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Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

Published online by Cambridge University Press:  12 August 2015

J. W. Murrough ,
L. Soleimani ,
K. E. DeWilde ,
K. A. Collins ,
K. A. Lapidus ,
B. M. Iacoviello ,
M. Lener ,
M. Kautz ,
J. Kim  and
J. B. Stern
...Show all authors
J. W. Murrough*
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
L. Soleimani
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
K. E. DeWilde
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
K. A. Collins
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
K. A. Lapidus
Affiliation:
Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY, USA
B. M. Iacoviello
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
M. Lener
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
M. Kautz
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
J. Kim
Affiliation:
Deparment of Psychology, UCLA, Los Angeles, CA, USA
J. B. Stern
Affiliation:
Department of Psychology, Drexel University, Philadelphia, PA, USA
R. B. Price
Affiliation:
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
A. M. Perez
Affiliation:
Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
J. W. Brallier
Affiliation:
Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
G. J. Rodriguez
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
W. K. Goodman
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
D. V. Iosifescu
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
D. S. Charney
Affiliation:
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, NY, New York, USA
*
*Address for correspondence: J. 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, USA. (Email: [email protected])
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Abstract

Background.

Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression.

Method.

We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery–Asberg Depression Rating Scale – Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point.

Results.

The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period.

Conclusions.

The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Keywords

Depressionglutamateketaminesuicidetreatment
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 16 , December 2015 , pp. 3571 - 3580
Copyright
Copyright © Cambridge University Press 2015 

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References

Aleman, A, Denys, D (2014). Mental health: a road map for suicide research and prevention. Nature 509, 421–423.CrossRefGoogle ScholarPubMed
Ballard, ED, Ionescu, DF, Vande Voort, JL, Niciu, MJ, Richards, EM, Luckenbaugh, DA, Brutsche, NE, Ameli, R, Furey, ML, Zarate, CA Jr. (2014). Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. Journal of Psychiatric Research 58, 161–166.Google Scholar
Barbui, C, Esposito, E, Cipriani, A (2009). Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. Canadian Medical Association Journal 180, 291–297.CrossRefGoogle ScholarPubMed
Beck, AT, Steer, RA, Ranieri, WF (1988). Scale for Suicide Ideation: psychometric properties of a self-report version. Journal of Clinical Psychology 44, 499–505.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
Bremner, JD, Krystal, JH, Putnam, FW, Southwick, SM, Marmar, C, Charney, DS, Mazure, CM (1998). Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). Journal of Traumatic Stress 11, 125–136.CrossRefGoogle ScholarPubMed
Brent, DA, Melhem, N (2008). Familial transmission of suicidal behavior. Psychiatric Clinics of North America 31, 157–177.CrossRefGoogle ScholarPubMed
Cavanagh, JT, Carson, AJ, Sharpe, M, Lawrie, SM (2003). Psychological autopsy studies of suicide: a systematic review. Psychological Medicine 33, 395–405.CrossRefGoogle ScholarPubMed
Choudary, PV, Molnar, M, Evans, SJ, Tomita, H, Li, JZ, Vawter, MP, Myers, RM, Bunney, WE Jr., Akil, H, Watson, SJ, Jones, EG (2005). Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proceedings of the National Academy of Sciences USA 102, 15653–15658.Google Scholar
Cipriani, A, Hawton, K, Stockton, S, Geddes, JR (2013). Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. British Medical Journal (Clinical Research Edition) 346, f3646.Google Scholar
Cipriani, A, Smith, K, Burgess, S, Carney, S, Goodwin, G, Geddes, J (2006). Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database of Systematic Reviews 18(4). Art. no. CD003492.Google Scholar
Crosby, AE, Han, B, Ortega, LA, Parks, SE, Gfroerer, J, Centers for Disease Control and Prevention (CDC) (2011). Suicidal thoughts and behaviors among adults aged ⩾18 years – United States, 2008–2009. Morbidity and Mortality Weekly Report. Surveillance Summaries 60, 1–22.Google Scholar
Diazgranados, N, Ibrahim, LA, Brutsche, NE, Ameli, R, Henter, ID, Luckenbaugh, DA, Machado-Vieira, R, Zarate, CA Jr. (2010 a). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychiatry 71, 1605–1611.Google Scholar
Diazgranados, N, Ibrahim, L, Brutsche, NE, Newberg, A, Kronstein, P, Khalife, S, Kammerer, WA, Quezado, Z, Luckenbaugh, DA, Salvadore, G, Machado-Vieira, R, Manji, HK, Zarate, CA Jr. (2010 b). A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 67, 793–802.Google Scholar
Duman, RS, Aghajanian, GK (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science (New York, NY) 338, 68–72.Google Scholar
Dwivedi, Y, Mondal, AC, Rizavi, HS, Conley, RR (2005). Suicide brain is associated with decreased expression of neurotrophins. Biological Psychiatry 58, 315–324.CrossRefGoogle ScholarPubMed
Erhardt, S, Lim, CK, Linderholm, KR, Janelidze, S, Lindqvist, D, Samuelsson, M, Lundberg, K, Postolache, TT, Traskman-Bendz, L, Guillemin, GJ, Brundin, L (2013). Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology 38, 743–752.CrossRefGoogle ScholarPubMed
Feyissa, AM, Chandran, A, Stockmeier, CA, Karolewicz, B (2009). Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Progress in Neuro-psychopharmacology & Biological Psychiatry 33, 70–75.CrossRefGoogle ScholarPubMed
Garakani, A, Martinez, JM, Yehuda, R, Gorman, JM (2013). Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment. Journal of Affective Disorders 146, 262–265.Google Scholar
Griffiths, JJ, Zarate, CA Jr., Rasimas, JJ (2014). Existing and novel biological therapeutics in suicide prevention. American Journal of Preventive Medicine 47, S195–S203.CrossRefGoogle ScholarPubMed
Kang, HJ, Kim, JM, Lee, JY, Kim, SY, Bae, KY, Kim, SW, Shin, IS, Kim, HR, Shin, MG, Yoon, JS (2013). BDNF promoter methylation and suicidal behavior in depressive patients. Journal of Affective Disorders 151, 679–685.CrossRefGoogle ScholarPubMed
Lapidus, KA, Levitch, CF, Perez, AM, Brallier, JW, Parides, MK, Soleimani, L, Feder, A, Iosifescu, DV, Charney, DS, Murrough, JW (2014). A randomized controlled trial of intranasal ketamine in major depressive disorder. Biological Psychiatry 76, 970–976.CrossRefGoogle ScholarPubMed
Larkin, GL, Beautrais, AL (2011). A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. International Journal of Neuropsychopharmacology 14, 1127–1131.CrossRefGoogle ScholarPubMed
Li, N, Lee, B, Liu, RJ, Banasr, M, Dwyer, JM, Iwata, M, Li, XY, Aghajanian, G, Duman, RS (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, NY) 329, 959–964.Google Scholar
Lindqvist, D, Janelidze, S, Hagell, P, Erhardt, S, Samuelsson, M, Minthon, L, Hansson, O, Bjorkqvist, M, Traskman-Bendz, L, Brundin, L (2009). Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biological Psychiatry 66, 287–292.Google Scholar
Mann, JJ (2003). Neurobiology of suicidal behaviour. Nature Reviews Neuroscience 4, 819–828.CrossRefGoogle ScholarPubMed
Mann, JJ (2005). The medical management of depression. New England Journal of Medicine 353, 1819–1834.CrossRefGoogle ScholarPubMed
Mann, JJ, Apter, A, Bertolote, J, Beautrais, A, Currier, D, Haas, A, Hegerl, U, Lonnqvist, J, Malone, K, Marusic, A, Mehlum, L, Patton, G, Phillips, M, Rutz, W, Rihmer, Z, Schmidtke, A, Shaffer, D, Silverman, M, Takahashi, Y, Varnik, A, Wasserman, D, Yip, P, Hendin, H (2005). Suicide prevention strategies: a systematic review. Journal of the American Medical Association 294, 2064–2074.Google Scholar
Mathew, SJ, Shah, A, Lapidus, K, Clark, C, Jarun, N, Ostermeyer, B, Murrough, JW (2012). Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs 26, 189–204.Google Scholar
Meltzer, HY, Alphs, L, Green, AI, Altamura, AC, Anand, R, Bertoldi, A, Bourgeois, M, Chouinard, G, Islam, MZ, Kane, J, Krishnan, R, Lindenmayer, JP, Potkin, S, International Suicide Prevention Trial Study Group (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of General Psychiatry 60, 82–91.CrossRefGoogle ScholarPubMed
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382–389.CrossRefGoogle ScholarPubMed
Murrough, JW (2012). Ketamine as a novel antidepressant: from synapse to behavior. Clinical Pharmacology and Therapeutics 91, 303–309.Google Scholar
Murrough, JW, Iosifescu, DV, Chang, LC, Al Jurdi, RK, Green, CE, Perez, AM, Iqbal, S, Pillemer, S, Foulkes, A, Shah, A, Charney, DS, Mathew, SJ (2013 a). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry 170, 1134–1142.CrossRefGoogle ScholarPubMed
Murrough, JW, Perez, AM, Pillemer, S, Stern, J, Parides, MK, aan het Rot, M, Collins, KA, Mathew, SJ, Charney, DS, Iosifescu, DV (2013 b). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry 74, 250–256.Google Scholar
Overall, JE, Gorham, DR, Shawver, JR (1961). Basic dimensions of change in the symptomatology of chronic schizophrenics. Journal of Abnormal and Social Psychology 63, 597–602.CrossRefGoogle ScholarPubMed
Posner, K, Oquendo, MA, Gould, M, Stanley, B, Davies, M (2007). Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. American Journal of Psychiatry 164, 1035–1043.CrossRefGoogle ScholarPubMed
Price, RB, Iosifescu, DV, Murrough, JW, Chang, LC, Al Jurdi, RK, Iqbal, SZ, Soleimani, L, Charney, DS, Foulkes, AL, Mathew, SJ (2014). Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depression and Anxiety 31, 335–343.Google Scholar
Price, RB, Nock, MK, Charney, DS, Mathew, SJ (2009). Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biological Psychiatry 66, 522–526.Google Scholar
Rockett, IR, Regier, MD, Kapusta, ND, Coben, JH, Miller, TR, Hanzlick, RL, Todd, KH, Sattin, RW, Kennedy, LW, Kleinig, J, Smith, GS (2012). Leading causes of unintentional and intentional injury mortality: United States, 2000–2009. American Journal of Public Health 102, e84–e92.CrossRefGoogle ScholarPubMed
Rush, AJ, Fava, M, Wisniewski, SR, Lavori, PW, Trivedi, MH, Sackeim, HA, Thase, ME, Nierenberg, AA, Quitkin, FM, Kashner, TM, Kupfer, DJ, Rosenbaum, JF, Alpert, J, Stewart, JW, McGrath, PJ, Biggs, MM, Shores-Wilson, K, Lebowitz, BD, Ritz, L, Niederehe, G, STAR*D Investigators Group (2004). Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials 25, 119–142.CrossRefGoogle ScholarPubMed
Rush, AJ, Trivedi, MH, Ibrahim, HM, Carmody, TJ, Arnow, B, Klein, DN, Markowitz, JC, Ninan, PT, Kornstein, S, Manber, R, Thase, ME, Kocsis, JH, Keller, MB (2003). The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological Psychiatry 54, 573–583.CrossRefGoogle ScholarPubMed
Sequeira, A, Mamdani, F, Ernst, C, Vawter, MP, Bunney, WE, Lebel, V, Rehal, S, Klempan, T, Gratton, A, Benkelfat, C, Rouleau, GA, Mechawar, N, Turecki, G (2009). Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4, e6585.Google Scholar
Serafini, G, Pompili, M, Innamorati, M, Dwivedi, Y, Brahmachari, G, Girardi, P (2013). Pharmacological properties of glutamatergic drugs targeting NMDA receptors and their application in major depression. Current Pharmaceutical Design 19, 1898–1922.CrossRefGoogle ScholarPubMed
Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, Hergueta, T, Baker, R, Dunbar, GC (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59 (Suppl. 20), 22–33; quiz 34–57.Google ScholarPubMed
Sowa-Kucma, M, Szewczyk, B, Sadlik, K, Piekoszewski, W, Trela, F, Opoka, W, Poleszak, E, Pilc, A, Nowak, G (2013). Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims. Journal of Affective Disorders 151, 924–931.Google Scholar
Trivedi, MH, Wisniewski, SR, Morris, DW, Fava, M, Gollan, JK, Warden, D, Nierenberg, AA, Gaynes, BN, Husain, MM, Luther, JF, Zisook, S, Rush, AJ (2011 a). Concise Health Risk Tracking scale: a brief self-report and clinician rating of suicidal risk. Journal of Clinical Psychiatry 72, 757–764.Google Scholar
Trivedi, MH, Wisniewski, SR, Morris, DW, Fava, M, Kurian, BT, Gollan, JK, Nierenberg, AA, Warden, D, Gaynes, BN, Luther, JF, Rush, AJ (2011 b). Concise Associated Symptoms Tracking scale: a brief self-report and clinician rating of symptoms associated with suicidality. Journal of Clinical Psychiatry 72, 765–774.CrossRefGoogle Scholar
Wan, LB, Levitch, CF, Perez, AM, Brallier, JW, Iosifescu, DV, Chang, LC, Foulkes, A, Mathew, SJ, Charney, DS, Murrough, JW (2014). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Journal of Clinical Psychiatry 76, 247–252.CrossRefGoogle Scholar
Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429–435.Google Scholar
Zarate, CA Jr., Brutsche, NE, Ibrahim, L, Franco-Chaves, J, Diazgranados, N, Cravchik, A, Selter, J, Marquardt, CA, Liberty, V, Luckenbaugh, DA (2012). Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biological Psychiatry 71, 939–946.Google Scholar
Zarate, CA Jr., Singh, JB, Carlson, PJ, Brutsche, NE, Ameli, R, Luckenbaugh, DA, Charney, DS, Manji, HK (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63, 856–864.Google Scholar
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