Arun V. Ravindran, MB, PhD, FRCPC, FRCPsych

1. Complementary and Alternative Medicine (CAM) Treatments for Mood Disorders: Are They Safe and Effective? Arun V. Ravindran,MB, PhD, FRCPC, FRCPsych Professor and Director, Global Mental Health and Fellowship Training, Department of Psychiatry, University of Toronto Chief, Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health, Toronto

2. Disclaimer Dr. Ravindran has no conflict of interest to report. He has no financial interest and has not received any form of support from any companies that produce or market any compound or instrument or procedure described in this presentation as a main treatment form.

3. CAM Therapies: Some Notable Statistics • Over 1/3 of adult population uses some form of CAM therapies • Visits to CAM practitioners exceed visits to primary care clinicians • CAM users tend to be female, younger, better educated and employed • Approximately 2/3 of patients with diagnosed depression and anxiety use CAM therapies as primary or adjunct treatments • The perceived helpfulness of CAM therapies is similar to that of conventional treatments Kessler et al., Am J Psychiatry, 2001

4. Evaluating CAM Treatments • “Natural is better and safer” – not necessarily true Limitations • Quality of evidence: • Few and poorer quality of RCTs • Variation in formulation and quality of agents • Mostly short-term studies • Few studies in severe forms of depression

5. Caveats and Cautions • In general, psychotherapy and pharmacotherapy should be considered before CAMs • More as adjunctive than as monotherapy • Only guideline and not “standard of care” • Evidence limited to English publications “Clinical support/use” – utility and practicality Ravindran et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. V. Complementary and alternative medicine treatments.J Affect Disord., 2009

6. Criteria for Levels of Evidence

7. Complementary & Alternative Therapies • Herbal Remedies • St. John’s Wort • Other herbal remedies • Physical Treatments • Light therapy • Sleep deprivation • Exercise • Yoga • Acupuncture • Nutraceuticals • Omega-3 fatty acids • DHEA • Tryptophan • SAMe

8. What is Light Therapy and How Effective is It for Mood Disorders? • Exposure to bright light using a device • Seasonal MDD • 1st line of treatment • As effective as SSRIs • No maintenance/prophylactic studies • Non-seasonal MDD • Less robust evidence • Combination with SSRIs is more effective • Bipolar Depression • Helps but may trigger mixed state

9. What Efficacy has Sleep Deprivation shown in MDD? • Total vs. partial treatment options • Difficult to design RCTs – mostly small studies • Comparison with light therapy, exercise and combinations with antidepressants • Drawbacks • Difficult to sustain treatment • Rebound depression • Tolerance of deprivation effects • Conclusion • Unlikely to be of value in day-to-day practice • Possible use as a 3rd line augmentation in mild to moderate depression • Co-administration of antidepressants may prolong benefit

10. Is Exercise Beneficial for MDD? • High vs. low frequency/intensity, aerobic vs. non-aerobic • Recommended – Min. 3x/week, 30 mins+ • Recent meta-analyses (2) – better than no treatment, mixed results against psychological treatments* • RCTs – exercise + medication superior to either alone • Some evidence for long-term benefit and prophylaxis • Recommendation • 2nd line augmentation in mild to moderate MDD Pinquart et al., Aging Ment Health, 2007

11. What is the Neuroscientific Basis for the Benefit of Exercise? • Increases expression of genes for neurotropins • Stimulates growth and development of new cells and increases neuronal plasticity • Increase in monoaminergic neurotransmission • Possible modulation of interleukin 6.

12. Just standing here doing nothing for TWENTY MINUTES! Boy, am I STRESSED! Hi, everybody. Let’s start de-stressing by just sitting quietly doing nothing for twenty minutes. YOGA Class

13. What is Yoga? • An ancient physical art incorporating controlled breathing, specialized postures and meditation • Yoga forms evaluated in depression: • SKY (emphasis on cyclical hyperventilative breathing) • MDD (2 RCTs, 3 open trials) and dysthymia (3 open trials) • Iyengar yoga (emphasis on precise postures, use of props) • MDD (1 RCT, 2 open trials) • Hatha yoga (emphasis on individualized practice) • MDD (1 RCT, 1 open trial) • Dysthymia (1 RCT, 1 open trial) • Advantages: • Low cost, non-invasive, self-supervised, highly tolerable

14. What Physiological Mechanisms Mediate the Beneficial Effects of Yoga? • Reducing sympathetic tone and normalizing heart rate variability • Normalization of HPA axis dysregulation • Effect on the limbic system • Activation of antagonistic neuromuscular system

15. Is Yoga Useful for MDD? • Most studies – 4-8 weeks, 4x/week • Difficulty in blinding and placebo control • RCTs • Better than no treatment in MDD • Few comparisons to medication • Yoga as good as TCAs in MDD • Combination superior to medication alone • Useful as monotherapy or augmentation in dysthymia • No published data in bipolar disorder • Recommendation • Use as 2nd line augmentation and for prophylaxis in mild to moderate depression

16. Efficacy Study of Yoga to Treat Residual Depressive Symptoms 16-week augmentation pilot study with a randomized, cross-over design in both unipolar and bipolar patients • Subjects: • Outpatients currently taking antidepressants • Experiencing significant residual depressive symptoms • 8 weeks of Breathing Focused Yoga + 8 weeks of psychoeducation, or the inverse • Primary efficacy measure – MADRS • Secondary efficacy measures – CGI, Q-LES-Q

17. Results * • On the MADRS and CGI, patients on yoga showed significant improvement compared to the psychoeducation group • Both yoga and psychoeducation improved quality of life *p<0.05

18. Efficacy Study of Yoga for Social Anxiety Disorder 8-week augmentation pilot study with a randomized, cross-over design in patients with moderate-severe social anxiety disorder • Subjects: • Outpatients, mostly unmedicated • Experiencing significant social anxiety symptoms that impact functionimg • 8 weeks of Breathing Focused Yoga or wait-list Primary efficacy measure – LSAS • Secondary efficacy measures – CGI, Q-LES-Q

19. Results – need new graphs • On the LSAS and CGI, patients on yoga showed significant improvement compared to wait-list • There was no impact on quality of life; however, the patient sample was also in the severe range *p<0.05

21. Assessing the Benefits of Acupuncture • Acupuncture has proven analgesic and anaesthetic effects • Benefits mediated by: • The opioid system • Nitric oxide through gracile nucleus/thalamus • Monoaminergic stimulation • Glutamate and GABA • Methodological problems, especially blinding

22. What is the Evidence for Acupuncture for MDD? • Treatments • 4-8 weeks with 2-16 needles • MDD • 2 RCTs – as good as antidepressants • No difference compared to sham treatment in 2 studies • Mixed results from other studies • One meta-analysis – benefits but small effect size • Bipolar Depression and Hypomania • Targeted and non-targeted treatment improved symptoms Overall, safe and well tolerated but current data is inadequate to make a recommendation (based on English literature only)

23. What are Nutraceuticals? • Non-prescription natural health products, usually concentrated forms of natural substances • They are often used to support general physical and mental well-being • Approved by Health Canada: Omega-3 fatty acids, tryptophan, S-adenosyl-L-methionine (SAM-e), folic acid, inositol, amino acids, and alpha-lactabumin (as an ingredient in approved compounds) • Not yet approved in Canada: Dehydroepiandrosterone (DHEA) and acetyl-L-carnitine are not currently licensed in Canada.

24. What are Omega-3 Fatty Acids and What Mediates Their Benefit? • Essential polyunsaturated fatty acids integrated in multiple biological systems • Focus on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) • Thought to improve brain and immune functioning • Mechanism of action still unknown • ? Improving integrity of neural cell membranes and myelin • Form & Usage • Variable duration of use – 4 to16 weeks • Variable dosing of EPA, DHA or combination (at least 1000 mg)

25. Do Omega-3 Fatty Acids Alleviate MDD? • Meta-analyses • 1 negative, 2 positive for use as monotherapy or augmentation in mild to moderate MDD • Safe and well tolerated • Diarrhoea, nausea and fishy taste • Watch for bleeding and switch to mania • Conclusion • Likely benefit as 2nd line monotherapy or augmentation to antidepressants in mild to moderate depression

26. RCTs Monotherapy (1) Stoll et al. (+) Adjunct (2) Frangou et al. (+) Keck et al. (-) How Useful Are Omega-3 Fatty Acids in Bipolar Disorder? • Rates of bipolar disorder correlate inversely with consumption of fish • As with MDD, EPA is more relevant • Data: • Likely more beneficial for bipolar depression than mania. • ? Stabilize membrane fluidity

27. EPA for Bipolar Depression • Two parallel studies of efficacy and biology Efficacy † 12 week double-blind RCT (n=51) Augmentation with EPA (1-2 gms) or Placebo **EPA superior to Placebo on HAM-D and CGI (p=0.04) Biology ‡ MRS before and after 12 weeks of EPA or Placebo augmentation (n=18 females) **Higher levels of N-acetyl aspartate (NAA) with EPA vs. Placebo (p=0.02) †Frangou et al., Brit J Psychiatry, 2006 ‡ Frangou et al., J Psychopharmacol., 2007

28. How Useful is S-adenosyl-L-methionine (SAMe) for MDD? • Amino acid functioning as methyl donor • Dose & duration • Oral – 800 mg to 1000 mg (2-8 weeks) • IV/IM – 200 mg to 400 mg (2-8 weeks) • Systematic reviews (6) – mostly small studies • Superior to placebo, equal to TCAs for mild to moderate depression • Good safety and tolerability • Short-term and monotherapy data only • Recommendation • 2nd line monotherapy in mild to moderate depression

29. Does Dehydroepiandrosterone (DHEA) have Benefits for MDD? • Anti-aging nutritional supplement • ? Effect on neurogenesis and neuroprotection • Dose & Duration • 30-45 mg/day for 6-8 weeks • Some evidence for benefit as monotherapy as well as augmentation in major and minor depression, and in medically ill • Paucity of safety data • Sex hormone effects • Recommendation • 3rd line augmentation agent • Short-term use only

30. What is the Evidence for Tryptophan in MDD? • 5-HT precursor • Dose and duration • 2-4 g/day, up to 12 weeks • Most data as adjunctive agent • Mostly negative • Some benefit for sleep • Association with E.M.S.? Specific to one manufacturer • Conclusion • Insufficient evidence to support use in MDD

31. Have Other Nutraceuticals been Evaluated in MDD? • Reasonable evidence: • Adjunctive folic acid • Preliminary evidence: • Acetyl-L-carnitine (monotherapy) • Amino acid mixture (augmentation) • Multivitamins (augmentation) • No evidence: • Alpha Lactalbumin • Inositol

33. What is St. John’s Wort? How Does It Work? • Herb commonly prescribed in Europe for depression • Mechanism of action unknown • May have serotonergic and dopaminergic effects • No regulation of formulation, though hyperforin is usually the main ingredient • Dose & duration • Variable formulations (500 mg to 1000 mg) • 4-12 weeks

34. What is the Efficacy of St. John’s Wort in MDD? • Early meta-analyses (2) – superior to placebo in MDD (but methodological problems) • Recent meta-analyses (5)– equal to antidepressants, mixed results vs. placebo • Cautions • Psychiatric drug interactions not well studied • Interaction with antibiotics, anti-coagulants, oral contraceptives, etc. • Reports of induced mania and serotonin syndrome • Recommendation • 1st line monotherapy in mild to moderate depression • 2nd line augmentation in more severe depression

35. Is St. John’s Wort Useful in Bipolar Disorder? • No RCTs in bipolar disorder, either as monotherapy or as adjunct • Many reported cases of SJW-induced hypomania • Increased risk of switch with advanced age Inadequate data to make recommendations

36. Free and Easy Wanderer Plus (FEWP) for Mood Disorders • Chinese herbal mixture for multiple mood and anxiety symptoms Maintenance Treatment as Adjunct ‡ (Bipolar Depression and Mania) 26 week continuation RCT (n=188) CBZ+FEWP, CBZ+Placebo **CBZ+FEWP = lower discontinuation rate, fewer side effects, lower CBZ plasma levels Acute Treatment as Adjunct † (Bipolar Depression and Mania) 12 week double-blind RCT (n=235) CBZ, CBZ+FEWP, CBZ+Placebo **CBZ superior to Placebo for Depression and Mania **CBZ+FEWP superior to CBZ for Depression Acute Treatment as Monotherapy ‡ (Unipolar and Bipolar Depression) 12 weeks double-blind RCT (n=149) FEWP or Placebo **FEWP superior to Placebo on HAM-D, MADRS and CGI for both illnesses †Zhang et al. J Psychiatr Res. 2007, 41, 360-369 ‡Zhang et al. J Psychiatr Res. 2007, 41, 828-836

37. What are the Data with Other Herbal Remedies? • Herbs studied: • Crocus sativus (saffron) • Echium amoenum (borage) • Gingko biloba • Lavandula (lavender) • Rhodiola rosea (roseroot) • Japanese herbal formulations

38. Other Herbal Remedies (Cont’d) • Few RCTs with small numbers • Variation in formulation, dose, duration • Short-term data only (4-8 weeks) • Recommendation: Crocus sativus for mild to moderate depression as a 2nd or 3rd line monotherapy • Insufficient evidence to recommend other herbs

39. Conclusions: CAM Treatments for Depressive Disorders • Most robust evidence – Light therapy in seasonal depression. • Evidence and clinical support in mild-moderate MDD • Light therapy – augmentation • Exercise/yoga – augmentation • Omega-3 fatty acids – monotherapy or augmentation • SAM-e – monotherapy • St. John’s Wort – monotherapy • Bipolar disorder • Omega-3 fatty acids - augmentation • Inconclusive evidence at present for other physical, herbal or nutraceutical therapies