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Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study

Published online by Cambridge University Press:  19 October 2015

Y.-D. Hu ,
Y.-T. Xiang ,
J.-X. Fang ,
S. Zu ,
S. Sha ,
H. Shi ,
G. S. Ungvari ,
C. U. Correll ,
H. F. K. Chiu  and
Y. Xue
...Show all authors
Y.-D. Hu
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China Department of Psychiatry, Capital Medical University, China & Center of Depression, Beijing Institute for Brain Disorders, Beijing, China Unit of Psychological Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
Y.-T. Xiang*
Affiliation:
Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China
J.-X. Fang
Affiliation:
Unit of Psychological Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
S. Zu
Affiliation:
Unit of Psychological Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
S. Sha
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
H. Shi
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China Unit of Psychological Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
G. S. Ungvari
Affiliation:
The University of Notre Dame Australia/Marian Centre, Perth, Australia School of Psychiatry & Clinical Neurosciences, University of Western Australia, Perth, Australia
C. U. Correll
Affiliation:
Division of Psychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY, USA
H. F. K. Chiu
Affiliation:
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
Y. Xue
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
T.-F. Tian
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
A.-S. Wu
Affiliation:
Unit of Psychological Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
X. Ma
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China Department of Psychiatry, Capital Medical University, China & Center of Depression, Beijing Institute for Brain Disorders, Beijing, China
G. Wang*
Affiliation:
China & Beijing Key Laboratory of Mental Disorders, The National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China Department of Psychiatry, Capital Medical University, China & Center of Depression, Beijing Institute for Brain Disorders, Beijing, China
*
*Address for correspondence: Dr G. Wang, Mood Disorders Center, Beijing Anding Hospital, Beijing, China. (Email: gangwangdoc@gmail.com) [G.W.] (Email: xyutly@gmail.com) [Y.-T.X.]
*Address for correspondence: Dr G. Wang, Mood Disorders Center, Beijing Anding Hospital, Beijing, China. (Email: gangwangdoc@gmail.com) [G.W.] (Email: xyutly@gmail.com) [Y.-T.X.]
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Abstract

Background

While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD).

Method

Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery–Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾50% MADRS score reduction) was the primary outcome.

Results

By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01–0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02–0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days–2 weeks; effect size (ES) = 1.08–1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation.

Conclusions

Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.

Keywords

Efficacyescitalopramketaminemajor depressionresponsetolerability
Type
Original Articles
Information
Psychological Medicine , Volume 46 , Issue 3 , February 2016 , pp. 623 - 635
Copyright
Copyright © Cambridge University Press 2015 

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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, 139–145.Google Scholar
Aan Het Rot, M, Zarate, CA Jr., Charney, DS, Mathew, SJ (2012) Ketamine for depression: where do we go from here? Biological Psychiatry 72, 537–547.Google Scholar
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
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, 351–354.Google Scholar
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.Google Scholar
Caddy, C, Giaroli, G, White, TP, Shergill, SS, Tracy, DK (2014). Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology 4, 75–99.Google Scholar
Chinese Medical Association (2003). Guideline for the Prevention and Treatment of Psychiatric Disorders in China. Chinese Medical Association: Beijing.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). 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
Fond, G, Loundou, A, Rabu, C, Macgregor, A, Lancon, C, Brittner, M, Micoulaud-Franchi, JA, Richieri, R, Courtet, P, Abbar, M, Roger, M, Leboyer, M, Boyer, L (2014). Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology 231, 3663–3676.CrossRefGoogle ScholarPubMed
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62.CrossRefGoogle ScholarPubMed
Husain, MM, Rush, AJ, Fink, M, Knapp, R, Petrides, G, Rummans, T, Biggs, MM, O'Connor, K, Rasmussen, K, Litle, M, Zhao, W, Bernstein, HJ, Smith, G, Mueller, M, McClintock, SM, Bailine, SH, Kellner, CH (2004). Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. Journal of Clinical Psychiatry 65, 485–491.Google Scholar
Ibrahim, L, Diazgranados, N, Franco-Chaves, J, Brutsche, N, Henter, ID, Kronstein, P, Moaddel, R, Wainer, I, Luckenbaugh, DA, Manji, HK, Zarate, CA Jr. (2012). Course of improvement in depressive symptoms to a single intravenous infusion of ketamine v. add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 37, 1526–1533.Google Scholar
Ibrahim, L, Diazgranados, N, Luckenbaugh, DA, Machado-Vieira, R, Baumann, J, Mallinger, AG, Zarate, CA Jr. (2011). Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 1155–1159.CrossRefGoogle ScholarPubMed
Jick, H, Kaye, JA, Jick, SS (2004). Antidepressants and the risk of suicidal behaviors. Journal of the American Medical Association 292, 338–343.CrossRefGoogle ScholarPubMed
Katalinic, N, Lai, R, Somogyi, A, Mitchell, PB, Glue, P, Loo, CK (2013). Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Australian and New Zealand Journal of Psychiatry 47, 710–727.Google Scholar
Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 617–627.Google Scholar
Lanning, CF, Harmel, MH (1975). Ketamine anesthesia. Annual Review of Medicine 26, 137–141.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.Google Scholar
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.Google Scholar
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 329, 959–964.Google Scholar
Liao, Y, Tang, J, Corlett, PR, Wang, X, Yang, M, Chen, H, Liu, T, Chen, X, Hao, W, Fletcher, PC (2011). Reduced dorsal prefrontal gray matter after chronic ketamine use. Biological Psychiatry 69, 42–48.Google Scholar
Liao, Y, Tang, J, Ma, M, Wu, Z, Yang, M, Wang, X, Liu, T, Chen, X, Fletcher, PC, Hao, W (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133, 2115–2122.Google Scholar
Liu, J, Xiang, YT, Wang, G, Zhu, XZ, Ungvari, GS, Kilbourne, AM, Lai, KY, Zhong, BL, Zhang, L, Zhang, Q, Zou, YC, Xiao, L, Zhao, Q, Li, Y, Wu, J, Zhang, GF, Chiu, HF (2013). Psychometric properties of the Chinese versions of the Quick Inventory of Depressive Symptomatology – Clinician Rating (C-QIDS-C) and Self-Report (C-QIDS-SR). Journal of Affective Disorders 147, 421–424.Google Scholar
Maeng, S, Zarate, CA Jr., Du, J, Schloesser, RJ, McCammon, J, Chen, G, Manji, HK (2008). Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biological Psychiatry 63, 349–352.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, 189–204.Google Scholar
McGirr, A, Berlim, MT, Bond, DJ, Fleck, MP, Yatham, LN, Lam, RW (2015). A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychological Medicine 45, 693–704.Google Scholar
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, 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
Naughton, M, Clarke, G, O'Leary, OF, Cryan, JF, Dinan, TG (2014). A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. Journal of Affective Disorders 156, 24–35.Google Scholar
O'Connor, RM, Finger, BC, Flor, PJ, Cryan, JF (2010). Metabotropic glutamate receptor 7: at the interface of cognition and emotion. European Journal of Pharmacology 639, 123–131.Google Scholar
Overall, JE, Gorham, DR (1962). The brief psychiatric rating scale. Psychological Report 10, 799–812.Google Scholar
Pagnin, D, de Queiroz, V, Pini, S, Cassano, GB (2004). Efficacy of ECT in depression: a meta-analytic review. Journal of ECT 20, 13–20.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
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.Google Scholar
Salvadore, G, Cornwell, BR, Colon-Rosario, V, Coppola, R, Grillon, C, Zarate, CA Jr., Manji, HK (2009). Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biological Psychiatry 65, 289–295.Google Scholar
Scheidegger, M, Walter, M, Lehmann, M, Metzger, C, Grimm, S, Boeker, H, Boesiger, P, Henning, A, Seifritz, E (2012). Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action. PLoS ONE 7, e44799.CrossRefGoogle ScholarPubMed
Skolnick, P, Popik, P, Trullas, R (2009). Glutamate-based antidepressants: 20 years on. Trends in Pharmacological Sciences 30, 563–569.Google Scholar
Taylor, MJ, Freemantle, N, Geddes, JR, Bhagwagar, Z (2006). Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Archives of General Psychiatry 63, 1217–1223.Google Scholar
Thakurta, RG, Das, R, Bhattacharya, AK, Saha, D, Sen, S, Singh, OP, Bisui, B (2012). Rapid response with ketamine on suicidal cognition in resistant depression. Indian Journal of Psychological Medicine 34, 170–175.Google Scholar
Trivedi, MH, Rush, AJ, Wisniewski, SR, Nierenberg, AA, Warden, D, Ritz, L, Norquist, G, Howland, RH, Lebowitz, B, McGrath, PJ, Shores-Wilson, K, Biggs, MM, Balasubramani, GK, Fava, M (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. American Journal of Psychiatry 163, 28–40.Google Scholar
Xie, GR, Shen, QJ (1984). Use of the Chinese version of the Hamilton rating scale for depression in general population and patients with major depression (in Chinese). Chinese Journal of Nervous and Mental Diseases 10, 346.Google 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
Zhang, MY, Zhou, TJ, Tang, SH, Chi, YF, Xia, ML, Wang, ZY (1983). The application of the Chinese version of the Brief Psychiatric Rating Scale (BPRS) (in Chinese). Chinese Journal of Nervous and Mental Diseases 9, 76–80.Google Scholar
Zhong, BL, Wang, Y, Chen, HH, Wang, XH (2011). Reliability, validity and sensitivity of Montgomery-Åsberg Depression Rating Scale for patients with current major depressive disorder [in Chinese]. Chinese Journal of Behavioural Medicine and Brain Sciences 20, 85–87.Google Scholar
Zhu, CM, Zhang, MG (1998). Scales on depression [in Chinese]. In Manual of Rating Scales in Psychiatry (ed. Zhang, M. Y.), pp. 121–132. Hunan Science & Technology Press: Hunan, China.Google Scholar
Zimmerman, M, Posternak, MA, Chelminski, I (2004). Derivation of a definition of remission on the Montgomery-Asberg depression rating scale corresponding to the definition of remission on the Hamilton rating scale for depression. Journal of Psychiatric Research 38, 577–582.Google Scholar
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