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A Mind-Body Perspective of Major Depressive Disorder

A Mind-Body Perspective of Major Depressive Disorder. Rakesh Jain, MD, MPH R/D Clinical Research, Inc. Lake Jackson, Texas, USA Texas Tech Health Sciences Center – Permian Basin Midland, Texas, USA. Let’s Not Underestimate Our Enemy: Depression is THE Leading Cause of Disability.

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A Mind-Body Perspective of Major Depressive Disorder

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  1. A Mind-Body Perspective of Major Depressive Disorder Rakesh Jain, MD, MPH R/D Clinical Research, Inc. Lake Jackson, Texas, USA Texas Tech Health Sciences Center – Permian Basin Midland, Texas, USA

  2. Let’s Not Underestimate Our Enemy: Depression is THE Leading Cause of Disability *DALYs represent total number of years lost to illness, disability, or premature death within a given population. They are calculated by adding number of years of life lost to number of years lived with disability for a certain disease or disorder. National Institute of Mental Health. http://www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed June 6, 2011.

  3. Why is Treatment of Depression so Important? Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008 UK Population 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.

  4. 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.

  5. Childhood Adversity Represents a Risk for Adulthood Disease Number of Adverse Childhood Experiences 70 0 (n=502) 60 1 (n=253) ≥2 (n=98) 50 40 % of Study Members With the Condition 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 32-year prospective study. Major depression (panel 1): z=4.94, P<.001. High-sensitivity C-reactive protein (hsCRP) level  3 mg/L (panel 2): z=3.24, P=.001. Clustering of metabolic risk markers (panel 3): z=4.58, P<.001. 1 age-related disease risks (panel 4): z=5.66, P<.001. Adapted from Danese A, et al. Arch PediatrAdolesc Med. 2009;163(12):1135-1143.

  6. Association of Depression and AnxietyWith Chronic Physical Conditions World Mental Health Survey (N=42,249) P<.05 for all comparisons vs persons with neither depression nor anxiety Depression Anxiety Depression and anxiety *Data show odds ratio with 95% confidence intervals (CI). HTN=hypertension. Scott KM, et al. J Affect Disord. 2007;103(1-3):113-120.

  7. Depression Decreased Long-term Survival After Myocardial Infarction (MI) Long-Term Survival After MI in Relation to Beck Depression Inventory (BDI) Score During Hospitalization 100 BDI <5 BDI 5 to 9 BDI 10 to 18 90 BDI ≥19 Cardiac Death-Free Survival (%) 80 70 N=896 60 0 365 730 1095 1460 1825 Days Postdischarge After MI Adapted from Lespérance F, et al. Circulation. 2002;105(9):1049-1053.

  8. Depression and MI: Importance of Depression and its Optimum Treatment Data derived from MIND-IT study, participants had post-MI depression Event Rate: Non-responders = 25.6 % Untreated controls = 11.2 % Responders = 7.4 % MI = myocardial infarction. de Jonge P, et al. Am J Psychiatry. 2007;164:1371-1378.

  9. MDD was Associated With Progression of Atherosclerosis 0.16 P for Linear Trend=.003 N=324 0.14 0.12 0.10 3-Year Change in Carotid IMT (mm) 0.08 0.06 0.04 0.02 0.00 0-1 2-4 5-19 BDI-II Total Score IMT=intima-media thickness; BDI-II=Beck Depression Inventory II. Adapted from Stewart JC, et al. Arch Gen Psychiatry. 2007;64(2):225-233.

  10. Relationship Between Obesity, Metabolic Syndrome, and Depression Associationbetweenmetabolicsyndrome(MetS)anddepressionineachbodymass index(BMI)category. Graphdisplaysoddsratio (OR)fordepressionafteradjustmentforage,gender,priorcardiovascular disease,employmentstatus,maritalstatus,smokingstatus,dietaryscore, andphysicalactivity.ObesitywasdefinedasBMI ≥30andoverweight statusasaBMIbetween25and30kg/m2 Odds Ratio - Depression Skilton MR, et al. Biol Psychiatry. 2007;62(11):1251-1257.

  11. Adipose Tissue: a Potent Source of InflammationOne more reason for Optimum Weight Management Shelton RC, Miller AH. ProgNeurobiol. 2010.91: 275-299.

  12. 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):1279-1283.

  13. Neuroendocrine, Autonomic, and Immune Dysregulation in MDD CRH = corticotropin-releasing hormone; NF-κB = nuclear factor kappa B; ACTH = adrenocorticotropic hormone. Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741. Reprinted with permission from Elsevier Limited.

  14. Inflammatory Cytokine Levels Were Associated With Symptom Severity in Patients With MDD A. Concentration B. Guilt C. Sadness 120 120 120 100 100 100 80 80 80 Daily Mean VAS Score (mm) 60 60 60 40 40 40 R2=0.5139 R2=0.4058 R2=0.6711 20 20 20 P=.02 P=.05 P=.004* 0 0 0 0 0.5 1.0 1.5 2.0 2.5 0 0.5 1.0 1.5 2.0 2.5 0 0.5 1.0 1.5 2.0 2.5 D. Self-Esteem E. Suicidal Thoughts F. Tiredness 120 120 120 100 100 100 80 80 80 60 Daily Mean VAS Score (mm) 60 60 40 40 40 R2=0.735 R2=0.7785 R2=0.566 20 20 20 P=.002* P=.0007* P=.02 0 0 0 1.5 0 0.5 1.0 2.0 2.5 0 0.5 1.0 1.5 2.0 2.5 0 0.5 1.0 1.5 2.0 2.5 Daily Mean Log IL-6 (pg/mL) Daily Mean Log IL-6 (pg/mL) Daily Mean Log IL-6 (pg/mL) *Correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction; VAS=Visual Analog Scale. Adapted from Alesci S, et al. J ClinEndocrinolMetab. 2005;90(5):2522-2530. Comparison of 5 Patients With MDD and 5 Matched Healthy Controls

  15. “The King is Dead – Long Live the King”: Beyond the Monoamine Hypothesis of Depression Gene transcription cascades Neurotrophins Systems Circuitry Neuronal Circuitry Intra-cellular Pathways Monoamine neurotransmitter-level view Marsden WN. Med Hypotheses. 2011.77:508-528.

  16. Macro- and Microscopic Structures Involved in Mood Disorders Schloesser RJ, et al. Neuropsychopharmacology. 2008;33:110-133.

  17. Examining the Neurotrophic Hypothesis of Depression Normal Treatment Depression Berton O, Nestler EJ. Nat Rev Neurosci.2006;7:137-151.

  18. 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.

  19. Neurotransmitter–Receptor–Intracellular–Gene Transcription Interactions Racagni G, et al. World J Biol Psychiatry. 2011;12:574-587.

  20. Circuitry in Depression: Examining Two Models An amygdala-centric circuit largely inspired by structural brain imaging and postmortem studies Another circuit model generated with a greater emphasis on functional imaging results Krishnan V, Nestler RJ. Am J Psychiatry. 2010;167(11):1305-1320.

  21. Inflammation and Depression: the Brain-Body Link Capuron L, Miller AH. PharmacolTher. 2011;130:226-238.

  22. Depression and Inflammation:What is the link ? Induction of indoleamine 2,3-dioxygenase (IDO) by IF and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites (such as kynurinate, and quinolinic acid) Stroke, AD, HD, PD, MS Psychological stress SERT 5-HT Melancholic symptoms Anxiety Fatigue and somatic symptoms L-tryptophan IFNy, IL-2, IL-1β, TNFα, IL-6 Microglial activation Neuroinflammation IDO TRYCATs IFNy, IL-2, IL-1β, TNFα, IL-6 Peripheral CMI activation and inflammation TRYCATs All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. IDO L-tryptophan CVD; COPD; RA; SLE; IBD; HIV Diabetes; Metabolic syndrome Postpartum period; Hemodialysis IFNα-immunotherapy; Predisposing factors: immune and inflammatory genes Lowered levels of peptidases (DPP IV and PEP) Leonard B, Maes M. NeurosciBiobehav Rev. 2012;36:764-785.

  23. A “Tripartite” Model of Mind-Body Link: Inflammatory, Autonomic, and HHPA Axis Abnormalities Jain R, et al. Curr Diab Rep. 2011;11:275-284.

  24. The Multi-channel Connections Between Mind and Body in Inflammatory Signaling Capuron L, Miller AH. PharmacolTher. 2011;130:226-238.

  25. What Are the Treatment Implications of This Emerging Mind-Body Neurobiology? Footnote goes here

  26. A Clinician’s View Of Major Depression: 16 out of 9 Symptoms! (All are Important to the Clinician) Obsessive rumination Brooding • Depressed mood • Decreased interest or pleasure • Significant appetite or weight change • Fatigue Tearfulness • Insomnia or hypersomnia • Psychomotor disturbances • Worthlessness/guilt • Impaired concentration • Thoughts of death/suicide Irritability Pain Excessive worry over physical health Anxiety or phobias DSM-IV diagnostic criteria Associated symptoms APA. DSM-IV-TR. 2000:352,356.

  27. Which Interventions to Pick for Optimally Treating this Mind-Body Condition – Depression ? Footnote goes here

  28. Cognitive Therapy and Behavioral Activation Were Advantageous in Delaying Relapse 1.0 Continued medication (n=28) 0.9 Placebo (n=21) Prior behavioral activation (n=27) 0.8 Prior cognitive therapy (n=30) 0.7 0.6 Survival 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time Since End of Treatment (Months) Participants were initially assigned to 16 weeks of antidepressant treatment (n=100), cognitive therapy (n=45), and behavioral activation (n=43); treatment responders on antidepressants were randomized to continue with medication or placebo; relapse was defined as HAM-D score of 14; recurrence was defined with same criteria during second year of follow-up AdaptedfromDobson KS, et al. J Consult Clin Psychol. 2008;76(3):468-477.

  29. Impact of Cognitive Therapy on Amygdala and Prefrontal (Dorsolateral PFC) Activity in MDD a. Emotional b. Cognitive Is it you? UGLY Put the digits in numerical order 7 4 3 1 5 Patients with depression (n=9) Controls (n=24) 0.30 0.15 0.25 0.10 0.20 0.15 BOLD Signal (% Change) 0.05 BOLD Signal (% Change) 0.10 0.00 0.05 0.00 -0.05 2 4 6 8 10 12 16 18 14 2 4 6 8 10 12 Time (Seconds) Time (Seconds) Pre 12 Weeks of Cognitive Therapy Post Control Adapted from DeRubeis RJ, et al. Nat Rev Neurosci. 2008;9(10):788-796. Reprinted with permission from Macmillan Publishers Ltd.

  30. CBT and Inflammation: Symptoms and Neurobiological Marker Improvement CRP=C-reactive protein; CABG=coronary artery bypass graft. Doering LV et.al. AlternTher Health Med. 2007;13(3):18-21.

  31. Psychotherapy and Receptor Changes: Is this even possible? This is first direct demonstration of a specific neurotransmitter mechanism involved in neurobiology of psychotherapy. Increased serotonin 5-HT1A receptor binding in multiple cortical regions following psychotherapy in patients with MDD Significant increase in 5-HT1A density in PSY group compared to FLU group in frontal, temporal, and parietal cortex (angular gyrus, medial prefrontal cortex, orbitofrontal cortex) Short-term psychodynamic psychotherapy (PSY, n=8) or fluoxetine (FLU, 20 mg/d, increased up to 40 mg/d if needed, n=15) for 16 weeks Karlsson H, et al. Psychol Med. 2010;40:523-528.

  32. Physical Exercise and Mental HealthIs It Time to Start Prescribing It?

  33. Neurobiology of Exercise: a Complex Cascade That Also involves Neurotransmitters and Receptors Disease Structure Function CNS Alzheimer’s Dementia Cognitive Controls Hippocampus, Cortex Learning and Memory • External Input • Visual • Olfactory • Acoustic • Gustatory • Somatosensory Repair Plasticity Protection Neurogenesis Transcription NA, 5-HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB • Behavior • Social • Sexual • Coping • Addictive • Escape • Fight & Flight • Stress • Sleep • Ingestive Schizophrenia Executive Controls Prefrontal andCingulate Cortex Depression Emotional Controls Amygdala, Prefrontal Cortex Sleep Disorders Motivational Controls Reward,Wanting,Selection Hypothalamus, Accumbens, VTA Internal Feedback “Consequences of exercise” DA ↓ Parkinson’s Disease ↑ ROS Obesity Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Energy Balance ANS and 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 ANS=autonomic nervous system; BDNF=brain-derived neurotrophic factor; CNS=central nervous system; CREB=cyclic adenosine monophosphate response element-binding protein; CVD=cardiovascular disease; DA=dopamine; ERK=extracellular signal-regulated kinase; 5-HT=5-hydroxytryptamine; GABA=gamma amino butyric acid; IBD=inflammatory bowel disease; NA=noradrenaline; NFκB=nuclear factor of kappaB; ROS=reactive oxygen species; TrkB=tyrosine residue kinase receptor-type 2; VTA=ventral tegmental area; WAT=white adipose tissue. Reprinted by permission from Macmillan Publishers Ltd: Dishman RK et al. Obesity. 2006;14(3):345-356.

  34. Clinical and Neurobiological Evidence for Exercise and Wellness: Receptors are Involved Here, too! Reduction in opioidreceptor availability after exercise (red is P<0.05) VAS Scores before and after exercise Euphoria and Happiness were significantly different (P<0.05) Boecker H et al. Cereb Cortex. 2008;18(11):2523-2531.

  35. Exercise’s Effects on Hippocampal Cell Proliferation and Neurogenesis Ki 67 positive newly generated cells DCX positive young neuronal cells # p<0.10 *** p<0.001 Van derBorght K, et al. Hippocampus. 2009;19:928-936.

  36. Physical Exercise: a Modulator of Inflammatory Cytokines Nicklas BJ, et al. J Am Geriatr Soc. 2008;56:2045-2052.

  37. Effect of Different Types of Exercise Mead GE, et al. Cochrane Database of Syst Rev. 2008 Oct 8;(4):CD004366.

  38. Depression and Aerobic Exercising: Emerging Evidence of Efficacy p=0.03 N = 80 16 T p=0.04 T 12 T Hamilton Rating Scale for Depression - 17 8 4 0 Control Low Dose Public Health Dose HAM-D 17 Reduction from Baseline 12 Weeks Duration Low Dose: 7.0-kcal/kg/week energy expenditure PHD: Public Health Dose -17.5-kcal/kg/week energy expenditure Dunn AL, et al. Am J Prev Med. 2005;28(1):1-8.

  39. Yoga as a Mind-Body Intervention Mean thalamic GABA levels in subjects with Major Depressive Disorder (MDD) and low back pain (LBP) (n=2) compared to normal subjects (n=19) before (Scan 1) and after (Scan 2) a 12-week yoga intervention Streeter CC, et al. Med Hypotheses. 2012;78:571-579.

  40. Mindfulness Based Cognitive Therapy (MBCT) Footnote goes here

  41. Walking Down the Street You're walking down the street. On the other side of the street you see somebody you know. You smile and wave. The person does not wave back and keeps walking.

  42. Old patterns intrude Memory bias Poor problem solving Wish for things to be different Mindlessness and Vulnerabilityto Depression Depression Non-awareness Rumination

  43. Old patterns intrude Safe “platform” Wish for things to be different Calm Connected Creative Mindfulness and Preventionof Relapse into Depression Freedom to choose not to “go there” Low mood Mindful awareness

  44. Volumetric Changes Over 8 Weeks of Mindfulness Based Therapy – Focus on Amygdala Stressed but otherwise healthy individuals (N 1⁄4 26) participated in 8-week mindfulness-based stress reduction intervention Holzel BK, et al. SCAN. 2010;5:11-17.

  45. Volumetric Changes in Hippocampus With 8 Weeks of Mindfulness Based Therapy 16 healthy, meditation-naïve participants were obtained before and after they underwent 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry, and compared with waiting list control group of 17 individuals. Holzel BK, el al. Psychiatry Res. 2011;191:36-43.

  46. ANS 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 three separate visits. Kiecolt-Glaser JK et al. Psychosom Med. 2010;72:113-121.

  47. Mindfulness Based Cognitive Therapy (MBCT) – Promising New Therapy M-ADM = Medication (anti-depressant continuation) MBCT= Mindfulness based CT Pla+Clin = Placebo plus clinical management Segal Z, et al. Arch Gen Psychiatry. 2010;67(12):1256-1264.

  48. Neurobiological Driven Rationale: Combination May be the Gold Standard Therapy in Depression Pharmacotherapy Cognitive-Behavioral Therapy Limbic Hyperactivity Dorsal Cortex Emotional/ Cognitive Dysregulation Pleasure Circuit Dampening Pharmacotherapy + Cognitive-Behavioral Therapy + Positive Activity Interventions Positive Activity Interventions Layous K, et al. J Altern Complement Med. 2011;17:675-683.

  49. Complete and Several Types of Incomplete States of Mental Health High subjective well-being symptoms Incomplete mental illness Complete mental health Struggling Flourishing High mental illness symptoms Low mental illness symptoms Floundering Languishing Complete mental illness Incomplete mental health Low subjective well-being symptoms Slade M. BMC Health Serv Res. 2010;10:26.

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