2. Objectives
• Identify the issue of Major Depressive Disorder.
• Discuss the two types of psychedelics:
• Ketamine and Exketamine
• Psilocybin
• Review their history and mechanism of action, side effect and
cost
• Reflect on possible future psychedelics drugs to treat
depression
9. Ketamine Discovery
In 1962, the team of
Professor Calvin Lee
Stevens, Ph.D., Professor of
Organic Chemistry at Wayne
State University in Detroit,
Michigan found a molecule
“Ketamine” a phencyclidine
(PCP) derivatives to be use
for anesthetic in humans. It
was originally used in
battlefield. FDA approved in
1970
Dorandeu, F. (2013).
10. Ketamine for Depression
• In the 1990s Dr.
Krystal and his
colleagues, at the Yale
School of Medicine
lead the research of
ketamine as an
antidepressant.
CHEN, J., (2019).
13. Ketamine Adverse Effects
Common
• BP changes
• blurred vision
• dizziness, drowsiness
• nausea, vomiting
• loss of appetite
• sleep problems
Severe
• severe confusion
• hallucinations
• unusual thoughts
• extreme fear
Stahl, S. M. (2008).
17. Ketamine specific for Depression
• FDA Approved: March 5, 2019
• Brand name: Spravato
• Generic name: esketamine
• Dosage form: Nasal Spray
• Company: Janssen Pharmaceuticals, Inc.
• Treatment for: Depression, Major Depressive
Disorder
18. Esketamine is not the same as
Ketamine
Esketamine
• Nasal spray
• Adjunct to oral
antidepressant
• Not use as anesthetic
• Not use in children
• Not use in pregnancy
Ketamine
• IV, MI, oral
• Monotherapy or adjunct
therapy
• Use for anesthetic
• Not use in children
• Not use in pregnancy
https://www.spravato.com
19. Esketamine Mechanism of
Action
• Esketamine, the S-enantiomer of racemic ketamine,
is a non-selective, noncompetitive antagonist of the
N-methyl-D-aspartate (NMDA) receptor, an
ionotropic glutamate receptor.
• The mechanism by which esketamine exerts its
antidepressant effect is still unknown
https://www.spravato.com/
20. Dosage Forms & Strengths
Schedule III
Induction phase
• Weeks 1-4
• Administer twice per week
• Day 1 starting dose: 56 mg
Subsequent doses: 56 mg or 84 mg
Maintenance phase
• Weeks 5-8
• Administer once weekly
• 56 mg or 84 mg
Week 9 and after
• Administer every 2 weeks or once
weekly at 56 mg or 84 mg
• Individualize dosing frequency is
matched to the least frequent dosing
to maintain remission/response
21. Who qualify for Spravato
• In the Spravato clinical trials, treatment-resistant depression was
defined as adults who are currently struggling with major depressive
disorder and have not responded adequately to at least two different
antidepressants of adequate dose and duration in the current episode.
• The provider enroll the patient in the SPRAVATO Risk Evaluation
Mitigation Strategy (REMS) Program.
• Referral to Spravato center
https://www.spravato.com/
22. Most common side effects of
SPRAVATO
Dissociation 41%
Dizziness 29%
Nausea 28%
Sedation 23%
Spinning sensation 23%
Reduced sense of touch
and sensation 18%
Anxiety 13%
Lack of energy 11%
HTN 10%
Emesis 9%
Feeling drunk 5%
https://www.spravato.com/
Side effects occur after taking Spravato and subside same day.
23. The Cost
• Cost of each treatment with esketamine will range
from $590 to $885, depending on the dose.
• No insurance coverage including Medicare or
Medicaid.
• Janssen CarePath
25. Discovery of Psilocybin
• Psilocybin was first isolated
by Albert Hofmann a
chemist from Switzerland in
1957 from the Central
American mushroom
Psilocybe Mexicana.
• He was also the founder of
lysergic acid diethylamide
LSD
26. 1992- NIDA and FDA
approved research of psychedelic agents.
28. QIDS depression scores were significantly reduced from baseline to 1 week and 3
months post-treatment, with the maximum effect at 2 weeks
Carhart-Harris RL, et al (2016)
36. In August 2018 The US Food and
Drug Administration (FDA) has
granted Breakthrough Therapy
designation to psilocybin-assisted
therapy from Compass Pathways for
patients with treatment-resistant
depression (TRD)
38. Decriminalize
Psilocybin
• Denver, Colorado vote pass
in May 2019
• Oakland, California, on June
4, 2019
• Oregon will present the
vote in 2020
• Lawmaker in Iowa
introduced similar measures
in February 2019
39.
40. References
Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D,
Pilling S, Curran VH, Nutt DJ (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label
feasibility study.. Lancet Psychiatry., 3(7):619-27.
Charles R., (2016). Mental Disorders Top The List Of The Most Costly Conditions In The United States: $201 Billion. Health Affairs.
Retrieve from: https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2015.1659#EX
Chen, J., (2019). How New Ketamine Drug Helps with Depression. Retrieved from: https://www.yalemedicine.org/stories/ketamine-
depression/
Daniel, J., Haberman, M. (2017). Clinical potential of psilocybin as a treatment for mental health conditions. The Mental Health Clinician,
7(1), 24–28.
Dorandeu F. (2013). Happy 50th anniversary ketamine. CNS neuroscience & therapeutics, 19(6), 369.
41. References
Duman, R.S., Aghajanian, G.K., Sanacora G., Krystal J.H. (2016). Synaptic plasticity and depression: new insights from stress and rapid-
acting antidepressants. Nature medicine, 22(3), 238–249.
Hedin, M., (2018). Hopkins researchers recommend reclassifying psilocybin, the drug in 'magic' mushrooms, from schedule I to schedule
IV. https://hub.jhu.edu/2018/09/26/psilocybin-scheduling-magic-mushrooms/
Kennedy, M., (2019). Oakland City Council Effectively Decriminalizes Psychedelic Mushrooms. National Public Radio. Retrieved from:
https://www.npr.org/2019/06/05/730061916/oakland-city-council-effectively-decriminalizes-psychedelic-mushrooms
Moda-Sava, R.N., Murdock, M.H., Parekh, P.K., Fetcho, R.N., Huang, B.S., Huynh, T.N., Witztum, J., Shaver, D.C., Rosentha,l D.L.,
Always, E.J., Lopez, K., Meng, Y., Nellissen, L., Grosenick, L., Milner, T.A., Deisseroth, K., Bito, H., Kasai, H., Liston, C.,
(2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science, 12, 364 (6436).
Psychedelic Research Timeline. Retrieved from: https://beckleyfoundation.org
42. References
Petri, G., Expert P., Turkheimer, F., Carhart-Harris, R., Nutt D., Hellyer, P. J., Vaccarino, F., (2014). Homological
scaffolds of brain functional networks. Journal of The Royal Society; Interface, 11, 101.
Stahl S.M., (2013). Stahl’s Essential Psychopharmacology (4th ed). New York, NY: Cambridge University Press. Retrieve from:
https://stahlonline.cambridge.org/essential_4th
Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved from
https://stahlonline.cambridge.org/prescribers_guide.jsf
Editor's Notes
Ketamine has a different mechanism of action and may provide relief and improve symptoms in severe cases and where other treatments have failed. Research shows that it can be beneficial in many different patients: