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Ketamine Infusion for Treatment Resistant Depression and Suicidal Ideation

18 Mar 2019 1:40 PM | Deleted user

Author:  Cecylee Lewis, PharmD Candidate 2019
University of Missouri – Kansas City School of Pharmacy at MU

Mentor: Austin Campbell, PharmD, BCPP
University of Missouri Hospital/Missouri Psychiatric Center


Mental illness is both prevalent and debilitating among adolescents and adults in the United States. Suicidal ideation has been increasing in recent years and with more attention in the social media spotlight1,2. In 2016, suicide was the 10th leading cause of death in the United States, consisting of 44,965 deaths or 1.6% of deaths overall3. Depression is the leading cause of disability in the United States affecting 6.7% of the population which is roughly 16.1 million adults aged 18 years or older4. Treatments for depression and suicidal ideation have evolved over the years and include psychotherapy and various medications. However, a major limitation of these treatment options is a delayed onset of action. New and novel medications have been a major topic of interest in mental health and should be investigated to provide alternative options for those who have failed standard therapy. Over the past decade, ketamine has been increasingly discussed as a useful tool in the management of treatment resistant depression (TRD) and eminent suicidal ideation (SI), and upon recent revelations esketamine seems to provide clinical benefit.

What is Ketamine?

Ketamine is a noncompetitive, glutamate N-methyl-D-aspartate (NMDA) receptor antagonist approved for general anesthesia, typically given intravenously. It has been known for its hallucinogenic and dissociative effects, which have resulted in misuse and potential abuse as a street drug. However, ketamine is a promising prospect in treatment resistant major depression and suicidal ideation5. When used for these disorders, the onset of action for ketamine is very rapid (within hours) as compared to the standard therapies which can take weeks to months to reach full effect. Currently ketamine is not FDA approved for depression or suicidal ideation, but has been used off-label in various clinical trials and inpatient settings6. Ketamine infusions are being used nationally and more recently here in Missouri at Missouri Psychiatric Center (MUPC) since November 2018, with very positive results.

Dosing?

Typical dosing for anesthesia ranges from 0.5-2mg/kg, but according to the manufacturer’s labeling, can have a max dose of 4.5mg/kg7. The most common dosing of intravenous ketamine for TRD and SI is 0.5mg/kg over 40 minutes. This dosing has been established through numerous trials which have determined it to be the optimal dose for response while minimizing potential side effects. Vidal et al8 conducted a recent study at Geneva University Hospitals with a new rapid intravenous ketamine injection of 0.5mg/kg over 1 minute. The adverse events were similar in nature to the 40 minute infusion, suggesting that this approach could be just as safe and with comparable efficacy. Although no long-term dosing regimen has been established, the amount of infusions needed for remission remains undetermined. Some studies have suggested that two infusions per week for up to six weeks have positive results5,9. Continuation or addition of antidepressants have not been well studied or established to maintain remission in patients treated with ketamine. This gray area of whether to add or keep antidepressant medications is up to the provider of whom is conducting the treatment.

What’s Next?

A recent breakthrough treatment that has been backed through the FDA advisory board is esketamine. It was voted through by a wide margin; 14 yes votes, 2 no, and 1 abstention10. This backing happened on February 12th, 2019 after a new drug application (NDA) was submitted by Janssen in September 2018. It is an intranasal inhalation of esketamine (Spravato), the S enantiomer and more potent form of ketamine, which is patient administered under medical supervision. Proposed adult dose of esketamine is 28-56mg with each administration and can be titrated to 84mg by week two10. Most common side effects included increased blood pressure, dizziness, and dissociation within the first two hours of administration. As of March 5th, 2019, Spavato (esketamine), in conjunction with an oral antidepressant, has been approved for treatment resistant depression. The FDA states that is must be administered in a certified doctor’s or clinical office and will include a REMS program for safe use11.

References:

  1. Campo-Flores A. Another Live-Streamed Suicide Puts Spotlight on Social Media Ethics. The Wall Street Journal. https://www.wsj.com/articles/another-live-streamed-suicide-puts-spotlight-on-social-media-ethics-1485388656. Published January 25th, 2017.
  2. Kelly L. Teen suicide rate suddenly rises with heavy use of smartphones, social media. The Washington Times. https://www.washingtontimes.com/news/2017/nov/14/teen-suicides-rise-with-smartphone-social-media-us/. Published November 14, 2017.
  3. Xu JQ, Murphy SL, Kochanek KD, Bastian B, Arias E. Deaths: Final data for 2016. National Vital Statistics Reports; vol 67 no 5. Hyattsville, MD: National Center for Health Statistics. 2018
  4. Facts & Statistics. Anxiety and Depression Association of America, ADAA. https://adaa.org/about-adaa/press-room/facts-statistics.
  5. Sanacora G, Frye MA, McDonald W, et al for the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments. JAMA Psychiatry 2017; 74(4): 399-405.
  6. Fond G, Laundou A, Rabu C, et al. Ketamine administration in depressive disorders: a systemic review and meta-analysis. Psychopharmacology 2014;231:3663-76.
  7. DailyMed - KETAMINE HYDROCHLORIDE- ketamine hydrochloride injection. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=58487c78-a641-4278-acc0-343596ee8683. Revised January 30th, 2019.
  8. Vidal S, Gex-Fabry M, Bancila V, et al. Efficacy and Safety of a Rapid Intravenous Injection of Ketamine 0.5 mg/kg in Treatment-Resistant Major Depression. J Clin Psychopharmacol 2018;38: 590–597
  9. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816-826.
  10. George J. FDA panel endorses esketamine for depression – Fast-acting nasal spray wins overwhelming support. MedPageToday. Published February 12th, 2019.
  11. U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. FDA.org. Published March 5th, 2019. 

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