Presentation on anti-inflammatory medication in MDD. Dr. Elisa Brietzke MD, PhD. Department of Psychiatry, Queen's University, Kingston, ON, Canada.

1. Unconventional Treatments with Unique
Treatments with Unique Mechanistic
Targets for Major Depressive Disorders:
Anti-Inflammatories
Dr. Elisa Brietzke MD, PhD
Professor, Department of Psychiatry, Queen’s University
Centre for Neuroscience Studies, Queen’s University
Attending Psychiatrist, Kingston General Hospital and Providence Care Hospital

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
• Consultant: Lundbeck
• No COI

3. Summary
• Pathophysiological links
• Evidence in humans
• RCTs and meta-analysis
• The concept of biophenotypes
• Future perspectives

4. Pathophysiological links
• Sickness behavior
Kent et al., 1992; Dantzer-
Hans Selye (1925): irrespective or their
diseases, all patients “felt and looked ill,
had a coated tongue, complained of more
or less diffuse aches and pain in the joints,
and of intestinal disturbances associated
with loss of appetite”
“Syndrome of just being sick”

5. Relationship between depression and inflammation is:
• Complex
• Bidirectional
• Affecting multiple dimensions of depressive
psychopathology
• Modulating multiple mechanisms
• Serotonin
• Dopamine
• Neuroendocrine responses
• Glutamate excitotoxicity
• Neuroplasticity

6. Miller et al., 2013; Musselman et al., 2001
Serotonin

7. Felger et al., 2016
Dopamine

8. Miller et al., 2016
Neuroendocrine responses

9. Coelho et al., 2014
Neuroendocrine responses

10. Caspi et al., 2003
Neuroendocrine responses

11. Brietzke et al., 2018; Rajkoska et al., 2013
Glutamate excitotoxicity
• Depression is associated with
astrocyte damage
post-mortem studies
↑ GFAP

12. Brietzke et al., 2018; Rajkoska et al., 2013
Neuroplasticity
↓ BDNF is reproduced in MDD
↑ BDNF is a common pathway in all
antidepressant interventions

13. Evidence in humans
• ↑ pro-inflammatory cytokines;
• Chemokines (cytokines with a role of attraction to the site of inflammation- makers of
immunosenesce);
• Dysfunction of specific receptors: Toll-like receptors (4).
• ↑ CRP (indirect systemic parameter)
• Subtypes of depression
• Melancholic
• Treatment-resistant
• General medical comorbidities
• Suicide?
Hungg et al., 2018; Pandey et al., 2014

14. RCTs and meta-analysis
• 36 RCTS
• Almost 10,000 subjects
• Most common agents:
13 NSAIDS (N= 4,214)
9 anti-cytokines (N= 3,345)
7 statins (N= 1,576)
3 minocycline (N= 151)
2 pioglitazone (N= 77)
2 glucocorticoids (N= 59)

15. RCTs and meta-analysis: MDD

16. RCTs and meta-analysis: severity of depressive symptoms

17. RCTs and meta-analysis: other outcomes
• Effect size is the same for add on or in monotherapy
• Response: RR= 1.76 (1.44- 2.16)
• Remission: RR= 2.14 (1.03- 4.48)
• Trend towards ↑ risk of infection

18. The concept of biophenotypes

19. The concept of biophenotypes
• Environment-related:
Childhood maltreatment
• Course-related: Treatment-
resistance
• Psychopathology-related:
anhedonia
• Systemic health- related:
metabolic syndrome
Brietzke et al., 2020
Enriched samples
Inter-individual variability
Intra-individual variability

20. Future perspectives: Neuroprogression?
Meyer et al., 2017; Kapczinski et al., 2019
• Clinical and pathophysiological
changes with the course of illness.
• Staging

21. Future perspectives: Microbiome
Park et al., 2018.
Improve inflammation modulating microbiome
fecal transplant
probiotics
diet

22. Ackowlegements
Flavio Kapczinski
McMaster University
Rodrigo Grassi-Oliveira
PUCRS
Roger McIntyre
University of Toronto
Elisa.brietzke@queensu.ca