Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA.
Neuropsychopharmacology. 2019 Jun;44(7):1233-1238. doi: 10.1038/s41386-019-0317-8. Epub 2019 Jan 17.
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.
这项研究的目的是通过对疗效试验结果进行患者水平分析，推断咪达唑仑作为对照药物在氯胺酮治疗心境障碍研究中保留盲法的效果。在这项综合数据分析中（k=9，N=367 名心境障碍患者），比较了以下四组的临床结果：氯胺酮（咪达唑仑对照）、氯胺酮（生理盐水对照）、咪达唑仑和生理盐水。氯胺酮的剂量范围为 0.5 至 0.54mg/kg，咪达唑仑的剂量范围为 0.02 至 0.045mg/kg。氯胺酮（咪达唑仑）与咪达唑仑相比，从基线到第 1 天的效应大小为 d=0.7（95%CI：0.4-0.9），氯胺酮（生理盐水）与生理盐水相比，效应大小为 d=1.8（95%CI：1.4-2.2）。在生理盐水对照研究中，氯胺酮的作用相对于对照药物的效果大于咪达唑仑对照研究（t（276）=2.32，p=0.02）。这是由于咪达唑仑对照下的效果比较大，而生理盐水对照下的效果较小（t（111）=5.40，p<0.0001），而氯胺酮（咪达唑仑）与氯胺酮（生理盐水）之间没有差异（t（177）=0.65，p=0.51）。模型估计的反应率（95%CI）也得到了类似的结果：氯胺酮（咪达唑仑），45%（34-56%）；氯胺酮（生理盐水），46%（34-58%）；咪达唑仑，18%（6-30%）；生理盐水，1%（0-11%）。氯胺酮的反应率高于生理盐水（t（353）=7.41，p<0.0001）和咪达唑仑（t（353）=4.59，p<0.0001）的对照条件。使用咪达唑仑作为对照的研究得出的氯胺酮效应小于使用生理盐水作为对照的研究，这是由于与生理盐水相比，咪达唑仑治疗后有更大的改善。
