Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study

Abstract

BackgroundKetamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD).MethodIn a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery–Åsberg Depression Rating Scale (MADRS).ResultsTwenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient.ConclusionsRepeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone.

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

“…Pooled data revealed a significant benefit of ketamine over placebo also in terms of response and remission, after exclusion of the study involving heavily pretreated patients with suicidal thoughts [30], due the reasons described below. As reported in included RCTs, antidepressant effects were maintained for about 1 week of follow-up after ketamine cessation [31,32]. Although data from uncontrolled studies showed that most patients relapse after a few weeks (usually before the end of the third week) after cessation of even repeated ketamine treatment [12,13,15], a very recent RCT on intranasal esketamine showed a sustained improvement in the mean MADRS ratings over the 8-week follow-up after treatment cessation [16].…”

“…Two of the RCTs investigating repeated ketamine administration used oral ketamine, and both of them confirmed that this route of administration was highly effective in amelioration of depressive symptoms at 2-3 weeks [31,33]. Oral dosing of ketamine is a recognized route of administration in chronic pain management [56] and would be a more practical and acceptable delivery method than Fig.…”

“…Among the four identified RCTs of repeated ketamine administration, we searched for the results reported for the last observation during the randomized phase of each study. That was 3 weeks in the studies by Ionescu et al [30] and Domany et al [31], and 4 weeks in the study by Singh et al [32]. However, Singh et al [32] reported that most patients from placebo groups crossed to ketamine treatment after day 15 according to the predefined protocol (due to lack of efficacy).…”

Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial

“…Ketamine, a glutamatergic modulator and a rapidly acting antidepressant (aan het Rot et al, 2010;Berman et al, 2000;Domany et al, 2018;Murrough et al, 2013;Singh et al, 2016;Zarate et al, 2006), has been shown to rapidly reduce suicidal ideation (Grunebaum et al, 2018;Ibrahim et al, 2011;Price, Nock, Charney, & Mathew, 2009). In addition, esketamine, the S enantiomer of racemic ketamine, has shown similar results (Canuso et al, 2018).…”

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

“…Only five recent human studies included a control group 9,[55][56][57][58] , and, strikingly, they showed contradictory results. Ketamine either maintained antidepressant efficacy 9,56,57 or failed to outperform placebo 58 and was ineffective 55 , additionally causing side effects 55,58 . The study of Canuso et al 56 demonstrated that although the depressive symptoms diminish after ketamine at all time points, the suicidal ideation reduces only at 4 h, and displays no improvement at 24 h or at end-point day 25.…”