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A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes

  • A. McGirr (a1), M. T. Berlim (a2) (a3), D. J. Bond (a4) (a5), M. P. Fleck (a3), L. N. Yatham (a1) (a5) and R. W. Lam (a1) (a5)...
Abstract
Background

There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes.

Method

We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model.

Results

Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches.

Conclusion

Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Copyright
Corresponding author
* Address for correspondence: A. McGirr, 11th Floor, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada (Email: alexander.mcgirr@alumni.ubc.ca)
References
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aan het Rot, M, Collins, KA, Murrough, JW, Perez, AM, Reich, DL, Charney, DS, Mathew, SJ (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biological Psychiatry 67, 139145.
aan het Rot, M, Zarate, CA Jr., Charney, DS, Mathew, SJ (2012). Ketamine for depression: where do we go from here? Biological Psychiatry 72, 537547.
APA (1994). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). American Psychiatric Association: Washington, , DC.
Bastos, M, Pereira, M, Pereira, E (2012). Effects of intra-operative sedation with low-doses of s-ketamine on depression: randomized double-blind controlled trial. 15th WFSA World Congress of Anaesthesiologists, Predio Ferial de Buenos Aires, Argentina. British Journal of Anaesthesia. Oxford University Press, 2012, 108 pp.
Berman, RM, Cappiello, A, Anand, A, Oren, DA, Heninger, GR, Charney, DS, Krystal, JH (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47, 351354.
Borenstein, M, Hedges, LV, Higgins, JPT, Rothstein, HR (2009). Introduction to Meta-Analysis. Wiley & Sons Ltd: West Sussex, England.
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, 125136.
Conradi, HJ, Ormel, J, de Jonge, P (2011). Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Medicine 41, 11651174.
Cooper, H, Hedges, LV, Valentine, JC (2009). The Handbook of Research Synthesis and Meta-Analysis. Russell Sage Foundation Publications: New York, US.
Deeks, JJ (2002). Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Statistics in Medicine 21, 15751600.
Deschwanden, A, Karolewicz, B, Feyissa, AM, Treyer, V, Ametamey, SM, Johayem, A, Burger, C, Auberson, YP, Sovago, J, Stockmeier, CA, Buck, A, Hasler, G (2011). Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. American Journal of Psychiatry 168, 727734.
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). A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 67, 793802.
Egger, M, Davey Smith, G, Schneider, M, Minder, C (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629634.
Fagiolini, A, Kupfer, DJ, Masalehdan, A, Scott, JA, Houck, PR, Frank, E (2005). Functional impairment in the remission phase of bipolar disorder. Bipolar Disorders 7, 281285.
Fergusson, D, Aaron, SD, Guyatt, G, Hebert, P (2002). Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. British Medical Journal 325, 652654.
Geddes, JR, Calabrese, JR, Goodwin, GM (2009). Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. British Journal of Psychiatry 194, 49.
Ghasemi, M, Kazemi, MH, Yoosefi, A, Ghasemi, A, Paragomi, P, Amini, H, Afzali, MH (2013). Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Research 28, 355361.
Haile, CN, Murrough, JW, Iosifescu, DV, Chang, LC, Al Jurdi, RK, Foulkes, A, Iqbal, S, Mahoney, JJ, De La Garza, R, Charney, DS, Newton, TF, Mathew, SJ (2014). Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. International Journal of Neuropsychopharmacology 17, 331336.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry 23, 5662.
Heresco-Levy, U, Gelfin, G, Bloch, B, Levin, R, Edelman, S, Javitt, DC, Kremer, I (2013). A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. International Journal of Neuropsychopharmacology 16, 501506.
Higgins, JP, Altman, DG, Gotzsche, PC, Juni, P, Moher, D, Oxman, AD, Savovic, J, Schulz, KF, Weeks, L, Sterne, JA (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. British Medical Journal 343, d5928.
Higgins, JPT, Green, S (2008). Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons Ltd: West Sussex, England.
Huang, CC, Wei, IH, Huang, CL, Chen, KT, Tsai, MH, Tsai, P, Tun, R, Huang, KH, Chang, YC, Lane, HY, Tsai, GE (2013). Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biological Psychiatry 74, 734741.
Irwin, SA, Iglewicz, A, Nelesen, RA, Lo, JY, Carr, CH, Romero, SD, Lloyd, LS (2013). Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. Journal of Palliative Medicine 16, 958–65.
Knable, MB, Barci, BM, Bartko, JJ, Webster, MJ, Torrey, EF (2002). Molecular abnormalities in the major psychiatric illnesses: classification and regression tree (CRT) analysis of post-mortem prefrontal markers. Molecular Psychiatry 7, 392404.
Kudoh, A, Takahira, Y, Katagai, H, Takazawa, T (2002). Small-dose ketamine improves the postoperative state of depressed patients. Anesthesia and Analgesia 95, 114118.
Lapidus, K, 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. Published online: 3 April 2014. doi:10.1016/j.biopsych.2014.03.026.
Lara, DR, Bisol, LW, Munari, LR (2013). Antidepressant, mood stabilizing and recognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. International Journal of Neuropsychopharmacology 16, 21112117.
Luckenbaugh, D, Niciu, MJ, Ionescu, DF, Nolan, NM, Richards, EM, Brutsche, NE, Guevara, S, Zarate, CA (2014). Do the dissociative effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders 159, 5861.
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, 189204.
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.
Murrough, JW (2012). Ketamine as a novel antidepressant: from synapse to behavior. Clinical Pharmacology and Therapeutics 91, 303309.
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, 11341142.
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, 250256.
Overall, JE, Gorham, DR (1962). The brief psychiatric rating scale. Psychological Reports 10, 799812.
Przegalinski, E, Tatarczynska, E, Deren-Wesolek, A, Chojnacka-Wojcik, E (1997). Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology 36, 3137.
Rasmussen, KG, Lineberry, TW, Galardy, CW, Kung, S, Lapid, MI, Palmer, BA, Ritter, MJ, Schak, KM, Sola, CL, Hanson, AJ, Frye, MA (2013). Serial infusions of low-dose ketamine for major depression. Journal of Psychopharmacology 27, 444450.
Riley, RD, Higgins, JP, Deeks, JJ (2011). Interpretation of random effects meta-analyses. British Medical Journal 342, d549.
Rosenthal, R (1979). The file drawer problem and tolerance for null results. Psychological Bulletin 86, 638641.
Rosenthal, R (1993). Meta-Analytic Procedures for Social Research. Sage Publications: Newbury Park, CA.
Rush, AJ, Trivedi, MH, Wisniewski, SR, Nierenberg, AA, Stewart, JW, Warden, D, Niederehe, G, Thase, ME, Lavori, PW, Lebowitz, BD, McGrath, PJ, Rosenbaum, JF, Sackeim, HA, Kupfer, DJ, Luther, J, Fava, M (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry 163, 19051917.
Sanacora, G, Smith, MA, Pathak, S, Su, HL, Boeijinga, PH, McCarthy, DJ, Quirk, MC (2013). Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Molecular Psychiatry. Published online: 15 October 2013. doi:10.1038/mp.2013.130.
Sanacora, G, Zarate, CA, Krystal, JH, Manji, HK (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery 7, 426437.
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.
Shiroma, PR, Johns, B, Kuskowski, M, Wels, J, Thuras, P, Albott, CS, Lim, KO (2014). Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. Journal of Affective Disorders 155, 123129.
Skolnick, P, Layer, RT, Popik, P, Nowak, G, Paul, IA, Trullas, R (1996). Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29, 2326.
Skolnick, P, Popik, P, Trullas, R (2009). Glutamate-based antidepressants: 20 years on. Trends in Pharmacological Science 30, 563569.
Sos, P, Klirova, M, Novak, T, Kohutova, B, Horacek, J, Palenicek, T (2013). Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinology Letters 34, 287293.
Trullas, R, Skolnick, P (1990). Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. European Journal of Pharmacology 185, 110.
WHO (1992). The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva, Switzerland.
WHO (2008). The Global Burden of Disease: 2004 Update. WHO Press: Geneva.
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, 939946.
Zarate, CA Jr., Mathews, D, Ibrahim, L, Chaves, JF, Marquardt, C, Ukoh, I, Jolkovsky, L, Brutsche, NE, Smith, MA, Luckenbaugh, DA (2013). A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biological Psychiatry 74, 257264.
Zarate, CA Jr., Payne, JL, Quiroz, J, Sporn, J, Denicoff, KK, Luckenbaugh, D, Charney, DS, Manji, HK (2004). An open-label trial of riluzole in patients with treatment-resistant major depression. American Journal of Psychiatry 161, 171174.
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, 856864.
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