusability and raise concerns regarding liability with longer-term use,” Schatzberg noted in his editorial.

The FDA approval established a restricted distribution system for esketamine under a Risk Evaluation and Mitigation Strategy that limits its administration to certified medical offices. Patients self-administer the spray under supervision of a healthcare provider and stay in the facility to be monitored for side effects. VA guidelines call for veterans to remain for observation for at least two hours. The spray cannot go home with a patient.

“There’s an obligation with a new treatment that in other forms have abuse potential to make sure that treatment is done in a safe and reasonable way,” Thase said.

In his view, the REMS program creates effective safeguards. “If you were using ketamine as a party drug, just 50% would be esketamine or the s-form,” he said, so the amount needed would be much higher.

Further, “users must take progressively higher doses to continue to get the euphoric effect. The two therapeutic doses given for antidepressant effect are just at the edge of the illusions or dissociation response that people sometimes have and doctors are not permitted to go above those levels, so they’re not at the dose that would lead to abuse,” he explained. “And, the restricted distribution system means patients don’t have access to the drug to self-administer.”

Caution is still in order, though. “In the VA setting, we have to be especially mindful of risk. We’re treating mostly older men with long-standing illness,” Thase noted. “None of the esketamine research has been done at VAMCs and the benefits for older people are not clearly established.”

1. Chen J. How New Ketamine Drug Helps with Depression. Yale Medicine. https://www.yalemedicine.org/stories/ketamine-depression/

2. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry 2019; 176:428–438

3. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630.

4. US Food and Drug Administration: Briefing information for the Feb 12, 2019 joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM).

5. Schatzberg AF. A Word to the Wise About Intranasal Esketamine. Am J Psychiatry. 2019 Jun 1;176(6):422-424.

6. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, Hawkins J, Birnbaum J, Lyons DM, Rodriguez CI, Schatzberg AF. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 2018; 175:1205–1215.