Evidence-based approach on Ketamine in treatment resistant depression

1. Elisa Brietzke MD, PhD.
Professor, Department of Psychiatry, Queen’s University
School of Medicine, Kingston, ON, Canada.
Centre for Neuroscience Studies, Queen’s University,
Kingston, ON, Canada
Intra-venous Ketamine:
an Evidence-Based Approach

2. Disclosure
• Research Grants: Faculty of Health Sciences (Research Establishment Grant), Centre for
Neuroscience Studies, Department of Psychiatry, Queen’s University, CNPq (Brazil),
SEAMO Innovation Grant (Co-PI).
• Speaker/Advisory Board: Daiichi-Sankyo, Janssen-Cilag (esketamine)
• Consultant: Lundbeck

4. Introduction
• Limitations of monoamine based antidepressants in MDD as well as treatment options for
bipolar depression.
• Involvement of NMDA receptor in depression: Preclinical data + data from conventional
antidepressants
• Pioneer study conducted by Berman et at.: small RCT with 9 subjects randomized to
Ketamine or placebo 72 hours

5. Introduction
• NMDA antagonists: Ketamine: off label; Esketamine: FDA, Health Canada, 28 European
countries.
• RCTs on Ketamine and Esketamine in the treatment of depression (unipolar and bipolar)
• Large RCTs on Ketamine: low probability of being conducted due to be no longer protected
by patent
• Off label use has been widespread: Studies of effectiveness (instead of efficacy)
• CAN-MAT Task Force on Ketamine (Swanson et al. 2020 submitted).
• Canadian Rapid Treatment Center of Excellence- Toronto, ON, Canada- Dr. R. McIntyre
• Ketamine Clinic – Providence Care Hospital, Kingston, ON, Canada- Dr. G. Vazquez
• APA Consensus 2017

6. 1. What is Ketamine?
• Multiple mechanisms of action
• Modulation of glutamatergic transmission: NMDA antagonism on GABAergic interneurons in
the prefrontal cortex
• Disinhibition and initiation of a cellular and molecular cascade resulting in promotion of
synaptogenesis in depression-related circuits which is dependent of:
• Epigenetic changes
• Protein synthesis
• BDNF production
Kang et at. In: Vazquez, Zarate, and Brietzke 2020 (in press)

7. 1. What is Ketamine?
Kang et at. In: Vazquez, Zarate, and Brietzke 2020 (in press); Williams et al., 2018.
Small RCT with
naltrexone
(N=14): inhibition
of the
antidepressant
effect

8. 2. What is the pharmakokinetics of Ketamine?
• Multiple routes of administration for Ketamine: Intra-venous (Intra-muscular, Oral,
Subcutaneous, Intra-nasal.
• IV: High bioavailability (90%), slow infusion (over 40 minutes), solid evidence of efficacy.
• Rapid diffusion to the brain
• Metabolism to norketamine by CYP3A4, CYP2C19, CYP2B6, CYP2A6
• Totally eliminated in 24 hours, but some metabolites can be detected up to 3 days.
• Esketamine: S-enantiomer of Ketamine
• Intra-nasal use by Janssen.
• Comparison with ketamine: one non-inferiority study (
Correia-de-Melo et al., 2020.

9. 3. What is the effectiveness of Ketamine in the
treatment of unipolar depression?
• 8 meta-analysis in the last 5 years, summarizing the results of placebo- and active-
controlled RCTs.
• Results:
• A single infusion of IV ketamine has an antidepressant effect that peaks in 24 h and
lasts 3-7 days – LEVEL 1.
• Average time of relapse: 10 days.
• Small samples
• Cross-over design
• Limited follow-up beyond 1 week. 2 RCTs followed patients for more than 30
days: sustained response were 45% and 19%.
• Doses: 0.5 mg/kg: higher doses are not more effective and lower doses were
ineffective in two RCTs.
McGirr et al., 2017; Wilkinson et al., 2017; Han et al., 2016; Kishimoto et al., 2016; Romeo et al., 2015

10. 3. What is the effectiveness of Ketamine in the
treatment of unipolar depression?
• Results of repeated infusions:
• Different protocols: 4-6 infusions minimum
• Large case series from China (unipolar and bipolar N=97): response 68%; remission:
51% after 6 infusions.
• Same patterns was seen in other open-label repeated studies.
• Ionescu et al. 2019: RCT with n=26 did not find difference from placebo.
• Ultra resistant patients, including to ECT.
• LEVEL 4
Zheng et al., 2018; Ionescu et al., 2019

11. 4. What is the effectiveness of Ketamine in the
treatment of bipolar depression?
• Most data come from studies that included both unipolar and bipolar depression.
• Few studies specifically designed to assess ketamine in BD
• Small sample sizes: feasibility: RCT Ketamine X Midazolam
• Open Label: Rybakowski et al., 2017: 51% of response (N=53)
• Improvement of cognition in patients with bipolar depression after 6 infusions.
Grunebaum et al., 2017; Rybakowski et al., 2017; Zhoung et al., 2019

12. 5. What are the long term benefits of
Ketamine?
• Potentially improvement of suicidal ideation: rapid reduction in suicidal thoughts which is not
totally dependent of global improvement of depression after a single infusion.
Phillips et al., 2020
• Potential change in the course of illness:
neuroprogression (reducing the chance of relapse).

13. 6. What are the most common side-effects of
Ketamine and how to manage them?
• Dissociative symptoms:
• Rarely for more than one hour
• Usually do not require any intervention, including interrupting infusion
• ↑ Blood pressure:
• Heterogeneous results
• Average increase in 3 mmHg in systolic or diastolic
• Only 9% of patients have significant increases in blood pressure in a large study
• ↑Heart rate
• Drowsiness
• Others: blurred vision, nausea, vomiting, headache, poor coordination, poor concentration,
restlessness

14. 7. What protocol should be used to administer
Ketamine?
• More than one protocol described in terms of number of infusions
• Not enough data to say what is more efficient.
• Providence Care Hospital Protocol
• 10 infusions in total
• Week 1: 3 infusions Monday, Wednesday, Friday
• Week 2: 3 infusions Monday, Wednesday, Friday
• Week 3: 2 infusions Monday, Friday
• Week 4: 2 infusions Monday, Friday
• 0.5 mg/kg in 40 minutes, plus 30 minutes minimum of observation

15. 8. What are the similarities and differences
between Ketamine and Esketamine?
• Both are indicated for TRD and are rapid action agents
• Both require supervision in administration
• Ketamine: IV, higher complexity, low cost of medication/high cost of administration.
• Esketamine: intra-nasal, lower complexity, lower cost of administration/higher cost of
medication
• Esketamine: better quality of evidence from experimental settings
• Ketamine: real-life

16. 9. What settings and personnel are required to
administer ketamine?
• Ketamine should be administered in a facility with cardiovascular and respiratory monitoring
and rescue medications to manage both psychiatric and medical side effects.
• The facility should have ACLS trained personnel
• Most jurisdictions, a physician will be the responsible person
• Specific sites: anesthesiologist, critical care physician, psychiatrist.
• Medical legal issues
• LEVEL 4

17. 10. What is the future in the studies on
Ketamine in bipolar disorder?
• Robust data on short-term efficacy of IV Ketamine
• Limited evidence for long-term efficacy
• Comparison with other interventions for TRD: algorithms of treatment
• Stratification of the levels of resistance
• Inter-individual variability
• Relapse prevention?
• Deep understanding of the mechanisms of action and development of “me too” strategies.

18. To learn more...
Vazquez GH, Zarate CA, Brietzke E. Ketamine for
Treatment-Resistant Depression. Elsevier, 2020 (in
press). www.elsevier.com www.amazon.ca

19. Acknowledgments
Queen’s University/ Department of Psychiatry
Ketamine Clinic Providence Care Hospital
Gustavo H Vazquez
Melody Kang
Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force for the Use of Racemic
Ketamine in Adults with Major Depressive Disorder
Jennifer Swainson, Alexander McGirr, Pierre Blier, Stéphane Richard-Devantoy, Nisha Ravindran, Jean Blier,
Serge Beaulieu, Benicio Frey, Sidney H. Kennedy, Roger S. McIntyre, Roumen Milev, Sagar Parikh, Ayal
Schaffer, Valerie Taylor, Valérie Tourjman, Michael van Ameringen, Lakshmi Yatham, Arun Ravindran, Raymond
Lam.
Canadian Rapid Treatment Center of Excellence (CRTCE)
Roger S. McIntyre, Joshua Rosenblat, Yena Lee
elisa.brietzke@queensu.ca