Physical Exercise & Mental Health Is it time to start Prescribing it ?

1. Physical Exercise & Mental Health Is it time to start Prescribing it? Rakesh Jain, MD, MPH

2. Exercise and Meditation -Deep Examination of Two Powerful Tools In Mental Health Treatment Rakesh Jain, MD, MPH

3. Neurobiology of Exercise – A Complex Cascade Structure Function Disease CNS External Input Visual Olfactory Accoustic Gustatory Somatosensory Repair Plasticity Protection Neurogenesis Transcription NA, 5-HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB 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 ANS & Endocrine Systems Humoral Factors Neural Primary Afferents Energy Balance Diabetes Muscle CVD Cardiovascular Consequences Immune Control Immune Disorder “Exercise” Metabolic Consequences Liver, WAT, Pancreas IBD, Constipation Colon Cancer Gastrointestinal Control Thermal Consequences Dishman RK et al. Obesity. 2006;14(3):345-356.

4. Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan Scatterplots showing increase in fitness (VO2 peak) is related to increase in hippocampal volume (cm3) Correlations significant for both left and right (even after including age, sex, years of education as covariates) Erickson KI, et al. Hippocampus. 2009; ahead of publication.

5. Exercise’s Effects on Hippocampal Cell Proliferation & Neurogenesis Ki 67 positive newly generated cells DCX positive young neuronal cells # p< 0.10 *** p< 0.001 Van der Borght K, et al. Hippocampus. 2009; ahead of publication.

6. Another Reason to Optimize Weight (through exercise and caloric intake regulation): Impact of Metabolic Syndrome on Inflammatory Markers Percentage difference: CRP = 89.5 % * IL-6 = 27.8 % * TNF-a = 9.0 % (*p <.05) Capuron L, et al. Biological Psychiatry. 2008;64:896-900.

7. Physical Exercise – A modulator of Inflammatory Cytokines Nicklaus BJ, et al. J Am Geriatrics Society. 2008;56:2045-2052.

8. Exercise Augments Endo-Cannabinoid Signaling Rat study, 8 days of voluntary exercise CB1 receptor site binding density Hill MN, et al. Hippocampus 2009; ahead of publication.

9. Endogenous Opioids & Exercise (“Runner’s High”) VAS Scores before and after exercise. Euphoria and Happiness were significantly different (p<.05) Reduction in opioid receptor availability after exercise (red is p<.05) Boecker H et al. Cerebral Cortex. 2008;18:2523-2531.

10. BDNF Changes with Exercise, Medication, and Combination WT – wild type mice CREBIR – mice with CREB knockout BDNF = brain-derived neurotrophic factor # WT>CREB p<.05 * ET> sedentary p<.05 Chen MJ, Russo-Neustadt AA. Hippocampus. 2009; ahead of publication.

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

12. A Quick Primer on Effect Sizes 0.8 large 0.5 medium small 0.3 Effect size = mean of one population – mean of another population standard deviation 0

13. Cochrane Database Weights On… • Meta-analysis of 25 studies • Exercise did improve symptoms of depression • Evidence suggests that exercise probably needs to be continued in the longer-term for benefits to be maintained • Comparison made with controls, psycho-therapy and pharmacotherapy Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.

14. Exercise vs. Control Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.

15. Exercise vs. Cognitive Therapy Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.

16. Exercise vs. Anti-depressants Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.

17. Effect of Different types of Exercise Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.

18. Exercise Intensity’s Effect on Anti-depressant Response of VO2 MAX of VO2 MAX Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

19. Exercise Frequency’s Effect on Depression Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

20. Type of Exercise, & its Effect on Anti-depressant Response Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

21. Exercise Duration (in weeks) and Effects on Depression Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

22. Exercise Duration and Effects on Depression (in minutes) Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

23. Age and Effects on Depression Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.

24. Male vs. Female – Exercise’s Effects on Depression Rethorst CD, et al. Sports Medicine 2009. 39(6):491-511.

25. What About Drop-outs With Exercise Rx.?? “ Analysis showed dropout rates for the exercise treatment were similar to those found in psychotherapeutic and drug interventions.” Rethorst CD, et al. Sports Medicine 2009. 39(6):491-511.

26. 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 12 Weeks Duration HAM-D 17 Reduction from Baseline 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.

27. Exercise, Medication, Compared to Combination 16 week study Medication = sertraline 50-200 mg per day Exercise = 3 times per week, total 45 minutes, at least 30 minutes at 70-85 % MHR Medication treatment, n=48 Exercise, n=53 Combined, n = 55 Blumenthal JA, et al. Arch Intern Med.1999;159:2349-2356.

28. Exercise Helpful in both Mildly, and Moderately/Severely ill patients Medication = sertraline 50-200 mg per day Exercise = 3 times per week, 45 minutes ,30 minutes at 70-85 % MHR Medication treatment, n=48 Exercise, n=53 Combined, n = 55 Blumenthal JA, et al. Arch Intern Med.1999;159:2349-2356.

29. Long Term Benefits of Exercise in Depression (6 month follow-up after Blumenthal study) Recovered = HDRS score of less than 8 and no DSM-IV depression Partially Recovered= no DSM-IV depression and HDRS score greater than 7 but less than 15 Exercise, n=25 Medication, n=29 Combined, n=29 Those in the exercise condition were more likely to be partially or fully recovered and were less likely to have relapsed Babyak M, et al. Psychosomatic Medicine. 2000; 62:633-638.

30. Augmentation of Anti-depressants with Exercise Average exercise frequency= 3/week; duration (mean) 55.3 minutes per session at week 1; 50.6 minutes at week 12 12 week study, open label. Patients were on anti-depressants and had a HDRS score of 14 or greater, all participants n=17; completer sample n = 8 Trivedi MH, et al. Journal of Psychiatric Practice. 2006;12:205-213.

31. The Best Designed Exercise vs. Medication Study yet… Remission defined as a HAM-D 17 score of 7 or less Home exercise n=53 Supervised exercise n =51 Sertraline n = 49 Placebo n= 49 • Remission Rates: • * Placebo = 31 % • * Home Exercise = 40 % • Supervised Exercise = 45 % • * Medication = 47 % 16 week study Exercise: 3/week Sertraline :50-200mg/day Blumenthal JA, et al. Psychosomatic Medicine. 2007;69:587-596.

32. Is there a Relationship between Exercise Dose and Well-being? Control 50% 100% 150% Control 50% 100% 150% ? Does ‘dose’ of exercise affect physical & mental functioning? ? Is weight loss necessary to benefit from exercise? Exercise dose = % of recommended daily energy expenditure- 8kcal/kg Martin CK, et al. Arch Intern Med. 2009;169(3):269-278.

33. And, what is the news from the world regarding Exercise Rx? “In Australia, …services of an exercise physiologist under the nation’s Medicare programme, allowing GPs to refer patients for a number of medical conditions, including depression” “A similar movement had begun in UK… encouraging GPs to use exercise as a front-line treatment for mild to moderate depression.” Rethorst CD, et al. Sports Medicine. 2009; 39(6):491-511.

34. Monitoring / Exercise Logs

36. In Conclusion – Final Words on Exercise Recommendations - • For general health, adults should achieve a minimum of 30 minutes a day, of at least moderate intensity, on five or more days of the week • For many people it is likely that 45-60 minutes of moderate intensity activity is needed to prevent obesity • It can be done either all in one session, or through several shorter bouts of activities 10 minutes or more Daley A. J Clin Psychol Med Settings.2008;15:140-147.

37. Who Can, and Should Exercise for Mental Health Benefits?? Exercise Everyone!

38. MINDFULNESS BASED COGNITIVE THERAPY (MBCT)

39. MINDFULNESS IN PSYCHIATRIC PRACTICE RAKESH JAIN, MD, MPH ASSOCIATE CLINICAL PROFESSOR UNIVERSITY OF TEXAS MEDICAL SCHOOL HOUSTON, TEXAS

40. RELAPSE: RECURRENT & PROBLEMATIC

41. STAR-D Reveals Its Secrets – The Dangers of Residual Symptoms • Sleep disturbance • Sad mood • Appetite/weight • Concentration • Outlook • Suicidal ideation • Involvement • Energy/fatigue • Psychomotor 1.00 Overall 40% relapse rate 0.75 Cumulative Probability of Relapse 0.50 0 domains 1 domain 2 domains 3 domains 4 domains 5 domains 0.25 0.00 0 10 20 30 40 50 60 QIDS-IVR Relapse Time (Weeks) Increasing number of symptom domains leads to increased risk of relapse (x2[5]=17.7155, P=0.0033) Nierenberg AA et al. Psychol Med. 2010;40(1):41–50.

42. Depression—More Episodes and Residual Symptoms Predict Worse Outcomes ____ no symptoms 1-3 121 224 ___ no symptoms 3+ 34 79 ___ 1+ mild symptoms 1-3 57 34 ___ 1+ mild symptoms 3+ 25 28 1.0 0.8 0.6 Survival Distribution Function 0.4 0.2 0.0 0 50 100 150 200 250 300 350 400 450 500 Weeks to First Relapse With Any Depressive Episode (Major, Minor, Dysthymic) Survival Distribution Function = cumulative proportion of cases surviving to given time interval Judd LL et al. J Affect Disord. 1998;50:97-108.

43. EXPERIENCE FIRST -- TEACH SECOND

44. Raisin Exercise

45. Raisin Exercise SENSATIONS THOUGHTS FEELINGS

46. 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.

47. MINDFULNESS: WHAT IS IT? PAYING ATTENTION IN A PARTICULAR WAY: ON PURPOSE, IN THE PRESENT MOMENT, AND NON-JUDGEMENTALLY. -- Dr. Jon Kabat-Zinn (Kabat-Zinn, 2005)

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

49. 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

50. 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.”