Abstract
The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD− (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine’s antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.
Highlights
The rapid antidepressant effect of ketamine, first published in 2000 [1] and further abundantly replicated [2], has become a breakthrough in the research and treatment of depression, including novel insight in its mechanisms of antidepressant effect [3, 4]
The rapid improvement of the depressive mood induced by ketamine may be mediated by the induction of the multiple processes involved in neuroplasticity, with synaptogenesis being a reputable explanation for its antidepressant effect [5,6,7,8]
Repeated measures analysis of variance (RM-ANOVA) with BZD+ and BZD− as a group variable and MADRS scores at four time points as a within subject repeated variable with the degree of freedom corrected for a lack of sphericity, was performed to find a different pattern of response to ketamine within the study period, if present
Summary
The rapid antidepressant effect of ketamine, first published in 2000 [1] and further abundantly replicated [2], has become a breakthrough in the research and treatment of depression, including novel insight in its mechanisms of antidepressant effect [3, 4]. The rapid improvement of the depressive mood induced by ketamine may be mediated by the induction of the multiple processes involved in neuroplasticity, with synaptogenesis being a reputable explanation for its antidepressant effect [5,6,7,8]. These mechanisms are allegedly triggered through ketamine’s antagonism of N-methyl-daspartate (NMDA) receptors on gamma-aminobutyric acid (GABA) interneurons and consequent activation of a-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [6, 9]. BZDs act as GABA-A receptor agonists, allosterically increasing the inhibitory tone of GABA-interneurons [21, 22] and may, thereby, interfere with the therapeutic effect of ketamine in light of ketamine’s blockage of NMDA receptors on the identical population of GABAergic interneurons [3, 9]
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