St. John's Wort

Using Herbs and Supplements to Treat Major Depressive Disorder: The Good, the Bad, and the Ugly

page 315 in syllabus

Rona J. Hu, MD Clinical Associate Professor, Department of Psychiatry and Behavioral Sciences; Medical Director, Acute Psychiatric Inpatient Unit, Stanford University School of Medicine

Sponsored by the Neuroscience Education Institute Additionally sponsored by Fairleigh Dickinson University School of Psychology

This activity is supported by educational grants from: Lilly USA, LLC; Otsuka America Pharmaceutical, Inc.; Pamlab, L.L.C.; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceuticals International, Inc., U.S. Region and Lundbeck Pharmaceutical Services, LLC; Teva Pharmaceutical Industries Ltd. with additional support from: Assurex Health, Inc.; JayMac Pharmaceuticals, LLC; Neuronetics, Inc.. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Individual Disclosure Statement

Faculty Author / Presenter Rona J. Hu, MD, is a clinical associate professor in the department of psychiatry and behavioral sciences and medical director of the acute psychiatric inpatient unit at Stanford University School of Medicine in Standford, CA No financial relationships to disclose.

• Ask patients about their use of herbal and supplemental treatments

• Explain the therapeutic and safety profiles of commonly used herbs and supplements

• Refer patients to credible sources for patient education materials on herbs and supplements

Do you specifically ask patients about their use of herbal and supplemental treatments?

1. Yes, all patients 2. Yes, some patients 3. No

A 24-year-old woman suffering from a major depressive episode (moderate) presents to your office. She has previously taken an SSRI for depression but expresses a desire to try something "natural." She specifically asks about St. John's wort. Which of the following would be your primary concern if the patient begins taking St. John's wort? 1. Lack of evidence of efficacy for depression 2. Side effect burden generally no better than with standard antidepressants 3. Numerous potential drug interactions

Which of the following has the best evidence of efficacy for treating symptoms of depression? 1.L-tryptophan 2.Melatonin 3.Omega-3 fatty acids 4.Vitamin D

• Intended to be taken by mouth as pill, capsule, tablet, or liquid – Herbal/botanical products – Vitamins and minerals – Probiotics, fish oils, glucosamine – Amino acid products – Enzyme supplements

• Reasons for use – Perception that "natural" = safe – Easy access, low cost

• Anything labeled "X supplement" (dietary, herbal, etc.) was brought to market without having to prove: – It meets FDA safety requirements – The accuracy of claims made in label

• Postmarketing – Safety and product information are monitored by FDA – Advertising is monitored by FTC

• A dietary supplement cannot be marketed as a treatment or cure for a specific disease or symptom

FDA. http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm050824.pdf. Accessed April 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. What Claims Can Manufacturers Make?

• Health claim – Reduces risk of certain disease or condition • Nutrient content claim – Relative amount of a nutrient in the product • Structure/function claim – How product affects organs or body systems; cannot mention specific disease • Must include disclaimer: "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease."

Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/DietarySupplements- HealthProfessional/. Accessed April 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Most Common Non-vitamin, Non-mineral Supplements (Adults, General Use)

40% 35% 30% 25% 20% 15% 10%

Adult Use in LastUseAdult in Days 30 5% 0%

NCCAM. http://nccam.nih.gov/news/2008/121008.htm. Accessed April 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Most Common Non-vitamin, Non-mineral Supplements (Children, General Use)

40% 35% 30% 25% 20% 15% 10%

Child Use in LastUse in ChildDays 30 5% 0%

• Is it safe?

• Does it work for the condition it is supposed to treat?

• If so, how?

• Does it interact with any medications or other supplements?

• Does it have side effects?

Hypericin Hyperforin • Early research suggested • Increases synaptic 5HT, MAO inhibition DA, NE, GABA, and L- • Levels needed are far glutamate INDIRECTLY greater than those by increasing intracellular + 2+ achieved with normal Na and Ca doses • Responsible for drug • Unclear therapeutic interactions effects • Unclear therapeutic effects

Klemow KM et al. In: Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. 2011. Copyright © 2013 Neuroscience Education Institute. All rights reserved. St. John's Wort: Early Evidence of Safety and Efficacy

• Early studies: superior to placebo and comparable to older antidepressants – Included trials of patients not meeting MDD criteria

• 2005 Cochrane Review: mixed data – Less favorable results in: • Larger, well-designed studies • Studies of MDD patients

Linde K, Mulrow CD. Cochrane Database Syst Rev 1998;(4):CD000448; Linde K et al. Cochrane Database Syst Rev 2005;(2):CD000448. Copyright © 2013 Neuroscience Education Institute. All rights reserved. St. John's Wort: 2008 Cochrane Review • Superior to placebo and comparable to standard antidepressants but with fewer side effects

• Only included double-blind, randomized trials of adult MDD patients

• High degree of heterogeneity among studies

• Slightly less favorable in: – Less precise studies – Studies from non-German speaking countries – Studies with higher HAM-D baseline scores

Linde K et al. Cochrane Database Syst Rev 2008;(4):CD000448. Copyright © 2013 Neuroscience Education Institute. All rights reserved. St. John's Wort: Post-Cochrane Review • Negative 12-week trial in minor depression1 – Neither SJW nor citalopram separated from placebo – High placebo response

• Positive 8-week trial in moderate depression2

• Positive 6-month trial in moderate depression3

• Negative 6-month trial in MDD4 – Neither SJW nor sertraline separated from placebo – High placebo response 1. Rapaport MN et al. J Psychiatr Res 2011;45(7):931-41. 2. Mannel M et al. J Psychiatr Res 2010;44(12):760-7. 3. Kasper S et al. Eur Neuropharmacol 2008;18(11):803-13. 4. Sarris J et al. Pharmacopsychiatry 2010;45(7):275-8. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Important Drug Interactions With St. John's Wort

Drug Effect on levels Mechanism Possible clinical effect IMMUNOSUPPRESSANTS cyclosporine ↓ 3A4 Organ rejection P-glycoprotein tacrolimus ↓ 3A4 Organ rejection P-glycoprotein ANTI-HIV DRUGS indinavir ↓ 3A4 Drug failure due to NTI P-glycoprotein nevirapine ↓ 3A4 Drug failure ANTICANCER DRUGS irinotecan ↓ 3A4 Drug failure due to NTI imatinib ↓ 3A4 Drug failure P-glycoprotein

Drug Effect on levels Mechanism Possible clinical effect HORMONE THERAPIES oral ↓ 3A4 Intermenstrual bleeding contraceptives Reduced efficacy ANTICOAGULANTS warfarin ↓ 3A4 Drug failure due to NTI phenprocoumon ↓ 3A4 Reduced efficacy rivaroxaban ↓ 3A4 Reduced efficacy P-glycoprotein apixaban ↓ 3A4 Reduced efficacy P-glycoprotein

Drug Effect on levels Mechanism Possible clinical effect ANTIHYPERLIPIDEMICS simvastatin ↓ 3A4 Reduced efficacy P-glycoprotein atorvastatin ↓ 3A4 Reduced efficacy ANESTHETIC fentanyl, Unknown Delayed emergence propofol, sevoflurane in O2, nitrous oxide

Drug Effect on levels Mechanism Possible clinical effect BENZODIAZEPINES alprazolam ↓ 3A4 Reduced efficacy midazolam ↓ 3A4 Drug failure due to NTI quazepam ↓ 3A4, 2C19 Reduced efficacy SEROTONERGIC DRUGS amitriptyline ↓ 3A4 Drug failure due to NTI P-glycoprotein SRI Additive Serotonin syndrome MAOI Additive Serotonin syndrome OPIOID WITHDRAWAL methadone ↓ 3A4 Withdrawal syndrome

Drug Effect on levels Mechanism Possible clinical effect CALCIUM CHANNEL BLOCKERS verapamil ↓ 3A4 Reduced efficacy nifedipine ↓ 3A4 Reduced efficacy BETA-ADRENERGIC BLOCKERS talinolol ↓ P-glycoprotein Reduced efficacy ANTIANGINAL ivabradine ↓ 3A4 Reduced efficacy CARDIAC INOTROPIC digoxin ↓ P-glycoprotein Drug failure due to NTI ANTIPLATELET clopidogrel ↓ 3A4 Enhanced actions (prodrug)

Drug Effect on levels Mechanism Possible clinical effect CENTRAL MUSCLE RELAXANT chlorzoxazone ↓ 2E1 Reduced efficacy RESPIRATORY fexofenadine ↓ P-glycoprotein Reduced efficacy HYPOGLYCEMIC gliclazide ↓ 2C9? Reduced efficacy ANTIMICROBIC voriconazole ↓ 3A4, 2C19 Reduced efficacy GI DRUGS omeprazole ↓ 3A4, 2C19 Reduced efficacy

BENEFIT RISKS  Modest for mild to  Numerous drug moderate depression interactions (with higher hyperforin content)  Insufficient data for:  Severe depression  Long-term use  Children and adolescents

• Unclear which components are necessary and in which amounts1

• Low-hyperforin products are preferable with concomitant medications1,2 – Standardization is based on hypericin content3,4 – Hyperforin is unstable, and it degrades rapidly under ambient conditions • Hyperforin content is often not disclosed

1. Linde K et al. Cochrane Database Syst Rev 2008;(4):CD000448. 2. Borrelli F, Izzo AA. AAPS J 2009;11(4):710-27. 3. Butterweck V. In: Botanical Medicine: From Bench to Bedside. 2009. 4. de los Reyes GC, Koda RT. Am J Health-Syst Pharm 2002;59:545-7. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Pharmaceutical-Grade Extracts

Extract* Brand name Active component(s) Formulation Manufacturer LI 160** Jarsin 300® Hypericin 0.28%, 300-mg tablet Lichtwer hyperforin 1–4% Pharma AG LI 160** Kira® Hypericin 0.28%, 100-mg tablet Lichtwer hyperforin 1–4% 300-mg tablet Pharma AG WS 5570** Neuroplant® Hypericin 0.12–0.28%, 300-mg tablet Schwabe hyperforin 3–6% 600-mg tablet WS 5572 Perika® Hypericin 0.12–0.28%, 300-mg tablet Schwabe hyperforin 3–6% Ze 117** Remotiv® Hypericin 0.2%, 250-mg tablet Zeller AG hyperforin <0.5% STEI 300 Aristo 350® Hypericin 0.2–0.3%, 350-mg capsule Steiner hyperforin 2–3% *Alcohol extracts from dried plant material **Used in clinical trials

Linde K et al. Cochrane Database Syst Rev 2008;(4):CD000448; Klemow KM et al. In: Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. 2011; Borrelli F, Izzo AA. AAPS J 2009;11(4):710-27. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Some Other St. John's Wort Products

Brand Active Formulation Manufacturer name component(s) Esbericum® Hyperforin 1.47% 60-mg capsule Schaper & Brümmer Hypericum Hypericin 0.055%, 2000-mg capsule* Nutra-Life 2000 Plus® hyperforin 0.75% Movina® Hyperforin 3–6% 300-mg capsule BI AB Solaray® Hypericin 0.12–0.3% 300-mg capsule Solaray TruNature® Hypericin 0.3% 300-mg softgel Leiner Health Products Hypericin 300 mcg 1000 mg/1 mL Nature's liquid Answer *Also contains 100 mg Ginkgo biloba and nutritional cofactors

• Dose – Clinical trials: 500–1200 mg/day (divided)1 – Generally recommended: 900–1800 mg/day (divided)2

• Side effects – Mild: nausea, constipation, dry mouth, headache, restlessness, tiredness, dizziness2 – Photosensitivity can occur2

1. Linde K et al. Cochrane Database Syst Rev 2008;(4):CD000448. 2. Howland RH. J Psychosoc Nurs Ment Health Services 2010;48(11):20-4. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of St. John's Wort

Do not take Other cautions • With immunosuppressants • With other drugs metabolized by 3A4, • With anti-HIV drugs P-glycoprotein, 1A2 • With anticancer drugs • With SSRIs or MAOIs • With digoxin • With anticoagulants • For 2–3 weeks before surgery

• Naturally occurring, endogenous substance produced from adenosine triphosphate and methionine1 • Called ademetionine (AdoMet) in Europe • Involved in functions throughout the body, notably in the brain and liver1 • Acts as a methyl donor; this presumably leads to increased monoamine levels2 • Low SAMe levels are reported in depressed patients3 • Increases in SAMe levels correlate with response4

1. NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013. 2. Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22. 3. Bottiglieri T et al. J Neurol Neurosurg Psychiatry 1990;53:1096-8. 4. Bell KM et al. Acta Neurol Scand Suppl 1994;154:15-8. Copyright © 2013 Neuroscience Education Institute. All rights reserved. SAMe: Methylation and Neurotransmitter Synthesis

methionine

methionine SAMe synthase

B12

SAH CH3 synthesis of gene products H H homocysteine MTHF H H

RNA

gene product

activated gene

CH3 H H MTHF SAMe Me DNMT H H

SAMe = S-adenosylmethionine DNMT = DNA methyltransferase

CH3 H H MTHF SAMe Me DNMT H H Me Me Me Me

RNA

gene product

silenced gene

Study Treatment Duration p-value Effect size Agnoli et al. SAMe 15 mg IM TID (n=20) 15 days p<0.05 1.6 1976 Placebo (n=10) Fava et al. SAMe 1600 mg/day PO (n=17) 6 weeks NS 0.16 1992 Placebo (n=21) Thomas et SAMe 200 mg/day IV bolus (n=9) 2 weeks NS 0.12 al. 1987 Placebo (n=11) Salmaggi SAMe 1600 mg/day PO (n=40) 30 days p<0.01 0.33 et al. 1993 Placebo (n=40) De Leo et SAMe 200 mg IM daily (n=20) 4 weeks p<0.05 0.61 al. 1987 Placebo (n=20) Janicak et SAMe 400 mg/day IV (n=7) 15 days p<0.02 1.46 al. 1989 Imipramine 150 mg/day IV (n=3) Placebo (n=5)

Carrieri et SAMe 1000 mg/day  Placebo (n=11) 15 days/ p<0.05 NC al. 1990 Placebo  SAMe 1000 mg/day (n=10) 15 days

Two additional studies did not provide p-value for comparison. NC: not calculable. Carpenter D. Alternative Med Rev 2011;16(1):17-39. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Evidence of Safety and Efficacy of SAMe: Severe Depression

Study Treatment Duration p-value Effect size Kagan et al. SAMe 1600 mg/day PO (n=9) 3 weeks p<0.05 0.79 1990 Placebo (n=6) Caruso et al. SAMe 200 mg IM daily (n=30) 3 weeks p<0.01 1.4 1987 Placebo (n=30) Delle Chiaie SAMe 800 mg/day IV (n=40) 3 weeks p=0.05 0.43 et al. 1997 Placebo (n=35) Muscettola et SAMe 150 mg IM daily (n=10) 15 days p<0.05 NC al. 1982 Placebo (n=10) Carney et al. SAMe 200 mg/day IV (n=16) 2 weeks NS; trend 0.36 1986 Placebo (n=16) favoring placebo Primary outcome: HAM-D total change. NC: not calculable.

• Small sample sizes

• Not restricted to MDD

• Do not present intent-to-treat analysis

• Many use IM or IV formulations – Low oral bioavailability – Unstable when exposed to air

SAMe Augmentation for Nonresponse to Antidepressants

6-Week Study in Major Depressive Disorder

P=0.1 P<0.02

SAMe 800 mg twice per day + AD: N=39 Placebo + AD: N=34

• May lower blood sugar levels1

• Drug interactions2 – Limited data but theoretical interaction with agents that increase serotonin (antidepressants, St. John's wort) – May decrease effects of levodopa

1. NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013. 2. Mayo Clinic. http://www.mayoclinic.com/health/same/NS_patient-same. Accessed May 2013.

• Promotes growth of the fungus Pneumocystis1,2 – Can cause pneumonia in people with suppressed immune systems

• Pregnancy – Used in third trimester for intrahepatic cholestasis with no reported AEs (small studies)1,2 – One study in second trimester: no reported AEs1

1. NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013. 2. Mayo Clinic. http://www.mayoclinic.com/health/same/NS_patient-same. Accessed May 2013.

BENEFIT RISKS  Possible benefit for mild,  May lower blood sugar moderate, and severe levels depression  Insufficient data, particularly for:  Long-term use  Children and adolescents

• Dose1,2 – 800–1600 mg/day (oral) or 200–400 mg/day (IM) – Best absorbed if taken 20 minutes before a meal

• Side effects2,3 – Uncommon – May include nausea and other GI symptoms, skin reactions (IM) – Possible activation or worsening of (hypo)mania in patients with bipolar disorder

1. Carpenter D. Alternative Med Rev 2011;16(1):17-39. 2. Williams AL et al. Clin Invest Med 2005;28(3):132-9. 3. NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of SAMe

Do not take1 Other cautions2 • Patients with bipolar • Patients with diabetes or disorder hypoglycemia; patients • Patients with Parkinson's taking any other disease substances that affect blood sugar • Patients with HIV – May need to monitor serum glucose levels • Not recommended in first trimester

1. NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013. 2. Mayo Clinic. http://www.mayoclinic.com/health/same/NS_patient-same. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. OMEGA-3 FATTY ACIDS

• Present in high levels in neurons; influence neuroendocrine function, membrane fluidity, inflammation, other functions1

• Dietary source is required to maintain adequate concentrations in peripheral and central tissues1 – Long chain: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) mainly come from fatty fish – Short chain: alpha-linolenic acid (ALA) comes from plant sources; can be converted in small amounts to EPA and DHA

• Meta-analysis of 14 case–control studies: MDD patients exhibit significant EPA + DHA deficits2

1. NCCAM. http://nccam.nih.gov/health/omega3. Accessed May 2013. 2. Lin PY et al. Biol Psychiatry 2010;68:140-7. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Omega-3 Fatty Acids: Evidence of Efficacy in Adults • Multiple meta-analyses in MDD: modest efficacy1-4 – EPA is the effective component (vs. DHA) – ≥60% EPA (of total EPA+DHA) is needed – Include both adjunct and monotherapy trials – Studies are highly heterogeneous in design • Meta-analysis in MDD and non-MDD: no benefit5 • Meta-analysis in bipolar depression: modest efficacy6 • APA endorses adjunctive treatment with EPA + DHA7 1. Sublette ME et al. J Clin Psychiatry 2011;72(12):1577-84. 2. Freeman MP et al. J Clin Psychiatry 2006; 67:1954–67. 3. Lin PY et al. Mol Psychiatry 2012;17:1161-3. 4. Martins JG et al. Mol Psychiatry 2012;17(12):1144-9. 5. Bloch MH, Hannestad J. Mol Psychiatry 2012;17:1272-82. 6. Sarris J et al. J Clin Psychiatry 2012;73(1):81-6. 7. Gelenberg AJ et al. MDD practice guideline. APA;2010. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Omega-3 Fatty Acids: Evidence of Efficacy in Special Populations

• Pregnancy – Controlled trial (n=126) found no benefit of EPA or DHA supplementation1

• Children and adolescents – Small (n=28) controlled study found significant improvement (ages 6–12)2 – Two small open-label studies in bipolar disorder found significant (modest) improvement (ages 6–17)3,4

1. Mozurkewich EL et al. Am J Obstet Gynecol 2013;208(4):313.e1-9. 2. Nemets H et al. Am J Psychiatry 2006;163:1098-100. 3. Wozniak J et al. Eur Neuropharmacol 2007;17:440-7. 4. Clayton EH et al. Eur J Clin Nutr 2009;63:1037-40. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Omega-3 Fatty Acids: Safety

• May theoretically increase risk of bleeding • May increase low-density lipoprotein (LDL) • Rare, mild elevation of liver function tests • Decreased estrogen receptor production • May theoretically increase blood sugar levels • Long-term use may cause vitamin E deficiency – Most supplements contain vitamin E • May worsen symptoms in patients with ventricular tachycardia

NCCAM. http://nccam.nih.gov/health/omega3. Accessed May 2013; Natural Standard. http://www.naturalstandard.com/databases/herbssupplements/fishoil.asp?. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Omega-3 Fatty Acids: Summary

BENEFITS RISKS  Possible benefit for mild,  Some possible negative moderate, and severe health effects (e.g., depression increased risk of  General health benefits* bleeding), but generally considered safe  Unlikely to have drug interactions  Some evidence of efficacy in children and adolescents *Not necessarily in supplement form

Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Adjunct Omega-3 Fatty Acids • Dose – Based on amount and ratio of EPA and DHA – APA: 1 g/day of EPA + DHA (2:1 EPA:DHA ratio)1 – 1–3 g/day is generally recognized as safe (including dietary intake)2 • Side effects2 – Mild, not as common at typical doses – Mainly GI-related (fishy taste, nausea, diarrhea, burping) • Reduced if pill is taken with food – Possible activation or worsening of (hypo)mania in patients with bipolar disorder

1. Freeman MP et al. J Clin Psychiatry 2006;67:1954-67. 2. McNamara RK, Strawn JR. PharmaNutr 2013;1:41-9. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Adjunct Omega-3 Fatty Acids: Cautions

• Patients at risk for bleeding and/or those taking anticoagulants • Patients with high LDL • Patients with ventricular tachycardia or ventricular arrhythmia • Patients with fish or shellfish allergies • Fish liver oil supplements contain vitamins A and D as well; large doses may lead to toxicity

• L-methylfolate is a required cofactor in the synthesis of all 3 monoamines1 • Can be converted from dietary folate or folate supplementation (folic acid)1 • Low folate blood levels correlate with risk of depression2 • Low folate levels have been associated with lack of response/slower response to fluoxetine3,4 • Higher folate levels at baseline correlate with better response to antidepressants5 1. Stahl SM. Stahl's essential psychopharmacology. 4th ed. 2013. 2. Gilbody S et al. J Epidemiol Community Health 2007;61:631-7. 3. Papakostas GI et al. J Clin Psychiatry 2004;65:1090-5. 4. Papakostas GI et al. Int J Neuropsychopharmacol 2005;8:523-8. 5. Alpert M et al. J Clin Psychopharmacol 2003;23:309-13. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Folate and Related Compounds: Methylation and Neurotransmitter Synthesis

methionine

folic acid methionine (supplement) SAMe synthase

dihydrofolate B12 (food) SAH CH3 synthesis of gene products H H homocysteine MTHF H H

Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22; Miller AL. Alternative Med Rev 2008;13(3):216-26. Copyright © 2013 Neuroscience Education Institute. All rights reserved. L-methylfolate and Neurotransmitter Synthesis

CH H 3 H BH MTHFR MTHF folate biopterin H H

tyrosine hydroxylase

BHBH DA NE

tyrosine

CH H 3 H BH MTHFR MTHF folate biopterin H H

tryptophan hydroxylase

BHBH 5HT

tryptophan

BH BH

biopterinbiopterin CH 3 H CH H H 3 H

MTHFRMTHFR MTHFMTHF H folate H H H BH

DADA NE

Copyright © 2013 Neuroscience Education Institute. All rights reserved. MTHFR Polymorphisms, Neurotransmitter Synthesis, and Depression IF THEN MTHFR activity is: L-methylfolate is: Homocysteine is: Methylation is: NT synthesis is:

High(C/C)

Low(C/T or T/T)

Pathway Gene Research Metabolism MTHFR C/T or TT: may be more likely to have depression; unclear whether these patients are more likely to respond to l-methylfolate or SAMe Metabolism MTHFR- MTHFR T allele + COMT Val/Val: dopamine is COMT degraded at an even higher rate interaction

Study Design Supplement Outcome Coppen et 12-mo DB randomized PBO- Folic acid Patients with highest al. 1986 controlled. N=75 patients on Li+ 200 mcg folate levels had greatest improvement Coppen 10-wk DB randomized PBO- Folic acid Significant and Bailey controlled. N=127 patients with 500 mcg improvement vs. 2000 MDD on fluoxetine 20 mg PBO in females only Alpert et al. 8-wk open-label. N=22 patients Folinic acid 31% response rate 2002 with MDD, SSRI nonresponse 19% remission rate

Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Folate and Related Compounds: Evidence of Efficacy Study Design Supplement Outcome Godfrey et 6-mo DB randomized PBO- MTHF 15 mg Significant al. 1990 controlled. N=41 patients w/ low improvement vs. PBO red cell folate (24 MDD, 17 schiz) Guaraldi et 6-wk open-label. N=20 elderly MTHF 50 mg 81% response rate al. 1993 depressed patients monotherapy Passeri et 8-wk DB controlled. N=96 patients MTHF 50 mg Significant al. 1993 w/ depression and dementia or trazodone improvement in both 100 mg groups Ginsberg et Retrospective analysis. N=242 L-MTHF 7.5 Improvement in 18.5% al. 2011 MDD patients on SSRI/SNRI (95 or 15 mg of adjunct group vs. received L-MTHF) 7.01% of monotherapy group Papakostas 2 DB randomized PBO-controlled L-MTHF Trial 1: NS et al. 2012 parallel sequential 30-day trials. 7.5 mg (Trial Trial 2: significant Trial 1: 148 patients w/ TRD 1) or 15 mg improvement vs. PBO Trial 2: 75 patients w/ TRD (Trial 2) Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Folate and Related Compounds: Safety • Can mask anemia due to B12 deficiency* • May interfere with anticancer effects of methotrexate (folate antagonist) • Folate and related supplements can reduce serum anticonvulsant levels • Some drugs can lower folate levels, including anticonvulsants, fluoxetine, and NSAIDs • High doses of folic acid (>800 mcg) can increase the amount of unmetabolized folic acid; this has been linked to accelerated growth of existing neoplasms in the colon* *May be less likely with l-methylfolate Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Folate and Related Compounds: Summary

BENEFITS RISKS  Possible benefit for mild,  Can mask anemia due to moderate, and severe B12 deficiency* depression  Insufficient data for:  General health benefits  Children and adolescents  Folic acid is Pregnancy Category A at recommended doses

*Anemia is no longer the basis for diagnosing B12 deficiency

• Consider screening for and treating folate deficiency • Sources include dietary intake, folic acid supplement, folinic acid supplement, and l-methylfolate supplement • Significantly greater increases in l-methylfolate levels with l-methylfolate supplementation vs. folic acid supplementation

Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/. Accessed May 2013; Willems FF et al. Br J Pharmacol 2004;141:825-30. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Folate and Related Compounds • Side effects are uncommon L-methylfolate Folic Acid Product Active Daily Age Daily upper ingredient dose tolerability limits Deplin l-methylfolate 7.5–15 Birth to 6 months N/A* mg 7–12 months N/A* DeltaFolate l-methylfolate 3.83 mg 1–3 years 300 mcg Complex folinic acid 2.4 mg folacin 2.5 mg 4–8 years 400 mcg EnLyte DeltaFolate 3.83 mg 9–13 years 600 mcg complex + iron, 2.4 mg 14–18 years** 800 mcg B vitamins 2.5 mg 19+ years** 1000 mcg *Breast milk, formula, and food should be the only sources of folate for infants **Includes pregnancy Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. MELATONIN

melatonin

retino- SCN hypothalamic pineal tract gland

melatonin

retino- SCN "phase delay" hypothalamic pineal tract gland

Depression

Healthy Control 7am 11pm 7am 11pm 7am

• Exogenous melatonin: not studied in depression1 • Slow-release melatonin: improves sleep but not depression2,3 • Ramelteon* (melatonin agonist): small, placebo- controlled study in bipolar disorder suggests antidepressant effects4 • Agomelatine* (melatonin agonist and 5HT2C antagonist): multiple positive studies in depression1 *Not available over the counter

1. Quera Salva MA et al. Curr Pharm Design 2011;17(15):1459-70. 2. Dolberg OT et al. Am J Psychiatry 1998;155(8):1119-21. 3. Serfaty MA et al. Int Clin Psychopharmacol 2010;25(3):132-42. 4. McElroy Sl et al. Int Clin Psychopharmacol 2011;26(1):48-53. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Melatonin: Safety

• Can alter hormone levels – Not generally recommended in children, particularly with hormonal conditions* – Not recommended in pregnancy – Can affect fertility • May lower blood pressure • May reduce glucose tolerance and insulin sensitivity • May lower seizure threshold (mixed data) *Some positive evidence in children with behavioral, developmental, and intellectual disorders

Natural Standard. http://www.naturalstandard.com/demo/demo-pro-melatonin.asp. Accessed May 2013; Mayo Clinic. http://www.mayoclinic.com/health/melatonin/NS_patient-melatonin. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Melatonin: Summary

BENEFITS RISKS  Possible benefit for  Insufficient data depression  Not recommended in  Can improve sleep pregnancy due to hormonal changes

Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Melatonin • For patients who can't fall asleep and wake up late – Melatonin in late afternoon/early evening – Advances circadian clock  earlier falling asleep and waking

• For patients who fall asleep early and wake up early – Melatonin in the morning – Theoretically delays circadian clock  later falling asleep and waking • May lack efficacy and cause daytime drowsiness

• Dose – 0.1–80 mg/night studied in various conditions – 5 mg/night is generally recommended as a safe dose • Consumer Lab evaluated 18 melatonin-containing supplements (12 were melatonin only) in 2002 • Products that "passed" – Nature's Bounty® Melatonin 1 mg and 3 mg tablets – Puritan's Pride® Inspired by Nature® Melatonin 3 mg tablets – Twinlab® Melatonin Caps, Highest Quality, Quick- Acting 3 mg tablets http://www.naturalstandard.com/demo/demo-pro-melatonin.asp. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Melatonin

• Side effects – Most common: daytime drowsiness, dizziness, headache, mild GI distress – May cause disorientation if used at high doses or at inappropriate times

• Interactions – Should not be used with other sedative hypnotics – Levels may be increased by CYP450 1A2 inhibitors (e.g., fluvoxamine) – Possible increased risk of bleeding with anticoagulants http://www.mayoclinic.com/health/melatonin/NS_patient-melatonin. Accessed May 2013. Copyright © 2013 Neuroscience Education Institute. All rights reserved. VITAMIN D

• Meta-analysis (14 studies, N=31,424) – Lower vitamin D levels in patients with depression vs. controls (SMD=0.60, 95% CI 0.23–0.97) – Cross-sectional studies (10) • Increased odds ratio of depression for lowest vs. highest vitamin D categories (OR=1.31, 95% CI 1.0–1.71) – Cohort studies (3) • Increased hazard ratio of depression for lowest vs. highest vitamin D categories (HH=2.21, 95% CI 1.40–3.49)

• Mixed results in trials of non-MDD patients1-4 – Wide range of doses

• One positive double-blind, randomized, placebo- controlled, 8-week study in MDD (N=42)5 – 1500 IU/day D3 as adjunct to fluoxetine – Significant decrease in depression severity (HDRS, BDI) – Superior to fluoxetine alone beginning at week 4 1. Kjærgaard M et al. Br J Psychiatry 2012;201(5):360-8. 2. Bertone-Johnson ER et al. Am J Epidemiol 2012;176(1):1-13. 3. Jorde R et al. J Intern Med 2008;264(6):599-609. 4. Sanders KM et al. Br J Psychiatry 2011;198:357-64. 5. Khoraminya N et al. Aust N Z J Psychiatry 2013;47(3):271-5. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Vitamin D: Summary

BENEFIT RISKS  ?  Insufficient data  Possibility of vitamin D toxicity

Copyright © 2013 Neuroscience Education Institute. All rights reserved. Practical Use of Vitamin D: Dietary Reference Intakes Life Stage Estimated Average Recommended Dietary Upper Level Intake (IU/d) Requirement (IU/d) Allowance (IU/d) Infants 0–6 mos 400 400 1000 Infants 6–12 mos 400 400 1500 1–3 yrs 400 600 2500 4–8 yrs 400 600 3000 9–13 yrs 400 600 4000 14–18 yrs 400 600 4000 19–30 yrs 400 600 4000 31–50 yrs 400 600 4000 51–70 yrs 400 600 4000 71+ yrs 400 800 4000 14–50 yrs 400 600 4000 pregnant/lactating http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx.

• Chaihu-Shugan-San1 – Positive results but study limitations • Xiao Yao San, Free and Easy Wanderer Plus1 – Positive results but study limitations • Saffron2 – Preliminary trials suggest efficacy of stigma and petal for mild to moderate depression – 30 mg/day, minimal side effects • Lavender2 – One low-dose trial vs. imipramine suggests efficacy as adjunct and possibly as monotherapy

1. Butler L, Pilkington K. Evidenced-Based Complementary Alternative Med 2013;2013:739716;Epub. 2. Dwyer AV et al. Alternative Med Rev 2010;16(1):40-9. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Other Supplements Used for Depression

• Echium (ox tongue) – Native to Iran, long history of use, good safety profile – One placebo-controlled trial suggests efficacy in mild to moderate depression (375 mg/day)

• Rhodiola rosea (golden root, roseroot) – Russia, Scandinavia – One placebo-controlled trial suggests efficacy in mild to moderate depression (340 mg/day and 680 mg/day)

• L-tryptophan1 – Many studies of poor quality; one small positive trial • Inositol2-4 – Inconsistent evidence; no significant effect for augmenting treatment in bipolar depression • N-acetylcysteine5 – Preliminary controlled trial of improved depression in bipolar disorder

1. Shaw K et al. Cochrane Database Syst Rev 2002;(1):CD003198. 2. Taylor MJ et al. Cochrane Database Syst Rev 2004;(2):CD004049. 3. Nierenberg AA et al. Am J Psychiatry 2006;163:210-16. 4. Eden Evins A at al. Bipolar Disord 2006;8(2):168-74. 5. Berk M et al. Trends Pharmacological Sci 2013;34(3):167-77. Copyright © 2013 Neuroscience Education Institute. All rights reserved. Other Supplements Used for Depression

• Kava – Used as a ceremonial beverage in the South Pacific – Not studied in depression – Linked to risk of severe liver damage, dystonia, drug interactions • Valerian – Insufficient data in depression; possibly helpful for insomnia – Safe at recommended doses for short-term use – Mild side effects (morning tiredness, headache, dizziness, upset stomach)

• Include a question on herb/supplement use on medical history form

• Ask patients to bring a list of therapies they use, including OTC, Rx, herbal, and all other complementary and alternative medicine (CAM)

• Questions should be nonjudgmental

• Check with healthcare provider before taking any supplement – Especially for a self-diagnosed condition – Especially in place of or in combination with a prescribed medication • Disclose all supplements/medications before surgery • Some supplement ingredients can be toxic or harmful in large amounts, over a long period of time, or in combination with other drugs, foods, or substances • Report adverse effects with a dietary supplement to the FDA (http://www.fda.gov/Food/DietarySupplements/ReportAdverse Event/default.htm) and/or the manufacturer (phone number on product label) • Natural does not equal safe

Does it work? Is it safe? St. John's wort Probably Yes (interactions) SAMe Maybe Yes Omega-3 Maybe Yes Folate Maybe (yes for Yes l-methylfolate) Melatonin Insufficient data Yes (not in pregnancy) Vitamin D Insufficient data Yes (at usual doses)

• National Center for Complementary and Alternative Medicine – nccam.nih.gov

• Office of Dietary Supplements – ods.od.nih.gov

Will you specifically ask patients about their use of herbal and supplemental treatments?

1. Yes, all patients 2. Yes, some patients 3. No

A 24-year-old woman suffering from a major depressive episode (moderate) presents to your office. She has previously taken an SSRI for depression but expresses a desire to try something "natural." She specifically asks about St. John's wort. Which of the following would be your primary concern if the patient begins taking St. John's wort? 1.Lack of evidence of efficacy for depression 2.Side effect burden generally no better than with standard antidepressants 3.Numerous potential drug interactions

Which of the following has the best evidence of efficacy for treating symptoms of depression? 1.L-tryptophan 2.Melatonin 3.Omega-3 fatty acids 4.Vitamin D