By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a nasal spray for treatment-resistant depression (TRD). Esketamine is the S-enantiomer of racemic ketamine, which has been approved for parenteral use as induction and maintenance of general anesthesia since 1970. Parenteral ketamine also has been used off-label to treat severe depression. Esketamine nasal spray was granted breakthrough therapy and fast-track designations. It will be available as Spravato under a Risk Evaluation and Mitigation Strategy.

INDICATIONS

Esketamine, in conjunction with an oral antidepressant, is indicated for the amelioration of TRD in adults.1

DOSAGE

The recommended dose for the induction phase is 56 mg (one spray in each nostril) on day 1.1 From week 1 to week 4, the dose is given twice per week (56 mg or 84 mg). For the maintenance phase (weeks 5-8), the dose is administered once weekly. For week 9 and beyond, the administration is every two weeks or once weekly. Dosage adjustment should be made based on efficacy and tolerability. Therapeutic benefits should be evaluated at the end of the induction phase to determine if treatment should continue. The dose should be administered under supervision of a healthcare provider in a certified healthcare setting. Blood pressure should be assessed before and after administration. The patient should be monitored for at least two hours after the self-administered dose and should be discharged only if he or she is clinically stable. Esketamine is available as a 56 mg dose kit that contains two 28 mg nasal spray devices and as an 84 mg dose kit that contains three 28 mg nasal spray devices.

POTENTIAL ADVANTAGES

Esketamine provides a new treatment option with a rapid onset of action for patients with TRD.

POTENTIAL DISADVANTAGES

Esketamine increases blood pressure and impairs attention, judgment, thinking, reaction speed, and motor skills.1 The most common adverse reactions are dissociation, dizziness, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, and feeling drunk. Approximately 8-17% of those who use the nasal spray (vs. 1-3% who took placebo) showed an increase in systolic blood pressure of 40 mmHg and/or an increase in diastolic blood pressure of 25 mmHg within the first 1.5 hours after administration at least once during the first four weeks of treatment. Patients with hypertension or pre-existing aneurysmal vascular disorders may be at a higher risk for adverse cardiovascular or cerebrovascular effects.

Between 61% and 75% of treated patients developed dissociation or perceptual changes, derealization, and depersonalization. Esketamine may cause fetal harm.1 Pregnancy planning and prevention should be considered in women of reproductive age. Patients should not drive until the next day after administration and after a restful sleep.1 Long-term safety (e.g., psychotomimetic and dissociation reactions) and effectiveness have not been established. Esketamine may be abused or diverted and has been used recreationally. It is a Schedule III controlled substance.

COMMENTS

Esketamine is an N-methyl-D-aspartate (NMDA) receptor blocker, although it is unclear if this is the primary mechanism of action.2 The efficacy was evaluated in three short-term studies and one long-term trial.3 Only one of the short-term studies met the criteria for effectiveness.1,3,4 Participants reported TRD and had not responded adequately to at least two different antidepressants with adequate dose and duration.1 Subjects discontinued prior therapy and were randomized to twice-weekly doses of intranasal esketamine (56 mg or 84 mg; n = 114) or intranasal placebo (n = 109). All subjects were started on a new oral antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine) at the judgment of the investigators. The primary efficacy endpoint was change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at the end of the four-week, double-blind induction phase. MADRS is a 10-item, clinician-rated scale that ranges from 0 to 60.

Esketamine produced a mean difference of -4 over placebo (53% reduction vs. 42.3% from baseline scores of 37 and 37.3, respectively). Benefit was observed at 24 hours and maintained to day 28. At day 28, 67% of subjects received 84 mg twice daily. In the longer-term study, subjects who were in stable remission or stable responders were treated for 16 weeks with esketamine and an oral antidepressant.1,5 Then, they were randomized to continue esketamine or intranasal placebo. The primary endpoint was time to relapse (defined as MADRS total score of 22 for two consecutive weeks), hospitalization for worsening depression, or other clinical indications of relapse. Subjects in the stable remission and stable responders groups showed significant delay in time to relapse compared to subjects taking placebo. IV ketamine (0.5 mg/kg) was compared to midazolam (0.02 mg/kg) in patients with major depression and a score 4 on the Scale for Suicidal Ideation (SSI).6 A reduction of SSI score was 4.96 greater after ketamine than with midazolam at day 1. Fifty-five percent were responders ( 50% reduction in SSI) compared to 30% for midazolam.

CLINICAL IMPLICATIONS

The generally accepted definition for TRD is a minimum of two prior treatment failures and confirmation of prior adequate dose and duration.7 Pharmacologic options for TRD have included augmentation, combination, and switching to another antidepressant.8 Esketamine is a rapid-acting antidepressant with possible antisuicidal effect. However, long-term effectiveness and safety, including abuse and misuse potential, remains to be established. The cost will be between $590 and $885 per treatment session, with the initial month of therapy costing between $4,700 and $6,785. Subsequent weeks will cost about half as much (not including physician and office fees).

REFERENCES

  1. Janssen Pharmaceuticals, Inc. Spravato Prescribing Information, March 2019. Available at: https://bit.ly/2Yo7fFA. Accessed March 25, 2019.
  2. Molero P, Ramos-Quiroga JA, Martin-Santos R, et al. Antidepressant efficacy and tolerability of ketamine and esketamine: A critical review. CNS Drugs 2018;32:411-420.
  3. U.S. Food & Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic, March 5, 2019. Available at: https://bit.ly/2EGkhF0. Accessed March 25, 2019.
  4. ClinicalTrials.gov. A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression. Available at: https://bit.ly/2CECP8K. Accessed March 25, 2019.
  5. ClinicalTrials.gov. A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression (SUSTAIN-1). Available at: https://bit.ly/2YmVdvP. Accessed March 25, 2019.
  6. 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;175:327-335.
  7. Gaynes BN, Asher G, Gartlehner G, et al. Definition of treatment-resistant depression in the Medicare population. Agency for Healthcare Research and Quality Technology Assessments. Available at: https://go.cms.gov/2FpvIS4. Accessed March 25, 2019.
  8. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am 2007;30:13-29.