From the Editor
March 5, 2019 turned out to be an important day for psychiatric providers as well as individuals suffering from treatment resistant depression (TRD). This was the day that esketamine (Spravato) was FDA approved as an intranasal spray to combine with a traditional oral antidepressant to treat individuals that, despite aggressive and adequate traditional psychopharmacological treatments, remained severely depressed. There are many stories within this story that I would like to explore.
Ketamine was discovered by chemist Calvin Stevens in 1962. After studies in animals demonstrated ketamine’s anesthetic effect, it was studied in human prisoners in 1964. Once ketamine proved itself to be an effective dissociative anesthetic, it was FDA approved in 1970. Unlike many anesthetics, ketamine demonstrated properties that were advantageous in acute trauma situations—specifically it did not cause respiratory depression and hypotension—and it was found to be quite useful for injured soldiers during the Vietnam War. Since that time it has continued to be used in medicine for the induction and maintenance of anesthesia, often in combination with other medications. Additionally, ketamine is commonly used in veterinary anesthesia, and is used as a first-line agent in equine surgery. In 2000, Berman and colleagues,1 at Yale University reported a significant antidepressant effect within 72 hours when 7 depressed individuals were treated with intravenous ketamine in contrast to a saline placebo.
This rapidly acting antidepressant effect of ketamine was replicated by numerous studies and led to significant excitement in the psychiatric community for the possibility of a novel mechanism of action for the treatment of depression. Up until esketamine’s FDA approval for TRD this year, all other FDA-approved antidepressants—monotherapy and augmentation agents—shared mechanisms of action that acted on the monoamine system, including the neurotransmitters serotonin, norepinephrine, and dopamine.
The monoamine hypothesis of depression dates to 1952 when both reserpine (used to treat hypertension) and iproniazid (used to treat tuberculosis) were shown to increase brain levels of the monoamines serotonin, norepinephrine and dopamine, and simultaneously treated symptoms of depression. Ultimately iproniazid was FDA approved as our first antidepressant medication in 1958, followed by imipramine in 1959. Although these and all subsequent antidepressants showed clinical effectiveness in the treatment of depression, it often takes 2 to 8 weeks to achieve improvement. Hence, the observation in 2000 that ketamine appeared to reduce depressive symptoms within 72 hours of the first treatment was a true and welcome paradigm shift.
Dr Miller reports that he is on Janssen’s Advisory Board and on the Speaker’s Bureau for Spravato.
1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
2. Wilkinson ST, Katz RB, Toprak M, et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry. 2018;79:pii:17m11731.
3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215.
4. Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry. 2019; 76:337-338.
5. Marton T, Barnes DE, Wallace A, et al. Concurrent use of buprenorphine, methadone, or naltrexone does not inhibit ketamine’s antidepressant activity. Biol Psychiatry. March 26, 2019; Epub ahead of print. ❒