Integrative Therapies in the Treatment of Depression and Mood Disorders

1. Integrative Therapies in the Treatment of Depression and Mood Disorders Dr. James M. Greenblatt, M.D. September 29, 2007

2. Integrative Medicine • Integrating the best of conventional medicine and evidence base complementary therapies emphasizing patient participation in health promotion, disease prevention and medical management. • “It might be too pretentious to say that such a growth at integrative medicine might restore the soul to medicine – the soul being that part of us that is the most important but the least easy to deliniate.” British Journal of Medicine 2001

3. Why is Psychiatry Different? • Medical treatment for mental disorders differs from treatment of all other medical specialties. • Psychiatrists typically do not use objective measurements to guide treatment of mental or addictive illness

4. Medical Testing includes • Blood, Urine, Saliva Assays • Microbiology • Tissue analysis • X-Ray, MRI, CT Scans, PET Scans • EKGs, EEGs • ETC…

5. Psychiatric Testing

6. Diagnosis and Treatment General Medical Treatment: Symptoms Measure Physiology “Anti”-physiology treatment Measure physiology and symptoms Psychiatric Treatment: Symptoms “Anti”-Symptom treatment given Measure symptoms

7. The “Art” of Psychopharmacology • Heterogeneity of medication response, • One class of medication treats multiple disorders • SSRI’s: • Panic Disorder • Generalized Anxiety • Social Phobia • “No name distress” • PMPD • SAD • MDD • Bulimia

8. Response to Psychopharmacologic Treatment • 50% improvement of the primary symptoms of depression is the standard measure of treatment response • 20-40% do not show substantial clinical improvement • 50% who show improvement have residual symptoms that impact functioning

9. Unresolved Symptoms of Depression

10. Factors Associated with Insufficient Symptom Improvement Following an Adequate Trial of Antidepressants Partial or Non-Response

12. Nutrition as “Alternative”

13. Nutrition and Health Understanding the role of Nutrition and Health is not Alternative Medicine

14. Nutrient Deficiencies Are Common Percentages of U.S. Population Not Meeting the DRI For Specific Nutrients Variability in Individual Nutrient Needs are Established

15. Medicine and Nutrition Medical Profession’s reluctance to change • Folic Acid • 25+ years • Aspirin • 15+ years

16. Neurotransmitters • At least 250 are known • Release of these chemicals causes electrical impulses throughout the brain resulting in: • Thoughts • Feelings • Behaviors • Neurotransmitter levels affect every facet of a biological system

17. All psychotropic medications effect levels of neurotransmitters in the brain

18. Neurotransmitters • Most neurotransmitters are under precursor control • Precursors are substances obtained in whole or part from our diet • Precursors are most easily obtained from meats and animal products

19. Folic Acid Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin B3 Neurotransmitter Synthesis L-Tryptophan 5-HTP ST L-Tyrosine L-Dopa DA NE Epi • Magnesium • Zinc • Iron • Copper

20. Neurotransmitters What causes Neurotransmitter Deficiencies? • Genes • Diet • Stress • Neurotoxins

21. Increasing Tryptophan in Diet Decreasing Tryptophan in Diet Increases Serotonin in the brain Decreases Serotonin in the brain Neurotransmitter Precursors In any normal diet animal based or vegetarian Tryptophan is the least plentiful of all 20 amino acids (9:1)

22. Tryptophan Supplementation Induces a Positive Bias in the Processing of Emotional Material in Healthy Female Volunteers Psychopharmacology July 2006 • 38 healthy female volunteers • 14 day DBPCT with 1 gm Tryptophan 3 times a days placebo • Tryptophan supplementation resulted in a positive bias in processing emotional material in women

23. Tryptophan boosts confidence and reduces aggression • 1 mg Tryptophan 3 X/day • 12 day DBPCT • Tryptophan increased agreeable behavior • and reduced quarrelsome behavior

25. Tryptophan • 1989, The FDA removed tryptophan due to outbreak of Eosinaphilia Myolgia (EMS) • Traced to a single batch of contaminated tryptophan from Japan

26. Folic Acid Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin B3 Neurotransmitter Synthesis L-Tryptophan 5-HTP ST L-Tyrosine L-Dopa DA NE Epi • Magnesium • Zinc • Iron • Copper

27. 5-Hydroxytryptophan (5-HTP) • Direct precursor to serotonin • Extracted from the seeds of the Giffonia plant • Not produced by bacterial fermenatis

28. 5-HTP A guided missile directly targets increased brain serotonin levels

29. 5-HTP • Converted from Tryptophan with a vitamin B3dependent enzyme • Converted to serotonin with a vitamin B6dependent enzyme • Easily crosses blood brain barrier • Not incorporated into proteins • Not utilized to make vitamin B3 • Response usually less than two weeks

30. 5-HTP 50-300 mg/day Empty stomach best Divided 2-4 does Start low and titrate dose Tryptophan 500-3000 mg/day Empty stomach best Divided 2-4 doses Clinical Applications Recommended Dosages:

31. Folic Acid Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin B3 Neurotransmitter Synthesis L-Tryptophan 5-HTP ST L-Tyrosine L-Dopa DA NE Epi • Magnesium • Zinc • Iron • Copper

32. Folic Acid and SAMe • The folate cycle synthesizes methyl groups, which are then used by SAMe in numerous methylation reactions including: Neurotransmitters synthesis

34. Folate and Depression • 11 relevant studies (15,315 participants, 3 case-control studies, 7 population surveys, and 1 cohort study) were systematically analyzed • A significant correlation between folate levels and depression – low folate status is linked to depression Gilbody et al. J Epidemiol Community Health 2007

35. Folate Deficiency and Depression • ≥ 56% of patients with affective disorders had folate deficiency • Lower serum folate concentrations are correlated with greater severity of depression • Red blood cell folate levels are significantly lower in depressive patients than those suffering from other psychiatric disorders

36. Causes of Folate Deficiency States • Inadequate intake: Dietary sources heat labile, easily oxidized (≥ 50% during food shortage and processing) • Malabsorption • Genetic polymorphism • Medications

37. Anticonvulsants (phenytoin, primidone, phenobarbital, carbamazepine) Oral contraceptives Sulfsalazine Methotrexate Triamterene Pyrmethamine Trimethoprim Alcohol Antacids Antibiotics Metformin Drugs that Can Cause Folate Deficiency States

38. Folate and Antidepressant Response • Folate deficiency may hinder antidepressant response to standard antidepressants - 213 adults (ages 18-65) with Major Depressive Disorder (MDD) treated with fluoxetine 20mg qd x 8 weeks • Low folate correlated with melancholia and lack of response • No correlation of levels and lack of appetite or weight loss

39. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial Alec Coppen, John Bailey Journal of Affective Disorder 60 (2000) 121-130 • Effective augmentation study of Prozac: • Placebo controlled study • 500 mcg/day • Effective in women, not men “Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressant agents.”

40. Folate Augmentation in First Episode Depression* • Double blind trial of 127 patients experiencing their first episode of depression. Patients randomized to receive either 20mg fluoxetine + 500mcg folate or 20mg fluoxetine + placebo. • Treatment with fluoxetine augmented with folate resulted in a significantly greater improvement in depression compared to fluoxetine alone. Folate treatment resulted in greater remission rates over placebo among women but not men with depression. • No additional adverse events were reported with the addition of folate. Percentage of women who achieved HAM-D <9 Percentage of Reported Side Effects * Coppen, Alec, Journal of Affective Disorders, 2000; 60:121-130.

41. Folate and Relapse • After 28 weeks of fluoxetine treatment, (71 pts) 20mg/day: • Relapse rate for patients with low folate levels (< 2.5ng/mL) was 42.9% • While relapse rate for patients with normal folate levels was only 3.2% Please Read This Again Papakostas et al, J Clin Psychiatry, 2004; 65: 1096-1098

42. 102 geriatric psychiatric inpatients Lower levels of folate and B12 predicted poorer cognitive status Lower levels of folate predicted a longer psychiatric hospitalization Severity of psychiatric illness correlated with lower folate levels Folate and Severity of Illness 15 Bell IR; Edman et al, Biological Psychiatry, 1990;15, 27(2):125-37.

43. Folic Acid and the Treatment of Depression • Low folate associated with increased incidence of depression • Low folate associated with poor response to antidepressants • Low folate associated with higher relapse rate • Folate supplementation enhances effect of Antidepressants

44. Folic Acid Supplementation in Depression “We suggest the use of 2mg of folic acid, which would be expected to increase plasma folate to more than 20ng/mL in both sexes…Adding 2mg of folic acid to antidepressant treatment would be easy in everyday clinical practice. The daily supplement could be easily taken. It is inexpensive and safe.” Abou-Saleh & Coppen, J Psychosom Res 2006

45. Folic Acid Supplements • Folic Acid: • Folinic Acid • Folinic Acid (Leucovorin) • L-Methylfolate (Deplin)

46. Folic Acid Conversion to L-methylfolate • Folic acid requires a 4 step transformation process to be converted to the active form of folate, L-methylfolate. Dietary folate requires 3-steps. • L-methylfolate is absorbed directly in the active form that can immediately cross the blood brain barrier for use. • L-methylfolate is unaffected by the CT polymorphism.

47. MTHFR Polymorphisms • Polymorphisms in the gene coding for methylenetetrahydrofolate reductase (MTHFR) reduce efficiency of folic acid metabolism • Polymorphisms increase risk of depression • Patients who have MTFR CT genotypes have a 1.36 times greater chance of developing depression • The odds of having the T/T genotype is twice as great in depressed patients verses the normal population

48. MTHFR Polymorphisms

49. The odds of having the T/T genotype is twice as great in depressed patients verses the normal population.1,4 Deplin, not Folic Acid, bypasses a common genetic mutation present in the majority of patients with MDD Prevalence of C→T Polymorphism in the Depressed Population1 • Allelic frequency of the C/T-T/T mutation is 70% in the depressed population.1 • Patients who have the MTHFR C→T genotypes have a 1.36 times greater chance of developing depression (and reported as high as 4 times the general population).2,3 1. Kelly B., Journal of Psychopharmacology 18(4) (2004) 567–571 3. Procopciuc L.M., Presented at Biological Psychiatry, Poster P86 2. Bjelland, I., et. al; . Arch. Gen. Psychiatry 2003, 618– 626 4. Arinami T, AM J. Medical Genetics 1997

50. How Deplin Differs from Folic Acid • Folic acid requires a 4 step transformation process to be converted to the active form of folate, L-methylfolate. Dietary folate requires 3-steps • L-methylfolate is absorbed directly in the active form that can immediately cross the blood brain barrier for use. • L-methylfolate is unaffected by the CT polymorphism 20