Ketamine for Depression: Where Do We Go from Here?

  • Marije aan het Rot
    Address correspondence to Marije aan het Rot, Ph.D., Experimental Psychopathology Program, Heymans Institute for Psychological Research, University of Groningen, Grote Kruisstraat 2/1, 9712TS Groningen, The Netherlands
    Department of Psychology and School of Behavioral and Cognitive Neuroscience, University of Groningen, The Netherlands
    Search for articles by this author
  • Carlos A. Zarate Jr.
    Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, Maryland
    Search for articles by this author
  • Dennis S. Charney
    Departments of Psychiatry, Neuroscience, and Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York
    Search for articles by this author
  • Sanjay J. Mathew
    Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas

    Michael E. Debakey Veterans Affairs Medical Center, Houston, Texas
    Search for articles by this author
      Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used and to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk–benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.

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


        • 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
        • Mathew S.J.
        • Manji H.K.
        • Charney D.S.
        Novel drugs and therapeutic targets for severe mood disorders.
        Neuropsychopharmacology. 2008; 33: 2080-2092
        • Sackeim H.A.
        The definition and meaning of treatment-resistant depression.
        J Clin Psychiatry. 2001; 62: 10-17
        • 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
        • Moukaddam N.J.
        • Hirschfeld R.M.A.
        Intravenous antidepressants: A review.
        Depress Anxiety. 2004; 19: 1-9
        • Dodd S.
        • Berk M.
        Predictors of antidepressant response: A selective review.
        Int J Psychiatry Clin Pract. 2004; 8: 91-100
        • Krystal A.D.
        • Weiner R.D.
        • Dean M.D.
        • Lindahl V.H.
        • Tramontozzi 3rd, L.A.
        • Falcone G.
        • et al.
        Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and methohexital anesthesia with ECT.
        J Neuropsychiatry Clin Neurosci. 2003; 15: 27-34
        • Hashimoto K.
        Emerging role of glutamate in the pathophysiology of major depressive disorder.
        Brain Res Rev. 2009; 61: 105-123
        • Machado-Vieira R.
        • Manji H.K.
        • Zarate C.A.
        The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders.
        Neuroscientist. 2009; 15: 525-539
        • Skolnick P.
        • Popik P.
        • Trullas R.
        Glutamate-based antidepressants: 20 years on.
        Trends Pharmacol Sci. 2009; 30: 563-569
        • Murrough J.W.
        Ketamine as a novel antidepressant: From synapse to behavior.
        Clin Pharmacol Ther. 2012; 91: 303-309
        • Bjerre J.
        • Fontenay C.
        Ketamin ved melankolsk depression.
        Ugeskr Læger. 2010; 172: 460-461
        • Glue P.
        • Gulati A.
        • Le Nedelec M.
        • Duffull S.
        Dose- and exposure-response to ketamine in depression.
        Biol Psychiatry. 2011; 70 (author reply e11–12): e9-e10
        • 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 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
        • Liebrenz M.
        • Borgeat A.
        • Leisinger R.
        • Stohler R.
        Intravenous ketamine therapy in a patient with a treatment-resistant major depression.
        Swiss Med Weekly. 2007; 137: 234-236
        • Liebrenz M.
        • Stohler R.
        • Borgeat A.
        Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression.
        World J Biol Psychiatry. 2009; 10: 1-4
        • Thase M.E.
        • Rush A.J.
        When at first you don't succeed: Sequential strategies for antidepressant nonresponders.
        J Clin Psychiatry. 1997; 58: 23-29
        • Paul R.
        • Schaaff N.
        • Padberg F.
        • Moller H.J.
        • Frodl T.
        Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: Report of two cases.
        World J Biol Psychiatry. 2009; 10: 241-244
        • Denk M.C.
        • Rewerts C.
        • Holsboer F.
        • Erhardt-Lehmann A.
        • Turck C.W.
        Monitoring ketamine treatment response in a depressed patient via peripheral mammalian target of rapamycin activation.
        Am J Psychiatry. 2011; 168: 751-752
        • Correll G.E.
        • Futter G.E.
        Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions.
        Pain Med. 2006; 7: 92-95
        • 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
        • Machado-Vieira R.
        • Yuan P.
        • Brutsche N.
        • DiazGranados N.
        • Luckenbaugh D.
        • Manji H.K.
        • et al.
        Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist.
        J Clin Psychiatry. 2009; 70: 1662-1666
        • 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
        • Ibrahim L.
        • Diazgranados N.
        • Luckenbaugh D.A.
        • Machado-Vieira R.
        • Baumann J.
        • Mallinger A.G.
        • et al.
        Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1155-1159
        • Ibrahim L.
        • DiazGranados N.
        • Franco-Chaves J.
        • Brutsche N.
        • Henter I.D.
        • Kronstein P.
        • et al.
        Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: Results from a 4-week, double-blind, placebo-controlled study.
        Neuropsychopharmacology. 2012; 37: 1526-1533
        • Salvadore G.
        • Cornwell B.R.
        • Sambataro F.
        • Latov D.
        • Colon-Rosario V.
        • Carver F.
        • et al.
        Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine.
        Neuropsychopharmacology. 2010; 35: 1415-1422
        • 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
        • Salvadore G.
        • van der Veen J.W.
        • Zhang Y.
        • Marenco S.
        • Machado-Vieira R.
        • Baumann Jr, J.
        • et al.
        An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.
        Int J Neuropsychopharmacol. 2011; ([published online ahead of print November 11])
        • Sackett D.L.
        • Strauss S.E.
        • Richardson W.S.
        • Rosenberg W.
        • Haynes R.B.
        Evidence-Based Medicine: How to Practice and Teach EBM.
        2nd ed. Churchill Livingstone, New York2000
        • 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 Neuroimaging. 2011; 191: 122-127
        • 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.
        • Mathew S.J.
        • Charney D.S.
        A case of sustained remission following an acute course of ketamine in treatment-resistant depression.
        J Clin Psychiatry. 2011; 72: 414-415
        • Goforth H.W.
        • Holsinger T.
        Rapid relief of severe major depressive disorder by use of preoperative ketamine and electroconvulsive therapy.
        J ECT. 2007; 23: 23-25
        • Nemeroff C.B.
        Prevalence and management of treatment-resistant depression.
        J Clin Psychiatry. 2007; 68: 17-25
        • Fekadu A.
        • Wooderson S.C.
        • Markopoulo K.
        • Donaldson C.
        • Papadopoulos A.
        • Cleare A.J.
        What happens to patients with treatment-resistant depression?.
        J Affect Disord. 2009; 116: 4-11
        • Arroll B.
        • Elley C.R.
        • Fishman T.
        • Goodyear-Smith F.A.
        • Kenealy T.
        • Blashki G.
        • et al.
        Antidepressants versus placebo for depression in primary care.
        Cochrane Database of Syst Rev. 2009; 3 (CD007954)
        • Zarate Jr, C.A.
        • Payne J.L.
        • Quiroz J.
        • Sporn J.
        • Denicoff K.K.
        • Luckenbaugh D.
        • et al.
        An open-label trial of riluzole in patients with treatment-resistant major depression.
        Am J Psychiatry. 2004; 161: 171-174
        • Zarate Jr, C.A.
        • Quiroz J.A.
        • Singh J.B.
        • Denicoff K.D.
        • De Jesus G.
        • Luckenbaugh D.A.
        • et al.
        An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.
        Biol Psychiatry. 2005; 57: 430-432
        • Sanacora G.
        • Kendell S.F.
        • Levin Y.
        • Simen A.A.
        • Fenton L.R.
        • Coric V.
        • et al.
        Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.
        Biol Psychiatry. 2007; 61: 822-825
        • 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
        • Murrough J.W.
        • Gallo J.M.
        • Collins K.A.
        • aan het Rot M.
        • Charney D.S.
        Reply to: Dose- and exposure-response to ketamine in depression.
        Biol Psychiatry. 2010; 70: e11-e12
        • Price R.B.
        • Nock M.K.
        • Charney D.S.
        • Mathew S.J.
        Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
        Biol Psychiatry. 2009; 66: 522-526
        • 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
        • Okamoto N.
        • Nakai T.
        • Sakamoto K.
        • Nagafusa Y.
        • Higuchi T.
        • Nishikawa T.
        Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: Comparing ketamine and propofol anesthesia.
        J ECT. 2010; 26: 223-227
        • Kranaster L.
        • Kammerer-Ciernioch J.
        • Hoyer C.
        • Sartorius A.
        Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: A retrospective study.
        Eur Arch Psychiatry Clin Neurosci. 2011; 261: 575-582
        • Newcomer J.W.
        • Farber N.B.
        • Jevtovic-Todorovic V.
        • Selke G.
        • Melson A.K.
        • Hershey T.
        • et al.
        Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis.
        Neuropsychopharmacology. 1999; 20: 106-118
        • Morgan C.J.A.
        • Muetzelfeldt L.
        • Curran H.V.
        Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study.
        Addiction. 2010; 105: 121-133
        • Loo C.
        • Sainsbury K.
        • Martin D.
        • MacPherson R.
        Synergistic antidepressant effects with ketamine and ECT.
        J ECT. 2009; 25: 150
        • Duman R.S.
        • Li N.
        • Liu R.-J.
        • Duric V.
        • Aghajanian G.
        Signaling pathways underlying the rapid antidepressant actions of ketamine.
        Neuropharmacology. 2012; 62: 35-41
        • Post R.M.
        Role of BDNF in bipolar and unipolar disorder: Clinical and theoretical implications.
        J Psychiatr Res. 2007; 41: 979-990
        • Jernigan C.S.
        • Goswami D.B.
        • Austin M.C.
        • Iyo A.H.
        • Chandran A.
        • Stockmeier C.A.
        • et al.
        The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1774-1779
        • 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
        • Taylor M.J.
        • Tiangga E.R.
        • NÃ Mhuircheartaigh Ri.
        • Cowen P.
        Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: A proton magnetic resonance spectroscopy study.
        J Psychopharmacol. 2012; 26: 733-737
        • 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
        • Covvey J.R.
        • Crawford A.N.
        • Lowe D.K.
        Intravenous ketamine for treatment-resistant major depressive disorder.
        Ann Pharmacother. 2012; 46: 117-123
        • Kollmar R.
        • Markovic K.
        • Thurauf N.
        • Schmitt H.
        • Kornhuber J.
        Ketamine followed by memantine for the treatment of major depressions.
        Aust N Z J Psychiatry. 2008; 42: 170
        • Stefanczyk-Sapieha L.
        • Oneschuk D.
        • Demas M.
        Intravenous ketamine “burst” for refractory depression in a patient with advanced cancer.
        J Palliative Med. 2008; 11: 1268-1271
        • Messer M.
        • Haller I.V.
        • Larson P.
        • Pattison-Crisotomo J.
        • Gessert C.E.
        The use of a series of ketamine infusions in two patients with treatment-resistant depression.
        J Neuropsychiatry Clin Neurosci. 2010; 22: 442-444

      Linked Article

      • Ketamine: The Hopes and the Hurdles
        Biological PsychiatryVol. 72Issue 7
        • Preview
          Ketamine and related drugs are arguably one of the most exciting developments in antidepressant pharmacology in more than half a century and are a potentially new mechanism capable of mediating antidepressant action. That mechanism is the antagonism of the N-methyl-d-aspartate (NMDA) receptor (NR) and possibly one or more subtypes of that receptor. By blocking NMDA receptors, ketamine and related drugs target glutamate, which is the major excitatory neurotransmitter in the brain and a transmitter not directly affected by any currently marketed antidepressant.
        • Full-Text
        • PDF