1. Natural Therapies for Adolescent Depression: Do they work? Are they safe? Kathi J. Kemper, MD, FAAP Caryl J Guth Chair for Holistic and Integrative Medicine Author, The Holistic Pediatrician Wake Forest University School of Medicine

2. Faculty Disclosure In the past 12 months, I have had no relevant financial relationships with the manufacturers of any commercial products and/or providers of commercial services discussed in this CME activity. I do not intend to discuss an unapproved or investigative use of a commercial product or device in my presentation.

3. Objectives (by the end of this session, you will be able to…): 1.Define the role of patient-centered communication for adolescent depression visits 2.Describe the importance of a healthy lifestyle and the safety and effectiveness of dietary supplements in promoting healthy moods. 3.Refer patients to evidence-based resources for additional information about lifestyle and complementary therapies to promote mental health

4. Depression Case A 17 year old girl who is sad, has had a drop in grades, recently broke up with her abusive boyfriend; less interested in participating in band, has stopped taking her SSRI after hearing about black box warnings. Her only medications are oral contraceptives. Will St. Johns wort help (the news reports are very confusing)? How do you advise her?

5. Management Issues Process (communication skills) Content (focus on healthy lifestyle; if it’s good for the heart, it’s probably good for mood) Speed (baby steps) Resources

6. Process: Communication Skills Standard approach Patient-centered care Health promotion focus

7. Standard approach Diagnose Provide diagnosis-specific treatment Challenges Making a diagnosis; what if they don’t meet criteria? Mastering medications Wissow and Gadomski, 2008

8. Parental expectations Don’t believe they are effective change agents Have prior beliefs about what will help Want help but afraid of what you might say Want empathy but expect child is the agenda Wissow and Gadomski, 2008

9. Adolescent Expectations Here to be “fixed” or punished Not used to having a substantive role in visit Uncertain about confidentiality Different agenda than parent Incomplete and stigmatizing views of “mental health” Wissow and Gadomski, 2008

10. Physician Expectations Will be presented with insoluble problems “Double drowning” – everyone will leave more hopeless and/or angry than they started Will lose control of time Wissow and Gadomski, 2008

11. Evidence-based skills Agenda setting Engaging both child and parent Prioritizing specific concerns; goals; define success Problem formulation and solving Finding reasons to hope and first steps to solutions Framework: health promotion and stress management Time management Managing rambling and interruptions Promoting hope and confidence Diagnosing and Advice giving Avoiding and managing resistance Pediatrics 2008 Feb;121:266-75.

12. Finding a common agenda Commitment to eliciting it from both parent and child/youth Setting up and “enforcing” turn-taking –Respecting confidentiality –Encouraging and modeling the ability to talk in front of each other

13. Crude 6-month change in child clinical measures as a function of change in provider’s patient-centeredness Change in SDQ symptom scoreChange in SDQ impact score p<.0001 adjusted for baseline symptomsp=.015 adjusted for baseline function

14. Content: Conventional Psychotherapy Medications

15. Cognitive Behavioral Therapy “From an evidence-based perspective, cognitive- behavioral therapy is currently the treatment of choice for anxiety and depressive disorders in children and adolescents.” Compton SN. JAm Acad Child Adolesc Psychiatry. 2004

16. Conventional Treatment: Rx –TCAs - no evidence of efficacy in pre- pubertal children –SSRIs - no overall evidence of efficacy in pre-pubertal children –SSRIs marginally better than placebo in teens with MDD; Prozac OK for teens by FDA –SSRIs are HELPFUL in OCD and anxiety disorders, even in pre-pubertal children Safer DJ. Pediatrics, 2006; 118 (3): 1248

17. SSRI Side effects 1 GI upset Headache; sleep disorders Sexual side effects Dizziness, Fatigue, Sweating Neonatal withdrawal syndrome Drug interactions

18. SSRI Side effects 2 Serotonergic syndrome (HTN, tachycardia, mania) Agitation and hostility Suicidal ideation, esp in those with agitation/hostility –Review of 22 RCT pediatric with 9 antidepressant drugs. –2298 patients with active drug; 1952 with placebo –Serious suicidal adverse events: 78/2298 versus 54/1952 Incidence rate ratio 1.89 (95% CI, 1.18- 3.04) Mosholder AD. J Child Adolesc Psychopharmacol. 2006

19. Psychiatric Meds in kids Little science of long term safety 1.6 million kids on 2 or more meds: ? science Neurological and hormonal impact mostly unknown

20. Content: natural therapies Depression is one of the top 10 diagnoses for which patients seek natural therapies Commonly used among depressed adolescents Fewer than 30% of depressed teens tell docs they are using natural therapies Clinicians need to ask!

21. Integrative Approach Lifestyle – Environment, Exercise/Sleep, Nutrition, Mind-Body Supplements Massage Acupuncture

22. Lifestyle - overview Environment: More Sunshine, Less TV Exercise/Sleep (more of both) Nutrition (Essential nutrients for optimal brain function, EFA, amino acids, vitamins, minerals) Mind-Body Therapies – manage stress –Meditation –Biofeedback

23. Sunshine, circadian rhythms and sleep Desynchronization of internal rhythms plays an important role in the pathophysiology of depression. Resetting normal circadian rhythms can have antidepressant effects. “Winter depression was first modeled on regulation of animal behavior by seasonal changes in day length, and led to application of light as the first successful chronobiological treatment in psychiatry.” Fuchs E. Int Clin Psychopharmacol, 2006 Wirz-Justice A. Int Clin Psychopharmacol. 2006

24. Light Therapy for Depression Plus 3 studies not included in this review, comparing dim light to bright light. Golden R. Am J Psychiatry. 2005

25. Light therapy Proven effective for SAD (Terman M Evid Based Ment Health, 2006) Meta-analysis of studies from 1987-2001: (effect size=0.53, 95% CI=0.18 to 0.89, similar to medications) for non-SAD RCT of 29 women with non- seasonal depression; light therapy for 28 days significantly better than control, (McEnany GW, 2005)

26. Light Therapy 2 Benefits onset within 2 days; effective in institutionalized elderly and community; effective in summer and winter Side effects: hypomania, autonomic hyperactivation ( Terman M, 2005)

27. Turn off Depressing TV Respondents who repeatedly saw "people falling or jumping from the towers of the World Trade Center" had higher prevalence of PTSD (17.4%) and depression (14.7%) than those who did not (6.2% and 5.3%, respectively). Depressive symptoms after the hurricane were predicted by watching television coverage of the looting that occurred in New Orleans Ahern, Psychiatry, 2002 McLeish. Depress Anx, 2008

28. Lifestyle 2: Exercise Depressed mood / fatigue are common in those deprived of usual exercise. Mood changes noted in patients with injuries and mono. Changes over time in kids’ exercise/gym/playground time Exercise benefits depression * Common sense precautions Berlin AA. Psychosomatic Med, 2006

29. Exercise as Therapy – Yes Lawlor DA. BMJ 2001

30. Yoga for depression Five RCTs --each used different forms of yoga. All trials reported positive findings No adverse effects except fatigue and breathlessness Pilkington K. J Affective Disord, 2005

31. Lifestyle 3: Sleep Poor sleep is barometer of depression Reduced sleep equals impaired focus and labile mood (ADHD, Learning problems) Sleep quality is a good screen for good mental health in pediatric population We sleep 20% less than we did 100 yrs ago Promote healthy sleep!

32. Lifestyle 3: Sleep Hygiene Regular time; Routine Hot bath; cool room; dark room Massage before bed Lavender, chamomile, melatonin? No caffeine within 8 hours of bedtime Music, calm, orderly, quiet NO TV IN BEDROOM NO vigorous exercise right before bed GET MORE versus intentional sleep reduction/deprivation (in those with excessive sleep)

33. 4: Nutrition – essential nutrients for optimal brain function Omega-3 fatty acids Amino acids (SAM-E, Trp, 5-HTP) Vitamins (B vitamins, Vitamin D) Minerals (Iron, Calcium, Magnesium, Zinc)

34. Omega-6 Fatty AcidsOmega-3 Fatty Acids Linoleic Acid (18:2n-6)a-Linolenic Acid (18:3n-3) (GLA)γ -Linolenic Acid (18:3n-6) (DHGLA) Dihomo-γ-Linolenic Acid (20:3n-6) (AA)Arachidonic Acid (20:4n-6) Eicosanoids Leukotriene 4-series Prostaglandins E 2 Thromboxanes A 2 Eicosanoids Stearidonic Acid (18:4n-3) Eicosatetraenoic Acid (20:4n-3) (EPA) Eicosapentaenoic Acid (20:5n-3) 24:5n-3 24:6n-3 (DHA) Docosahexaenoic Acid (22:6n-3) Eicosanoids Leukotriene 5-series Prostaglandins E 3 Thromboxanes A 3 ∆-6 Desaturase Elongase ∆-5 Desaturase Elongase ∆-6 Desaturase β-Oxidation

35. Omega 3 EFA’s: mechanism Neuronal membrane structure and function Brain development Second messenger inside cells

36. Mood and Omega-3’s Inverse correlation between fish intake and depression (Hibbeln: Lancet 1998; 351:1213; Crowe: Am J Clin Nutr, 2007) Effective for bipolar patients (Stoll: Arch. of Gen. Psych. 1999; 56: 407-12) Effective for major depression (Nemets: Am. J. Psych. 2002: 159 (3) 477-9) Effective for depression in Children ( Am J Psychiatry 2006;163:1098-0)

37. Fish Oil –Doses, Safety, Brands Dose: 1 gram daily of EPA probably enough.(Peet M, 2002); Frangou S. Br J Psychiatry, 2006) Safety: fish allergies, taste, belching; very high doses, increased risk of bleeding, nosebleeds? Little risk of mercury, dioxin, PCB’s; Brands: Compare brands at www.consumerlabs.com www.consumerlabs.com My family takes Coromega, Carlson’s or Nordic Natural Read labels: Omega 3 does NOT necessarily all equal EPA/DHA

38. Amino Acids: SAM-E Produced from ATP and methionine Low folate can lead to low levels Meta-analysis: SAMe significantly improves depression, comparable to antidepressant medications (http://www.ahrq.gov/clinic/epcsums/samesu m.htm)http://www.ahrq.gov/clinic/epcsums/samesu m.htm In an open trial of 30 adults with MDD for whom antidepressant meds ineffective, SAM-E led to significant improvements in 50% and remission in 43% (Alpert, 2004) All tested products approved by ConsumerLab; buy on sale!

39. SAM-E Doses, duration, products Dose: 800 – 1600 mg daily (adult) Benefits appear within 2-4 weeks of starting daily use Problems –poorly absorbed (need enteric coating); mania in bipolar patients; interactions with SSRI meds; see: http://www.consumerlabs.com/result s/same.asp http://www.consumerlabs.com/result s/same.asp http://www.umm.edu/altmed/ConsSu pplements/SAdenosylmethionineSA Mecs.htmlhttp://www.umm.edu/altmed/ConsSu pplements/SAdenosylmethionineSA Mecs.html

40. Amino Acids: 5-HTP and L-tryp Acute tryp depletion leads to depression Dietary L-tryp -> 5-HTP -> serotonin Meta-analysis: 5-HTP and L- trp better than placebo for depression (Shaw K, Cochrane. 2002) Food sources – dairy, eggs, poultry, meat, soy, tofu, nuts; WHEY protein

41. L-tryp doses and side effects Doses - start at 50 mg TID; max dose 1200 mg daily Side effects – EMS related to contaminated lot from one manufacturer; nausea, drowsiness; May potentiate SSRI medications; decreased carbohydrate intake and weight loss?

42. Vitamin B6 - pyridoxine Low levels of pyridoxal phosphate (PLP) are associated with depressive symptoms (Hvas AM 2004) Dose: 100 – 200 mg daily benefits PMS- depression; Odds ratio ~2.(Wyatt KM. BMJ, 1999) Side effects: nausea, vomiting, abd. pain, anorexia, headache, somnolence, lower B12 levels, sensory neuropathy (typically with doses over 1000 mg daily, can occur lower) Food: Beans, nuts, legumes, fish, meat

43. Folate and B12 Folate –Lower levels of folate in depressed persons –Low folate associated with poorer response to antidepressant meds –Supplemental folate can improve response to meds B12 –Lower levels in depressed persons

44. Bottom line on Amino acids andB vitamins Healthy diet rich in green vegetables and nutritious protein sources Consider B-complex supplement

45. Vitamin D and depression Vitamin D receptors in brain Low level of serum 25-hydroxyvitamin D and high PTH are significantly associated with depression (Jorde, 2005) 25-hydroxyvitamin D3 and 1,25- dihydroxvitamin D3 levels are significantly lower in psychiatric patients than in normal controls (Schneider, 2000) RCT of 44 Australian patients (none, 400 IU versus 800 IU vitamin D) vitamin D3 significantly enhanced mood (Landsdowne, 1998)

46. Mood and Minerals: Iron Iron deficiency associated with depression Correcting iron deficiency helps with mood and attention Beard JL. J Nutr, 2005 LE Murray-Kolb. Am J Clin Nutr, 2007

47. Mood and Minerals: Calcium Lower levels of calcium in depressed persons Higher PTH in depressed persons Estrogen regulates calcium and PTH metabolism; sometimes dysregulates? (Thys-Jacobs S. J Am Coll Nutr, 2000) Supplementation may benefit women with PMS-related depression (Dickerson LM. Am Fam Physician, 2003) 1000 – 1200 mg daily

48. Non-dairy sources of calcium Soy beans, tofu Calcium fortified OJ Green leafy vegetables (broccoli)

49. Nutrition Summary Healthy fat (omega 3); not fried foods, saturated fats Healthy protein (essential amino acids) Foods rich in minerals and vitamins (vegetables, beans, grains) Multivitamin-mineral supplement Fish oil supplement Consider SAM-E, B vitamins, Calcium Iron if deficient

50. Lifestyle: Stress management Stress is common Stress commonly triggers mood problems Managing stress: exercise, sleep, nutrition, mind/emotion/body/spirit –Meditation –Biofeedback

51. Meditation Meditation training ↑ left-sided anterior activation, a pattern associated with positive affect, in meditators compared with the nonmeditators No RCTs specifically on depression, though positive effects on anxiety Few side effects; can combine mindfulness with CBT Davidson RJ Psychosom Med, 2003

52. Stress, Emotion, and Physiological Activation High Arousal/High Energy SYMPATHETIC PARASYMPATHETIC Low Arousal/Low Energy

53. Stress, Emotion, and Physiological Activation High Arousal/High Energy SYMPATHETIC PARASYMPATHETIC Low Arousal/Low Energy Negative Emotion Positive Emotion “Fight-or-Flight”

54. Stress, Emotion, and Physiological Activation High Arousal/High Energy SYMPATHETIC PARASYMPATHETIC Low Arousal/Low Energy Negative Emotion Positive Emotion “Fight-or-Flight” Frustration, Anger, Hostility, Fear, Worry Anxiety Judgment, Resentment, Feeling Overwhelmed, Anguish Hopelessness, Submission, Despair, Depression Burnout, Withdrawal, Boredom, Apathy Exhilaration, Passion, Love, Care, Joy, Happiness Kindness, Appreciation Compassion, Tolerance, Acceptance, Forgiveness Serenity, Inner Balance, Reflection, Contentment

55. Stress management: biofeedback HRV biofeedback appears to be a useful adjunctive treatment for the treatment of MDD Significant improvements in –Hamilton Depression Scale (HAM-D) –Beck Depression Inventory (BDI-II) by week 4, Karavidas, et al. Appl Psychophysiol Biofeedback. 2007 Nolan RP. Am Heart J, 2005

56. Promote Social Support Religiosity (participation) helps protect against depression Participation in extracurricular clubs helps protect teens against depression Participation in organized athletics is protective Ongoing volunteer work is protective Connected people are happier people

57. After lifestyle and stress management, what? St. Johns’ wort Massage Acupuncture

58. Saint Johns wort Most commonly used CAM therapy for depression Comparable to sertraline in German RCT of 241 depressed adults (Gastpar. Pharmacopsychiatry, 2005) 2 open label trials in teens showed improvement within 2 weeks in 25/33 and 9/11 patients (Findling, 2003; Simeon, 2005); Improvement in 2 weeks predicts long- term response; if no benefit in 2 weeks, stop “Current evidence regarding hypericum extracts is inconsistent and confusing”; different products used in different trials, different kinds of patients; in some studies St. Johns wort is as effective as standard medications, but no more effective than placebo. ( 2005 Cochrane review)

59. Herb- drug interactions: SJW Speeds elimination of many drugs: digitalis, theophylline, clarithromycin, erythromycin, protease inhibitors and OCPs

60. SJW safety Other side effects - photosensitivity, serotonergic syndrome Product variability; see www.consumerlabs.com: Gaia, Kira, Sundown, Nature’s Bountywww.consumerlabs.com Products used in POSITIVE TRIALS: Laif 900 (German STW3-VI); LI160 (Kira), WS5572; WS5570 (Perika by Nature’s Way) St. Johns wort patient handouts are available from: University of MarylandUniversity of Maryland Medical Center Wake Forest University Baptist Medical CenterWake Forest University Baptist Medical Center’s Best Health internet site (www.besthealth.com)www.besthealth.com

61. Massage Increased blood flow and lymphatic drainage; Muscle relaxation; Stress reduction Balances R & L prefrontal cortex activity in those with right dominance (Jones N Adolescence. 1999) Decreased levels of cortisol and increased levels of serotonin and dopamine in depressed adults (Field T. Int J Neurosci. 2005) In depressed pregnant women, massage, compared with progressive relaxation, led to higher dopamine and serotonin levels and lower levels of cortisol and norepinephrine (Field T. J Psychosom Obstet Gynaecol. 2004 ) Who volunteers?

62. Acupuncture RCT of 30 patients: BDI scores fell from baseline by 16.1 points in the intervention group versus 6.8 points in the sham controls (P<0.001) (Acupunct Med. 2005) Meta-analysis: the effect of electroacupuncture similar to antidepressant medication( Mukaino Y Acupuncture Med, 2005 ). Good safety profile. Rare infections, broken needles, forgotten needles, bleeding, bruising

63. Depression SUMMARY 1 Listen to patients and families Negotiate clear goals and agreements Support healthy lifestyle, including sunshine, sleep, exercise, nutrition (supplement when necessary), and stress management

64. Depression SUMMARY 2 Correct deficiencies of B vitamins and minerals Consider supplements of fish oil, SAM-E, 5-HTP Consider safe therapies, including massage and acupuncture Beware of potential interactions, e.g., Saint Johns wort Be PRACTICAL – How?

65. How: Behavioral Pediatrics Identify the goal Consider various strategies Pick a strategy Identify a small, achievable step that the patient and family can support Explore pros and cons of change Anticipate barriers; identify resources Plan rewards/celebrations! Re-evaluate; take the next step

66. Goal-setting Pick a POSITIVE goal –E.g., healthier lifestyle.

67. Example: Healthier lifestyle To promote Better mood Better focus or concentration Greater calmMore resilience More cheerfulnessGreater adaptability More confidenceMore creative More clarity Better memory More harmonious relationships Higher self esteem More consistent with personal values other?

68. Pick a specific strategy More exercise Better nutrition Judicious use of supplements Better sleep Healthier environment Stress management; biofeedback; journal; meditation Use medication Massage, psychotherapy, acupuncture or other professional help

69. Identify a small, achievable step Rome was not built in a day; habits are not changed overnight: BABY STEPS. For exercise, go from sedentary, to 5 minute walks with the dog 5 days a week. Be specific (with or without an MP3 player; with or without a parent; regardless of weather?; distance vs. time)

70. How important is this to you? 0 1 2 3 4 5 6 7 8 9 10 Not Very Why did you pick that number and not a lower number? (e.g. a 7 instead of a 5) Asking this question helps the patient/family provide their own rationale for why this is important. They talk themselves into it!

71. How confident are you that you can do this for one month? 0 1 2 3 4 5 6 7 8 9 10 Not Very If they pick an 8 or higher (pretty confident), proceed with next step of making a chart and planning rewards and follow-up. If they pick a number less than 8, “What would it take for you to go from the number you picked to a higher number?” Begin to explore their ambivalence…. It’s OK to be ambivalent about change!

72. Identify Pros and Cons PROCON Change More cheerfulChange routine More fit and coolBrother might tease Clothes fit betterYucky dog clean up Better sleep Better self-esteem No Change EasyContinued mood probs Mom does yucky jobGet fat Feel ugly Sleep badly Unhappy with myself

73. Identify Barriers and Resources In addition to (cons listed above), what other barriers or challenges might you anticipate as you try to make this change? Need new tennis shoes; need leash; need pooper-scooper What resources do you have/need to help you make this change? Will Mom commit to getting new shoes, leash, etc. ? Will the child want/need a reminder? Is it helpful for Dad to do that? Do they need a chore chart? A calendar?

74. Plan celebrations/rewards Pick a tangible reward and timing (will it be offered after week 1, 2, 3, 4?) Samples: extra time with mom or dad; extra phone minutes; new walking shoes; get to pick vegetable for dinner!; get to pick family movie; stickers for younger kids; money for older kids – controversial in some families. Support the family and child choices. Emphasize the importance of the reward/celebration. If the family says they expect “good” behavior, suggest they consider celebrating it (instead of rewarding it).

75. Sample behavior diary (OK to copy) Goal Sample: MTWThFriSaSuTotal Walk dog 5 minutes 5 days a week √ √√√√ 5 Week 1 Week 2 Week 3 Week 4 Re-evaluate. Celebrate. Next steps?

76. Follow Up Follow- up in 4-6 weeks. Ask family/child to bring chart and say you plan to be proud of them (build expectation of success) and will ask them what they’d like to do for next step (involve them in problem solving). Do it!

77. Behavioral Pediatrics Identify the goal Consider various strategies Pick a strategy Identify a small, achievable step that the patient and family can support Explore pros and cons of change Anticipate barriers; identify resources Plan rewards/celebrations! Re-evaluate; take the next step

78. Resources Kemper KJ, Shannon S. Complementary and alternative medicine therapies to promote healthy moods.Pediatr Clin North Am. 2007 Dec;54(6):901-26 Motivational Interviewing: Preparing People to Change by Miller and Roznik Natural Medicines Comprehensive Database Natural Standards http://www.besthealth.com/Integrated +Medicine/