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Integrative Medicine and Psychiatry: An Evidence Based Approach Part I

Integrative Medicine and Psychiatry: An Evidence Based Approach Part I. Marlene P. Freeman, M.D. Associate Professor, Harvard Medical School Director of Clinical Services, Perinatal and Reproductive Psychiatry Program; Medical Director, CTNI Massachusetts General Hospital.

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Integrative Medicine and Psychiatry: An Evidence Based Approach Part I

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  1. Integrative Medicine and Psychiatry: An Evidence Based ApproachPart I Marlene P. Freeman, M.D. Associate Professor, Harvard Medical School Director of Clinical Services, Perinatal and Reproductive Psychiatry Program; Medical Director, CTNI Massachusetts General Hospital

  2. Disclosure: Past 12 months • Grant Support: Forest, Lilly, Glaxo SmithKline (Investigator Initiated Trials) • Consulting: PamLab, Bristol Myers Squibb • Honoraria for medical editing: DSM Nutritionals • No promotional speaking, No stock; No consulting

  3. Complementary and Alternative Medicine (CAM) • Defined as “a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine (NCCAM, 2002)” • The American Psychiatric Association developed a task force to assess CAM in psychiatry • Evidence Base and Safety for CAM treatments in Major Depressive Disorder

  4. Why Focus on CAM? • Use of CAM treatments has increased over past several decades • Approximately 40% of adults in the U.S. use at least one CAM therapy annually • CAM use among children approximately 12%, or about 1 in 9 children; Children are five times more likely to use CAM if a parent/other relative uses CAM. • Americans spend over $33 Billion annually out of pocket on CAM therapies Barnes et al., 2008; Eisenberg et al., 1998; Nahin et al., 2007

  5. CAM: the Most Commonly Used by US Adults • Natural nonvitamin/nonmineral products (18%) • Most common: fish oil/omega 3/DHA, glucosamine, echinacea, flaxseed oil or pills, and ginseng • Deep breathing exercises (12.7 %) • Meditation (9.4 %) • Chiropractic or osteopathic manipulation (8.6 %) • Massage (8.3 %) • Yoga (6.1 %) Barnes et al., 2008

  6. CAM: Associations with Likelihood of Use Use greatest among: • Women (42.8%, compared to men 33.5%) • Ages 30-69 (30-39 years: 40%, 40-49 years: 40%, 50-59 years: 44%, 60-69 years: 41%) • Higher levels of education (Masters, doctorate or professional: 55%) • Higher income (poor: 28.9 percent, near poor: 30.9 percent, not poor: 43.3 percent) Barnes et al., 2008

  7. Prevalence of CAM Use • Use in psychiatry: • One study showed use by 63% of inpatients • MDD most common indication • Over half of those with Major Depressive Disorder (MDD) and/or other depressive disorders use CAM treatments • Most patients did NOT disclose use of CAM to their psychiatrist Tindle et al., 2005; Elkins et al, 2005; Kessler et al., 2001;

  8. Considerations in Evaluating the Evidence Base • CAM treatments are popular and appealing to patients • Internet and other sources may inflate perception of data base • Patient preference and accessibility sometimes precludes full evaluation, risk/benefit discussions in optimal medical decision-making process • Psychiatrists often not well educated about CAM; may be uncomfortable discussing

  9. Googled results • Omega-3 and depression: > 6,550,000 hits • Folate and depression: > 1,140,000 hits • Acupuncture and depression: >9,510,000 hits • St John’s Wort and depression: > 2,200,000 hits

  10. Considerations in Evaluating the Evidence Base • Few CAM treatments have been systematically studied for clear psychiatric indications with adequate outcome measures • Control conditions: finding appropriate control conditions can be challenging (i.e., exercise) • Some treatments have long-standing use in other cultures; may have literature available in other languages – cultural biases, language access issues

  11. How to sort it out?The APA CAM Task Force Process • Identification of widely used treatments with some randomized controlled trials (RCTs) for major depressive disorder – clinical relevance • Process of preparing and reviewing evidence tables for efficacy from published trials, discussions of methodology and safety [adapted from APA treatment guideline process] • Review of efficacy, risks, treatment recommendations, future research directions APA CAM Task Force Members: M. Freeman; M. Fava, M. Trivedi, J. Lake; D. Mischoulon; K. Wisner

  12. The APA CAM Task Force Process:Highlights: Selected CAM treatments for MDD • Omega-3 fatty acids • St. John’s Wort • S-adenosyl-methionine (SAMe) • Folate • Light therapy • Acupuncture • Exercise • Mindfulness based psychotherapies APA Task Force Report, JCP, 2010

  13. Omega-3 fatty acids • Studied as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (not the plant source alpha-linolenic acid) • Meta-analyses show benefit over placebo for unipolar and bipolar depression, with substantial heterogeneity • Few studies demonstrate benefit as monotherapy Parker et al., 2006; Freeman et al., 2006; Su et al., 2008; Nemets et al, 2007

  14. Monounsaturated H2 desaturase R-CH2-C=C-CH2-CH3 H H Polyunsaturated Omega-6 Omega-3 CH2 Omega-9 5 RCH=CH CH=CHCH=CH-CH2-CH3 10 9 6 3 2 1 7 4 8 CH2 Structures of fatty acids Saturated H H H H H H H R-C-C-C-C-C-C-C-H HOOC- H H H H H H H Hibbeln J

  15. Essential Fats: Metabolism and Dietary Sources O C- OH 18:2n-6 linoleic acid, LA Canola oil Walnuts Soy bean oil Safflower oil Corn oil Flax seed competition for D6 and D5 desaturase and elongation enzymes Leaf plants O O C- OH C- OH 20:5n-3, eicosapentaenoic acid, 20:4n-6, arachidonic acid EPA AA Fish Meat, Seafood Organs Seaweed Series 2 Series 3 O Prostaglandins Prostaglandins Thromboxanes Thromboxanes C- OH Series 4 Series 5 Leukotrienes Leukotrienes 22:6n-3, docosahexaenoic acid, DHA platelet activity (brain, retina, testis) immune responses smooth muscle Bone health Omega-6 Omega-3 O C- OH 18:3n-3 linolenic acid, LNA Hibbeln J

  16. APA Subcommittee on Omega-3 Fatty Acids • American Psychiatric Association’s Committee on Research on Psychiatric Treatments assembled a subcommittee (2003-2006) • Omega-3 Subcommittee: invited participants with expertise in omega-3 fatty acids and psychiatry • Charged with examining the evidence for omega-3 fatty acids across disorders, critical evaluation of treatment data, and recommendations for future research

  17. American Heart Association Recommendations • Cardiovascular Benefits • Decreased risk for arrhythmias, thrombosis • Decrease triglycerides • Decrease atherosclerotic plaque growth • Improve endothelial function • May lower blood pressure • Reduce inflammatory response Kris-Etherton et al., AHA Nutrition Committee, 2003

  18. American Heart Association Recommendations • AHA Recommendations: • All adults should eat fish > 2 times per week • Patients with coronary heart disease should consume 1 g EPA + DHA per day • A supplement may be useful in patients with hypertriglyceridemia (2-4 g per day) • >3 g per day should be monitored by a physician Kris-Etherton et al., AHA Nutrition Committee, 2003

  19. Omega-3 FA: Putative Mechanisms of Action • Increased serotonergic, dopaminergic neurotransmission • Alteration of protein phosphorylation, protein kinases • Impact on protein kinase C • Decreased phosphatidylinositol-associated second messenger activity • Immunological effects • Vagal mechanisms • Increased dendritic arborization and synaptogenesis • Regulation of gene expression • Increased membrane fluidity Hibbeln et al., 1998; Yao et al., 2004; Chalon, 2006; Coull et al., 2000; Popoli et al., 2000; Mirnikjoo et al., 2001; Kinsella et al., 1990; Logan and Katzman, 2005; Villa et al., 2002; Calderon and Kim, 2004; Wainwright, 2002; Kitajka et al., 2002; Carlezon et al., 2005

  20. Meta-analysis: Mood disorders • Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p=0.02) • Results were highly heterogeneous • important to examine the characteristics of each individual study to note the differences in methodology Freeman et al., American Psychiatric Association Subcommittee Report, 2006

  21. Placebo-controlled trials of omega-3 fatty acids in Unipolar MDD

  22. APA Omega-3 FA Subcommittee: Treatment Recommendations • Endorsed AHA guidelines • Considered particularly relevant • high comorbidity between psychiatric disorders and cardiovascular disease • lifestyle factors (e.g., smoking, obesity) in populations with psychiatric diagnoses, • metabolic effects of some psychotropics Freeman et al., 2006

  23. APA Omega-3 FA Subcommittee: Treatment Recommendations • Adults should consume fish > twice/week • Patients with mood, impulse-control, or psychotic disorders should consume 1 g EPA + DHA per day • Supplements may be useful in patients with mood disorders, 1-9 g per day (> 3 g per day should be monitored by a physician) Freeman et al., 2006

  24. St. John’s Wort • Herbal remedy with great popularity in Europe; mixed opinions in the U.S. • Usually studied as hypericum extract • Some randomized controlled trials in MDD favorable, especially in mild to moderate MDD • Less convincing in more severe MDD, and large federally funded studies in the U.S. diminished interest Shelton et al., 2001; Hypericum Study Group, 2002; Lecrubier et al., 2002; Linde et al., 2005

  25. St. John’s Wort • Two U.S. large trials (HAM-D scores >20): did not demonstrate difference between St. John’s Wort and placebo on primary outcomes • Shelton et al. (2001) • 200 participants: St. John’s Wort or placebo for eight weeks • No statistically significant difference between groups - primary outcome was decrease on HAM-D • Hypericum Study Group trial (2002) • 340 patients: St. John’s Wort, sertraline, or placebo, 8 wks • Both St. John’s Wort and sertraline performed similarly to placebo on the primary outcome of change on HAM-D scores, response rates (HAM-D, CGI). • Highlights concerns about placebo-response rates and methodology in MDD studies, since sertraline did not perform better than placebo • Other studies: positive results: • Lecrubier et al. 2002: another large trials, investigators did find a significant difference between St. John’s Wort and placebo in mild to moderate depression (N=375) • Fava et al, 2005: modest but significant advantage over fluoxetine and placebo (N=135)

  26. St. John’s Wort • Important drug-drug interactions • Appears to induce metabolism of concomitant medication via the cytochrome P450 system • May reduce efficacy of other drugs, including: • Antiretrovirals • Immunosuppressants • Antineoplastic agents • Anticoagulants \Digoxin • Oral contraceptives (unintended pregnancies have been reported) Roby et al., 2000; Mannel et al., 2004; Schwarz et al., 2003

  27. Accessibility, Challenges of Study • Example: accessibility may add to the methodological challenges of study • Study of St. John’s Wort vs. Placebo: • those assigned to St. John’s Wort had variable adherence verified by metabolite blood levels • placebo group was found to have a surprising number of participants with notable St. John’s Wort metabolite levels (Vitiello et al., 2005)

  28. S-adenosyl-L-methionine (SAMe) • Occurs naturally in humans; needed as a methyl donor in synthesis of important compounds with implications for mood • Agency for Healthcare Research and Quality (AHRQ) systematically assessed database for MDD, and found evidence to support further research • Studies generally show benefit over placebo and equivalence to tricyclics • Studied mostly as monotherapy; small study supported role as augmentation strategy Papakostas et al., 2003; AHRQ, 2002; Mischoulon and Fava, 2002; Delle Chiaie et al., 2002; Bressa et al., 1994

  29. SAMe • Available orally, although intramuscular and intravenous available and used in some early studies • Published studies support that SAMe 1600 mg provided orally for trials of 3-6 weeks (ranges studied 200-1600 mg/d) • Some studies show benefit by 10 days of treatment over placebo • Studies have generally been of short duration (4-6 weeks)

  30. SAMe • Side effects/Considerations: • Expensive • Generally well tolerated; reports of mild gastrointestinal symptoms, sweating, dizziness, anxiety • Mania reported in studies of bipolar depression • Better tolerated than tricyclic antidepressants Goren et al., 2004; Alpert et al., 2004; Mischoulon and Fava, 2002; Delle Chiaie et al., 2002

  31. Augmentation with SAMe • Papakostas et al., 2010 N=73 SRI nonresponders with MDD, 6-week, double-blind, randomized trial of adjunctive oral SAMe (target dose: 800 mg/twice daily). • HAM-D response and remission rates were higher for patients treated with adjunctive SAMe (36.1% and 25.8%, respectively) than adjunctive placebo (17.6% versus 11.7%, respectively). • No statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason (20.6% versus 29.5%, respectively), due to adverse events (5.1% versus 8.8%, respectively), or due to inefficacy (5.1% versus 11.7%, respectively) • SAMe may be an effective, well-tolerated, and safe adjunctive treatment strategy for MDD Am J Psychiatry, 2010

  32. Folate • Low folate levels associated with poorer and slower response to SSRIs • Treatment studies as adjunctive treatment showed benefit for patients on fluoxetine, most pronounced for women • Those who received folate vs. placebo more likely to be responders, have less side effects (0.5 mg/d) Papakostas et al., 2004; Papakostas et al., 2005; Coppen and Bailey, 2000

  33. Figure by Mischoulon, D; from Freeman et al JCP in press.

  34. Folate • No evidence for monotherapy • Low risk • Protective against birth defects– 0.4-1 mg recommended for women of reproductive age • Reasonable to suggest use as an adjunctive strategy in addition to antidepressants, especially for women

  35. Folate: Perinatal Considerations • No specific study of folate as an intervention for perinatal depression • Women who are pregnant or planning to become pregnant are advised to take 0.4-1 mg of folate daily to decrease birth defects, particularly neural tube defects (McDonald et al., 2003) • However, one epidemiological study did not find a relationship between folate intake and postpartum depression (Miyake et al., 2006)

  36. Bright light therapy • Few rigorously done studies with adequate controls, outcome measures • Meta-analysis done by APA subcommittee found that significant benefit in seasonal and non-seasonal MDD, although number of studies that reached criteria for inclusion based on design were small • Some reports of mania Golden et al., 2005; Epperson et al., 2004; Kripke et al., 1992

  37. Acupuncture • Part of Traditional Chinese Medicine, some have voiced concerns about its study as separate entity • Systematic reviews and meta-analyses fail to demonstrate consistently positive results over control conditions • Control conditions challenging- some use “sham” points, other conditions (i.e., massage) • Evidence base is limited by flawed methodology, very inconclusive evidence at this time for efficacy • Generally low risk Halbreich , 2008; Wang et al., in press; Leo and Ligot, 2007; Smith and Hay, 2005

  38. Exercise • For most individuals, exercise is important and indicated for overall health benefits • Epidemiological studies support benefits for decreased risk of depression • Methodological weaknesses in studies include: difficulty selecting appropriate control conditions, difficulty blinding to condition, adequate follow-up of effects • Dose of exercise very important component in terms of design, assessment of efficacy Brown et al., 2005; Strawbridge et al., 2002; Lawlor et al., 2001; Dunn et al., 2001; Trivedi et al., 2006

  39. Exercise • Treatment studies support further research as an adjunctive treatment; role as monotherapy • May be especially important considering the high comorbidity with cardiovascular disease, obesity, and other medical problems experienced at high rates by those with mood disorders • Unless there are medical contraindications, should be recommended as part of overall treatment plan • Dunn et al., 2005; Blumenthal et al., 2007; Trivedi et al., 2006

  40. Vitamin D • Vitamin D – different forms, groups of steroids • Pro-hormone calcidiol • Vitamin D3 – calcitriol • 1, 25 dihydroxy cholecalciferol (calcitriol) • produced when ultraviolet light interacts with 7-dehydrocholesterol • Binds to vitamin D receptors (steroid receptors, including those in the brain) • More production with natural sun exposure (high UV index), some from tanning beds • Light boxes- filter out UV rays to deliver bright white light • Unclear if supplementation with vitamin D2 equivalent

  41. Vitamin D • Deficiency- bone softening disorders such as rickets • Most studies suggesting health benefits are association studies (not treatment studies) • Hypervitaminosis D- excess supplementation can be toxic, generates hypercalcemia, can cause birth defects, renal impairment • Typically up to 250 micrograms/day (10,000 IU) in adults recommended • Benefits of supplementation unclear

  42. Vitamin D

  43. Vitamin D and Depression:Association Studies • Number of association studies demonstrating lower vitamin D levels inversely associated with depression (although not all studies show this) • Examples: Hoogendijk et al., Arch Gen Psychiatry, 2008; Hoang et al., Mayo Clin Proc 2011; Ganji et al., Int Arch Med 2010; Wilkins et al., Am J Geriatr Psychiatry • Higher intake of vitamin D associated with lower risk of depression in older women (Bertone-Johnson et al., Am J Clin Nutr, 2011)

  44. Vitamin D and Prevention?Prospective Study • Milaneschi et al., J Clin Endocrinol Metab 2010 • Prospective cohort study, N=531 women, 423 men > 65 years of age • Serum 25(OH)D levels at baseline, 3 and 6 years • Center for Epidemiological Studies Depression Scale (CES-D) >16 identified as depressed • Low vit D defined as < 50 nmol/liter • Both women and men experienced a significantly greater risk of developing depressive symptoms with lower vitamin D levels, relationship more robust in women • Women – Hazard ratio of 2.0 • Men- Hazard ratio of 1.6

  45. Treatment Studies • Vitamin D supplementation on symptoms of depression in overweight/obese subjects • N=441; used Beck Depression Inventory BDI • At baseline, did a cross-sectional study: • Low D3 levels (<40 nmol/liter associated with higher BDI scores • Treatment Study • Randomized to Vit D 20,000 IU or 40,000 IU or placebo per week for one year • Significant improvement in depressive scores among the two vitamin D groups compared to placebo after one year • (Jorde et al., J Internal Med 2008)

  46. Treatment Studies • Prevention of Seasonal Affective Disorder? • Women aged 70 or older, N=1621 • Vitamin D 800 IU vs no supplementation (randomized) • No difference in depression scores between May and October

  47. Treatment Studies • Healthy young adults randomized to assess cognitive and emotional functioning (not depressed) • N=128, double-blind, placebo controlled • 5000 IU cholecalciferol or placebo x 6 weeks • No differences on cognitive or emotional batteries • History of mood disorder exclusionary Dean et al., PLOS ONE, Nov 2011

  48. Vitamin D and Perinatal Depression • Deficiency increases risk of obstetrical complications • Inversely related to risk of gestational diabetes and glycemic control • Reported to increase the risk of pre-eclampsia, although not consistently Vitamin D deficiency is more likely in African American women compared to Caucasian women • Vitamin D and Perinatal Depression? • One study did not find Vitamin D related to risk of MDD during pregnancy • Lower levels of vitamin D associated with higher EPDS scores in one postpartum sample (N=97) • Mothers with low vitamin D status have lower levels in breastmilk, putting infants at risk of deficiency • Beneficial to assess vitamin D status in pregnant and lactating women? • impact upon depression risk is unclear at this time McLeod et al., Diabet Med 2011; Brannon and Picciano, Annu Rev Nutr 2011; Bodnar et al., Public Health Nutr 2011; Murphy et al., J Am Psychiatr Nurses Assoc, 2010; Haggerty, Breastfeed Med, 2011

  49. Googled… • “Vitamin D and Depression” • About 8,030,000 results

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