Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients With Treatment-Refractory Depression: An Observational Study

Balwinder Singh, MD, MS; Simon Kung, MD; Vanessa Pazdernik, MS; Kathryn M. Schak, MD; Jennifer Geske, MS; Phillip J. Schulte, PhD; Mark A. Frye, MD; Jennifer L. Vande Voort, MD

J Clin Psychiatry 2023;84(2):22m14548

ABSTRACT

Objective: Ketamine has been redeveloped as a rapid-acting antidepressant for treatment-resistant depression (TRD). There is a paucity of literature comparing subanesthetic intravenous (IV) ketamine and US Food and Drug Administration (FDA)–approved intranasal (IN) esketamine for TRD in real-world clinical settings. We compared the efficacy and time to achieve remission/response with repeated ketamine and esketamine.

Methods: An observational study of adults with TRD received up to 6 IV ketamine (0.5 mg/kg over 40 minutes) or up to 8 IN esketamine (56- or 84-mg) treatments from August 17, 2017, to June 24, 2021. Depressive symptoms were measured utilizing the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) before and 24 hours after treatment. Cox proportional hazard models were used to evaluate associations between time to response ( ≥ 50% change in QIDS-SR score) and remission (QIDS-SR score ≤ 5).

Results: Sixty-two adults (median age = 50 years, 65% female) received IV ketamine (76%, n = 47) or IN esketamine (24%, n = 15). Neither baseline-to-endpoint change in QIDS-SR score nor response/remission rates were significantly different between groups. Time to remission, defined as number of treatments (adjusting for age, body mass index [BMI], sex, and baseline QIDS-SR score), was faster for IV versus IN treatment (HR = 5.0, P = .02).

Conclusions: Intravenous ketamine and intranasal esketamine showed similar rates of response and remission in TRD patients, but the number of treatments required to achieve remission was significantly lower with IV ketamine compared to IN esketamine. These findings need to be investigated in a randomized control trial comparing these two treatment interventions.

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References (38)

Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry. 2018;75(4):336–346. PubMed CrossRef
Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61(suppl 6):4–6. PubMed
Rush AJ, Trivedi MH, Wisniewski SR, 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(11):1905–1917. PubMed CrossRef
Johnston KM, Powell LC, Anderson IM, et al. The burden of treatment-resistant depression: a systematic review of the economic and quality of life literature. J Affect Disord. 2019;242:195–210. PubMed CrossRef
Singh B, Port JD, Voort JLV, et al. A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration. Psychiatry Res. 2021;301:113953. PubMed CrossRef
Singh B, Port JD, Pazdernik V, et al. Racemic ketamine treatment attenuates anterior cingulate cortex GABA deficits among remitters in treatment-resistant depression: a pilot study. Psychiatry Res Neuroimaging. 2022;320:111432. PubMed CrossRef
Vande Voort JL, Morgan RJ, Kung S, et al. Continuation phase intravenous ketamine in adults with treatment-resistant depression. J Affect Disord. 2016;206:300–304. PubMed CrossRef
Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864. PubMed CrossRef
Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802. PubMed CrossRef
A new indication for esketamine nasal spray (Spravato). Med Lett Drugs Ther. 2020;62(1607):151. PubMed
Nuñez NA, Joseph B, Pahwa M, et al. An update on the efficacy and tolerability of oral ketamine for major depression: a systematic review and meta-analysis. Psychopharmacol Bull. 2020;50(4):137–163. PubMed
Joseph B, Parsaik AK, Ahmed AT, et al. A systematic review on the efficacy of intravenous racemic ketamine for bipolar depression. J Clin Psychopharmacol. 2021;41(1):71–75. PubMed CrossRef
Singh B, Vande Voort JL, Frye MA, et al. Can ketamine be a safe option for treatment-resistant bipolar depression? Expert Opin Drug Saf. 2022;21(6):717–720. PubMed CrossRef
Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401–409. PubMed CrossRef
O’Brien B, Wilkinson ST, Mathew SJ. An update on community ketamine practices. Am J Psychiatry. 2022;179(5):393–394. PubMed CrossRef
Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542–555. PubMed CrossRef
Singh B, Bobo WV, Rasmussen KG, et al. The association between body mass index and remission rates in patients with treatment-resistant depression who received intravenous ketamine. J Clin Psychiatry. 2019;80(6):19l12852. PubMed CrossRef
Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol. 2013;27(5):444–450. PubMed CrossRef
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(5):573–583. PubMed CrossRef
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382–389. PubMed CrossRef
Carmody TJ, Rush AJ, Bernstein IH, et al. Making clinicians lives easier: guidance on use of the QIDS self-report in place of the MADRS. J Affect Disord. 2006;95(1–3):115–118. PubMed CrossRef
McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399. PubMed CrossRef
Quibell R, Fallon M, Mihalyo M, et al. Ketamine. J Pain Symptom Manage. 2015;50(2):268–278. PubMed CrossRef
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998;11(1):125–136. PubMed CrossRef
Wilkinson ST, Toprak M, Turner MS, et al. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017;174(7):695–696. PubMed CrossRef
Riva-Posse P, Reiff CM, Edwards JA, et al. Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord. 2018;236:291–297. PubMed CrossRef
Yang C, Shirayama Y, Zhang JC, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5(9):e632. PubMed CrossRef
Wei Y, Chang L, Hashimoto K. Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor. Mol Psychiatry. 2022;27(1):559–573. PubMed CrossRef
Leal GC, Bandeira ID, Correia-Melo FS, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci. 2021;271(3):577–582. PubMed CrossRef
Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. 2022;79(7):736–738. PubMed CrossRef
Javorcikova Z, Dangoisse M, Nikis S, et al. The place of S-ketamine in fibromyalgia treatment (ESKEFIB): study protocol for a prospective, single-center, double-blind, randomized, parallel-group, dose-escalation controlled trial. Trials. 2021;22(1):853. PubMed CrossRef
Pastrak M, Abd-Elsayed A, Ma F, et al. Systematic review of the use of intravenous ketamine for fibromyalgia. Ochsner J. 2021;21(4):387–394. PubMed CrossRef
Drevets WC, Popova V, Daly EJ, et al. Comments to Drs. Bahji, Vazquez, and Zarate. J Affect Disord. 2021;283:262–264. PubMed CrossRef
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. PubMed CrossRef
Correia-Melo FS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527–534. PubMed CrossRef
Frye MA, Blier P, Tye SJ. Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. J Clin Psychopharmacol. 2015;35(3):334–336. PubMed CrossRef
Price RB, Kissel N, Baumeister A, et al. International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators [published online ahead of print September 7, 2022]. Mol Psychiatry. 2022. PubMed CrossRef
Singh B, Vande Voort JL, Kung S. Ketamine for treatment-resistant bipolar depression-need for more data! Bipolar Disord. 2021;23(7):728–729. PubMed CrossRef