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Regular Research Article| Volume 29, ISSUE 9, P899-913, September 2021

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Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series

  • Orly Lipsitz
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • Joshua D. Di Vincenzo
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Department of Pharmacology and Toxicology, University of Toronto (JDV, RSM), Toronto, ON, Canada
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  • Nelson B. Rodrigues
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • Danielle S. Cha
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    School of Medicine, Faculty of Medicine, University of Queensland (DSC), Brisbane, QLD, Australia
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  • Yena Lee
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • David Greenberg
    Affiliations
    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • Kayla M. Teopiz
    Affiliations
    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • Roger C. Ho
    Affiliations
    Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore (RCH), Singapore

    Institute for Health Innovation and Technology (iHealthtech), National University of Singapore (RCH), Singapore
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  • Bing Cao
    Affiliations
    Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University (BC), Chongqing, 400715, PR China
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  • Kangguang Lin
    Affiliations
    Department of Affective Disorder, The Affiliated Brain Hospital of Guangzhou Medical University, (Guangzhou Huiai Hospital), Guangzhou Medical University (KL), Guangzhou, China

    Laboratory of Emotion and Cognition, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University (KL), Guangzhou, China
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  • Mehala Subramaniapillai
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada
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  • Alastair J. Flint
    Affiliations
    Department of Psychiatry, University of Toronto (AJF, RSM, JDR), Toronto, ON, Canada

    Centre for Mental Health, University Health Network (AJF), Toronto, ON, Canada
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  • Kevin Kratiuk
    Affiliations
    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada

    Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
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  • Roger S. McIntyre
    Correspondence
    Send correspondence and reprint requests to Roger S. McIntyre, MD, University Health Network, 399 Bathurst Street, MP 9-325, Toronto, ON M5T 2S8, Canada.
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada

    Department of Psychiatry, University of Toronto (AJF, RSM, JDR), Toronto, ON, Canada

    Department of Pharmacology and Toxicology, University of Toronto (JDV, RSM), Toronto, ON, Canada
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  • Joshua D. Rosenblat
    Affiliations
    Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada

    Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada

    Department of Psychiatry, University of Toronto (AJF, RSM, JDR), Toronto, ON, Canada
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Published:January 09, 2021DOI:https://doi.org/10.1016/j.jagp.2020.12.032

      Highlights

      • What is the primary question addressed by this study?Is repeat-dose intravenous (IV) ketamine treatment safe, effective, and well-tolerated in older adults with treatment-resistant depression receiving care at a specialized community-based clinic?
      • What is the main finding of this study?Twenty-seven percent of older adults responded to IV ketamine after four infusions (i.e., ≥50% symptomatic improvement compared to pre-treatment), and three individuals dropped out of treatment due to increased anxiety and/or inability to tolerate dissociative symptoms. Sixty-nine percent of participants experienced treatment-emergent hypertension during at least one infusion.
      • What is the meaning of the finding?Intravenous ketamine treatment was associated with transient treatment-emergent hypertension, and response rates in older adults were comparable to those previously reported in general adult populations.

      ABSTRACT

      Objective

      To evaluate the safety, tolerability, and effectiveness of repeated doses of intravenous (IV) ketamine in older adults (i.e., ≥60 years of age) with treatment-resistant depression.

      Method

      In this case series, fifty-three older adults (Mage = 67, SD = 6; 57% female [n = 30]) received 4 IV ketamine infusions, administered over 1–2 weeks. Effectiveness of IV ketamine was measured using the Quick Inventory for Depressive Symptomatology–Self Report 16 (QIDS-SR16) approximately 2 days after infusions 1–3, and 1–2 weeks after infusion 4. Safety was measured as hemodynamic changes before, during, immediately after, and 20 minutes after each infusion. Tolerability was assessed via systematic reporting of treatment-emergent adverse events during and after each infusion, in addition to symptoms of dissociation measured using the Clinician Administered Dissociative States Scale. Partial response (25%–50% symptomatic improvement from baseline), response (≥50% symptomatic improvement from baseline), clinically significant improvements (≥25% symptomatic improvement from baseline), and remission rates (QIDS-SR16 ≤5) were also calculated.

      Results

      Participants reported significant decreases in depressive symptoms (i.e., as measured by the QIDS-SR16) with repeated ketamine infusions (F(4, 92) = 7.412, p <0.001). The mean QIDS-SR16 score was 17.12 (SD = 5.33) at baseline and decreased to 12.52 (SD = 5.79) following 4 infusions. After 4 infusions, 31% (n = 8) of participants partially responded to IV ketamine, 27% (n = 7) responded, 58% (n = 15) experienced clinically significant improvements, and 10% (n = 3) met remission criteria. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73).

      Conclusion

      Ketamine was associated with transient treatment-emergent hypertension. Response and remission rates were comparable to those reported in general adult samples. Findings are limited by the open-label, chart review nature of this study.

      Key Words

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      References

        • Haigh EAP
        • Bogucki OE
        • Sigmon ST
        • et al.
        Depression among older adults: a 20-year update on five common myths and misconceptions.
        Am J Geriatr Psychiatry. 2018; 26 (Available at): 107-122
        • Ford BC
        • Bullard KM
        • Taylor RJ
        • et al.
        Lifetime and 12-month prevalence of diagnostic and statistical manual of mental disorders, disorders among older African Americans: findings from the National Survey of American Life.
        Am J Geriatr Psychiatry. 2007; 15: 652-659
        • Eaton WW
        • Kalaydjian A
        • Scharfstein DO
        • et al.
        Prevalence and incidence of depressive disorder: the Baltimore ECA follow-up, 1981–2004.
        Acta Psychiatrica Scandinavica. 2007; 116 (Available at): 182-188
        • Gum AM
        • King-Kallimanis B
        • Kohn R
        Prevalence of mood, anxiety, and substance-abuse disorders for older Americans in the National Comorbidity Survey-Replication The American.
        J Geriatr Psychiatry. 2009; 17 (Available at): 769-781
        • Trollor J
        • Brodaty H
        • Andrews G
        • et al.
        Prevalence of mental disorders in the elderly: the Australian National Mental Health and Well-being.
        Survey Acta Neuropsychiatrica. 2006; 18 (Available at): 271-272
        • Thakur M
        • Blazer DG
        Depression in long-term care.
        J Am Med Dir Assoc. 2008; 9: 82-87
        • Seitz D
        • Purandare N
        • Conn D
        Prevalence of psychiatric disorders among older adults in long-term care homes: a systematic review.
        Int Psychogeriatr. 2010; 22: 1025
      1. Alexopoulos GS: Mechanisms and treatment of late-life depression translational psychiatry 2019; 9. Available athttp://dx.doi.org/10.1038/s41398-019-0514-6.

        • Penninx BWJH
        Depression and cardiovascular disease: epidemiological evidence on their linking mechanisms.
        Neurosci Biobehav Rev. 2017; 74: 277-286
        • Buigues C
        • Padilla-Sánchez C
        • Garrido JF
        • et al.
        The relationship between depression and frailty syndrome: a systematic review.
        Aging Ment Health. 2015; 19: 762-772
        • Alexopoulos GS
        Depression in the elderly.
        Lancet. 2005; 365 (Available at): 1961-1970
        • Taylor WD
        • Aizenstein HJ
        • Alexopoulos GS
        The vascular depression hypothesis: mechanisms linking vascular disease with depression.
        Mol Psychiatry. 2013; 18: 963-974
        • Beekman ATF
        • Geerlings SW
        • Deeg DJH
        • et al.
        The natural history of late-life depression: a 6-year prospective study in the community.
        Arch Gen Psychiatry. 2002; 59: 605-611
        • Lyness JM
        • King DA
        • Cox C
        • et al.
        The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability.
        J Am Geriatr Soc. 1999; 47: 647-652
        • Mitchell AJ
        • Subramaniam H
        Prognosis of depression in old age compared to middle age: a systematic review of comparative studies.
        Am J Psychiatry. 2005; 162: 1588-1601
        • Deng Y
        • McQuoid DR
        • Potter GG
        • et al.
        Predictors of recurrence in remitted late-life depression.
        Depress Anxiety. 2018; 35: 658-667
        • Schneider LS
        • Craig Nelson J
        • Clary CM
        • et al.
        An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression American.
        J Psychiatry. 2003; 160 (Available at): 1277-1285
        • Sheikh JI
        • Cassidy EL
        • Doraiswamy PM
        • et al.
        Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness.
        J Am Geriatr Soc. 2004; 52: 86-92
        • Tollefson GD
        • Bosomworth JC
        • Heiligenstein JH
        • et al.
        A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric patients with major depression.
        Int Psychogeriatr. 1995; 7: 89-104
        • Rapaport MH
        • Schneider LS
        • Dunner DL
        • et al.
        Efficacy of controlled-release paroxetine in the treatment of late-life depression.
        J Clin Psychiatry. 2003; 64: 1065-1074
        • Taylor WD
        Depression in the elderly.
        N Engl J Med. 2014; 371: 1228-1236
        • Bose A
        • Li D
        • Gandhi C
        Escitalopram in the acute treatment of depressed patients aged 60 years or older.
        Am J Geriatr Psychiatry. 2008; 16: 14-20
        • Raskin J
        • Wiltse CG
        • Siegal A
        • et al.
        Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial.
        Am J Psychiatry. 2007; 164: 900-909
        • Schatzberg A
        • Roose S
        A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression.
        Am J Geriatr Psychiatry. 2006; 14: 361-370
        • Oslin DW
        • Ten Have TR
        • Streim JE
        • et al.
        Probing the safety of medications in the frail elderly: evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents.
        J Clin Psychiatry. 2003; 64: 875-882
        • Kirby D
        • Harrigan S
        • Ames D
        Hyponatraemia in elderly psychiatric patients treated with selective serotonin reuptake inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit.
        Int J Geriatr Psychiatry. 2002; 17: 231-237
        • Laporte S
        • Chapelle C
        • Caillet P
        • et al.
        Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies.
        Pharmacol Res. 2017; 118: 19-32
        • Lavretsky H
        • Kumar A
        Methylphenidate augmentation of citalopram in elderly depressed patients.
        Am J Geriatr Psychiatry. 2001; 9: 298-303
        • Lenze EJ
        • Mulsant BH
        • Blumberger DM
        • et al.
        Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.
        Lancet. 2015; 386: 2404-2412
        • Rush AJ
        • John Rush A
        • Trivedi MH
        • et al.
        Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.
        Am J Psychiatry. 2006; 163 (Available at): 1905-1917
        • Machado-Vieira R
        • Baumann J
        • Wheeler-Castillo C
        • et al.
        The timing of antidepressant effects: a comparison of diverse.
        Pharmacol Somat Treat Pharm. 2010; 3: 19-41
        • Murrough JW
        • Iosifescu DV
        • Chang LC
        • et al.
        Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.
        Am J Psychiatry. 2013; 170: 1134-1142
        • Rosenblat JD
        • Carvalho AF
        • Li M
        • et al.
        Oral ketamine for depression: a systematic review.
        J Clin Psychiatry. 2019; 80: 18r12475
        • aan het Rot M
        • Collins KA
        • Murrough JW
        • et al.
        Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
        Biol Psychiatry. 2010; 67: 139-145
        • Coyle CM
        • Laws KR
        The use of ketamine as an antidepressant: a systematic review and meta-analysis human psychopharmacology.
        Clin Exp. 2015; 30: 152-163
        • George D
        • Gálvez V
        • Martin D
        • et al.
        Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression.
        Am J Geriatr Psychiatry. 2017; 25: 1199-1209
        • Ochs-Ross R
        • Daly EJ
        • Zhang Y
        • et al.
        Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression—TRANSFORM-3.
        Am J Geriatr Psychiatry. 2020; 28: 121-141
        • McIntyre RS
        • Rodrigues NB
        • Lee Y
        • et al.
        The effectiveness of repeated intravenous ketamine on depressive symptoms, suicidal ideation and functional disability in adults with major depressive disorder and bipolar disorder: Results from the Canadian Rapid Treatment Center of Excellence.
        J Affect Disord. 2020; 274: 903-910
        • Thase ME
        • Rush AJ
        When at first you don't succeed: sequential strategies for antidepressant nonresponders.
        J Clin Psychiatry. 1997; 58: 23-29
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders (DSM-5®).
        American Psychiatric Pub, 2013 (Available at)
        • Rodrigues NB
        • McIntyre RS
        • Lipsitz O
        • et al.
        Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence.
        Expert Opin Drug Saf. 2020; 19: 1-10
        • Rush AJ
        • Trivedi MH
        • Ibrahim HM
        • et al.
        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.
        Biol Psychiatry. 2003; 54: 573-583
        • Cusin C
        • Ionescu DF
        • Pavone KJ
        • et al.
        Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation.
        Aust N Z J Psychiatry. 2017; 51: 55-64
        • Bremner JD
        • Douglas Bremner J
        • Krystal JH
        • et al.
        Measurement of dissociative states with the clinician-administered dissociative states scale (CADSS).
        J Trauma Stress. 1998; 11 (Available at): 125-136
        • Singh JB
        • Fedgchin M
        • Daly E
        • et al.
        Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization.
        Placebo-Controlled Study Biol Psychiatry. 2016; 80: 424-431
        • Rong C
        • Park C
        • Rosenblat J
        • et al.
        Predictors of response to ketamine in treatment resistant major depressive disorder and bipolar disorder.
        Int J Environ Res Public Health. 2018; 15 (Available at): 771
        • Spitzer RL
        • Kroenke K
        • Williams JBW
        • et al.
        A brief measure for assessing generalized anxiety disorder: the GAD-7.
        Arch Intern Med. 2006; 166: 1092-1097
        • Thorpe KE
        How to construct regression models for observational studies (and how NOT to do it!).
        Canadian J Anesth/J Canadien d'anesthésie. 2017; 64 (Available at): 461-470
        • Hsu JH
        • Mulsant BH
        • Lenze EJ
        • et al.
        Impact of prior treatment on remission of late-life depression with venlafaxine and subsequent aripiprazole or placebo augmentation.
        Am J Geriatr Psychiatry. 2016; 24: 918-922
        • Niciu MJ
        • Shovestul BJ
        • Jaso BA
        • et al.
        Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression.
        J Affect Disord. 2018; 232: 310-315
        • van Schalkwyk GI
        • Wilkinson ST
        • Davidson L
        • et al.
        Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: analysis of the clinician administered dissociative state scale.
        J Affect Disord. 2018; 227: 11-16
        • Zanos P
        • Moaddel R
        • Morris PJ
        • et al.
        Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms.
        Pharmacol Rev. 2018; 70 (Available at): 621-660
        • Ochs-Ross R
        • Daly EJ
        • Zhang Y
        • et al.
        Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression.
        Am J Geriatr Psychiatry. 2019; 27 (Available at): S180-S181
        • McIntyre RS
        • Carvalho IP
        • Lui LMW
        • et al.
        The effect of intravenous, intranasal, and oral ketamine in mood disorders: a meta-analysis.
        J Affect Disord. 2020; 276: 576-584
        • Irwin SA
        • Iglewicz A
        • Nelesen RA
        • et al.
        Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept.
        Trial J Palliat Med. 2013; 16: 958-965
        • McIntyre RS
        • Cha DS
        • Soczynska JK
        • et al.
        Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions.
        Depress Anxiety. 2013; 30: 515-527
        • McIntyre RS
        • Lee Y
        Cognition in major depressive disorder: a “systemically important functional index” (SIFI).
        Curr Opin Psychiatry. 2016; 29: 48-55