Inflammation in Depression: What We Know & What Can We Do About it?

1. Inflammation in Depression: • What We Know • & • What Can We Do About it? • Rakesh Jain, MD, MPH

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3. In Psychiatry, Inflammation Is An Important Contributory to Suffering Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008. UK Pop. MDD Life expectancy was reduced by 10.6 years for males and 7.2 years in females with MDD compared with UK population. Chang CK, et al. PLoS One. 2011;6:e19590.

6. Childhood Adversity Represents a Risk for Adulthood Disease Study Members with the Condition (%) 32-year ProspectiveStudy 70 No. of AdverseChildhood Experiences 60 0 (n=502) 1 (n=253) ≥2 (n=98) 50 40 30 20 10 0 Panel 1: Major Depression Panel 2:hsCRP >3 mg/L Panel 3: Clustering of Metabolic Risk Markers Panel 4:≥1 Disease Risk Panel 1: z=4.94, p<0.001; hsCRP level >3 mg/L . Panel 2: z=3.24, p=0.001; clustering of metabolic risk markers. Panel 3: z=4.58, p<0.001; and ≥1 age-related disease risks. Panel 4: z=5.66, p<0.001. CRP=C-reactive protein; hsCRP=High-sensitivity C-reactive protein level. Danese A, et al. Arch PediatrAdolesc Med. 2009;163:1135–1143.

7. Mean hs-CRP values in patients with current major depression vs. non-depressed subjects hs-CRP (mg/dl) t=2.04, p=0.04 Z=2.48, p=0.01 n=38 n=461 MDD current No MDD Raison et al, in preparation

8. Patients With MDD Who Did Not Respond to Antidepressants Had Higher Inflammatory Cytokine Levels TNF- IL-6 p=0.01 p=0.004 IL-6(pg/ml) TNF-(pg/ml) Controls Depressed Euthymic Controls Depressed Euthymic 24 healthy controls and 28 patients with depression (HAMD17 >20) after 6 weeks of SSRI treatment and 16 euthymic patients (previously resistant to SSRIs) currently successfully treated with an SNRI or an addition of lithium to SSRI treatment. HAM-D=Hamilton depression score; MDD=Major depressivedisorder; SNRI=Serotonin–norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor; TNF=Tumor necrosis factor. O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331.

9. O’Brian Study Conclusions - “Suppression of pro-inflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery” O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331.

10. Why does psychosocial stress induce inflammation?

11. From an Evolutionary Perspective Stress is….. Hunting and being hunted….

12. From an Evolutionary Perspective Stress is….. The struggle for dominance and sexual access

13. HPA Axis ANS INNATE IMMUNE RESPONSE: Activation of systemic inflammatory response to prime the immune system for tissue damage from danger situation Danger Circuits PVN: CRF AVP “Stress perception by the brain may serve as an early warning signal” to activate the immune system in preparation for a markedly increased likelihood of subsequent infection.” FirdausDhabhar LOCUS CERULEUS: Norepinephrine (NE) PITUITARY: ACTH ADRENAL: NE, Epi ADRENAL: Cortisol FLIGHT RESPONSE: Production, mobilization, and direction of energy. Shut down of all nonessential bodily, vegetative, functions. Narrowing of attentional focus to perceived danger.

14. Divisions of the Immune System: Innate vs. Acquired Epitope: A part of an antigen to which an antibody binds. Also called an antigenic determinant.

15. INNATE IMMUNITY ACQUIRED IMMUNITY • Non-specific recognition of pathogens, tissue damage and danger signals • Rapid (hours to days) imprecise, relatively metabolically cheap • Contains threat but at the cost of generalized wear and tear on bodily tissues • Activation promotes sickness and depressive symptoms • Specific recognition of pathogens and danger signals • Delayed (days to a week), precise, metabolically expensive • Contains threat without appreciable damage to bodily tissues except in case of autoimmunity • Activation resolves sickness and may protect against depression

16. Stress and inflammation in MDD IL-1, TNF-, IL-6 Psychosocial stress, social isolation, personality factors A IL-6 IL-10, TGF- Major depression sickness behavior Euthymia Stress resilience G HPA - axis k t Immunoregulation i - c IL-10, TGF- /-AR IL-1, NE TNF-, IL-6 NF-B 7nAChr GR ACh TLR Infection, tissue trauma, neoplasm GCs Macrophage Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224

17. Glia-Neuron Interaction May Influence Neurotrophic Factors 5-HT=serotonin. BDNF=brain-derived neurotrophic factor. CNS=central nervous system. GLU=glutamate. IDO=indoleamine 2,3 dioxygenase. IFN=interferon. IL=interleukin. NMDA=N-methyl-D-aspartate. QUIN=quinolinic acid. RNS=reactive nitrogen species. ROS=reactive oxygen species. TNF=tumor necrosis factor. TRP=tryptophan. Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741. Reprinted with permission from Elsevier Limited.

18. Inflammatory Markers Predict the Future Development of Depression Tertile 1 (low) 100 – Tertile 2 (medium) Tertile 3 (high) 98 – Percent 96 – 94 – 92 – 90 – 0 3 4 6 8 10 Time, years In a cohort of 644 initially non-depressed females, 48 developed de novo MDD over an approximate 10 year follow up. Survival plot (Kaplan-Meier) showing the probability of remaining free of de novo major depressive disorder for women stratified into tertiles of hsCRP. The concentration of hsCRP in each tertile is: low, <1.12 mg/l; mid, 1.12-2.97 mg/l; and high, >2.97 mg.l. Pasco et al. Brit J Psychiatry 2010, 197:372-377.

19. Inflammatory Cytokine Levels May Be Associated With Symptom Severity in MDD Patients Comparison of 9 MDD patients with 9 matched healthy controls *Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction IL-6=Interleukin-6; MDD=Major depressive disorder; VAS=Visual analogue scale. Alesci et al. J Clin Endocrinol Metab 2005;90(5):2522-30.

20. Obesity and Depression:Another Modern Problem That is Increasing Risk for Depression

21. Relationship Between Obesity, Metabolic Syndrome and Depression Association between the metabolic syndrome (MetS) and depression in each body massindex (BMI) category. Graph displays the odds ratio (OR) for depression after adjustment for age, gender, prior cardiovascular disease, employment status, marital status, smoking status, dietary score, and physical activity. Obesity was defined as a BMI 30 and overweight status as a BMI between 25 and 30 kg/m2 Odds Ratio - Depression Skilton et al, 2007, Biol Psychiatry, 62(11): 1251-7.

22. MDD, Adiposity and Inflammatory Markers 50 MDD patients compared with 50 healthy matched controls Miller GE et al. Am J of Cardiol. 2002;90(12):1279-83

23. Survival Free of Major Depression (%) Incidence of Major Depression During the First 12 weeks of IFN-alpha 100 80 60 40 20 0 12 0 2 4 6 8 10 Weeks on IFN-alpha Musselman et al., New England Journal of Medicine, 344:961-966, 2001.

24. Survival Free of Major Depression (%) Paroxetine Pretreatment Reduces the Incidence of Major Depression During the First 12 weeks of IFN-alpha 100 80 60 40 Paroxetine Placebo 20 0 12 0 2 4 6 8 10 Weeks on IFN-alpha Musselman et al., New England Journal of Medicine, 344:961-966, 2001.

25. The Trier Social Stress Test (TSST)

26. Control (n = 13) Major Depression (n = 14) *Between group comparison, p < 0.05 *Between group comparison, p < 0.05 +Within group comparison vs. 0 min time pt, p < 0.05 +Within group comparison vs. 0 min time pt, p < 0.05 Psychological Stress, a Well-Known Precipitant of Depressive Illness, Induces an Inflammatory Response: A Possible Link Between Stress, Depression and Illness Control (n = 13) * + 6 Major Depression (n = 14) 6 + + 5 5 4 + + 4 + Plasma IL-6, pg/ ml + * 3 Plasma IL-6, pg/ ml + * 3 2 2 90 1 1 80 0 -15 0 15 45 -15 0 15 30 0 45 60 75 90 120 130 -15 0 15 30 TST TSST Time (min) TSST *-the majority of the depressed patients in this sample also endorsed significant early life stress as measured by the CTQ Pace et al., Am J Psychiatry, 2006.

27. Double-Blind, Parallel-Group, Randomized Study of Peripheral Cytokine Antagonist Wk 8 Wk 10 Wk 12 Baseline Wk 3 Wk 6 Wk 1 Wk 2 Wk 4 TRD Pts (N=60) INFLIX (5mg/kg) N =30 Stratification Male vs Female CRP >2 vs CRP ≤2 Randomization N =30 PLACEBO INFUSION INFUSION INFUSION Clinician-Administered Psychiatric Assessments (HAM-D, CGI) Adverse Events Evaluation Blood Draw for Inflammatory Markers and Safety Labs

28. Baseline CRP Interacts with Group Assignment To Predict End of Treatment (12 Wks) HAM-D-17 score and Treatment Response as defined by 50% reduction in HAM-D 17 at 12 Wks End of Treatment HAM-D 50% Reduction in HAM-D 17 hs-CRP Tertiles: Low: 0-1.56 mg/L Medium: 1.56-5.12 mg/L High: >5.12 mg/L

29. Representative Changes from Baseline to End of Treatment in HAM-D 17 as a Function of Baseline hs-CRP

30. Symptoms Responsive to Infliximab and Placebo in TRD subjects with Baseline CRP >5 mg/L

31. BalancingSurvivalPriorities Infection Injury Stress INFLAMMATION On the Look Out Laying Low Protection from Attack Pathogen Neutralization Wound Healing Behavioral Changes Reduced Activity Anhedonia Fatigue Depression Behavioral Changes Insomnia Hyperarousal Hypersensitivity Anxiety Neurobiological Changes Increased dACC activation Increased Time Awake Decreased Sleep Efficiency Neurobiological Changes Decreased Dopamine and Serotonin Neurotransmission NEUROPSYCHIATRIC DISORDERS

32. BalancingSurvivalPriorities Infection Injury Stress Genetics Environment INFLAMMATION On the Look Out Protection from Attack Laying Low Pathogen Neutralization Wound Healing Behavioral Changes Insomnia Hyperarousal Hypersensitivity Anxiety Behavioral Changes Reduced Activity Anhedonia Fatigue Depression Neurobiological Changes Increased dACC activation Increased Time Awake Decreased Sleep Efficiency Neurobiological Changes Decreased Dopamine and Serotonin Neurotransmission NEUROPSYCHIATRIC DISORDERS

33. BalancingSurvivalPriorities Infection Injury Stress Genetics Environment INFLAMMATION Laying Low Pathogen Neutralization Wound Healing On the Look Out Protection from Attack Behavioral Changes Reduced Activity Anhedonia Fatigue Depression Behavioral Changes Insomnia Hyperarousal Hypersensitivity Anxiety Neurobiological Changes Decreased Dopamine and Serotonin Neurotransmission Neurobiological Changes Increased dACC activation Increased Time Awake Decreased Sleep Efficiency NEUROPSYCHIATRIC DISORDERS

34. Lessons From Inflammation: Treatment

35. Neurobiology of Exercise – A Complex Cascade Structure Disease Function CNS Repair Plasticity Protection Neurogenesis Transcription NA, 5-HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB External Input Visual Olfactory Acoustic Gustatory Somatosensory Cognitive Controls Hippocampus, Cortex Learning & Memory Alzheimer’s Dementia Executive Controls Prefrontal & Cingulate Cortex • Behavior • Social • Sexual • Coping • Addictive • Escape • Fight & Flight • Stress • Sleep • Ingestive Schizophrenia Emotional Controls Amygdala, Prefrontal Cortex Depression Internal Feedback “Consequences of exercise” Motivational Controls Reward, Wanting, Selection Hypothalamus, Accumbens, VTA Sleep Disorders DA ↓ Parkinson’s Disease ↑ ROS Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Obesity Energy Balance ANS & Endocrine Systems Humoral Factors Neural Primary Afferents Diabetes CVD Muscle Cardiovascular Consequences Immune Control Immune Disorder “Exercise” Metabolic Consequences Liver, WAT, Pancreas Gastrointestinal Control IBD, Constipation Colon Cancer Thermal Consequences Dishman RK et al. (2006), Obesity 14(3):345-356; VTA = ventral tegmental area; ROS = reactive oxygen species; WAT = white adipose tissue; NFKB = nuclear factor kappa B; ANS = autonomic nervous system ; CVD = cardiovascular disease

36. Are Cytokines Pro-inflammatory in Adipose Tissues and Anti-inflammatory in Skeletal Muscles? C = controls ED = immediately after exercise E2 = 2 hrs after exercise E6 = 6 hrs after exercise Adipose tissue Muscle tissue Rosa Neto JC et al. Eur J Appl Physiol. 2009;106(5):697-704.

37. Exercise – Effects on Immune System, Skeletal System, Adipose tissue and Brain Pedersen BK, Febbraio MA. Physiol Rev. 2008;88:1379-1406.

38. Exercise And Cytokines – Exercise’s Modulating Effects Blood was obtained 40 minutes before, and 20 minutes after single bout of exercise Before exercise After exercise *, **, *** p <.05 9 athletes, oarsmen, single session exercise till exhaustion, 15-20 minutes Smits HH, et al. Clin Exp Immunology. 1998;111:463-468.

39. Practicing Mindfulness (Attention) Mind on chosen target (Nonjudgmental) Observe wandering, begin again Attention wanders (Present Moment) “If your attention wanders a hundred times, simply bring it back a hundred times.”

40. Autonomic Nervous System and Inflammatory Responses, Stress, and Meditation 50 healthy women (mean age=41.32, range=30-65), 25 novices and 25 experts, were exposed to each of the conditions (yoga, movement control, and passive-video control) during 3 separate visits. Kiecolt-Glaser JK et al. Psychosom Med. 201;72(2):113-121.

41. Antidepressants and Inflammation • TCAs and SSRIs inhibit proinflammatory cytokine production from monocytes and lymphocytes • PDE4 inhibitors (i.e. rolipram) are antidepressants in humans. These agents increase c-AMP signaling, suppress in vivo and in vitro TNF-alpha production and block autoimmune encephalomyelitis, a rodent model for multiple sclerosis • Chronic, but not acute, antidepressant administration attenuates in vivo cytokine responses to immune challenge in rodents • Fluoxetine and amitriptyline suppress NO and PGE release from LPS stimulated human cells in vitro • Chronic SRI treatment lowered TNF-alpha/CRP levels in depressed humans • Chronic ECT lowered TNF-alpha levels in severely depressed patients • Chronic antidepressant administration blocks behavioral effects of proinflammatory cytokines in rodents Maes, Adv Exp Med & Biol, 1999; Griswold et al. J Pharm & Exp Ther, 1998; Shen et al. Life Sciences, 1999; Yaron et al. Arth & Rheum 1999; Tuglu et al. Psychopharm 2003; Hestad et al. J ECT 2003; Yirmiya et al. Neuropsychopharm 2001.

42. Müller N et al, Molecular Psychiatry 2006;11:680–684 Anti-inflammatory Add on Therapy – Preliminary Data looks Promising Comparison of HamD scores during therapy with celecoxib or placebo (ANOVA, estimated marginal means; advantage of celecoxib group: Greenhouse–Geisser-corrected F= 3.220; df 2.434; P= 0.035) *Pp0.05.

43. 30 25 20 15 10 5 0 40 35 30 25 20 15 10 5 0 BT AT 9 8 7 6 5 4 3 2 1 0 BT AT BT AT Anti-depressant Treatment and Effects on Pro- & Anti-inflammatory Cytokines IL-12 (pg/ml) HDRS Interleukin-12 (IL-12) levels IL-4 (pg/ml) Hamilton Depression Rating Scale – scores before and after treatment BT - before Treatment AT - after treatment Interleukin-4 (IL-4) levels Sutcigil L, et.al. Clinical and Developmental Immunology.2007.

44. Cytokines (e.g. IFN-alpha, IL-1, IL-6, TNF-alpha) Immune Activation (e.g. secondary to infection, autoimmunity, cancer, surgery, radiation, chemotherapy tissue damage or destruction) To Summarize the Complex Issue Stress/ Depression Endocrine System Medical Illness (e.g. CVD, diabetes, cancer) Behavioral Morbidity (depression, fatigue, cognitive dysfunction and pain) CNS INFLAMMATION

45. A Clinician’s Integrative View of “Mind-Body” Disruptions in Psychiatric Mood Disorders Substance misuse Pain Coronary artery disease Mood disorders Inflammation Obesity, insulin and lipid abnormalities Sleep disorders Osteoporosis Neuropsychological impairment Neurodegeneration Adapted from Goldstein BI, et al. J Clin Psychiatry. 2009;70(8):1078-1090. Adapted from Szelényi J, Vizi ES. Ann N Y Acad Sci. 2007;1113:311-324.

46. Inflammatory and Neurodegenerative (I&ND) Hypothesis of Depression ACUTE PHASE RESPONSE in the LIVER Lower tryptophan + changes in 5HT1A and 5-HT2 receptors Depression symptoms, recurrence, treatment resistance, bipolar illness External stressors (psycho-social) IDO induction TRYCATs cytokines and intracellular inflammation O&NS Internal stressors - postnatal - inflammation (CHD, MS, IBD, RA, IMD) Increased HPA -axis activity and GR downregulation Neurodegeneration and cell death in hippocampus O&NS damage to functional peptides and membrane fatty acid Decreased neurogenesis BDNF, FGF, NCAM Leaky Gut Lower DPP IV Lower n-3 status GENETIC PREDISPOSITION IN ANY OF THE BIOMARKERS CHD = coronary heart disease; MS = multiple sclerosis; IBD = irritable bowel disease; RA = rheumatoid arthritis; IMD = immunodeficiency; DPP = dipeptidyl peptidase; IDO = indoleamine 2,3-dioxygenase; TRYCATs = tryptophan catabolites ; O&NS = oxidative & nitrosative stress; GR = glucocorticoid receptor ; FGF= fibroblast growth factor; NCAM = neural cell adhesion molecule Maes M, et.al Metab Brain Dis. 2009;24:27-53

47. Loss of pleasure* Loss of appetite* Weight loss* Cognitive disturbance* Decreased sexual energy* Fatigue* Physicalslowness* Sleepdisturbance* Social isolation* Increased pain* Fever * Sad mood† Suicidal ideation† Worthlessness/guilt† Loss of pleasure* Loss of appetite* Weight loss* Cognitive disturbance* Decreased sexual energy* Fatigue* Physicalslowness* Sleepdisturbance* Social isolation* Increased pain complaints* Increased body temperature * Sad mood† Suicidal ideation† Worthlessness/guilt† “Real” Depression Inflammation Induced “Sickness” Raison et al. Biol Psychiatry 2003

48. In Conclusion - Lessons From Inflammation Research Stress/depression increases the risk of the following: INFLAMMATION increases the risk of the following: • Coronary artery disease, heart attacks, sudden cardiac death • Obesity, diabetes • Alzheimer’s disease • Developing a cold upon virus exposure • Progression of HIV disease • Progression of cancer • Poor response to vaccination • DEPRESSION

49. Treatment Implications: Mind-Body Approach for Patients may be our best tool Treatment / s ?? Understanding

50. Rakesh Jain:JainTexas@gmail.comCome see Us in TexasMi Case, Su Casa !