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Exploring Nonpharmacological Anti-inflammatory Strategies in

Mental Health: Connecting Science to Clinical Practice

Otsuka Pharmaceutical Development & Commercialization, Inc.

© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD. June 2017 MRC2.CORP.D.00261

Lundbeck, LLC

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PsychU Virtual Forum:Rules of Engagement



This presentation was developed with the support of Otsuka Pharmaceutical Development &

Commercialization, Inc. (OPDC) and Lundbeck, LLC

Dr. Jain is a compensated contractor of OPDC



Rakesh Jain, MD, MPHClinical Professor

Department of PsychiatryTexas Tech University School of Medicine

Midland, Texas



Learning Objectives

Review underlying mechanisms of inflammation and understand how they may affect physical and mental health

Discuss nonpharmacological interventions that may have anti-inflammatory effects

Explore practical approaches for implementing nonpharmacological interventions


Inflammation: Effects on Physical and Mental Health



Role of Immunity Has Evolved Alongside Human Development

Hunter-gatherer period• High mortality• Acute stress

– Predators – Pathogens– Interhuman conflict

• Immunity– Wound healing– Fighting infection

Miller and Raison. Nat Rev Immunol. 2016;16:22-34.

Modern life • Low mortality• Chronic stress

– Environmental stress– Medical illness– Psychosocial stress

• Immunity– High inflammation– High autoimmunity



Inflammatory Responses: Balance Between Neuroprotection and Neurotoxicity

1. Soczynska et al. Behav Brain Res. 2012;235:302-317. 2. Che et al. J Psychiatry Neurosci. 2010;35:296-302

Pro-inflammatory cytokinesReactive oxygen species

Anti-inflammatory cytokinesAntioxidants

Neurotrophic factors

Serotonin

Tryptophan

KynurenineKynurenic

acidQuinolinic

acid

Unchecked excitotoxicity can lead to cell death and eventual tissue atrophy, potentially making the brain unable to respond and adapt to stimuli1 and

manifesting as a mental illness2

Excitotoxicity



Stress Activates Inflammatory Pathways in Peripheral Blood Mononuclear Cells

DAMPs, danger-associated molecular patterns.Miller AH, et al. Nat Rev Immunol. 2016;16(1):22-34.

Stress activates the sympathetic nervous system, stimulating bone marrow to produce and release monocytes

Activated macrophages in the brain can perpetuate these inflammatory responses

Monocytes throughout the body interact with injured tissue, DAMPs, bacteria, and bacterial products, activating additional inflammatory signaling pathways and stimulating the release of other pro-inflammatory cytokines that can enter the brain

Bone marrow



Stress Can Create a Pro-inflammatory Feedback Loop

The greater a person’s inflammatory response to a psychosocial stressor, the

more likely he/she is to develop depression over subsequent months

Psychosocial stress can activate immune responses

throughout the body

Peripheral inflammation

Psychosocial stress

Miller et al. Nat Rev Immunol. 2016;16:22-34.



1. Eraly et al. JAMA Psychiatry. 2014;71:423-431. 2. Najjar et al. J Neuroinflammation. 2013;10:43. 3. Lindqvist. Psychoneuroendocrinology. 2017;76:197-205. 4. Puzianowska-Kuźnicka et al. Immun Ageing. 2016;13:21.

Chronic mild inflammation mayincrease the risk of mental and physical disorders

Chronic Mild Inflammation May Have Lasting Effects

Posttraumatic stress disorder1

Bipolar disorder2

Major depressive disorder3

Cardiovascular disease4

Cancer4

Diabetes4



Inflammatory Cytokines Are Increased in Patients With Major Depressive Disorder

Patients with MDD* demonstrated significantly elevated plasma levels of IL-6 (P<0.001) and TNF-α (P<0.001) compared with healthy controls

Healthy controls

n=55

Patients with MDD

n=50

Healthy controls

n=55

Patients with MDD

n=50

IL-6 TNF-α

*Patients were diagnosed with major depressive disorder without psychotic features (DSM-IV-TR) and scored >17 on the 17-item Hamilton Depression Rating Scale. All patients were free of any psychotropic mediations for at least 6 weeks prior to enrollment in the study. DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; IL-6, interleukin 6; MDD, major depressive disorder. TNF-α, tumor necrosis factor alpha.Lindqvist et al. Psychoneuroendocrinology. 2017; 76:197-205.

Reprinted from Psychoneuroendocrinology, Vol 76, Lindqvist D, Dhabhar FS, James SJ, et al, Oxidative stress, inflammation and treatment response in major depression, 197-205, 2017, with permission from Elsevier.



Depression Severity Influences Cytokine and Neurotrophic Factor Expression

BDNF, brain-derived neurotrophic factor; HAM-D, Hamilton Rating Scale for Depression; IL-6, interleukin 6; Yoshimura et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:722-726.

More severe depression is correlated with lower levels of BDNF

More severe depression is correlated with higher levels of IL-6

Increasing concentration of IL-6

Incr

ease

s in

HAM

-D

Incr

ease

s in

HAM

-D

Increasing concentration of BDNF

P=0.0012P=0.0062


Targeting Inflammation: Beyond Pharmacology



Exercise2

Mindfulness3

Sleep4

Nutrition5

Socialization1

Some Nonpharmacological Interventions Target Discrete Components of Wellness

1. Lacey et al. Psychoneuroendocrinology. 2014;50:85-94. 2. You et al. Sports Med. 2013;43:243-256. 3. Rosenkranz et al. Brain Behav Immun. 2013;27:174-184. 4. Depner et al. Curr Diab Rep. 2014;14:507. 5. Fardet and Boirie. Nutr Rev. 2014;72:741-762.


Discussion



Adipose cells Angiogenesis Blood supply Vasoconstriction Hypoxia

Exercise Can Reduce ChronicInflammation Through Multiple Mechanisms

You et al. Sports Med. 2013;43:243-256.

Exercise

Muscle cells Interleukin-6 Pro-inflammatory cytokines Anti-inflammatory cytokines

Endothelial cells Adhesion molecules Cell regeneration

Immune cells Toll-like receptors Inflammatory monocytes Regulatory T cells



Exercise Induces Muscles and Astrocytes to Express Neuroprotective Genes

PGC-1α1, peroxisome proliferator-activated receptor-γ coactivator 1-alpha 1.1. Soczynska et al. Behav Brain Res. 2012;235:302-317. 2. Schlittler et al. Am J Physiol Cell Physiol. 2016;310:C836-C840. 3. Agudelo et al. Cell. 2014;159:33-45.

Anti-inflammatory cytokinesAntioxidants

Neurotrophic factors

Serotonin

Tryptophan

KynurenineKynurenic

acidQuinolinic

acid

Exercise

Excitotoxicity

Exercise can promote neuroprotective gene expression and maintain healthy tissue

PGC-1α1Exercise

Pro-inflammatory cytokinesReactive oxygen species



Evidence for Increased Remission Rates With Add-on Exercise in Patients With Nonremitted MDD

Adjusted rate of remission, as measured by IDS-C30, in patients with inadequate response to SSRI who received add-on exercise in the TREAD study

IDS-C30, 30-Item Inventory of Depressive Symptomology (Clinician-Rated); MDD, major depressive disorder; NNT, number needed to treat; SSRI, selective serotonin reuptake inhibitor; TREAD, Treatment with Exercise Augmentation for Depression study.*NNT of 7.8 for high-exercise vs low-exercise group based on remission rate at week 12.Trivedi et al. J Clin Psychiatry. 2011;72:677-684.

Exercise

15.5

28.3

0

10

20

30

40

50

Low add-on exercise4 kcal/kg/wk (n=61)

High add-on exercise16 kcal/kg/wk (n=61)

Patie

nts,

% *

There was a trend for higher remission rates in the higher-dose exercise group (P<0.06)



Audience Polling Question

All mechanisms that contribute to possible anti-inflammatory effects of exercise training depend on weight loss

A. TRUE

B. FALSE



Mindfulness Training May Positively AffectInflammatory Responses

*Participants included 49 volunteers without previous experience with meditation or other mind-body techniques. †Program consisted of 8 weekly 2.5-hour sessions + 1 full-day session + daily home-based practice, 45 minutes to 1 hour. ‡HEP program matched MBSR in structure, instructor expertise, and content. Test is the Trier Social Stress Test.HEP, health enhancement program; MBSR, mindfulness-based stress reduction. Rosenkranz et al. Brain Behav Immun. 2013;27:174-184.

Mindfulness training reduced cortisol production in response to a psychological stressor*

Mindfulness

Test Test

Mindfulness-based stress reduction (MBSR)† Health enhancement program (HEP)‡

Baseline Post-test 10 min 20 min 30 min Baseline Post-test 10 min 20 min 30 min

MBSR training resulted in a significantly smaller post-stress inflammatory response compared to HEP, despite equivalent levels of stress hormones



Sleep Is Connected to Inflammation and Metabolic Disorders

Depner et al. Curr Diab Rep. 2014;14:507.

Insufficient sleepPeriodic limb movement disorder

Insomnia with short sleep durationNarcolepsy

InflammationOxidative stress

Impaired glucose toleranceInsulin resistance

Circadian misalignment

Night shift, shift-work disorder

Sleep apnea

Obesity

Sleep deficiency

Type 2 diabetes

Sleep



Disturbances in Sleep Are AssociatedWith Increases in IL-6

CRP, C-reactive protein; IL-6, interleukin 6.1. Friedman et al. Proc Natl Acad Sci U S A. 2005;102:18757-18762. 2. Irwin et al. Biol Psychiatry. 2016;80:40-52.

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

20 30 40 50 60 70 80 90 100

In a meta-analysis of 72 studies (N >50,000), increasing disturbances in sleep were associated with increases in the circulating inflammatory markers CRP and IL-62

Association of IL-6 levels with sleep efficiency1

Sleep

Plas

ma

IL-6

(log

10 tr

ansf

orm

ed)

Sleep efficiency



Sleep Significantly Affects CRP and Health-Related Quality of Life

CRP, C-reactive protein.Heinzelmann et al. Sleep Med. 2014;1565-1570.

Sleep

In an observational study of United States military personnel (N=66), participants who experienced restorative sleep demonstrated significant reductions in plasma CRP levels

• Participants who experienced restorative sleep also demonstrated significant‒ Reductions in fatigue and depressive symptoms‒ Increases in emotional well-being, social functioning, and physical functioning

Mea

n C

RP

conc

entra

tion,

pg/

mL



Childhood Social Isolation May Lead to High Inflammation in Adulthood

*Social isolation classified as social rejection or withdrawal and assessed via survey at age 7 and 11 years. †Data from National Child Development Study that aimed to recruit all infants born in Great Britain during 1 week of 1958 (N=17,414). Participants were surveyed at the following ages: 7, 11, 16, 23, 33, 42, 44, 46, and 50 years.CRP, C-reactive protein; BMI, body mass index. Lacey et al. Psychoneuroendocrinology. 2014;50:85-94.

Negative consequences of early social isolation* may manifest in adulthood†

Decrease in

Education

Social class

Increase in

CRP

BMI

Psychological distress

Socialization



Low Social Network Ties Are Linked With Higher Inflammation

*National Health and Nutrition Examination Survey III (1988-1994). †Social network index score based on marital status, frequency of social interactions, religious attendance, and membership in social organizations.CRP, C-reactive protein.Yang et al. Biodemography Soc Biol. 2014;60:21-37.

In a national survey of 1,075 American adults with a history of cancer,* those with lower social ties demonstrated higher levels of the inflammatory marker CRP

Increasing number of social ties

Incr

easi

ng le

vel o

f CR

P

Association of predicted CRP levels with social network index†

Socialization



Select Foods Are Associated With Diet-Related Chronic Illness

*Based on an assessment of pooled/meta-analyses and systematic reviews (N=304) published between 1950 and 2013.Fardet and Boirie. Nutr Rev. 2014;72:741-762.

Ref

eren

ces

indi

catin

g as

soci

atio

n w

ith in

flam

mat

ory

dise

ases

, %Nutrition

Select foods may have differential effects on diet-related chronic illness (eg, cardiovascular disease, cancer, obesity, mental illness)*

0

10

20

30

40

50

60

70

Milk Wine Sweetenedbeverages

Fruits andvegetables

Whole grains Dairyproducts

Red/Processed

meat

Fish

Protective association Neutral association Deleterious association



*MIND diet demonstrated a reduction in cognitive decline associated with aging in patients (N=960) participating in the Memory and Aging Project. DASH, dietary approach to systolic hypertension; MIND, Mediterranean-DASH diet intervention for neurodegenerative delay.Morris et al. Alzheimers Dement. 2015;1:1015-1022.

Certain Diets May Emphasize Foods With Anti-inflammatory Effects

MIND diet recommendations

ProteinFish (not fried), ≥1 meal per week

Poultry (not fried), ≥2 meals per weekRed meats, <4 meals per week

Nuts, ≥5 servings per week

CarbohydratesWhole grains, ≥3 servings per day

Pastries/sweets, <5 servings per weekWine, 1 glass per day

Oils and CheeseOlive oil as the primary oil used

Fast fried foods, <1 time per weekButter or margarine, <1 tablespoon per day

Cheese, <1 serving per week

Fruits and Vegetables Green leafy vegetables, ≥6 servings per week

Other vegetables, ≥1 serving per dayBerries, ≥2 servings per week

Beans, >3 meals per week

For example, Mediterranean-based diets promote fresh foods, discourage sweets and processed foods, and may positively affect physical and mental health*

Nutrition


Discussion



Implementing Nonpharmacological Interventions May Improve Overall Wellness

*P<0.01 vs baseline score. GAD-7, Generalized Anxiety Disorder 7-item; PHQ-9, Patient Health Questionaire-9; WHO-5, World Health Organization Wellbeing Index. Jain et al. Poster presented at: 28th Annual US Psychiatric Congress Annual Meeting; September 10-13, 2015; San Diego, CA.

7.3

4

0

5

10

15

20

Baseline After 30-dayintervention

Scor

e

Adults (N=36) who implemented nonpharmacological strategies targeting 5 domains for 30 days demonstrated significant improvement in anxiety, depression,

and overall well-being

GAD-7

8.5

4.9

0

4

8

12

16

20


Scor

e

PHQ-9

10.7

15.6

0

5

10

15

20


Scor

e

WHO-5

* *

*


Practical Approaches To Implementing

Nonpharmacological Techniques



Simple Suggestions for Implementing Interventions Toward Achieving Wellness*

Exercise

Mindfulness

Sleep

Nutrition

Social Connectedness

*Information based on Dr. Jain’s own experience in psychiatric settings.Jain et al. Poster presented at: 28th Annual US Psychiatric Congress Annual Meeting; September 10-13, 2015; San Diego, CA.

Text or call a family member or friend daily for 30 days

Log what you eat daily for 30 days

Exercise 30 minutes 6 of 7 days for 30 days at

moderate intensity

Practice mindfulness

>8 minutes each day for 30 days

Implement prosleep hygiene practices each day for 30 days



Initiate and Maintain Anti-inflammatory Wellness Habits*

Provide resources Recommend daily practice

Provide encouragementInitiate

Continue to provide encouragement

Check in at regular intervals on

progressBe a gentle coach

Remind patient of the studies

demonstrating benefits of practices

Recommend increasing practice with early signs of

stress

Maintain

*Information based on Dr. Jain’s own experience in psychiatric settings.


Discussion



Audience Polling Question

How likely are you to implement these strategies into your clinical practice?

A. Definitely will

B. Probably will

D. Probably won’t

E. Definitely won’t

C. Not sure



Summary

Inflammation may have lasting effects on physical and mental health

Exercise, mindfulness, sleep, nutrition, and social connectedness have been demonstrated to influence inflammatory responses

Nonpharmacological interventions, including those aimed at encouraging exercise and mindfulness and optimizing sleep, nutrition, and socialization, may positively affect both physical and mental health


Questions?

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