Skip to main content Accessibility help
×
Home
Hostname: page-component-544b6db54f-zts5g Total loading time: 0.35 Render date: 2021-10-18T22:43:54.886Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

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

Published online by Cambridge University Press:  10 July 2014

A. McGirr*
Affiliation:
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
M. T. Berlim
Affiliation:
Neuromodulation Research Clinic, Douglas Mental Health University Institute and McGill University, Montréal, Québec, Canada Depressive Disorders Program, Douglas Mental Health University Institute and McGill University, Montréal, Québec, Canada
D. J. Bond
Affiliation:
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, BC, Canada
M. P. Fleck
Affiliation:
Depressive Disorders Program, Douglas Mental Health University Institute and McGill University, Montréal, Québec, Canada
L. N. Yatham
Affiliation:
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, BC, Canada
R. W. Lam
Affiliation:
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, BC, Canada
*
* Address for correspondence: A. McGirr, 11th Floor, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada (Email: alexander.mcgirr@alumni.ubc.ca)

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.

Type
Review Articles
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
APA (1994). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). American Psychiatric Association: Washington, , DC. Google ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
Borenstein, M, Hedges, LV, Higgins, JPT, Rothstein, HR (2009). Introduction to Meta-Analysis. Wiley & Sons Ltd: West Sussex, England.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, 125136.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Cooper, H, Hedges, LV, Valentine, JC (2009). The Handbook of Research Synthesis and Meta-Analysis. Russell Sage Foundation Publications: New York, US.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
Hamilton, M (1960). A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry 23, 5662.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Higgins, JPT, Green, S (2008). Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons Ltd: West Sussex, England.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Kudoh, A, Takahira, Y, Katagai, H, Takazawa, T (2002). Small-dose ketamine improves the postoperative state of depressed patients. Anesthesia and Analgesia 95, 114118.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.CrossRefGoogle ScholarPubMed
Murrough, JW (2012). Ketamine as a novel antidepressant: from synapse to behavior. Clinical Pharmacology and Therapeutics 91, 303309.CrossRefGoogle 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, 11341142.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, 250256.CrossRefGoogle ScholarPubMed
Overall, JE, Gorham, DR (1962). The brief psychiatric rating scale. Psychological Reports 10, 799812.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Riley, RD, Higgins, JP, Deeks, JJ (2011). Interpretation of random effects meta-analyses. British Medical Journal 342, d549.CrossRefGoogle ScholarPubMed
Rosenthal, R (1979). The file drawer problem and tolerance for null results. Psychological Bulletin 86, 638641.CrossRefGoogle Scholar
Rosenthal, R (1993). Meta-Analytic Procedures for Social Research. Sage Publications: Newbury Park, CA.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Skolnick, P, Popik, P, Trullas, R (2009). Glutamate-based antidepressants: 20 years on. Trends in Pharmacological Science 30, 563569.CrossRefGoogle Scholar
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.Google ScholarPubMed
Trullas, R, Skolnick, P (1990). Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. European Journal of Pharmacology 185, 110.CrossRefGoogle ScholarPubMed
WHO (1992). The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva, Switzerland.Google ScholarPubMed
WHO (2008). The Global Burden of Disease: 2004 Update. WHO Press: Geneva.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, 939946.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Supplementary material: Image

McGirr Supplementary Material

Figure S5

Download McGirr Supplementary Material(Image)
Image 3 MB
Supplementary material: Image

McGirr Supplementary Material

Figure S6

Download McGirr Supplementary Material(Image)
Image 5 MB
Supplementary material: Image

McGirr Supplementary Material

Figure S7

Download McGirr Supplementary Material(Image)
Image 5 MB
Supplementary material: Image

McGirr Supplementary Material

Figure S8

Download McGirr Supplementary Material(Image)
Image 2 MB
Supplementary material: File

McGirr Supplementary Material

Tables S1-S2 and Figures S1-S4

Download McGirr Supplementary Material(File)
File 628 KB
199
Cited by

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

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

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

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

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

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

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *