Newer pharmacotherapies such as ketamine, esketamine, and psilocybin show promise for treating major depressive disorder. Ketamine and esketamine work through NMDA receptor antagonism to rapidly reduce depressive symptoms, while psilocybin's mechanism is unknown. Side effects are usually mild and transient. Psilocybin and ketamine research demonstrate their potential as fast-acting antidepressants, but regulatory approval and coverage can limit patient access. Continued research aims to develop additional options for treatment-resistant depression.

1. Newer Pharmacotherapies for
Major Depressive Disorder
PMH 682 Psychopharmacology
Dr. Hamilton and Mr. Kyle Phillips

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

3. Ten medical conditions with the highest
estimated spending in 2013
© 2016 by Project HOPE – The People-to-People Health Foundation, Inc.
https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2015.1659#EX

4. Personal health spending by diagnostic category and
medical condition, selected years 1996–2013
Medical Condition 1996 2003 2013 Annual
growth
Heart conditions $105 $128 $147 2%
Mental Disorder $79 $123 $201 6%
Anxiety and depression $29 $56 $87 7%
https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2015.1659#EX
© 2016 by Project HOPE – The People-to-People Health Foundation, Inc.

5. Major Depressive Disorder

6. Stahl's Essential Psychopharmacology. Retrieved from: https://stahlonline.cambridge.org

7. New psychopharmacologies

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).

11. Ketamine may treat
• Depression, Anxiety, Bipolar Disorder
• Chronic Headaches, Migraines
• Chronic Pain, Cancer Pain
• PTSD
• Fibromyalgia
• Neuropathy

12. Duman, R. S., et al (2016)

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).

14. Ketamine
Promotes
Neuroplasticity
Ketamine triggers
reactions in the
cortex that enable
brain connections
to regrow.
Moda-Sava, R.N., (2019)

16. https://www.spravato.com/

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

24. Psychedelics

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.

27. Safety of Psychedelics
Daniel, J., Haberman, M. (2018).

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)

29. 6 Months Follow-up
Carhart-Harris RL, (2018)

30. The results are from a Pubmed keyword search for psilocybin.
beckleyfoundation.org

31. https://biologicmodels.com

32. Psilocybin is converted to psilocin, which has mind-
altering effects similar to
LSD, Mescaline, and DMT.

33. Placebo Psilocybin
Communication between brain networks
MRI scans of 15 people after being injected with psilocybin
Petri, G., (2014)

34. Adverse Effects
• Dizziness
• Blurred vision
• Dilated pupils
• Tremors
• Increased BP
• Increased Pulse
• distorted visual perception of shapes, colors

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)

37. John Hopkins
researchers
recommend
reclassifying
psilocybin, from
schedule I to
schedule IV
Hedin, M., (2018)

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

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