Hostname: page-component-76fb5796d-vfjqv Total loading time: 0 Render date: 2024-04-26T03:32:58.638Z Has data issue: false hasContentIssue false
  • English
  • Français

A systematic review of ketamine for the treatment of depression among older adults

Published online by Cambridge University Press:  30 June 2020

Aarti Gupta ,
Romika Dhar ,
Palak Patadia ,
Melissa Funaro ,
Gargi Bhattacharya ,
Syeda A. Farheen  and
Rajesh R. Tampi
Aarti Gupta
Affiliation:
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
Romika Dhar
Affiliation:
Department of Medicine, West Virginia University School of Medicine, Morgantown, WV, USA
Palak Patadia
Affiliation:
Northeast Ohio Medical University (NEOMED), Rootstown, OH, USA
Melissa Funaro
Affiliation:
Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA
Gargi Bhattacharya
Affiliation:
Purdue University, West Lafayette, IN, USA
Syeda A. Farheen
Affiliation:
Department of Psychiatry, Case Western Reserve University MetroHealth Program, Cleveland, OH, USA
Rajesh R. Tampi*
Affiliation:
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA Department of Psychiatry and Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH, USA Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
*
Correspondence should be addressed to: Rajesh R. Tampi, Cleveland Clinic Akron General, 1 Akron General Avenue, Akron, Ohio, 44307, USA. Phone: (203) 809-5223, Fax: (330)-344-2943. Email: rajesh.tampi@yale.edu.
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

To review the currently available data on the use of ketamine in the treatment of depression among older adults from randomized controlled studies.

Design:

Randomized controlled trials.

Setting:

Variable.

Participants:

60 years and older with depression.

Intervention:

Ketamine.

Measurements:

Change in Montgomery–Asberg Depression Rating Scale (MADRS) scores.

Results:

Two studies met the inclusion criteria. The first study showed a significant reduction in depression symptoms with use of repeated subcutaneous ketamine administration among older adults with depression. The second study failed to achieve significance on its primary outcome measure but did show a decrease in MADRS scores with intranasal ketamine along with a higher response and remission rates in esketamine group compared with the placebo group. The adverse effects from ketamine generally lasted only a few hours and abated spontaneously. No cognitive adverse effects were noted in either trial from the use of ketamine.

Conclusions:

The current evidence for use of ketamine among older adults with depression indicates some benefits with one positive and one negative trial. Although one of the trials did not achieve significance on the primary outcome measure, it still showed benefit of ketamine in reducing depressive symptoms. Ketamine was well tolerated in both studies with adverse effects being mild and transient.

Keywords

ketamineolder adultsmajor depressive disordertreatment-resistant depressionbipolar depression
Type
Review Article
Information
International Psychogeriatrics , Volume 33 , Special Issue 2: Issue Theme: Schizophrenia and Depression in Older Adults , February 2021 , pp. 179 - 191
Copyright
© International Psychogeriatric Association 2020

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

Abdallah, C.G., Averill, L.A. and Krystal, J.H. (2015). Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Annals of the New York Academy of Sciences, 1344, 66–77. doi: 10.1111/nyas.12718 CrossRefGoogle ScholarPubMed
Abdallah, C.G., Fasula, M., Kelmendi, B., Sanacora, G. and Ostroff, R. (2012). Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. Journal of ECT, 28, 157–161. doi: 10.1097/YCT.0b013e31824f8296 CrossRefGoogle ScholarPubMed
Alexopoulos, G.S. (2019). Mechanisms and treatment of late-life depression. Translational Psychiatry, 9, 188. doi: 10.1038/s41398-019-0514-6 CrossRefGoogle ScholarPubMed
American Geriatrics Society. (2019). Updated AGS beers criteria(R) for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 67, 674–694. doi: 10.1111/jgs.15767 Google Scholar
Andrade, C. (2017). Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and at what frequency? Journal of Clinical Psychiatry, 78, e852–e857. doi: 10.4088/JCP.17f11738 CrossRefGoogle ScholarPubMed
Arean, P.A., Raue, P.J., Sirey, J.A. and Snowden, M. (2012). Implementing evidence-based psychotherapies in settings serving older adults: challenges and solutions. Psychiatric Services, 63, 605–607. doi: 10.1176/appi.ps.201100078 CrossRefGoogle ScholarPubMed
Berman, R.M. et al. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47, 351–354. doi: 10.1016/s0006-3223(99)00230-9 CrossRefGoogle ScholarPubMed
Brenes, G.A. (2007). Anxiety, depression, and quality of life in primary care patients. Primary Care Companion to the Journal of Clinical Psychiatry, 9, 437–443. doi: 10.4088/pcc.v09n0606 CrossRefGoogle ScholarPubMed
Chen, C.H., Lee, M.H., Chen, Y.C. and Lin, M.F. (2011). Ketamine-snorting associated cystitis. Journal of the Formosan Medical Association, 110, 787–791. doi: 10.1016/j.jfma.2011.11.010 CrossRefGoogle ScholarPubMed
Chen, M.H. et al. (2018). Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: a randomized, double-blind control study. Psychiatry Research, 269, 207–211. doi: 10.1016/j.psychres.2018.08.078 CrossRefGoogle ScholarPubMed
Chilukuri, H., Reddy, N.P., Pathapati, R.M., Manu, A.N., Jollu, S. and Shaik, A.B. (2014). Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian Journal of Psychological Medicine, 36, 71–76. doi: 10.4103/0253-7176.127258 CrossRefGoogle ScholarPubMed
Daly, E.J. et al. (2018). Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry, 75, 139–148. doi: 10.1001/jamapsychiatry.2017.3739 CrossRefGoogle ScholarPubMed
Daly, E.J. et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2019.1189 CrossRefGoogle ScholarPubMed
De Gioannis, A. and De Leo, D. (2014). Oral ketamine augmentation for chronic suicidality in treatment-resistant depression. Australian and New Zealand Journal of Psychiatry, 48, 686. doi: 10.1177/0004867414520754 CrossRefGoogle ScholarPubMed
Deng, Y., Mcquoid, D.R., Potter, G.G., Steffens, D.C. and Albert, K. (2018). Predictors of recurrence in remitted late-life depression. Depression & Anxiety, 35, 658–667. doi: 10.1002/da.22772 CrossRefGoogle ScholarPubMed
Diazgranados, N. et al. (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. doi: 10.1001/archgenpsychiatry.2010.90 CrossRefGoogle ScholarPubMed
Dinis-Oliveira, R.J. (2017). Metabolism and metabolomics of ketamine: a toxicological approach. Forensic Sciences Research, 2, 2–10. doi: 10.1080/20961790.2017.1285219 CrossRefGoogle ScholarPubMed
Domino, E.F. (2010). Taming the ketamine tiger. 1965. Anesthesiology, 113, 678–684. doi: 10.1097/ALN.0b013e3181ed09a2 CrossRefGoogle ScholarPubMed
Fda. Gov. Esketamine [Online]. Available at https://www.fda.gov/media/121379/download; last accessed 29 April 2020.Google Scholar
Fedgchin, M. et al. (2019). Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). International Journal of Neuropsychopharmacology, 22, 616–630. doi: 10.1093/ijnp/pyz039 CrossRefGoogle Scholar
Food and Drug Administration. (2019). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic [Online]. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified; last accessed 2 September 2019.Google Scholar
Fried, L.P. et al. (2001). Frailty in older adults: evidence for a phenotype. Journal of Gerontology Series A: Biological Sciences and Medical Sciences, 56, M146–M156. doi: 10.1093/gerona/56.3.m146 CrossRefGoogle ScholarPubMed
Geduldig, E.T. and Kellner, C.H. (2016). Electroconvulsive therapy in the elderly: new findings in geriatric depression. Current Psychiatry Reports, 18, 40. doi: 10.1007/s11920-016-0674-5 CrossRefGoogle ScholarPubMed
George, D. et al. (2017). Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression. American Journal of Geriatric Psychiatry, 25, 1199–1209. doi: 10.1016/j.jagp.2017.06.007 CrossRefGoogle ScholarPubMed
Grossetta Nardini, H. and Wang, L. (2019). The Yale MeSh Analyzer [Online]. Available at: http://mesh.med.yale.edu/; last accessed 13 August 2018.Google Scholar
Grott Zanicotti, C., Perez, D. and Glue, P. (2013). Case report: long-term mood response to repeat dose intramuscular ketamine in a depressed patient with advanced cancer. Journal of Palliative Medicine, 16, 719–720. doi: 10.1089/jpm.2013.0057 CrossRefGoogle Scholar
Hartberg, J., Garrett-Walcott, S. and De Gioannis, A. (2018). Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study. Psychopharmacology, 235, 393–398. doi: 10.1007/s00213-017-4786-3 CrossRefGoogle ScholarPubMed
Hartvig, P. et al. (1995). Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clinical Pharmacology and Therapeutics, 58, 165–173. doi: 10.1016/0009-9236(95)90194-9 CrossRefGoogle ScholarPubMed
Himmelseher, S. and Pfenninger, E. (1998). The clinical use of S-(+)-ketamine – a determination of its place. Anasthesiology Intensivmed Notfallmed Schmerzther, 33, 764–770. doi: 10.1055/s-2007-994851 CrossRefGoogle ScholarPubMed
Jadad, A.R. et al. (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 17, 1–12. doi: 10.1016/0197-2456(95)00134-4 CrossRefGoogle ScholarPubMed
Jarventausta, K. et al. (2013). Effects of S-ketamine as an anesthetic adjuvant to propofol on treatment response to electroconvulsive therapy in treatment-resistant depression: a randomized pilot study. Journal of ECT, 29, 158–161. doi: 10.1097/YCT.0b013e318283b7e9 CrossRefGoogle ScholarPubMed
Jelovac, A., Kolshus, E. and Mcloughlin, D.M. (2013). Relapse following successful electroconvulsive therapy for major depression: a meta-analysis. Neuropsychopharmacology, 38, 2467–2474. doi: 10.1038/npp.2013.149 CrossRefGoogle ScholarPubMed
Jia, H., Zack, M.M., Thompson, W.W., Crosby, A.E. and Gottesman, I. (2015). Impact of depression on quality-adjusted life expectancy (QALE) directly as well as indirectly through suicide. Social Psychiatry and Psychiatry Epidemiology, 50, 939–949. doi: 10.1007/s00127-015-1019-0 CrossRefGoogle ScholarPubMed
Kalsi, S.S., Wood, D.M. and Dargan, P.I. (2011). The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerging Health Threats Journal, 4, 7107. doi: 10.3402/ehtj.v4i0.7107 CrossRefGoogle ScholarPubMed
Kohrs, R. and Durieux, M.E. (1998). Ketamine: teaching an old drug new tricks. Anesthesia Research Analgesia, 87, 1186–1193. doi: 10.1097/00000539-199811000-00039 Google ScholarPubMed
Krause, M., Gutsmiedl, K., Bighelli, I., Schneider-Thoma, J., Chaimani, A. and Leucht, S. (2019). Efficacy and tolerability of pharmacological and non-pharmacological interventions in older patients with major depressive disorder: a systematic review, pairwise and network meta-analysis. European Neuropsychopharmacology. doi: 10.1016/j.euroneuro.2019.07.130 CrossRefGoogle ScholarPubMed
Lai, R. et al. (2014). Pilot dose-response trial of i.v. ketamine in treatment-resistant depression. World Journal of Biological Psychiatry, 15, 579–584. doi: 10.3109/15622975.2014.922697 CrossRefGoogle ScholarPubMed
Lara, D.R., Bisol, L.W. and Munari, L.R. (2013). Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. International Journal of Neuropsychopharmacology, 16, 2111–2117. doi: 10.1017/s1461145713000485 CrossRefGoogle ScholarPubMed
Lindblad, A.J., Clarke, J.A. and Lu, S. (2019). Antidepressants in the elderly. Canadian Family Physician, 65, 340.Google ScholarPubMed
Liu, Y., Lin, D., Wu, B. and Zhou, W. (2016). Ketamine abuse potential and use disorder. Brain Research Bulletin, 126, 68–73. doi: 10.1016/j.brainresbull.2016.05.016 CrossRefGoogle ScholarPubMed
Loo, C.K. et al. (2016). Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatrica Scandinavica, 134, 48–56. doi: 10.1111/acps.12572 CrossRefGoogle ScholarPubMed
Mathew, S.J. et al. (2012). Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs, 26, 189–204. doi: 10.2165/11599770-000000000-00000 CrossRefGoogle ScholarPubMed
Mathews, D.C. and Zarate, C.A. (2013). Current status of ketamine and related compounds for depression. Journal of Clinical Psychiatry, 74, 516–517. doi: 10.4088/JCP.13ac08382 CrossRefGoogle ScholarPubMed
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. and PRISMA Group. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine, 151, 264–269.CrossRefGoogle ScholarPubMed
Nelson, J.C., Delucchi, K. and Schneider, L.S. (2008). Efficacy of second generation antidepressants in late-life depression: a meta-analysis of the evidence. American Journal of Geriatric Psychiatry, 16, 558–567. doi: 10.1097/JGP.0b013e3181693288 CrossRefGoogle Scholar
Nelson, J.C. and Devanand, D.P. (2011). A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. Journal of the American Geriatrics Society, 59, 577–585. doi: 10.1111/j.1532-5415.2011.03355.x CrossRefGoogle ScholarPubMed
Newport, D.J., Carpenter, L.L., Mcdonald, W.M., Potash, J.B., Tohen, M. and Nemeroff, C.B. (2015). Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. American Journal of Psychiatry, 172, 950–966. doi: 10.1176/appi.ajp.2015.15040465 CrossRefGoogle ScholarPubMed
Ochs-Ross, R. et al. (2020). Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. American Journal of Geriatric Psychiatry, 28, 121–141. doi: 10.1016/j.jagp.2019.10.008 CrossRefGoogle ScholarPubMed
Paslakis, G., Gilles, M., Meyer-Lindenberg, A. and Deuschle, M. (2010). Oral administration of the NMDA receptor antagonist S-ketamine as add-on therapy of depression: a case series. Pharmacopsychiatry, 43, 33–35. doi: 10.1055/s-0029-1237375 CrossRefGoogle ScholarPubMed
Peltoniemi, M.A., Hagelberg, N.M., Olkkola, K.T. and Saari, T.I. (2016). Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clinical Pharmacokinetics, 55, 1059–1077. doi: 10.1007/s40262-016-0383-6 CrossRefGoogle ScholarPubMed
Pinquart, M., Duberstein, P.R. and Lyness, J.M. (2006). Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. American Journal of Psychiatry, 163, 1493–1501. doi: 10.1176/ajp.2006.163.9.1493 CrossRefGoogle Scholar
Raue, P.J., Mcgovern, A.R., Kiosses, D.N. and Sirey, J.A. (2017). Advances in psychotherapy for depressed older adults. Current Psychiatry Reports, 19, 57. doi: 10.1007/s11920-017-0812-8 CrossRefGoogle ScholarPubMed
Reynolds, K., Pietrzak, R.H., El-Gabalawy, R., Mackenzie, C.S. and Sareen, J. (2015). Prevalence of psychiatric disorders in US older adults: findings from a nationally representative survey. World Psychiatry, 14, 74–81. doi: 10.1002/wps.20193 CrossRefGoogle Scholar
Rhebergen, D. et al. (2015). Older age is associated with rapid remission of depression after electroconvulsive therapy: a latent class growth analysis. American Journal of Geriatric Psychiatry, 23, 274–282. doi: 10.1016/j.jagp.2014.05.002 CrossRefGoogle ScholarPubMed
Saeed Mirza, S., Ikram, M.A., Freak-Poli, R., Hofman, A., Rizopoulos, D. and Tiemeier, H. (2018). 12 year trajectories of depressive symptoms in community-dwelling older adults and the subsequent risk of death over 13 years. Journal of Gerontology Series A: Biological Sciences and Medical Sciences, 73, 820–827. doi: 10.1093/gerona/glx215 CrossRefGoogle ScholarPubMed
Shah, A., Bhat, R., Zarate-Escudero, S., Deleo, D. and Erlangsen, A. (2016). Suicide rates in five-year age-bands after the age of 60 years: the international landscape. Aging & Mental Health, 20, 131–138. doi: 10.1080/13607863.2015.1055552 CrossRefGoogle ScholarPubMed
Short, B., Fong, J., Galvez, V., Shelker, W. and Loo, C.K. (2018). Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry, 5, 65–78. doi: 10.1016/s2215-0366(17)30272-9 CrossRefGoogle ScholarPubMed
Skolnick, P., Layer, R.T., Popik, P., Nowak, G., Paul, I.A. and Trullas, R. (1996). Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry, 29, 23–26. doi: 10.1055/s-2007-979537 CrossRefGoogle ScholarPubMed
Spaans, H.P. et al. (2015). Speed of remission in elderly patients with depression: electroconvulsive therapy v. medication. British Journal of Psychiatry, 206, 67–71. doi: 10.1192/bjp.bp.114.148213 CrossRefGoogle ScholarPubMed
Tedeschini, E., Levkovitz, Y., Iovieno, N., Ameral, V.E., Nelson, J.C. and Papakostas, G.I. (2011). Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. Journal of Clinical Psychiatry, 72, 1660–1668. doi: 10.4088/JCP.10r06531 CrossRefGoogle ScholarPubMed
Trevithick, L. et al. (2015). Study protocol for the randomised controlled trial: ketamine augmentation of ECT to improve outcomes in depression (ketamine-ECT study). BMC Psychiatry, 15, 257. doi: 10.1186/s12888-015-0641-4 CrossRefGoogle Scholar
Van Marwijk, H.W., Van Der Kooy, K.G., Stehouwer, C.D., Beekman, A.T. and Van Hout, H.P. (2015). Depression increases the onset of cardiovascular disease over and above other determinants in older primary care patients, a cohort study. BMC Cardiovascular Disorders, 15, 40. doi: 10.1186/s12872-015-0036-y CrossRefGoogle ScholarPubMed
Vidal, S. et al. (2018). Efficacy and safety of a rapid intravenous injection of ketamine 0.5 mg/kg in treatment-resistant major depression: an open 4-week longitudinal study. Journal of Clinical Psychopharmacology, 38, 590–597. doi: 10.1097/jcp.0000000000000960 CrossRefGoogle ScholarPubMed
Wells, K.B. et al. (1989). The functioning and well-being of depressed patients. Results from the medical outcomes study. JAMA, 262, 914–919.CrossRefGoogle ScholarPubMed
Wilson, K.C., Mottram, P.G. and Vassilas, C.A. (2008). Psychotherapeutic treatments for older depressed people. Cochrane Database of Systematic Reviews, Cd004853. doi: 10.1002/14651858.CD004853.pub2 CrossRefGoogle ScholarPubMed
Winger, G., Hursh, S.R., Casey, K.L. and Woods, J.H. (2002). Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action. Journal of Pharmacology and Experimental Therapeutics, 301, 690–697. doi: 10.1124/jpet.301.2.690 CrossRefGoogle ScholarPubMed
World Health Organization. (2017). Mental health of older adults [Online]. Available at: https://www.who.int/news-room/fact-sheets/detail/mental-health-of-older-adults; last accessed 2 September 2019.Google Scholar
Yanagihara, Y. et al. (2003). Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharmaceutics & Drug Disposition, 24, 37–43. doi: 10.1002/bdd.336 CrossRefGoogle ScholarPubMed
Yoosefi, A. et al. (2014). Comparing effects of ketamine and thiopental administration during electroconvulsive therapy in patients with major depressive disorder: a randomized, double-blind study. Journal of ECT, 30, 15–21. doi: 10.1097/YCT.0b013e3182a4b4c6 CrossRefGoogle ScholarPubMed
Zanos, P. and Gould, T.D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 23, 801–811. doi: 10.1038/mp.2017.255 CrossRefGoogle ScholarPubMed
Zarate, C.A. Jr. et al. (2012). Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biological Psychiatry, 71, 939–946. doi: 10.1016/j.biopsych.2011.12.010 CrossRefGoogle ScholarPubMed
Zhang, Y., Chen, Y. and Ma, L. (2018). Depression and cardiovascular disease in elderly: current understanding. Journal of Clinical Neuroscience, 47, 1–5. doi: 10.1016/j.jocn.2017.09.022 CrossRefGoogle ScholarPubMed