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
In a randomized, double-blind, crossover study, 20 patients with major depression
were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine
hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was
change in depression severity 24 hours after ketamine or placebo, measured using the
Montgomery-Åsberg 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 after ketamine
compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference
of 7.6 ± 3.7; 95% confidence interval, 3.9–11.3). Response criteria were met by 8
of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18
(6%) after placebo (p = .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.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Grand challenges in global mental health.Nature. 2011; 475: 27-30
- Definition and epidemiology of treatment-resistant depression.Psychiatr Clin North Am. 1996; 19: 179-200
- Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice.Am J Psychiatry. 2006; 163: 28-40
- Linking molecules to mood: New insight into the biology of depression.Am J Psychiatry. 2010; 167: 1305-1320
- Novel glutamatergic drugs for the treatment of mood disorders.Neuropsychiatr Dis Treat. 2013; 9: 1101-1112
- Is there anything really novel on the antidepressant horizon?.Curr Psychiatry Rep. 2012; 14: 643-649
- Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study.Biol Psychiatry. 2000; 47: 305-313
- Reduced anterior cingulate glutamate in pediatric major depression: A magnetic resonance spectroscopy study.Biol Psychiatry. 2005; 58: 700-704
- Increased levels of glutamate in brains from patients with mood disorders.Biol Psychiatry. 2007; 62: 1310-1316
- Emerging role of glutamate in the pathophysiology of major depressive disorder.Brain Res Rev. 2009; 61: 105-123
- A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch Gen Psychiatry. 2006; 63: 856-864
- Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: A pilot randomized, placebo-controlled continuation trial.Int J Neuropsychopharmacol. 2010; 13: 71-82
- Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.Biol Psychiatry. 2010; 67: 139-145
- Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.Biol Psychiatry. 2013; 74: 250-256
- Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial.Am J Psychiatry. 2013; 170: 1134-1142
- Nasal ketamine for paediatric premedication.Can J Anaesth. 1993; 40: 119-121
- Nasal midazolam and ketamine for paediatric sedation during computerised tomography.Acta Anaesthesiol Scand. 1994; 38: 259-261
- Intranasal ketamine preinduction of paediatric outpatients.Paediatr Anaesth. 1997; 7: 273-278
- Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children.Can J Anaesth. 2003; 50: 470-475
- Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: A prospective, double-blind, randomized comparison.Anesth Prog. 2004; 51: 114-121
- Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine.Neurology. 2000; 55: 139-141
- Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain.Eur J Pain. 2010; 14: 387-394
- Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: A randomized, double-blind, placebo-controlled, crossover study.Pain. 2004; 108: 17-27
- Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision.American Psychiatric Press, Washington, DC2000
- The definition and meaning of treatment-resistant depression.J Clin Psychiatry. 2001; 62: 10-17
- The Inventory for Depressive Symptomatology (IDS): Preliminary findings.Psychiatry Res. 1986; 18: 65-87
- A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.Arch Gen Psychiatry. 2010; 67: 793-802
- Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: A preliminary positron emission tomography study.Biol Psychiatry. 2013; 73: 1213-1221
- Antidepressant effects of ketamine in depressed patients.Biol Psychiatry. 2000; 47: 351-354
- Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: Implications for antidepressant effect.Psychol Med. 2010; 40: 1443-1451
- Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression.Biol Psychiatry. 2012; 72: 331-338
- Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial.Biol Psychiatry. 2012; 71: 939-946
- Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.J Clin Psychiatry. 2010; 71: 1605-1611
- Increased anterior cingulate cortical activity in response to fearful faces: A neurophysiological biomarker that predicts rapid antidepressant response to ketamine.Biol Psychiatry. 2009; 65: 289-295
- Ketamine for treatment-resistant unipolar depression: Current evidence.CNS Drugs. 2012; 26: 189-204
- Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.Biopharm Drug Dispos. 2003; 24: 37-43
- Diagnosis and definition of treatment-resistant depression.Biol Psychiatry. 2003; 53: 649-659
- Ketamine for treatment-resistant depression: Ready or not for clinical use?.Am J Psychiatry. 2013; 170: 1079-1081
Article Info
Publication History
Published online: April 04, 2014
Accepted:
March 19,
2014
Received in revised form:
March 16,
2014
Received:
December 10,
2013
Footnotes
Authors DSC and JWM contributed equally to this work.
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
