Integrative Therapies in the Treatment of Depression and Mood Disorders

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

2. Integrative Medicine • Integrating the best of conventional medicine and evidence base complementary therapies. • “It might be too pretentious to say that such a growth of 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. 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

8. Unresolved Symptoms of Depression

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

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

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

14. All psychotropic medications effect levels of neurotransmitters in the brain • Most neurotransmitters are • under precursor control. • Precursors are substances obtained • in whole or part from our diet

15. 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

16. 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)

17. Tryptophan Supplementation Induces a Positive Bias in the Processing of Emotional Material in Healthy Female Volunteers • 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 Psychopharmacology July 2006

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

20. 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

22. 5-Hydroxytryptophan (5-HTP) • Direct precursor to serotonin • Extracted from the seeds of the Giffonia plant • Not produced by bacterial fermentation • Converted from Tryptophan with a vitamin B3dependent enzyme • Converted to serotonin with a vitamin B6 dependent enzyme • Easily crosses blood brain barrier • Not incorporated into proteins

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

25. Homocysteine • Homocysteine is a functional marker of folate deficiency • Increased Homocysteine levels are found in depressed patients • CAD and depression both associated with increased Homocysteine and decreased folate

26. Homocysteine level as a marker for folate deficiency in severe depression • Depressed patients with increased homocysteine levels had significantly lower serum, RBC and CSF folate and • CSF SAMe • CSF Monoamine metabolites Bottiglieri et al J. Neurol Neurosurg Psychiatry 2001 70(3) 419

27. The Homocysteine Hypothesis of Depression

28. Folate and Depression Since the 1960’s the association between low folate and depression was described

29. CNS Spectrum October 2007

30. 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

31. 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

32. 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 lack of response • No correlation of levels and lack of appetite or weight loss

33. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial • 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.” Coppen, Alec, Journal of Affective Disorders, 2000; 60:121-130.

34. 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.

35. Folate and Relapse • After 28 weeks of fluoxetine treatment, (71 pts) 20mg/day: • Relapse rate for patients with low folate levels (< 2.5ng/mL) was42.9% • While relapse rate for patients with normal folate levels was only3.2% Papakostas et al, J Clin Psychiatry, 2004; 65: 1096-1098

36. 102 geriatric psychiatric inpatients 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.

37. 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

38. 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

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

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

41. 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.

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

43. 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

44. MTHFR Polymorphisms

45. 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

46. Deplinvs. Folic Acid DeplinFolic Acid Bioequivalent Dose1 7.5mg (1 tablet) 52.5 mg (52.5 1mg tablets) Yes No Unlikely to mask pernicious anemia from a B-12 deficiency2 Unaffected by MTHFR C>T Polymorphism (70% in the depressed population)5 Yes No Able to Cross Blood Brain Barrier & aid in the synthesis of neurotransmitters6,7 Yes No Does not bind to BBB receptors inhibiting L-methylfolate absorption into the CNS4,8 Yes No* Reduction in risk of NTD(Significant improvement in folate status. P=0.001)9 67% 58% * Unmetabolized folic acid (especially doses > 1.0mg) binds to the “folate receptor” transport mechanism with a greater affinity than 5-MTHF resulting in a reduction in the transfer of MTHF across the BBB, which may lead to a lowering of the CNS MTHF level4 • Willems, et al, British Jrnl of Pharmacology, 2004 6. Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, 2005 • Scott, J.M. et al. Lancet. 1981 2:337-340 7. Wu, D and Pardridge WM, Pharmaceutical Research, 1999; 16, 415-419 • Troen AM, et al, J. Nutrition. 136: 189-194, 2006. 8. Reynolds, EH, J. Neurol. Neurosurg. Psychiatry 2002;72;567-571. • College of Medicine, University of South Alabama (data file) 9. Lamers Y, et al. CUVILLIER VERLAG, Gottingen 2006 pp 43-59: • Popakostas , J. Clinical Psychiatry; 2004, 1090-1095

47. Crossing the Blood Brain Barrier • Unmetabolized folic acid is unable to cross the blood brain barrier (BBB) and may become bound to receptors (folate binding protein) on the membrane, thereby blocking the absorption of L-methylfolate*. • Consequently, the amount of L-methylfolate crossing the BBB into cerebral spinal fluid (CSF) is reduced. • L-methylfolate, in the absence of unmetabolized folic acid, passes more readily into the CSF which aids in neurotransmitter synthesis. *University of South Alabama, College of Medicine; Data on file

48. Well tolerated in both acute and chronic therapy • Folate augmentation to standard psychotropic medication was well tolerated in acute and maintenance trials(12 months).1,2,6,7 • Up to 90mg 5-MTHF (45mg L-methylfolate) has been administered for 4 weeks with good tolerability4 • Deplin is not contraindicated with any medications • Does not appear to be associated with weight gain, sexual dysfunction, or sleep disturbances1-7 • Suicide/Overdose • No suicidal ideation or suicides were reported with folate.1-7 • Up to a 1,000mg of folate (more than 4 months of Deplin) was administered for 1-3 weeks in 4 patients with no adverse events reported8 L-methylfolateSafety Profile • Pregnancy • L-methylfolate does not currently have a pregnancy category • Up to 1mg of folate is approved by the FDA as Pregnancy Category A.9 • L-methylfolate was shown to be more effective in increasing folate concentrations and reducing NTD risk compared to folic acid.10 No titration required 7. Alpert, JE, et al Annals of Clin Psychi, 2002; 14: 33-38 1. Coppen, A. et al, J. Affective Disorders, 1986. 121-130 4. Passeri, M., et al. Aging Clin. Exp. Res, 1993; 63-71 8. Carney M.,J Nerv Mental Disorders 1970 2. Godfrey, PSA., et al. The Lancet, 1990; 392-395 5. Di Palma, C., et al. Therapeutic Research, 1994 9. Folic acid prescribing info, Watson Labs 2005 6. Coppen, A et al J. of Affective Disorders, 2000; 9-13 10. Lamer Y., et al. CUVILLIER VERLAG, Gottingen 2006 3. Guaraldi et al. Annals Clin Psych 1993; 101-105

49. A ubiquitous methyl doner located throughout the body. • A key role in numerous metabolic pathways that invoke transfer of methyl group. • Neurotransmitter Synthesis • Formed in the body by methinine