Ketamine and Esketamine in the Management of Treatment-Resistant Depression

Educational Objectives

The goal of this program is to improve management of treatment-resistant depression. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the mechanism of antidepressant effect for ketamine.
2. Evaluate the efficacy of intravenous ketamine in the management of treatment-resistant depression.
3. Prescribe appropriate dosing for ketamine and intranasal esketamine for patients with treatment-resistant depression.

Summary

Introduction: ketamine, a synthetic derivative of phencyclidine (PCP), is a dissociative anesthetic that does not cause significant respiratory depression; although it is an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine is best described as having glutamate-modulating effects; esketamine (the S enantiomer) has 2- to 3-fold greater affinity for the NMDA receptor; off-target effects — include opioidergic effects; a study showed that pretreatment with naltrexone completely eliminates the antidepressant response to ketamine; ketamine also has dopamine agonist and anticholinergic effects

Toxicity: ketamine overdose may lead to excessive dissociation, psychosis, and sympathomimetic effects (eg, hypertension, tachycardia, risk for urinary cystitis) but is rarely lethal

Effects of ketamine: NMDA antagonism of ketamine results in a glutamate surge; preferential activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor leads to a rapid increase in intracellular sodium and activation of a complex downstream cascade of signaling events (eg, mammalian target of rapamycin, release of brain-derived neurotrophic factor); these events cause significant changes in electrophysiologic and morphologic properties of synapses; psychiatric drugs (eg, ketamine) should be considered circuit-level modulators; areas implicated in ketamine response (decrease in synaptic connectivity) include the prefrontal cortex, caudate, anterior cingulate cortex, and amygdala

Antidepressant effects: patients who received ketamine for other indications reported improved mood; in a study, ketamine was shown to have a rapid-acting antidepressant effect (separating from placebo at 240 min) that was sustained for 72 hr; adverse effects (eg, hallucinations, delusional thinking, paranoia) spike during infusion but subside by ≈120 min after infusion and are temporally dissociated from antidepressant response; Zarate et al (2006) — randomized patients with treatment-resistant depression (TRD) to ketamine or inert placebo; clear separation in the Hamilton Depression Rating Scale score occurred 110 min after infusion and persisted for ≈7 days; little placebo response was observed

Bipolar disorder: in a crossover study (Diazgranados et al [2010]), patients with bipolar depression on therapeutic doses of mood stabilizers were randomized to ketamine or placebo; antidepressant effects of ketamine remained statistically significant through day 3; little placebo effect was noted

Two-site randomized trial: Murrough et al (2013) randomized patients with TRD to ketamine or midazolam in a 2:1 ratio; the scores separated at day 1 (significantly higher rate of response to ketamine); antidepressant response to ketamine persisted through day 7

Dose-finding trial: 0.5 mg/kg over 40 min is the standard dose for a single infusion of ketamine; in a multisite dose-ranging study, Fava et al (2020) randomized patients with TRD to 4 different doses of ketamine (0.1, 0.2, 0.5, and 1.0 mg/kg) or midazolam; a rapid-acting depression rating scale score was used; the clear separation at day 1 for ketamine was sustained throughout the 3-day trial; the 2 higher doses of ketamine were effective and the 2 lower doses were not; risk for significant adverse effects increases with higher doses

Antisuicidal effects: Grunebaum et al (2018) randomized patients with major depression and Scale for Suicidal Ideation (SSI) scores >4 to ketamine or midazolam; rapid-acting antisuicidal effect that was sustained for 6 wk was observed for ketamine; nonresponders on midazolam received open-label ketamine and also showed improvement in SSI scores; in an analogous study (Grunebaum et al [2017]), patients with bipolar depression showed improvement on SSI after ketamine infusion

Dose-frequency trials: in a study, patients with TRD received repeated infusions (6) over 2 wk and were followed for 90 days after the third infusion; based on response at 24 hr, patients were stratified into responders and nonresponders; ≈33% of patients did not relapse during the follow-up period; Phillips et al (2019) — randomized patients with TRD to a single infusion of ketamine or midazolam (crossover, phase 1), after which they received ketamine infusions 3 times/wk for 2 wk; in the maintenance phase, they received 4 once-weekly infusions; responders to a single infusion of ketamine continued to improve with repeated infusions, reaching 50% response after infusion 3; weekly maintenance infusions in ketamine responders prevented relapse; Jannsen study — showed no statistical difference between dosing 2 times vs 3 times per week

Automated self-association training (ASAT): Price et al (2022) randomized patients to 3 arms, ie, a single infusion of ketamine plus active ASAT (“Pavlovian conditioning to promote positive self-associations and self-worth”), ketamine plus sham ASAT, or saline plus active ASAT; brief ASAT sessions (2 times daily for 4 days, started 1 day after infusion) consisted of presenting supraliminal and subliminal stimuli to reinforce association of attractive images with positive self-reinforcement; saline plus active ASAT showed some benefit; ketamine plus active ASAT was associated with significantly better maintenance of antidepressant response (to ≈30 days), compared with ketamine plus sham ASAT

Intranasal esketamine (INEK; Spravato): the high (84-mg) dose of esketamine has some tolerability issues; in a double-blind study, patients with demonstrated resistance to multiple antidepressants were randomized to esketamine or placebo; the esketamine group demonstrated antidepressant effect that separated from placebo; 77% of patients on esketamine reported improvement in suicidal ideation, compared with 50% on placebo; in multiple adjunctive studies, significant placebo responses were observed; predictors of response to esketamine include significant disability and high number of drug trials

Intravenous (IV) ketamine vs INEK: individual studies show antidepressant efficacy for both routes; a meta-analysis suggests better response and remission rates (and fewer adverse effects) with IV ketamine

Treatment algorithm: INEK may be the next step after multiple antidepressant augmentation trials, including evidence-based psychotherapies; although electroconvulsive therapy (ECT) is the gold standard for TRD, INEK may be suggested before ECT; IV ketamine may be tried before ECT (off-label use; costly); nonresponders to IV ketamine may not respond to INEK and vice versa

Indications: major depressive disorder (MDD), defined by at least 2 failed antidepressant trials in the current episode, is the primary indication; INEK is not approved for bipolar disorder and ketamine may be destabilizing in those with rapid cycling (use would require a concurrent mood stabilizer); patients with psychotic spectrum disorders are not candidates for ketamine; ketamine may be considered on a case-by-case basis in patients with a substance use disorder; patients on opiate maintenance are not treated with ketamine or INEK; substance-naive patients and those with dissociative disorders may find ketamine unpleasant or triggering; women with reproductive potential need a negative pregnancy test prior to each administration

Ketamine infusion: no oral intake for ≥4 hr; no alcohol, benzodiazepines, or opiates for ≥8 hr; evaluation before infusion is necessary to demonstrate improvement; patients are evaluated after infusion; adverse effects — commonly include sympathomimetic, dissociative, and psychomimetic effects; frank paranoia is rare; dysphoria during infusion does not predict a poor outcome; common neurologic side effects include sedation, dysgeusia, perioral numbness, dizziness, vertigo, and nausea and vomiting (frequent with INEK); rare effects include fainting, arrhythmia, asystole, and malignant hyperthermia

Repeated infusions: may result in interstitial cystitis, hepatobiliary effects, and risk for substance abuse; antidepressant tolerance has not been reported

Management of adverse effects: stop the infusion and allow slow recovery; adjunctive medications may be administered

Postinfusion restrictions: patients are advised to refrain from operating heavy machinery and consuming alcohol or drugs that were not prescribed

INEK administration: office based; approved by the Food and Drug Administration (FDA) for MDD and MDD with acute suicidal ideation or behavior; the Risk Evaluation and Mitigation Strategy (REMS) for INEK involves registration of site, pharmacy, and the patient; the devices must be provided to the patient in a supervised setting (not at home); blood pressure, sedation, and dissociation should be monitored at baseline and at 40 min and ≥2 hr after administration

Induction phase: twice-weekly dosing for wk 1 through 4; the first dose is FDA-mandated at 56 mg; subsequent doses can be increased (usually for the fourth dose)

Maintenance phase: once-weekly dosing for wk 5 through 8 (56 or 84 mg); patients may receive a weekly maintenance dose indefinitely; not recommended for nonresponders (ie, <50% improvement) after wk 4

REMS requirements: include clinical information, preexisting medical conditions, current medications, patient consent, date and dose of administration, duration of stay, and adverse effects (sedation and dissociation)

Questions and Answers

Duration of maintenance INEK: longer-term maintenance may be considered; if patients relapse after cessation, they may be restarted on an index series; should be discussed with patients on a case-by-case basis

Testing positive for PCP in drug panels: ketamine metabolites may be sufficiently different from PCP to prevent cross-reactivity

Oral antidepressant use during treatment: patients are generally advised to remain on their current treatment regimen; dose adjustments may be made

Personality disorders plus depression: borderline personality disorder (BPD) tends to interfere with the overall effectiveness; data for other disorders are inadequate; patients who have a primary major mood disorder in addition to BPD may improve with ketamine or ECT

Naltrexone and antidepressant efficacy: in a study, no reduction in antidepressant efficacy of ketamine was observed in patients on naltrexone; patients on naltrexone may be treated, depending on response

Insurance approval for INEK: insurance companies strictly adhere to FDA guidelines; INEK is approved as an adjunctive treatment; discontinuation of oral antidepressants during INEK therapy is not recommended

Readings

Alario AA, Niciu MJ. (Es)Ketamine for suicidal ideation and behavior: clinical efficacy. Chronic Stress (Thousand Oaks). 2022;6:24705470221128016. doi:10.1177/24705470221128017; Bozymski KM, Crouse EL, Titus-Lay EN, et al. Esketamine: a novel option for treatment-resistant depression. Ann Pharmacother. 2020;54(6):567-576. doi:10.1177/1060028019892644; 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. doi:10.1001/archgenpsychiatry.2010.90; Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25(7):1592-1603. doi:10.1038/s41380-018-0256-5; Grunebaum MF, Ellis SP, Keilp JG, et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar Disord. 2017;19(3):176-183. doi:10.1111/bdi.12487; Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175(4):327-335. doi:10.1176/appi.ajp.2017.17060647; Jelen LA, Stone JM. Ketamine for depression. Int Rev Psychiatry. 2021;33(3):207-228. doi:10.1080/09540261.2020.1854194; Jesus-Nunes AP, Leal GC, Correia-Melo FS, et al. Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression. Hum Psychopharmacol. 2022;37(4):e2836. doi:10.1002/hup.2836; 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(10):1134-1142. doi:10.1176/appi.ajp.2013.13030392; Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256. doi:10.1016/j.biopsych.2012.06.022; 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. doi:10.1176/appi.ajp.2018.18070834; Price RB, Spotts C, Panny B, et al. A novel, brief, fully automated intervention to extend the antidepressant effect of a single ketamine infusion: a randomized clinical trial. Am J Psychiatry. 2022;179(12):959-968. doi:10.1176/appi.ajp.20220216; Tashakkori M, Ford A, Dragovic M, et al. The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis. Australas Psychiatry. 2021;29(1):80-87. doi:10.1177/1039856220961642; Zarate CA, 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. doi:10.1001/archpsyc.63.8.856.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Niciu is a principal investigator for Johnson & Johnson/Janssen. Members of the planning committee reported nothing relevant to disclose. Dr. Niciu's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Niciu was recorded at the 2022 Iowa Psychiatric Physicians Society Post Graduate Fall Symposium, held on October 7, 2022, in Coralville, IA, and presented by the Iowa Psychiatric Physicians Society. For information about upcoming CME activities from this presenter, please visit Iowa.psychiatry.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

PS520501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.