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Neuropsychopharmacology. 2019 Jan 17. doi: 10.1038/s41386-019-0317-8. [Epub ahead of print]

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant.

Author information

1
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. samuel.wilkinson@yale.edu.
2
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA.
3
Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, USA.
4
Mental Health Care Line, Michael E. Debakey VA Medical Center, Houston, USA.
5
Department of Psychiatry, Columbia University, Medical Center and New York State Psychiatric Institute, New York, USA.
6
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
7
Department of Psychiatry, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
8
Beijing Anding Hospital, Capital University of Medical Sciences, Beijing, China.
9
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
10
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

Abstract

The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving the blind in ketamine studies for mood disorders through patient-level analyses of efficacy trial outcomes. In this integrative data analysis (k = 9, N = 367 patients with mood disorders), clinical outcomes were compared across four groups: ketamine (midazolam-controlled), ketamine (saline-controlled), midazolam, and saline. Ketamine doses ranged from 0.5 to 0.54 mg/kg and midazolam doses ranged from 0.02 to 0.045 mg/kg. The baseline-to-Day 1 effect size was d = 0.7 (95% CI: 0.4-0.9) for ketamine (midazolam) versus midazolam and d = 1.8 (95% CI: 1.4-2.2) for ketamine (saline) versus saline. The effect of ketamine relative to control was larger in saline-controlled studies than in midazolam-controlled studies (t(276) = 2.32, p = 0.02). This was driven by a comparatively larger effect under midazolam than saline (t(111) = 5.40, p < 0.0001), whereas there was no difference between ketamine (midazolam) versus ketamine (saline) (t(177) = 0.65, p = 0.51). Model-estimated rates of response (with 95% CI) yielded similar results: ketamine (midazolam), 45% (34-56%); ketamine (saline), 46% (34-58%); midazolam, 18% (6-30%); saline, 1% (0-11%). The response rate for ketamine was higher than the control condition for both saline (t(353) = 7.41, p < 0.0001) and midazolam (t(353) = 4.59, p < 0.0001). Studies that used midazolam as a comparator yielded smaller effects of ketamine than those which used saline, which was accounted for by greater improvement following midazolam compared to saline.

PMID:
30653192
DOI:
10.1038/s41386-019-0317-8

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