This small randomized double blind study examined the effects of intranasal ketamine in the treatment of resistant depression  published December 27, 2017  by Ella J. Daly, MD1 et al in JAMA Psychiatry and found significant improvement of depressive symptoms.  Depression was assessed by the Montgomery-Åsberg Depression Rating Scale total score, and was observed after 1 week with intranasal esketamine, and compared 28 to 84 mg administered twice weekly.   Improvement appeared to be sustained with reduced dosing frequency for up to 9 weeks.

Background information includes

Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.

This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.

Interventions  In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.

Main Outcomes and Measures  The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Results  Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84 mg: −9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (−7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).

Conclusions and Relevance  In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.

Trial Registration identifier: NCT01998958


Major depressive disorder (MDD) is a common and disabling illness, with a lifetime prevalence of approximately 20% in the United States.1,2 Major depressive disorder impairs socio-occupational functioning3 and increases suicide risk,4 adverse sequelae of other common comorbid medical conditions (eg, cardiovascular disease, type 2 diabetes, and obesity), and mortality.5– 9 Limitations of currently available antidepressant therapies include delayed onset of efficacy and low remission rates after multiple courses of pharmacotherapy.10

Research on mood disorder pathophysiology implicated abnormalities in glutamatergic transmission, along with synaptic and dendritic atrophy, in neural circuits that modulate emotional behavior.11 Several studies have shown antidepressant efficacy with the N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine.12– 17 One limitation of ketamine for treating depression is that it may require intravenous administration, reducing its applicability in outpatient settings.

Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer18 and is being developed as an intranasal formulation for therapy in treatment-resistant depression (TRD). Rapid onset of antidepressant effects has been observed following intravenous administration of esketamine.19 We report findings from a study of intranasal esketamine, assessing its efficacy and safety compared with placebo in individuals with TRD.


Source: Efficacy and Safety of Intranasal Esketamine in Depression