Advertisement

A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

  • Kyle A.B. Lapidus
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Cara F. Levitch
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Andrew M. Perez
    Affiliations
    Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Jess W. Brallier
    Affiliations
    Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Michael K. Parides
    Affiliations
    Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Laili Soleimani
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    James J. Peters Veterans Affairs Medical Center, Bronx, New York
    Search for articles by this author
  • Adriana Feder
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Dan V. Iosifescu
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York

    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • Dennis S. Charney
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York

    Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author
  • James W. Murrough
    Correspondence
    Address correspondence to James W. Murrough, M.D., 1 Gustave L. Levy Place, Box 1230, New York, NY 10029
    Affiliations
    Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York

    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York
    Search for articles by this author

      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 access
      One-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 Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Collins P.Y.
        • Patel V.
        • Joestl S.S.
        • March D.
        • Insel T.R.
        • Daar A.S.
        • et al.
        Grand challenges in global mental health.
        Nature. 2011; 475: 27-30
        • Fava M.
        • Davidson K.G.
        Definition and epidemiology of treatment-resistant depression.
        Psychiatr Clin North Am. 1996; 19: 179-200
        • Trivedi M.H.
        • Rush A.J.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Warden D.
        • Ritz L.
        • et al.
        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
        • Krishnan V.
        • Nestler E.J.
        Linking molecules to mood: New insight into the biology of depression.
        Am J Psychiatry. 2010; 167: 1305-1320
        • Lapidus K.A.
        • Soleimani L.
        • Murrough J.W.
        Novel glutamatergic drugs for the treatment of mood disorders.
        Neuropsychiatr Dis Treat. 2013; 9: 1101-1112
        • Murrough J.W.
        • Charney D.S.
        Is there anything really novel on the antidepressant horizon?.
        Curr Psychiatry Rep. 2012; 14: 643-649
        • Auer D.P.
        • Putz B.
        • Kraft E.
        • Lipinski B.
        • Schill J.
        • Holsboer F.
        Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study.
        Biol Psychiatry. 2000; 47: 305-313
        • Rosenberg D.R.
        • Macmaster F.P.
        • Mirza Y.
        • Smith J.M.
        • Easter P.C.
        • Banerjee S.P.
        • et al.
        Reduced anterior cingulate glutamate in pediatric major depression: A magnetic resonance spectroscopy study.
        Biol Psychiatry. 2005; 58: 700-704
        • Hashimoto K.
        • Sawa A.
        • Iyo M.
        Increased levels of glutamate in brains from patients with mood disorders.
        Biol Psychiatry. 2007; 62: 1310-1316
        • Hashimoto K.
        Emerging role of glutamate in the pathophysiology of major depressive disorder.
        Brain Res Rev. 2009; 61: 105-123
        • Zarate Jr, C.A.
        • Singh J.B.
        • Carlson P.J.
        • Brutsche N.E.
        • Ameli R.
        • Luckenbaugh D.A.
        • et al.
        A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
        Arch Gen Psychiatry. 2006; 63: 856-864
        • Mathew S.J.
        • Murrough J.W.
        • aan het Rot M.
        • Collins K.A.
        • Reich D.L.
        • Charney D.S.
        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
        • aan het Rot M.
        • Collins K.A.
        • Murrough J.W.
        • Perez A.M.
        • Reich D.L.
        • Charney D.S.
        • et al.
        Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
        Biol Psychiatry. 2010; 67: 139-145
        • Murrough J.W.
        • Perez A.M.
        • Pillemer S.
        • Stern J.
        • Parides M.K.
        • Aan Het Rot M.
        • et al.
        Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.
        Biol Psychiatry. 2013; 74: 250-256
        • Murrough J.W.
        • Iosifescu D.V.
        • Chang L.C.
        • Al Jurdi R.K.
        • Green C.E.
        • Perez A.M.
        • et al.
        Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial.
        Am J Psychiatry. 2013; 170: 1134-1142
        • Weksler N.
        • Ovadia L.
        • Muati G.
        • Stav A.
        Nasal ketamine for paediatric premedication.
        Can J Anaesth. 1993; 40: 119-121
        • Louon A.
        • Reddy V.G.
        Nasal midazolam and ketamine for paediatric sedation during computerised tomography.
        Acta Anaesthesiol Scand. 1994; 38: 259-261
        • Diaz J.H.
        Intranasal ketamine preinduction of paediatric outpatients.
        Paediatr Anaesth. 1997; 7: 273-278
        • Weber F.
        • Wulf H.
        • el Saeidi G.
        Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children.
        Can J Anaesth. 2003; 50: 470-475
        • Roelofse J.A.
        • Shipton E.A.
        • de la Harpe C.J.
        • Blignaut R.J.
        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
        • Kaube H.
        • Herzog J.
        • Kaufer T.
        • Dichgans M.
        • Diener H.C.
        Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine.
        Neurology. 2000; 55: 139-141
        • Huge V.
        • Lauchart M.
        • Magerl W.
        • Schelling G.
        • Beyer A.
        • Thieme D.
        • et al.
        Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain.
        Eur J Pain. 2010; 14: 387-394
        • Carr D.B.
        • Goudas L.C.
        • Denman W.T.
        • Brookoff D.
        • Staats P.S.
        • Brennen L.
        • et al.
        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
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision.
        American Psychiatric Press, Washington, DC2000
        • Sackeim H.A.
        The definition and meaning of treatment-resistant depression.
        J Clin Psychiatry. 2001; 62: 10-17
        • Rush A.J.
        • Giles D.E.
        • Schlesser M.A.
        • Fulton C.L.
        • Weissenburger J.
        • Burns C.
        The Inventory for Depressive Symptomatology (IDS): Preliminary findings.
        Psychiatry Res. 1986; 18: 65-87
        • Diazgranados N.
        • Ibrahim L.
        • Brutsche N.E.
        • Newberg A.
        • Kronstein P.
        • Khalife S.
        • et al.
        A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
        Arch Gen Psychiatry. 2010; 67: 793-802
        • Carlson P.J.
        • Diazgranados N.
        • Nugent A.C.
        • Ibrahim L.
        • Luckenbaugh D.A.
        • Brutsche N.
        • et al.
        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
        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • et al.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • Horacek J.
        • Brunovsky M.
        • Novak T.
        • Tislerova B.
        • Palenicek T.
        • Bubenikova-Valesova V.
        • et al.
        Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: Implications for antidepressant effect.
        Psychol Med. 2010; 40: 1443-1451
        • Zarate Jr, C.A.
        • Brutsche N.
        • Laje G.
        • Luckenbaugh D.A.
        • Venkata S.L.
        • Ramamoorthy A.
        • et al.
        Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression.
        Biol Psychiatry. 2012; 72: 331-338
        • Zarate Jr, C.A.
        • Brutsche N.E.
        • Ibrahim L.
        • Franco-Chaves J.
        • Diazgranados N.
        • Cravchik A.
        • et al.
        Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial.
        Biol Psychiatry. 2012; 71: 939-946
        • DiazGranados N.
        • Ibrahim L.A.
        • Brutsche N.E.
        • Ameli R.
        • Henter I.D.
        • Luckenbaugh D.A.
        • et al.
        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
        • Salvadore G.
        • Cornwell B.R.
        • Colon-Rosario V.
        • Coppola R.
        • Grillon C.
        • Zarate Jr, C.A.
        • et al.
        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
        • Mathew S.J.
        • Shah A.
        • Lapidus K.
        • Clark C.
        • Jarun N.
        • Ostermeyer B.
        • et al.
        Ketamine for treatment-resistant unipolar depression: Current evidence.
        CNS Drugs. 2012; 26: 189-204
        • Yanagihara Y.
        • Ohtani M.
        • Kariya S.
        • Uchino K.
        • Hiraishi T.
        • Ashizawa N.
        • et al.
        Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.
        Biopharm Drug Dispos. 2003; 24: 37-43
        • Fava M.
        Diagnosis and definition of treatment-resistant depression.
        Biol Psychiatry. 2003; 53: 649-659
        • Rush A.J.
        Ketamine for treatment-resistant depression: Ready or not for clinical use?.
        Am J Psychiatry. 2013; 170: 1079-1081