A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

Abstract

Background The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods Twenty patients with major depression were randomized and 18 completed two treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized, double-blind, crossover study. The primary efficacy outcome measure was change in depression severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24 hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression. Trial Registration clinicaltrials.gov identifier NCT01304147

Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

“…However, alternative routes of administration need to be considered for clinical practice. The first controlled randomized, double-blind, crossover study in 20 patients with major depression reported significant improvements in symptoms (based on the Montgomery-Å sberg Depression Rating Scale) 24 h after intranasal administration of ketamine hydrochloride (50 mg) [61]. The advantage of intranasal administration over intravenous administration is that the intranasal route produces rapid antidepressant effects (within 5-40 min) with fewer dissociative side-effects and no drug-induced euphoria [62].…”

Intranasal Drug Delivery in Neuropsychiatry: Focus on Intranasal Ketamine for Refractory Depression

“…INDD can improve the convenience of drug administration, as with intranasally administered ketamine 17 in place of intravenously infused ketamine for patients with refractory depression. Table 2 lists a few examples of INDD applications in neuropsychiatry; in this regard, ketamine and oxytocin are perhaps the best-studied agents.…”

“…A case report also showed benefits with intranasal ketamine in depression. 35 In a randomized, double-blind, saline-controlled, crossover trial conducted in 20 patients with major depression, Lapidus et al 17 found that a single intranasal dose of ketamine (50 mg) outperformed saline by 7.6 points on the Montgomery-Asberg Depression Rating Scale as assessed 24 hours after dosing; the response rate was 44% vs 6%, respectively. Anxiety ratings also decreased significantly more with ketamine.…”

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

“…While more work is needed to further explore repeated dosing, other studies have examined alternative methods of delivery: oral [Irwin and Iglewicz, 2010;Paslakis et al 2010;Irwin et al 2013;De Gioannis and De Leo, 2014], intramuscular [Cusin et al 2012], sublingual [Lara et al 2013], and most recently, intranasal [Lapidus et al 2014], which will be reviewed in detail as follows.…”