Use of Ketamine and Esketamine in the Management of Treatment-resistant Depression

Educational Objectives

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

1. Explain the neurotrophic hypothesis of depression.

2. Sketch the mechanism of action of ketamine and related agents.

3. Summarize the findings of randomized trials that established the efficacy of ketamine and esketamine for treatment of depression.

Summary

Overview: early studies on ketamine (racemic mixture) gave rise to development of enantiomer S-ketamine (esketamine); worldwide, depression associated with more years lived with disability than any other medical, psychiatric, or substance use disorder; depression can be recurrent, chronic, and disabling; current treatments cannot cure depression, and some patients do not respond to traditional treatments; depression is considered treatment resistant if patient does not respond to 2 adequate trials of medication

Findings from STAR*D trial: study of >3000 patients suggested that one-third achieve remission when treated with first-line selective serotonin reuptake inhibitor; study also evaluated switching and augmentation with several different drugs; no clearly superior treatment option emerged (rates of remission similar among options at each step); however, remission less likely in patients who did not respond to first 2 treatments

Mechanism of action: most conventional antidepressants increase synaptic levels of monoamines such as norepinephrine and serotonin, typically by blocking reuptake; some drugs bind to post- or presynaptic G protein-coupled receptors (GPCRs); ketamine is modulator of glutamate

Neurotrophic hypothesis of depression: postulates that chronic stress leads to behavioral changes that resemble depression or anxiety; hippocampus or cortex may show retraction or shrinkage of synapses and dendritic arborization; cellular atrophy from chronic stress and accompanying behavioral changes may be reversed with fluoxetine or imipramine; however, reversal takes time; changes seen in cell surface receptors that interact with monoamines, brain-derived neurotrophic factor (BDNF), inflammatory mediators (eg, cytokines), stress hormones, and glucocorticoids; long-term treatment with antidepressants increases serotonin levels in synapse and favors protrophic, BDNF-dependent pathways

New targets: include glutamate, γ-aminobutyric acid (GABA), inflammatory factors, and opioid system; glutamate may bind to N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors; these fast-acting ion channels excite cells and trigger BDNF-dependent protrophic processes

Animal study of ketamine (Duman et al): in animals subjected to chronic stress, low-dose ketamine rapidly reversed depression; study demonstrated increased prosynaptic proteins and increased number and function of spine synapses 24 hr after dose; weeks of treatment with, eg, imipramine required to produce same effect

Glutamate system and ketamine: complex but offers new target for treatment; some glutamate receptors are ionotropic (eg, NMDA receptors); primary pharmacologic action of ketamine is high-affinity blockage of NMDA receptor; drug interrupts cortical signaling, causing amnestic, anesthetic, and dissociated state; fast transmission via AMPA receptors is involved in learning and memory and triggers protrophic pathways that may mitigate effects of chronic stress; other glutamate receptors include metabotropic GPCRs that produce longer-term, more subtle effects on intracellular machinery

Clinical studies: when Newport et al (2015) published review on ketamine and depression, intravenous (IV) ketamine already being used off label for refractory depression; seminal article by Zarate et al reported that giving single low-dose IV infusion to patients with refractory depression yielded peak affect 1 to 3 days after administration (however, patients returned to baseline state ≤7 days); Charney and Manji (2004) found that stress is linked to depression and that cellular changes could be reversed by antidepressants; Murrough et al (2013) studied treatment-resistant depression (TRD); patients were currently not being treated or underwent washout of previous antidepressant, then randomized to IV ketamine or midazolam (Versed); ketamine exhibited rapid effect similar to that in previous studies; 2010 open-label study of repeated dosing (3 times per week for 2 wk) found that if patients improved, the improvements were long-lasting; larger replication study determined that response or nonresponse usually evident ≤4 hr of single dose; most patients relapsed ≤3 mo, but others continued to do well; study of intranasal administration (50 mg, single dose) found it to be effective; another study demonstrated more rapid antisuicidal effects than midazolam; Fava et al (2018) explored dose in 100 patients with unipolar TRD; 25% of usual anesthetic dose found optimal

Esketamine: both 56 mg and 84 mg doses of intranasal esketamine found superior to placebo; study in acutely suicidal inpatients showed esketamine rapidly superior to placebo, although it did not modify long-term suicidal ideation;

Approval: 3 trials submitted to Food and Drug Administration for approval; 2 trials considered negative, but third study in adults with TRD that permitted flexible dosing found esketamine superior to placebo; FDA decided to also consider relapse-prevention study, which found that among patients treated with traditional antidepressants plus esketamine, risk for relapse higher in patients taken off esketamine; this led to drug’s approval

Administration of esketamine: during induction phase, patients treated twice weekly for 1 to 4 wk; in maintenance phase, given weekly, then every other week, and finally as infrequently as required to maintain response; initial dose 56 mg (may be increased to 84 mg); enrollment in Risk Evaluation and Mitigation Strategies program required; drug self-administered in outpatient clinic; one spray placed in each nostril, 5 min apart; physician and crash cart must be on site; vital signs must be followed; ketamine sympathomimetic and increases blood pressure; drug contraindicated in, eg, patient with history of aneurysm; IV ketamine also still used, sometimes because of cost considerations

Future consideration: ongoing ELEKT-D study is evaluating patients with unipolar TRD referred for electroconvulsive therapy (ECT); patients randomized to ECT or IV ketamine; positive allosteric modulator of GABA receptor recently tested in adults with major depressive disorder; modulators of glutamate and GABA may be important in future; metabolites of ketamine (eg, hydroxynorketamine) may affect opioid system; failed trials of other compounds that interact with NMDA receptor suggest that other targets may be important

Readings

Aleksandrova LR et al: Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci 2017 Jun;42(4):222-229; Bozymski KM et al: Esketamine: a novel option for treatment-resistant depression. Ann Pharmacother 2019 Dec 4:1060028019892644 [Epub ahead of print]; Daly EJ et al: Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2019 Jun 5 [Epub ahead of print]; Murrough JW et al: Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013 Aug 15;74(4):250-6; Spalding KL et al: Dynamics of hippocampal neurogenesis in adult humans. Cell 2013 Jun 6;153(6):1219-1227.

Disclosures

For this program, the following has been disclosed: Dr. Murrough is a consultant for Allergan, Boehringer Ingelheim GmbH, Global Medical Education, Otsuka, and Sage Therapeutics. For this program, the planning committee reported nothing to disclose. Dr. Murrough presents information in his lecture related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Murrough was recorded at the 18th Annual Psychopharmacology Update, jointly presented by the University of Cincinnati and the Global Academy for Medical Education and held October 25-26, 2019, in Cincinnati, OH. For information on the 19th Annual Psychopharmacology Update, scheduled for October 24, 2020, in Cincinnati, OH, please go to globalacademycme.com. The Audio Digest Foundation thanks the speakers and the sponsors 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 0 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 0 CE contact hours.

Lecture ID:

PS490701

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.