10/19/12. Depression and Inflammation: The Interplay With Autoimmune Disease. Charles B. Nemeroff, MD, PhD

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1 1/19/12 Depression and Inflammation: The Interplay With Autoimmune Disease Charles B. Nemeroff, MD, PhD Leonard M. Miller School of Medicine University of Miami Miami, FL Charles B. Nemeroff, MD, PhD Disclosures Research/Grants: Agency for Healthcare Research and Quality (AHRQ); National Institutes of Health (NIH) Consultant: Eli Lilly and Company; Shire Pharmaceuticals Inc.; SK Pharma; Roche; Takeda Pharmaceuticals North America, Inc.; Xhale, Inc. Stockholder: CeNeRx BioPharma; NovaDel Pharma, Inc.; PharmaNeuroBoost, Revaax Pharmaceuticals LLC; Xhale, Inc. Other Financial Interest: CeNeRx BioPharma; PharmaNeuroBoost Patents: Method and devices for transdermal delivery of lithium (US 6,375,99B1) Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,27B2) Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP); Anxiety Disorders Association of America (ADAA); CeNeRx BioPharma; National Alliance for Research on Schizophrenia and Depression (NARSAD); PharmaNeuroBoost; Xhale, Inc.; Skyland Trail; AstraZeneca Pharmaceuticals (29) Board of Directors: American Foundation for Suicide Prevention (AFSP); Gratitude America; Mt. Cook Pharma. Inc. (21); NovaDel Pharma, Inc. (211); Skyland Trail 1

2 1/19/12 Learning Objective Recognize the interplay of inflammation and depression and use this knowledge to accurately and consistently assess patients with inflammatory disease for depression Proinflammatory Cytokines Play a Central Role in Classic Autoimmune Conditions Rheumatoid arthritis Inflammatory bowel disease Multiple sclerosis Psoriasis Ankylosing spondylitis But also: Coronary artery disease Diabetes and the metabolic syndrome Cancer Alzheimer s disease Major Clinical Disorders Associated with Inflammation Cardiovascular disease Inflammatory markers (CRP/IL-6) are potent predictors of disease outcome; involvement of inflammation in plaque formation and cardiac irritability Diabetes/metabolic syndrome/obesity High correlation between insulin resistance and IL-6 and other inflammatory markers Cancer Activation of inflammatory signaling pathways (e.g., NF-kB) implicated as a fundamental mechanism of carcinogenesis and chemotherapy resistance 2

3 Stress, Depression Endocrine System Depression/ Sickness Behavior CNS IMMUNE SYSTEM Immune- Based Diseases Cytokines (e.g. IFN-alpha, IL-1, IL-6, TNF-alpha) Inflammation/ Immune Activation (e.g. secondary to infection, trauma, surgery, radiation, chemotherapy, stress, etc.) Miller AH, et al. Biol Psychiatry. 29;65(9): Major Depressive Disorder and Systemic Illnesses Patients with MDD have a doubling of mortality and coronary artery disease at any age, independent of smoking, hypertension, and other risk factors for poor health 1 2% to 25% premenopausal patients with MDD have premature osteopenia and osteoporosis MDD is associated with an ~ 2-fold increase in the risk for Type II diabetes Is Major Depressive Disorder a Pro-Inflammatory State? 1. Wulsin LR. Harv Rev Psychiatry. 24;12(2): PMID:

4 Endothelial cell Innate Immunity/Inflammation Leukocyte Diapedesis Chemokines Stromal cell Adhesion molecules Local Local Effects - Increased vascular permeability - Vasodilation - Chemokine production - Expression of adhesion molecules - Pain tumor rubor calor dolor Macrophage NF-κB TNF, IL-1, IL-6 IFN-alpha Pathogen (e.g. bacteria), Cellular Debris Toll-like TNF receptors IL-1 (TLRs) IL-6 IFN-alpha Systemic Effects on Liver Acute Phase Response - C-reactive protein - Serum amyloid A - Haptoglobin - Alpha 1-antichymotrypsin Effects on Brain - Fever - Fatigue - Anorexia - Anhedonia - Altered sleep sickness behavior/ depression Conservation of energy resources to promote increased metabolic demands of fighting infection and mounting a fever Basis for the Hypothesis that Inflammation and an Activated Innate Immune Response May Play a Role in Depression Patients with depression (both medically ill and medically healthy) have been found to exhibit all the cardinal features of inflammation Increased plasma and CSF concentrations of innate immune cytokines (IL-6 most reliable) Increased acute phase reactants (CRP most reliable) Increased chemokines Increased cellular adhesion molecules In the majority of studies, inflammatory markers decrease with successful antidepressant therapy ( state marker ) Depressed patients with increased inflammatory markers are more likely to be treatment resistant In our study, 2/3 with high inflammation according to CDC/AHA guidelines with CRP > 3mg/L - ~5 million depressed individuals in US 1/3 with CRP > 5mg/L ~3 million depressed individuals in US Depression is Associated with Elevated Body Temperature in Medically Healthy Patients 37.6 Depression No Depression Temp ( o C) : AM 3: PM 11: PM 6: AM Time Szuba, et al. Biol Psychiatry

5 IL-6 Concentrations In Patients With Depression And Cancer Plasma IL-6 Concentration (pg/ml) Healthy Controls (n = 1) Depressed Controls (n = 12) Study Group Cancer Patients (n = 13) Depressed CA Patients with highest IL-6 plasma concentrations (H = 13.9, df = 3, p =.3) Musselman DL, et al. Am J Psychiatry. 21:158(8): Depressed Cancer Patients (n = 8) Basis for the Hypothesis that Inflammation May Play a Role in Depression Positive correlation between depressive symptom severity and innate immune cytokines Elevated innate immune cytokines predict poor response to antidepressant therapies and are elevated in patients with treatment resistance. Cytokine gene polymorphisms (IL-1, TNF) predict antidepressant treatment response Administration of innate immune cytokines, especially IL-1, TNF-alpha, and IL-6, as well as IFN-alpha, produce behavioral changes in laboratory animals and humans that resemble major depression Inhibition of cytokine signaling has been found to alleviate depressive and anxiety behaviors in patients with inflammatory disorders and in laboratory animals Basis for the Hypothesis that Proinflammatory Cytokines Play a Role in Depression and Depressive Symptoms Cytokines released peripherally have access to the brain Passage through leaky regions in the BBB Active transport Transmission through afferent nerve fibers (vagus) There is a cytokine network in the CNS Glia (microglia) and neurons express/produce cytokines and express cytokine receptors Cytokines have effects on neurotransmitter turnover, neuroendocrine function, and behavior (sickness behavior) 5

6 Childhood Abuse = Unhealed Wounds More Psychological Problems (such as depression anxiety, somatization, low self esteem, substance abuse, suicide attempts) Women who experienced no abuse Women who experienced childhood abuse = Women experiencing current abuse Women who have experienced childhood abuse and are experiencing current abuse Physical Symptoms Less (such as back pain, headaches, pelvic pain, abdominal symptoms, etc.) McCauley J, et al. JAMA. 1997;277(17): PMID: More Chronic Pelvic Pain, Fatigue, and Physical Symptoms Acyclic Chronic Pelvic Pain Loss of Energy/ Fatigue General Health Checklist Prevalence of CPP (%) Prevalence of Fatigue (%) Controls ELS ELS/PTSD General Dermatological Visual Audio/Olfactoric MTN Cardiological Endocrinological Orthopedical Gastrointestinal Neurological OB-GYN/Urological Controls ELS ELS/PTSD Controls ELS ELS/PTSD Dotted bar: Loss of energy Filled bar: Tired all the time Number of Symptoms in the Past Month Patients with Major Depression Exhibit an Exaggerated Inflammatory Response to Stress A Possible Link Between Stress, Depression, and Illness Plasma IL-6, pg/ ml 6 5 Control (n = 13) Major Depression (n = 14) Control (n = 13) Major Depression + (n = 14) Plasma IL-6, pg/ ml NF-kB DNA-binding (% of baseline) Control (n = 16) Major Depression (n = 1) TSST Time (Min) TSST TSST Time (Min) Between group comparison, p < Between.5 group comparison, p <.5 + Within group comparison vs. +Within min time group pt, comparison p <.5 vs. min time pt, p <.5 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. 26;163(9): PMID:

7 Childhood Maltreatment Predicts Adult Inflammation in a Life-Course Study The life-course association between childhood maltreatment and adult inflammation was examined in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels, 2 years later The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood Danese A, et al. Proc Natl Acad Sci USA. 27;14(4): PMID: The Association of Childhood Maltreatment with Biomarkers of Inflammation Danese A, et al. Proc Natl Acad Sci U S A. 27;14(4): PMID: Questions Do proinflammatory cytokines, and therefore, the immune system contribute to the pathophysiology of major depression in the medically ill? What mechanisms are involved? What are the treatment implications? 7

8 Interferon-Alpha as a Model System to Study Cytokine- Induced Depression Antiviral/antiproliferative cytokine used to treat viral infections and cancer Potent inducer of innate immune response including innate immune cytokines (especially IL-6) Potent inducer of behavioral toxicity including symptoms of major depression in humans and non-human primates IFN-Alpha-Induced Behavioral Symptoms in Patients with Malignant Melanoma Placebo-treated patients (%) experiencing moderate-to-severe intensity in the listed symptom during IFNalpha therapy Capuron L, et al. Neuropsychopharmacology. 22;26(5): PMID: High-Dose Interferon in Malignant Melanoma Paroxetine Pretreatment Randomized, Double-Blind Treatment (N = 4) Paroxetine x 2 Weeks Placebo x 2 Weeks IV IFN-α x 4 Weeks 2 x 1 6 U/m 2 SQ IFN-α up to 48 Weeks 1 x 1 6 U/m 2 Paroxetine Arm 2-4 mg Placebo Arm Week Week 4 Week 8 Week 12 Musselman DL, et al. N Engl J Med. 21;344(13): PMID:

9 Incidence of Major Depression During the First 12 weeks of IFN-alpha 1 Survival Free of Major Depression (%) n = Weeks on IFN-alpha Musselman DL, et al. N Engl J Med. 21;344(13): PMID: Paroxetine Pre-treatment Reduces the Incidence of Major Depression During the First 12 weeks of High Dose IFN-alpha for Malignant Melanoma 1 Survival Free of Major Depression (%) Paroxetine (n = 18) Placebo (n = 2) Weeks on IFN-alpha Musselman DL, et al. N Engl J Med. 21;344(13): PMID: IFN-alpha-induced Depression is Associated with Tryptophan (TRP) Depletion TRP IFN-alpha/ Cytokines ACTH IDO Kynurenine Quinolinic Acid CRH Serotonin IDO indolamine 2,3 dioxygenase Capuron L, et al. Mol Psychiatry. 22;7: PMID: IFN-alpha-induced Depression is Associated with Exaggerated HPA Activation Depression/ Sickness Behavior Adrenal Gland Cortisol IFN-alpha/ cytokines Capuron L, et al. Am J Psychiatry. 23;16: PMID:

10 IFN-alpha-induced Depressive-like Behavior ( Huddling ) is Associated with Exaggerated HPA Activation in Monkeys 25 2 Taken from Kalin,, N.H., 1985 [12] ICV CRH sc IFN-alpha (2 million units/m 2 ) Huddling: a fetal-like self-enclosed position with head at or below shoulders. ACTH (pg/ml) p <.1 Non- Huddler Huddler Maximal ACTH response to IFN-alpha in huddlers vs. non-huddlers McKinney WT Jr., et al. Dis Nerv Syst. 1971;32(11): PMID: Kalin NH, et al. Life Sci. 1985;36(12): PMID: IFN-alpha Effects on Basal Ganglia Function Correlate with Fatigue Capuron L, et al. Neuropsychopharmacology. 27;32(11): PMID: CSF Homovanillic Acid (HVA), the Major Metabolite of Dopamine, Correlates with Fatigue and CSF IL-6 in IFN-alpha-treated Patients 1 r = -.43, p <.5 1 r = -.43, p < CSF HVA (ng/ml) CSF HVA (ng/ml) CSF IL-6 (pg/ml) Fatigue (Total Score) IFN-alpha IL-6 dopamine HVA fatigue 1

11 Prevalence of Moderate/ Severe Depressive Symptoms During Treatment with Pegylated IFN-alpha % of Patients with SDS Index Exponential Trend Line p <.1 (Cochran-Armitage Trend Test) Baseline Week 4 Week 8 Week 12 Week 24 Significantly different from baseline (p <.5) Raison CL, et al. J Clin Psychiatry. 25;66(1): PMID: Rates of Depression Are Uniformly Elevated in Inflammatory Conditions Depressive syndromes are a risk factor for the development of CAD, metabolic syndrome, cancer Depression increases morbidity in all inflammatory conditions and has been repeatedly shown to increase risk of mortality in context of CAD and cancer (and its treatment) Translational Targets IFN-a Raison, Capuron, Miller. Trends in Immunology. 26;227: PMID:

12 Inflammation and Treatment Resistance Clinical Predictor of Antidepressant Non-Response Obesity Early Life Stress Medical Illness Personality Disorders/Anxiety Relation to Inflammation Dose response relationship between BMI and inflammatory markers Increased inflammation and inflammatory response to stress in individuals exposed to early life stress Increased inflammatory markers in cancer and cardiovascular disease Increased inflammatory markers in patients with Anxiety Disorders, Borderline Personality Disorder and Neuroticism Inflammation and Depression: The Perfect Storm Cytokines and Treatment Resistance Cytokines reduce monoamine synthesis (IDO) and increase reuptake (p38 MAPK) Conventional antidepressants act through increasing the availability of monoamines (block reuptake) Cytokines inhibit neurogenesis Conventional antidepressants are less effective in the absence of neurogenesis 1 Cytokines impact glutamate metabolism Conventional antidepressants target monoamines and do not act on glutamate metabolism Ketamine, a glutamate antagonist, is effective in treatment-resistant depression 2 IDO = indoleamine 2,3 dioxygenase; MAPK = mitogen activated protein kinase 1. Santarelli, et al. Science. 23;31: PMID: aan het Rot M, et al. Biological Psychiatry. 21;67: PMID: Etanercept and Clinical Outcomes, Fatigue, and Depression in Psoriasis Double-Blind Placebo-Controlled Randomized Phase III Trial Improvement in symptoms of depression were not correlated with objective measures of skin clearance or joint pain Tyring S, et al. Lancet. 26;367(954): PMID:

13 Testing the Cytokine Hypothesis of Depression Does blockade of inflammatory cytokines reverse depression in patients with treatment-resistant depression (TRD)? Goal: To Test the Cytokine Hypothesis of Depression in Patients with TRD TNF-alpha Antagonist Scientific Reasons TNF-alpha reliably elevated in MDD TNF-alpha and its soluble receptor correlates with IFN-alpha-induced depression TNF-alpha antagonist improved depressed mood in patients with inflammatory disorders TNF receptor KO mice exhibit antidepressant-like response and decreased anxiety following immune stimulation Goal: To Test the Cytokine Hypothesis of Depression in Patients with TRD (cont d.) TNF-alpha Antagonist Infliximab monoclonal antibody directed at TNF-alpha Used to treat autoimmune and inflammatory disorders Pharmacologic reasons Biologics (monoclonal antibodies) have no off-target effects or drug-drug interactions (directly test the cytokine hypothesis of depression) Limited brain penetrance (central vs. peripheral effects) No compliance issues with infusions Off label use 13

14 Double-Blind, Parallel- Group, Randomized Design TRD Pts (N = 6) INFLIX (5mg/kg) Baseline N = 3 Wk 1 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 1 Wk 12 Stratification Male vs. Female CRP >2 vs. CRP 2 Randomization PLACEBO N = 3 INFUSION INFUSION INFUSION Clinician-Administered Psychiatric Assessments (HAM-D, CGI) Adverse Events Evaluation Blood Draw for Inflammatory Markers and Safety Labs Off label use Inclusion/Exclusion Criteria Males/Females ages 25-6 Medically Healthy (Normal PE and labs) MDD or Bipolar depressed by SCID QIDS-16 score 14 On stable antidepressant regimen or off meds for at least 4 weeks No psychotic symptoms or hx of psychosis No substance abuse X 6 months Not suicidal Non-pregnant on birth control Demographic Characteristics of Study Sample Infliximab (n = 3) Placebo (n = 3) Age (yrs.) mean (SD) 42.5 (8.2) 44.3 (9.4) Sex (female) no. (%) 2 (66%) 2 (66%) Ethnic Origin - no. (%) Caucasian Black Other Education (Highest Degree) no. (%) Graduate Degree College Graduate Partial College High School Graduate 23 (77%) 6 (2%) 1 (3%) 8 (27%) 13 (43%) 8 (27%) 1 (3%) 23 (77%) 5 (17%) 2 (6%) 7 (23%) 13 (43%) 9 (3%) 1 (3%) Unemployed no. (%) 12 (4%) 12 (4%) Off label use 14

15 Clinical Characteristics of Study Sample Infiximab Placebo Age of Onset of MDD (yrs.) mean (SD) 19.1 (8.3) 18.9 (1.7) Lifetime Episodes of MDD no. (SD) 8.7 (24.8) 7.8 (24.8) Duration of Current Episode (mos.) mean (SD) (148.8) (165.25) Antidepressant Trials in Current Episode no. (SD) 4.6 (3.2) 3.7 (2.1) MGH-S score mean (SD) 7.73 (6.6) 6.1 (3.5) Family History of MDD no. (%) 27 (9%) 23 (77%) Mood-Relevant Psychotropic Medication no. (%) 16 (53%) 21 (7%) Co-Morbid Medical Illness no. (%) 13 (43%) 19 (63%) Bipolar Disorder no. (%) 3 (1%) 6 (2%) Clinical Characteristics of Study Sample (cont d.) Infiximab Placebo BMI (kg/m2) mean (SD) 31.2 (6.9) 32.7 (8.) Baseline hs-crp (mg/l) mean (SD) 6.21 (9.1) 5.7 (8.1) Baseline HAM-D 17 mean (SD) 24.1 (4.) 23.6 (3.8) Baseline CGI-severity mean (SD) 4.8 (.59) 4.8 (.81) Change in HAM-D-17 in Infliximab vs. Placebo- Treated TRD Patients LS Mean (SEM) Change in HAM- D-17 from Baseline Significant interaction among treatment, time and log hs-crp (t = 2.65, df = 32, p =.1) Off label use 15

16 Change in HAM-D-17 Score from Baseline to Week 12 (Infliximab- Placebo) in TRD Patients Subgrouped By Baseline Plasma hs-crp Off label use Standardized Effect Size =.41 favoring infliximab at CRP > 5mg/L Change in HAM-D-17 Scores from Baseline to Week 12 in Infliximab- or Placebo-Treated TRD Patients with a Baseline CRP > 5 mg/l versus 5mg/L A. CRP > 5mg/L B. CRP 5mg/L Off label use Percent Treatment Responders in Infliximab- vs. Placebo-Treated TRD Patients with a Baseline hs-crp 5mg/L or >5mg/L Treatment Response ( 5 reduction in HAM-D-17 at any point during treatment) Off label use 16

17 Symptoms Responsive to Infliximab and Placebo in TRD Subjects with Baseline hs-crp>5 Off label use Hitting the Sweet Spot Summary Depression is associated with evidence of increased inflammation, which in turn may contribute to the impact of depression on comorbid medical disorders Stress is capable of activating the inflammatory response (likely through SNS pathways) Activation of the inflammatory response can induce behavioral symptoms that overlap with MDD 17

18 1/19/12 Summary (cont d.) Cytokine (IFN-alpha)-induced depression appears to be mediated by alterations in serotonin metabolism, activation of CRH pathways, and alterations in basal ganglia circuitry Aggressive preventative treatment strategies can be used to limit depression in high-risk medically ill Treatments targeting the immune system may be relevant for the treatment of depression in both medically ill and medically healthy patients Co-sponsored by Save the Date! 6th Annual Chair Summit September 26-28, 213 Westin Tampa Harbour Island Tampa, Florida Check out for the most recent information on Chair Summit 213. Registration will be open soon. See you in Tampa! 18