By Mark J. Niciu, MD, PhD
Assistant Professor of Psychiatry/Iowa Neuroscience Institute
University of Iowa Health Care
Dr. Niciu’s lecture was entitled “Es/ketamine for Treatment-Resistant Depression.” After briefly reviewing his potential conflicts of interest and CME objectives, he provided an outline of the talk. The first segment was a brief discussion of the putative mechanisms of action and functional brain response to the N-methyl-D-aspartate receptor antagonist and glutamate modulator ketamine in preclinical and human neuroimaging studies. Dr. Niciu then provided a clinical review of the intravenous subanesthetic dose ketamine literature for major depression, with a historical perspective dating back to the first randomized controlled trial in 2000. Subanesthetic dose ketamine has rapid-acting antidepressant efficacy, on the order of hours-to-days, with a larger effect size than seen with traditional/monoaminergic antidepressants and other medication augmentation strategies. Yet, a major critique has been functional unblinding. In response, several studies were presented using the short-acting intravenous benzodiazepine midazolam as a psychoactive comparator. Intravenous ketamine has also been demonstrated to have anti-suicidal efficacy in treatment-resistant major depressive disorder and bipolar disorder. Finally, alternative dose and frequency studies were presented, which demonstrated that 0.5-1.0 mg/kg appears to be the optimal antidepressant dosing, and 2-3x/week the optimal frequency for an acute/index series.
To date, subanesthetic dose ketamine infusion remains off-label for all psychiatric indications including treatment-resistant major depressive disorder (MDD) and bipolar depression. As a result, very few insurance companies will reimburse treatment costs, so the model remains mostly fee-for-service/out-of-pocket. In 2019, a proprietary intranasal formulation of the S-enantiomer of ketamine, Spravato® (intranasal esketamine), was approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant MDD. A second indication for MDD with acute suicidal ideation or behavior followed on the heels of the initial approval in 2020. Dr. Niciu stressed that both approvals are first-in-class, i.e. intranasal esketamine is the first glutamate-based antidepressant and anti-suicidal medication approved for MDD. Dr. Niciu then reviewed the clinical studies leading to intranasal esketamine’s approval for both indications. He also presented a meta-analysis comparing the efficacy and adverse effects of intravenous ketamine and intranasal esketamine, indicating intravenous ketamine as more effective with fewer adverse effects than intranasal esketamine.
In the third portion and final portion of his lecture, Dr. Niciu presented recommendations for both intravenous ketamine and intranasal esketamine in the treatment algorithm for treatment-refractory MDD and bipolar depression. To wit, he presented some of his absolute, e.g. psychotic spectrum disorder diagnosis and pregnancy/lactation, and relative contraindications, e.g. substance use disorder and illicit substance naïve, to ketamine. He then discussed his hands-on experience with intravenous ketamine and intranasal esketamine including dosing, ancillary support, and setting. For intranasal esketamine, Dr. Niciu introduced the audience to the FDA-mandated Risk Evaluation and Mitigation Strategy (REMS), including the compliance challenges, e.g. mandatory registration, post-administration monitoring and paperwork burden. Dr. Niciu then concluded his talk with several “take home” points and fielded questions from the attendees to conclude our afternoon panel.
