Advertisement

Ketamine for Depression: An Update

  • James W. Murrough
    Correspondence
    Address correspondence to: James W. Murrough, M.D., Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One 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, New York

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

    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author
      A decade has now passed since research into the antidepressant effects of ketamine began in earnest, after the clinical trial reported by Zarate et al. in 2006 (
      • 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.
      ). In that proof-of-concept study, 18 medication-free patients with treatment-resistant major depressive disorder (TRD) showed a large reduction in core depressive symptoms within hours of receiving a single low-dose 0.5 mg/kg intravenous infusion of ketamine as measured by the 21-item Hamilton Depression Rating Scale compared with saline placebo. Perhaps most strikingly, the antidepressant effects persisted without additional dosing of ketamine for days or up to several weeks in some cases. While these unexpected findings have been met with justifiable skepticism, replication from independent research programs is now fostering a degree of consensus in the field that ketamine is in fact associated with a true rapid-onset and persistent antidepressant effect, even in patients with TRD (
      • 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.
      ,
      • Newport D.J.
      • Carpenter L.L.
      • McDonald W.M.
      • Potash J.B.
      • Tohen M.
      • Nemeroff C.B.
      • et al.
      Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression.
      ). If the observed effect is true, what are the implications and what are the critical research questions to now be asked?
      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

        • 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
        • 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
        • Newport D.J.
        • Carpenter L.L.
        • McDonald W.M.
        • Potash J.B.
        • Tohen M.
        • Nemeroff C.B.
        • et al.
        Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression.
        Am J Psychiatry. 2015; 172: 950-966
        • Sarkar A.
        • Kabbaj M.
        Sex differences in effects of ketamine on behavior, spine density, and synaptic proteins in socially isolated rats.
        Biol Psychiatry. 2016; 80: 448-456
        • Ren Z.
        • Pribiag H.
        • Jefferson S.J.
        • Shorey M.
        • Fuchs T.
        • Stellwagen D.
        • et al.
        Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment.
        Biol Psychiatry. 2016; 80: 457-468
        • Singh J.B.
        • Fedgchin M.
        • Daly E.
        • Xi L.
        • Melman C.
        • De Bruecker G.
        • et al.
        Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study.
        Biol Psychiatry. 2016; 80: 424-431
        • 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
        • Popp S.
        • Behl B.
        • Joshi J.J.
        • Lanz T.A.
        • Spedding M.
        • Schenker E.
        • et al.
        In search of the mechanisms of ketamine’s antidepressant effects: How robust is the evidence behind the mTor activation hypothesis.
        F1000Research. 2016; 5: 634
        • Zanos P.
        • Moaddel R.
        • Morris P.J.
        • Georgiou P.
        • Fischell J.
        • Elmer G.I.
        • et al.
        NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
        Nature. 2016; 533: 481-486

      Linked Article