SAN FRANCISCO – The anesthetic ketamine produced a significant and rapid antidepressant effect in a randomized, blinded, proof-of-concept study in *72 patients with treatment-resistant depression.
Within 24 hours, 64% of patients given an intravenous infusion of ketamine (47 patients) showed a response, compared with 28% of patients who showed a response in a control group given the anesthetic midazolam (25 patients), which mimics the anesthetic effects of ketamine but without any antidepressant effects, Dr. James W. Murrough and his associates reported.
Patients were assessed for depression before the infusion, 24 hours later, and again at days 2, 3 and 7 using the Montgomery-Asberg Depression Scale (MADRS). The ketamine group showed sustained improvement in MADRS scores up to a week after the infusion, Dr. Murrough said during a press briefing at the annual meeting of the American Psychiatric Association.
Ketamine is not approved to treat depression, and it’s premature to say that it should be, he noted. Data are needed on the efficacy and safety of taking ketamine over time, among other research questions, said Dr. Murrough of the departments of psychiatry and neuroscience at Mount Sinai School of Medicine, New York. Previous studies had suggested that ketamine may have a rapid antidepressant effect in treatment-resistant depression, but those studies were limited by small sample sizes, single-site cohorts, and other limitations.
Dr. James W. Murrough
Patients were randomized 2:1 to receive either 0.5 mg/kg of ketamine or 0.045 mg/kg of midazolam over 40 minutes. The patients were supervised and monitored by an anesthesiologist and spent the night on the clinical research unit.
The MADRS scores before treatment were approximately 32 in both groups. Within 24 hours, the primary endpoint, MADRS scores were approximately 16 in the ketamine group, a significant improvement, compared with 22 in the midazolam group, a nonsignificant change from baseline. Among secondary endpoints, MADRS scores held steady in both groups on days 2 and 3. By day 7, MADRS scores were approximately 18 in the ketamine group and 24 in the midazolam group, with ketamine’s effect no longer being statistically significant.
Dr. Murrough acknowledged that some psychiatrists use ketamine off label for patients with severe, refractory depression. His institution does not do so outside of trials and "we don’t recommend it," he said.
Ketamine is a drug of abuse on the streets, though usually in doses much higher than the dose in the study, he added. When chronically abused, ketamine can cause cognitive problems and schizoid effects, prior reports have suggested. A long history of ketamine use in anesthesia, however, shows that it is safe when used short-term in small doses under close medical supervision, he said. Data are needed to assess its safety beyond those parameters.
Future studies should look at the biomarkers and mechanisms of action when using ketamine to treat depression, its long-term safety and efficacy, and novel therapeutic targets.
Dr. Murrough reported research funding from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Affective Disorders, the American Foundation for Suicide Prevention, Janssen Pharmaceuticals, Avanir Pharmaceuticals, and Evotec/Roche. If ketamine were to be approved to treat depression, his institution and one of its deans could benefit financially.
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*This article was updated on 5/22/13.