Exploring Nonpharmacological Anti-inflammatory Strategies in Mental Health: Connecting Science to Clinical Practice

Transcription

1 Exploring Nonpharmacological Anti-inflammatory Strategies in Mental Health: Connecting Science to Clinical Practice Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD. June 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

2 PsychU Virtual Forum: Rules of Engagement Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck, LLC. have entered into collaboration with OPEN MINDS to explore new ways of bringing/increasing awareness around serious mental illness OPDC/Lundbeck s interaction with OPEN MINDS is through PsychU, an online, non-branded portal dedicated to providing information and resources on important disease state and care delivery topics related to mental illness. One of the methods employed for the sharing of information will be the hosting of virtual fora. Virtual fora conducted by OPDC/Lundbeck are based on the following parameters: When conducting medical dialogue, whether by presentation or debate, OPDC/Lundbeck and/or its paid consultants aim to provide the viewer with information that is accurate, not misleading, scientifically rigorous, and does not promote OPDC/Lundbeck products OPDC/Lundbeck and/or their paid consultants do not expect to be able to answer every question or comment during a PsychU Virtual Forum; however, they will do their best to address important topics and themes that arise. OPDC/Lundbeck and/or their paid consultants are not able to provide clinical advice or answer questions relating to specific patient s condition. Otsuka and Lundbeck employees and contractors should not participate in this program (e.g., submit questions or comments) unless they have received express approval to do so from Otsuka Legal Affairs. OPDC/Lundbeck operate in a highly regulated and scrutinized industry. Therefore, we may not be able to discuss every issue or topic that you are interested in, but we will do our best to communicate openly and directly. The lack of response to certain questions or comments should not be taken as an agreement with the view posed or an admission of any kind. 2

3 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 3

4 Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech University School of Medicine Midland, Texas 4

5 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 5

6 Inflammation: Effects on Physical and Mental Health advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

7 Role of Immunity Has Evolved Alongside Human Development Hunter-gatherer period High mortality Acute stress Predators Pathogens Interhuman conflict Immunity Wound healing Fighting infection Modern life Low mortality Chronic stress Environmental stress Medical illness Psychosocial stress Immunity High inflammation High autoimmunity Miller and Raison. Nat Rev Immunol. 2016;16:

8 Role of Immunity Has Evolved Alongside Human Development Hunter-gatherer period High mortality Acute stress Predators Pathogens Interhuman conflict Immunity Wound healing Fighting infection Modern life Low mortality Chronic stress Environmental stress Medical illness Psychosocial stress Immunity High inflammation High autoimmunity Miller and Raison. Nat Rev Immunol. 2016;16:

9 Inflammatory Responses: Balance Between Neuroprotection and Neurotoxicity Serotonin Anti-inflammatory cytokines Antioxidants Neurotrophic factors Tryptophan Pro-inflammatory cytokines Reactive oxygen species Kynurenic acid Kynurenine Quinolinic acid Excitotoxicity Unchecked excitotoxicity can lead to cell death and eventual tissue atrophy, potentially making the brain unable to respond and adapt to stimuli 1 and manifesting as a mental illness 2 1. Soczynska et al. Behav Brain Res. 2012;235: Che et al. J Psychiatry Neurosci. 2010;35:

10 Stress Activates Inflammatory Pathways in Peripheral Blood Mononuclear Cells Bone marrow Stress activates the sympathetic nervous system, stimulating bone marrow to produce and release monocytes Monocytes throughout the body interact with injured tissue, DAMPs, bacteria, and bacterial products, activating additional inflammatory signaling pathways and stimulating the release of other proinflammatory cytokines that can enter the brain Activated macrophages in the brain can perpetuate these inflammatory responses DAMPs, danger-associated molecular patterns. Miller AH, et al. Nat Rev Immunol. 2016;16(1):

11 Stress Can Create a Pro-inflammatory Feedback Loop Psychosocial stress Peripheral inflammation Psychosocial stress can activate immune responses throughout the body The greater a person s inflammatory response to a psychosocial stressor, the more likely he/she is to develop depression over subsequent months Miller et al. Nat Rev Immunol. 2016;16:

12 Chronic Mild Inflammation May Have Lasting Effects Chronic mild inflammation may increase the risk of mental and physical disorders Posttraumatic stress disorder 1 Cardiovascular disease 4 Bipolar disorder 2 Cancer 4 Major depressive disorder 3 Diabetes 4 1. Eraly et al. JAMA Psychiatry. 2014;71: Najjar et al. J Neuroinflammation. 2013;10: Lindqvist. Psychoneuroendocrinology. 2017;76: Puzianowska-Kuźnicka et al. Immun Ageing. 2016;13:21. 12

13 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 IL-6 TNF-α Healthy controls n=55 Patients with MDD n=50 Healthy controls n=55 Patients with MDD n=50 Reprinted from Psychoneuroendocrinology, Vol 76, Lindqvist D, Dhabhar FS, James SJ, et al, Oxidative stress, inflammation and treatment response in major depression, , 2017, with permission from Elsevier. *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:

14 Depression Severity Influences Cytokine and Neurotrophic Factor Expression More severe depression is correlated with higher levels of IL-6 More severe depression is correlated with lower levels of BDNF Increases in HAM-D P= Increases in HAM-D P= Increasing concentration of IL-6 Increasing concentration of BDNF 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:

15 Targeting Inflammation: Beyond Pharmacology advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

16 Some Nonpharmacological Interventions Target Discrete Components of Wellness Socialization 1 Exercise 2 Nutrition 5 Mindfulness 3 Sleep 4 1. Lacey et al. Psychoneuroendocrinology. 2014;50: You et al. Sports Med. 2013;43: Rosenkranz et al. Brain Behav Immun. 2013;27: Depner et al. Curr Diab Rep. 2014;14: Fardet and Boirie. Nutr Rev. 2014;72:

17 Discussion advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

18 Exercise Can Reduce Chronic Inflammation Through Multiple Mechanisms Exercise Adipose cells Angiogenesis Blood supply Vasoconstriction Hypoxia Endothelial cells Adhesion molecules Cell regeneration Immune cells Toll-like receptors Inflammatory monocytes Regulatory T cells Muscle cells Interleukin-6 Pro-inflammatory cytokines Anti-inflammatory cytokines You et al. Sports Med. 2013;43:

19 Exercise Induces Muscles and Astrocytes to Express Neuroprotective Genes Exercise Anti-inflammatory cytokines Antioxidants Neurotrophic factors Serotonin Tryptophan Pro-inflammatory cytokines Reactive oxygen species Kynurenic acid Kynurenine Quinolinic acid Exercise PGC-1α1 Excitotoxicity 19 Exercise can promote neuroprotective gene expression and maintain healthy tissue PGC-1α1, peroxisome proliferator-activated receptor-γ coactivator 1-alpha Soczynska et al. Behav Brain Res. 2012;235: Schlittler et al. Am J Physiol Cell Physiol. 2016;310:C836-C Agudelo et al. Cell. 2014;159:33-45.

20 Evidence for Increased Remission Rates With Add-on Exercise in Patients With Nonremitted MDD Exercise Adjusted rate of remission, as measured by IDS-C 30, in patients with inadequate response to SSRI who received add-on exercise in the TREAD study Patients, % * 10 0 Low add-on exercise 4 kcal/kg/wk (n=61) High add-on exercise 16 kcal/kg/wk (n=61) There was a trend for higher remission rates in the higher-dose exercise group (P<0.06) IDS-C 30, 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:

21 Audience Polling Question All mechanisms that contribute to possible anti-inflammatory effects of exercise training depend on weight loss A. TRUE B. FALSE 21

22 Mindfulness Training May Positively Affect Inflammatory Responses Mindfulness Mindfulness training reduced cortisol production in response to a psychological stressor* Mindfulness-based stress reduction (MBSR) Health enhancement program (HEP) Test Test 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 *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:

23 Sleep Is Connected to Inflammation and Metabolic Disorders Sleep Circadian misalignment Night shift, shift-work disorder Sleep apnea Obesity Sleep deficiency Inflammation Oxidative stress Impaired glucose tolerance Insulin resistance Insufficient sleep Periodic limb movement disorder Insomnia with short sleep duration Narcolepsy Type 2 diabetes Depner et al. Curr Diab Rep. 2014;14:

24 Disturbances in Sleep Are Associated With Increases in IL-6 Sleep Association of IL-6 levels with sleep efficiency 1 Plasma IL-6 (log10 transformed) Sleep efficiency 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-6 2 CRP, C-reactive protein; IL-6, interleukin Friedman et al. Proc Natl Acad Sci U S A. 2005;102: Irwin et al. Biol Psychiatry. 2016;80:

25 Sleep Significantly Affects CRP and Health-Related Quality of Life Sleep In an observational study of United States military personnel (N=66), participants who experienced restorative sleep demonstrated significant reductions in plasma CRP levels Mean CRP concentration, pg/ml Participants who experienced restorative sleep also demonstrated significant Reductions in fatigue and depressive symptoms Increases in emotional well-being, social functioning, and physical functioning CRP, C-reactive protein. Heinzelmann et al. Sleep Med. 2014;

26 Childhood Social Isolation May Lead to High Inflammation in Adulthood Socialization Negative consequences of early social isolation* may manifest in adulthood Decrease in Education Social class Increase in CRP BMI Psychological distress *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:

27 Low Social Network Ties Are Linked With Higher Inflammation Socialization 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 level of CRP Association of predicted CRP levels with social network index Increasing number of social ties *National Health and Nutrition Examination Survey III ( ). 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:

28 Select Foods Are Associated With Diet-Related Chronic Illness Nutrition References indicating association with inflammatory diseases, % Select foods may have differential effects on diet-related chronic illness (eg, cardiovascular disease, cancer, obesity, mental illness)* Milk Wine Sweetened beverages Fruits and vegetables Whole grains Dairy products Red/ Processed meat Protective association Neutral association Deleterious association Fish *Based on an assessment of pooled/meta-analyses and systematic reviews (N=304) published between 1950 and Fardet and Boirie. Nutr Rev. 2014;72:

29 Certain Diets May Emphasize Foods With Anti-inflammatory Effects Nutrition For example, Mediterranean-based diets promote fresh foods, discourage sweets and processed foods, and may positively affect physical and mental health* Fruits and Vegetables Green leafy vegetables, 6 servings per week Other vegetables, 1 serving per day Berries, 2 servings per week Beans, >3 meals per week Oils and Cheese Olive oil as the primary oil used Fast fried foods, <1 time per week Butter or margarine, <1 tablespoon per day Cheese, <1 serving per week MIND diet recommendations Protein Fish (not fried), 1 meal per week Poultry (not fried), 2 meals per week Red meats, <4 meals per week Nuts, 5 servings per week Carbohydrates Whole grains, 3 servings per day Pastries/sweets, <5 servings per week Wine, 1 glass per day *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:

30 Discussion advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

31 Implementing Nonpharmacological Interventions May Improve Overall Wellness Adults (N=36) who implemented nonpharmacological strategies targeting 5 domains for 30 days demonstrated significant improvement in anxiety, depression, and overall well-being 20 GAD-7 20 PHQ-9 20 WHO-5 Score Score * * 4.9 Score * Baseline After 30-day intervention 0 Baseline After 30-day intervention 0 Baseline After 30-day intervention *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. 31

32 Practical Approaches To Implementing Nonpharmacological Techniques advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

33 Simple Suggestions for Implementing Interventions Toward Achieving Wellness* Text or call a family member or friend daily for 30 days Social Connectedness Exercise Exercise 30 minutes 6 of 7 days for 30 days at moderate intensity Log what you eat daily for 30 days Nutrition Mindfulness Practice mindfulness >8 minutes each day for 30 days 33 Sleep *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. Implement prosleep hygiene practices each day for 30 days

34 Initiate and Maintain Anti-inflammatory Wellness Habits * Initiate Provide encouragement Provide resources Recommend daily practice Maintain Continue to provide encouragement Remind patient of the studies demonstrating benefits of practices Check in at regular intervals on progress Recommend increasing practice with early signs of stress Be a gentle coach 34 *Information based on Dr. Jain s own experience in psychiatric settings.

35 Discussion advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

36 Audience Polling Question How likely are you to implement these strategies into your clinical practice? A. Definitely will B. Probably will C. Not sure D. Probably won t E. Definitely won t 36

37 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 37

38 Questions? advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.