Advertisement

A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression

  • Carlos A. Zarate Jr.
    Correspondence
    Address correspondence to Carlos A. Zarate Jr., M.D., National Institutes of Health, and Department of Health and Human Services, Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, 10 Center Drive, CRC, Unit 7 Southeast, Room 7-3445, Bethesda, Maryland, 20892
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Daniel Mathews
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, 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 and Pathophysiology Branch, 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 and Pathophysiology Branch, 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 Marquardt
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Immaculata Ukoh
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Libby Jolkovsky
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, 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 and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland
    Search for articles by this author
  • Mark A. Smith
    Affiliations
    AstraZeneca Pharmaceuticals, Wilmington, Delaware
    Search for articles by this author
  • David A. Luckenbaugh
    Affiliations
    Experimental Therapeutics and Pathophysiology Branch, 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:December 03, 2012DOI:https://doi.org/10.1016/j.biopsych.2012.10.019

      Background

      The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).

      Methods

      In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.

      Results

      Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.

      Conclusions

      In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

      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

        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • Insel T.R.
        • Wang P.S.
        The STAR*D trial: Revealing the need for better treatments.
        Psychiatr Serv. 2009; 60: 1466-1467
        • aan het Rot M.
        • Zarate Jr, C.A.
        • Charney D.S.
        • Mathew S.J.
        Ketamine for depression: Where do we go from here?.
        Biol Psychiatry. 2012; 72: 537-547
        • Skolnick P.
        • Popik P.
        • Trullas R.
        Glutamate-based antidepressants: 20 years on.
        Trends Pharmacol Sci. 2009; 30: 563-569
        • Feyissa A.M.
        • Chandran A.
        • Stockmeier C.A.
        • Karolewicz B.
        Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 70-75
        • Taniguchi S.
        • Nakazawa T.
        • Tanimura A.
        • Kiyama Y.
        • Tezuka T.
        • Watabe A.M.
        • et al.
        Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour.
        EMBO J. 2009; 28: 3717-3729
        • Maeng S.
        • Zarate Jr, C.A.
        • Du J.
        • Schloesser R.J.
        • McCammon J.
        • Chen G.
        • et al.
        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
        • Preskorn S.H.
        • Baker B.
        • Kolluri S.
        • Menniti F.S.
        • Krams M.
        • Landen J.W.
        An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.
        J Clin Psychopharmacol. 2008; 28: 631-637
        • Ibrahim L.
        • Diazgranados N.
        • Jolkovsky L.
        • Brutsche N.
        • Luckenbaugh D.A.
        • Herring W.J.
        • et al.
        A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.
        J Clin Psychopharmacol. 2012; 32: 551-557
        • Mealing G.A.
        • Lanthorn T.H.
        • Murray C.L.
        • Small D.L.
        • Morley P.
        Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block.
        J Pharmacol Exp Ther. 1999; 288: 204-210
        • Ginski M.J.
        • Witkin J.M.
        Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists.
        Psychopharmacology (Berl). 1994; 114: 573-582
        • 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. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
        Arch Gen Psychiatry. 1994; 51: 199-214
        • Parsons C.G.
        • Quack G.
        • Bresink I.
        • Baran L.
        • Przegalinski E.
        • Kostowski W.
        • et al.
        Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo.
        Neuropharmacology. 1995; 34: 1239-1258
        • Palmer G.C.
        • Miller J.A.
        • Cregan E.F.
        • Gendron P.
        • Peeling J.
        Low-affinity NMDA receptor antagonists. The neuroprotective potential of ARL 15896AR.
        Ann N Y Acad Sci. 1997; 825: 220-231
        • Monaghan D.T.
        • Larsen H.
        NR1 and NR2 subunit contributions to N-methyl-D-aspartate receptor channel blocker pharmacology.
        J Pharmacol Exp Ther. 1997; 280: 614-620
        • Zarate Jr, C.A.
        Modulating the NMDA receptor complex in developing therapeutics for bipolar disorder and major depressive disorder. Paper presented at: 28th CINP World Congress of Neuropsychopharmacology; June 3–7, 2012;.
        Stockholm, Sweden, 2012
        • Lees K.R.
        • Dyker A.G.
        • Sharma A.
        • Ford G.A.
        • Ardron M.E.
        • Grosset D.G.
        Tolerability of the low-affinity, use-dependent NMDA antagonist AR-R15896AR in stroke patients: A dose-ranging study.
        Stroke. 2001; 32: 466-472
        • Nibuya M.
        • Morinobu S.
        • Duman R.S.
        Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
        J Neurosci. 1995; 15: 7539-7547
        • Hellweg R.
        • Ziegenhorn A.
        • Heuser I.
        • Deuschle M.
        Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.
        Pharmacopsychiatry. 2008; 41: 66-71
        • Ibrahim L.
        • Duncan W.
        • Luckenbaugh D.A.
        • Yuan P.
        • Machado-Vieira R.
        • Zarate Jr, C.A.
        Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): A pilot study.
        Brain Res Bull. 2011; 86: 129-133
        • 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
        • Beck A.T.
        • Kovacs M.
        • Weissman A.
        Assessment of suicidal intention: The Scale for Suicide Ideation.
        J Consult Clin Psychol. 1979; 47: 343-352
        • 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.
        • et al.
        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
        • 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
        • Bech P.
        • Allerup P.
        • Gram L.F.
        • Reisby N.
        • Rosenberg R.
        • Jacobsen O.
        • et al.
        The Hamilton depression scale. Evaluation of objectivity using logistic models.
        Acta Psychiatr Scand. 1981; 63: 290-299
        • Bech P.
        • Gram L.F.
        • Dein E.
        • Jacobsen O.
        • Vitger J.
        • Bolwig T.G.
        Quantitative rating of depressive states.
        Acta Psychiatr Scand. 1975; 51: 161-170
        • Faries D.
        • Herrera J.
        • Rayamajhi J.
        • DeBrota D.
        • Demitrack M.
        • Potter W.Z.
        The responsiveness of the Hamilton Depression Rating Scale.
        J Psychiatr Res. 2000; 34: 3-10
        • 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
        • Iga J.
        • Ueno S.
        • Yamauchi K.
        • Numata S.
        • Tayoshi-Shibuya S.
        • Kinouchi S.
        • et al.
        Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder.
        Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 658-663
        • Ventriglia M.
        • Zanardini R.
        • Pedrini L.
        • Placentino A.
        • Nielsen M.G.
        • Gennarelli M.
        • et al.
        VEGF serum levels in depressed patients during SSRI antidepressant treatment.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 146-149
        • 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
        • Beurel E.
        • Yeh W.I.
        • Michalek S.M.
        • Harrington L.E.
        • Jope R.S.
        Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells.
        J Immunol. 2011; 186: 1391-1398
        • Anand A.
        • Charney D.S.
        • Oren D.A.
        • Berman R.M.
        • Hu X.S.
        • Cappiello A.
        • et al.
        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