Advertisement

Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

  • Carlos A. Zarate Jr.
    Correspondence
    Address correspondence to Carlos A. Zarate, Jr., M.D., National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Intramural Research Program, Experimental Therapeutics & Pathophysiology Branch, 10 Center Drive, CRC, Unit 7 Southeast, Room 7-3445, Bethesda, MD20892
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Nancy E. Brutsche
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Lobna Ibrahim
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Jose Franco-Chaves
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Nancy Diazgranados
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Anibal Cravchik
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Jessica Selter
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Craig A. Marquardt
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Victoria Liberty
    Affiliations
    Clinical Center Nursing, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • David A. Luckenbaugh
    Affiliations
    Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
Published:February 02, 2012DOI:https://doi.org/10.1016/j.biopsych.2011.12.010

      Background

      Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample.

      Methods

      In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion.

      Results

      Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point.

      Conclusions

      This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

      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

        • Nock M.K.
        • Hwang I.
        • Sampson N.
        • Kessler R.C.
        • Angermeyer M.
        • Beautrais A.
        • et al.
        Cross-national analysis of the associations among mental disorders and suicidal behavior: Findings from the WHO World Mental Health Surveys.
        PLoS Med. 2009; 6: e1000123
        • Nordentoft M.
        • Mortensen P.B.
        • Pedersen C.B.
        Absolute risk of suicide after first hospital contact in mental disorder.
        Arch Gen Psychiatry. 2011; 68: 1058-1064
        • Post R.M.
        • Leverich G.S.
        • Altshuler L.L.
        • Frye M.A.
        • Suppes T.
        • Keck P.E.
        • et al.
        Differential clinical characteristics, medication usage, and treatment response of bipolar disorder in the US versus The Netherlands and Germany.
        Int Clin Psychopharmacol. 2011; 26: 96-106
        • 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
        • Machado-Vieira R.
        • Salvadore G.
        • Luckenbaugh D.A.
        • Manji H.K.
        • Zarate Jr, C.A.
        Rapid onset of antidepressant action: A new paradigm in the research and treatment of major depressive disorder.
        J Clin Psychiatry. 2008; 69: 946-958
        • Sanacora G.
        • Zarate C.A.
        • Krystal J.H.
        • Manji H.K.
        Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders.
        Nat Rev Drug Discov. 2008; 7: 426-437
        • McCullumsmith R.E.
        • Kristiansen L.V.
        • Beneyto M.
        • Scarr E.
        • Dean B.
        • Meador-Woodruff J.H.
        Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.
        Brain Res. 2007; 1127: 108-118
        • Clinton S.M.
        • Meador-Woodruff J.H.
        Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder.
        Neuropsychopharmacology. 2004; 29: 1353-1362
        • Toro C.
        • Deakin J.F.
        NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder.
        Schizophr Res. 2005; 80: 323-330
        • Itokawa M.
        • Yamada K.
        • Iwayama-Shigeno Y.
        • Ishitsuka Y.
        • Detera-Wadleigh S.
        • Yoshikawa T.
        Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans.
        Neurosci Lett. 2003; 345: 53-56
        • Martucci L.
        • Wong A.H.
        • De Luca V.
        • Likhodi O.
        • Wong G.W.
        • King N.
        • Kennedy J.L.
        N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.
        Schizophr Res. 2006; 84: 214-221
        • Mundo E.
        • Tharmalingham S.
        • Neves-Pereira M.
        • Dalton E.J.
        • Macciardi F.
        • Parikh S.V.
        • et al.
        Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.
        Mol Psychiatry. 2003; 8: 241-245
        • Szczepankiewicz A.
        • Skibinska M.
        • Suwalska A.
        • Hauser J.
        • Rybakowski J.K.
        No association of three GRIN2B polymorphisms with lithium response in bipolar patients.
        Pharmacol Rep. 2009; 61: 448-452
        • Laje G.
        • Paddock S.
        • Manji H.K.
        • Rush A.J.
        • Wilson A.F.
        • Charney D.S.
        • McMahon F.J.
        Genetic markers of suicidal ideation emerging during citalopram treatment of major depression.
        Am J Psychiatry. 2007; 164: 1530-1538
        • Menke A.
        • Lucae S.
        • Kloiber S.
        • Horstmann S.
        • Bettecken T.
        • Uhr M.
        • et al.
        Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation.
        Am J Psychiatry. 2008; 165: 917-918
        • Nowak G.
        • Ordway G.A.
        • Paul I.A.
        Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims.
        Brain Res. 1995; 675: 157-164
        • Holemans S.
        • De Paermentier F.
        • Horton R.W.
        • Crompton M.R.
        • Katona C.L.
        • Maloteaux J.M.
        NMDA glutamatergic receptors, labelled with [3H]MK-801, in brain samples from drug-free depressed suicides.
        Brain Res. 1993; 616: 138-143
        • Aguado L.
        • San Antonio A.
        • Perez L.
        • del Valle R.
        • Gomez J.
        Effects of the NMDA receptor antagonist ketamine on flavor memory: Conditioned aversion, latent inhibition, and habituation of neophobia.
        Behav Neural Biol. 1994; 61: 271-281
        • Garcia L.S.
        • Comim C.M.
        • Valvassori S.S.
        • Reus G.Z.
        • Barbosa L.M.
        • Andreazza A.C.
        • et al.
        Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 140-144
        • Maeng S.
        • Zarate Jr, C.A.
        • Du J.
        • Schloesser R.J.
        • McCammon J.
        • Chen G.
        • Manji H.K.
        Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.
        Biol Psychiatry. 2008; 63: 349-352
        • Li N.
        • Lee B.
        • Liu R.J.
        • Banasr M.
        • Dwyer J.M.
        • Iwata M.
        • et al.
        mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
        Science. 2010; 329: 959-964
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • Krystal J.H.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • 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
        • aan het Rot M.
        • Collins K.A.
        • Murrough J.W.
        • Perez A.M.
        • Reich D.L.
        • Charney D.
        • Mathew S.J.
        Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
        Biol Psychiatry. 2010; 67: 139-145
        • Phelps L.E.
        • Brutsche N.
        • Moral J.R.
        • Luckenbaugh D.A.
        • Manji H.K.
        • Zarate Jr, C.A.
        Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.
        Biol Psychiatry. 2009; 65: 181-184
        • Valentine G.W.
        • Mason G.F.
        • Gomez R.
        • Fasula M.
        • Watzl J.
        • Pittman B.
        • et al.
        The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS.
        Psychiatry Res. 2011; 191: 122-127
        • Bunney B.G.
        • Bunney W.E.
        Rapid-acting antidepressant strategies: Mechanisms of action [published online ahead of print July 7].
        Int J Neuropsychopharmacol. 2011;
        • 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
        • Price R.B.
        • Nock M.K.
        • Charney D.
        • Mathew S.J.
        Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
        Biol Psychiatry. 2009; 66: 522-529
        • Larkin G.L.
        • Beautrais A.L.
        A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department.
        Int J Neuropsychopharmacol. 2011; 14: 1127-1131
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams A.R.
        Structured Clinical Interview for DSM-IV TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P).
        New York State Psychiatric Institute, Biometrics Research, New York2001
        • Sackeim H.A.
        The definition and meaning of treatment-resistant depression.
        J Clin Psychiatry. 2001; 62: 10-17
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Beck A.T.
        • Beamesderfer A.
        Assessment of depression: The depression inventory.
        Mod Probl Pharmacopsychiatry. 1974; 7: 151-169
        • Aitken R.C.
        Measurement of feelings using visual analogue scales.
        Proc R Soc Med. 1969; 62: 989-993
        • Hamilton M.
        The assessment of anxiety states by rating.
        Br J Med Psychol. 1959; 32: 50-55
        • Overall J.E.
        • Gorham D.R.
        The Brief Psychiatric Rating Scale.
        Psychol Rep. 1962; 10: 799-812
        • Bremner J.D.
        • Krystal J.H.
        • Putnam F.W.
        • Southwick S.M.
        • Marmar C.
        • Charney D.S.
        • Mazure C.M.
        Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS).
        J Trauma Stress. 1998; 11: 125-136
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: Reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • Pacchiarotti I.
        • Mazzarini L.
        • Colom F.
        • Sanchez-Moreno J.
        • Girardi P.
        • Kotzalidis G.D.
        • Vieta E.
        Treatment-resistant bipolar depression: Towards a new definition.
        Acta Psychiatr Scand. 2009; 120: 429-440
        • Anand A.
        • Charney D.S.
        • Oren D.A.
        • Berman R.M.
        • Hu X.S.
        • Cappiello A.
        • Krystal J.H.
        Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: Support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists.
        Arch Gen Psychiatry. 2000; 57: 270-276
        • Krystal J.H.
        • Karper L.P.
        • Seibyl J.P.
        • Freeman G.K.
        • Delaney R.
        • Bremner J.D.
        • et al.
        Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.
        Arch Gen Psychiatry. 1994; 51: 199-214