Antidepressant Effects of Ketamine in Depressed Patients: A Randomized Double-Blind Placebo-Controlled Crossover Pilot

Randomized, double-blind, placebo-controlled crossover pilot (Department of Psychiatry, Yale University School of Medicine, New Haven CT; investigators: Ronald M. Berman, Angelo Cappiello, Amit Anand, David A. Oren, George R. Heninger, Dennis S. Charney, John H. Krystal) of a single 40-minute IV infusion of ketamine hydrochloride 0.5 mg/kg versus normal saline in 9 adults (4 men, 5 women; mean age 37 ± 10 years, range 23–56; 2 Hispanic, 7 Caucasian) meeting DSM-IV criteria for a major depressive episode (8 with recurrent unipolar MDD, 1 with bipolar disorder depressed phase), all medically healthy and unmedicated ≥2 weeks (confirmed by toxicology). Two treatment days separated by ≥1 week; 4 of 9 participants received ketamine first. Two participants withdrew before completing the second treatment day, leaving 7 who completed both conditions. Primary outcome: Hamilton Depression Rating Scale (HDRS-25) at baseline and 80 min, 230 min, 24h, 48h, and 72h post-infusion. Secondary outcomes: Beck Depression Inventory (BDI) at the same time points plus 10, 40, and 110 min; Brief Psychiatric Rating Scale (BPRS) at baseline and 10, 40, 80, 110, and 230 min; Visual Analogue Scale for "feeling high" (VAS-high) at baseline and 10, 40, 80, and 110 min. Analysed with repeated-measures ANOVA (Huynh–Feldt correction), condition × time interaction. IRB approved; no trial registry entry: the study pre-dates the ICMJE 2005 registration mandate by five years and the FDAAA 2007 requirement by seven years. This is the first reported randomized trial of ketamine as an antidepressant and is the foundational citation for the field.