Alan F. Schatzberg, MD

The Significance of Opioid Properties of Ketamine

In recent years, there has been considerable attention paid to the opioid effects of ketamine.   This presentation reviews the literature on the preclinical and clinical effects of ketamine on mu opioid mediated activity. Our interest began with clinical studies of others that pointed to rapid and somewhat sustained effects of intravenous ketamine in depressed patients. These data have been viewed as due to the drug’s NMDA receptor antagonism. However, other NMDA antagonists have not been associated with antidepressant effects in man, let alone rapid relief of depressive symptoms. Further, ketamine has long been known to have mild affinity for mu opioid receptors (MOR’s) suggesting an alternative mechanism of action. We hypothesized that the MOR effects were responsible for the rapid antidepressant response and that the MoA could be tested by randomizing patients who are receiving ketamine to being pretreated with naltrexone or placebo.  We then tested the hypothesis and demonstrated that naltrexone does block the antidepressant effects of ketamine.  Results of that study have been replicated in a number of preclinical studies and a direct clinical replication. The clinical implications of these studies for patients’ receiving ketamine are discussed as are the importance for future antidepressant development.

Alan F. Schatzberg, MD received his MD from NYU in 1968. He completed his psychiatric residency at the Massachusetts Mental Health Center and a clinical fellowship in psychiatry at Harvard Medical School. After serving in the United States Air Force, he joined the staff at McLean Hospital and served in several leadership positions there. He became clinical director of the Massachusetts Mental Health Center and professor of psychiatry at Harvard Medical School, while continuing his research program at McLean Hospital on the biology and treatment of depression. In 1991, Dr. Schatzberg became the Kenneth T. Norris, Jr., Professor and Chairman of the Department of Psychiatry and Behavioral Sciences at Stanford University, where he served as chair until 2010. He now directs the Stanford Mood Disorders Center. Dr. Schatzberg has been an active investigator in the biology and psychopharmacology of depressive disorders. He has authored over 700 publications and abstracts and co-edited the Textbook of Psychopharmacology (now in its Sixth Edition) and the Manual of Clinical Psychopharmacology (now in its 10^th Edition. He has been president of the American Psychiatric Association (APA), the American College of Neuropsychopharmacology (ACNP), and the Society of Biological Psychiatry (SOBP). He has received numerous awards for excellence and leadership from the APA, ACNP, SOBP, Max Planck Psychiatric Institute, Brain and Behavior Foundation, Anna Monika Foundation, University of Pennsylvania, Weill Cornell Medical College, etc. He has three honorary doctorates and has been elected to the National Academy of Medicine.

Reading List

Bonaventura, Jordi, et al. “Pharmacological and behavioral divergence of ketamine enantiomers: Implications for abuse liability.” Molecular Psychiatry, vol. 26, no. 11, 15 Apr. 2021, pp. 6704–6722, https://doi.org/10.1038/s41380-021-01093-2.

Sanacora, Gerard, and Alan F Schatzberg. “Erratum: Ketamine: Promising path or false prophecy in the development of Novel Therapeutics for Mood Disorders?” Neuropsychopharmacology, vol. 40, no. 5, 13 Mar. 2015, pp. 1307–1307, https://doi.org/10.1038/npp.2014.338.

Sanacora, Gerard, and Alan F Schatzberg. “Ketamine: Promising path or false prophecy in the development of Novel Therapeutics for Mood Disorders?” Neuropsychopharmacology, vol. 40, no. 2, 26 Sept. 2014, pp. 259–267, https://doi.org/10.1038/npp.2014.261.

Schatzberg, Alan F. “A word to the wise about intranasal esketamine.” American Journal of Psychiatry, vol. 176, no. 6, 1 June 2019, pp. 422–424, https://doi.org/10.1176/appi.ajp.2019.19040423.

Schatzberg, Alan F. “A word to the wise about ketamine.” American Journal of Psychiatry, vol. 171, no. 3, Mar. 2014, pp. 262–264, https://doi.org/10.1176/appi.ajp.2014.13101434.

Williams, Nolan R., Boris D. Heifets, Brandon S. Bentzley, et al. “Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism.” Molecular Psychiatry, vol. 24, no. 12, 29 Aug. 2019, pp. 1779–1786, https://doi.org/10.1038/s41380-019-0503-4.

Williams, Nolan R., Boris D. Heifets, Christine Blasey, et al. “Attenuation of antidepressant effects of ketamine by opioid receptor antagonism.” American Journal of Psychiatry, vol. 175, no. 12, 1 Dec. 2018, pp. 1205–1215, https://doi.org/10.1176/appi.ajp.2018.18020138.