using herbs and supplements to treat major depressive...

Copyright © 2013 Neuroscience Education Institute. All rights reserved.

Using Herbs and Supplements to

Treat Major Depressive Disorder:

The Good, the Bad, and the Ugly

page 315 in syllabus

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.

Rona J. Hu, MD Clinical Associate Professor, Department of Psychiatry and

Behavioral Sciences; Medical Director, Acute Psychiatric Inpatient Unit,

Stanford University School of Medicine


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.


Learning Objectives

• 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

Pre-Poll Question 1


Pretest Question 1

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


Pretest Question 2

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


Natural Products or Dietary Supplements

• 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

NCCAM. http://nccam.nih.gov/health/whatiscam. Accessed April 2013.

http://nccam.nih.gov/health/whatiscam


Government Regulation of

Dietary Supplements

• 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.

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm050824.pdf


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.

http://ods.od.nih.gov/factsheets/DietarySupplements-HealthProfessional/




Most Common Non-vitamin, Non-mineral

Supplements (Adults, General Use)

0%

5%

10%

15%

20%

25%

30%

35%

40%

NCCAM. http://nccam.nih.gov/news/2008/121008.htm. Accessed April 2013.

Adult U

se in L

ast

30 D

ays

http://nccam.nih.gov/news/2008/121008.htm


Most Common Non-vitamin, Non-mineral

Supplements (Children, General Use)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Child

Use in L

ast

30 D

ays

NCCAM. http://nccam.nih.gov/news/2008/121008.htm. Accessed April 2013.

http://nccam.nih.gov/news/2008/121008.htm


Natural Products or Dietary

Supplements: Key Questions

• 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?

Copyright © 2013 Neuroscience Education Institute. All rights reserved. Copyright © 2013 Neuroscience Education Institute. All rights reserved.

ST. JOHN'S WORT

(HYPERICUM)


Antidepressant Mechanism

of St. John's Wort

Hypericin

• Early research suggested

MAO inhibition

• Levels needed are far

greater than those

achieved with normal

doses

• Unclear therapeutic

effects

Hyperforin

• Increases synaptic 5HT,

DA, NE, GABA, and L-

glutamate INDIRECTLY

by increasing intracellular

Na+ and Ca2+

• Responsible for drug

interactions

• Unclear therapeutic

effects

Klemow KM et al. In: Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. 2011.

7 groups of active compounds


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.


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.


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.


Important Drug Interactions

With St. John's Wort

Drug Effect on levels Mechanism Possible clinical effect

IMMUNOSUPPRESSANTS

cyclosporine ↓ 3A4

P-glycoprotein

Organ rejection

tacrolimus ↓ 3A4

P-glycoprotein

Organ rejection

ANTI-HIV DRUGS

indinavir ↓ 3A4

P-glycoprotein

Drug failure due to NTI

nevirapine ↓ 3A4 Drug failure

ANTICANCER DRUGS

irinotecan ↓ 3A4 Drug failure due to NTI

imatinib ↓ 3A4

P-glycoprotein

Drug failure

Borrelli F, Izzo AA. AAPS J 2009;11(4):710-27.





HORMONE THERAPIES

oral

contraceptives

↓ 3A4 Intermenstrual bleeding

Reduced efficacy

ANTICOAGULANTS

warfarin ↓ 3A4 Drug failure due to NTI

phenprocoumon ↓ 3A4 Reduced efficacy

rivaroxaban ↓ 3A4

P-glycoprotein

Reduced efficacy

apixaban ↓ 3A4

P-glycoprotein

Reduced efficacy






ANTIHYPERLIPIDEMICS

simvastatin ↓ 3A4

P-glycoprotein

Reduced efficacy

atorvastatin ↓ 3A4 Reduced efficacy

ANESTHETIC

fentanyl,

propofol,

sevoflurane in O2,

nitrous oxide

Unknown Delayed emergence






BENZODIAZEPINES

alprazolam ↓ 3A4 Reduced efficacy

midazolam ↓ 3A4 Drug failure due to NTI

quazepam ↓ 3A4, 2C19 Reduced efficacy

SEROTONERGIC DRUGS

amitriptyline ↓ 3A4

P-glycoprotein

Drug failure due to NTI

SRI Additive Serotonin syndrome

MAOI Additive Serotonin syndrome

OPIOID WITHDRAWAL

methadone ↓ 3A4 Withdrawal syndrome






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)






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



St. John's Wort (Hypericum):

Summary

BENEFIT

Modest for mild to

moderate depression

RISKS

Numerous drug

interactions (with higher

hyperforin content)

Insufficient data for:

Severe depression

Long-term use

Children and adolescents


Practical Use of St. John's Wort:

Which Extract / Preparation?

• 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.


Pharmaceutical-Grade Extracts

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;


Extract* Brand name Active component(s) Formulation Manufacturer

LI 160** Jarsin 300® Hypericin 0.28%,

hyperforin 1–4%

300-mg tablet Lichtwer

Pharma AG

LI 160** Kira® Hypericin 0.28%,

hyperforin 1–4%

100-mg tablet

300-mg tablet

Lichtwer

Pharma AG

WS 5570** Neuroplant® Hypericin 0.12–0.28%,

hyperforin 3–6%

300-mg tablet

600-mg tablet

Schwabe

WS 5572 Perika® Hypericin 0.12–0.28%,

hyperforin 3–6%

300-mg tablet Schwabe

Ze 117** Remotiv® Hypericin 0.2%,

hyperforin <0.5%

250-mg tablet Zeller AG

STEI 300 Aristo 350® Hypericin 0.2–0.3%,

hyperforin 2–3%

350-mg capsule Steiner

*Alcohol extracts from dried plant material **Used in clinical trials


Some Other St. John's Wort Products

Brand

name

Active

component(s)

Formulation Manufacturer

Esbericum® Hyperforin 1.47% 60-mg capsule Schaper &

Brümmer

Hypericum

2000 Plus®

Hypericin 0.055%,

hyperforin 0.75%

2000-mg capsule* Nutra-Life

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

liquid

Nature's

Answer

*Also contains 100 mg Ginkgo biloba and nutritional cofactors



Practical Use of St. John's Wort:

Prescribing Information

• 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.


Practical Use of St. John's Wort

Do not take

• With immunosuppressants

• With anti-HIV drugs

• With anticancer drugs

• With digoxin

• With anticoagulants

• For 2–3 weeks before

surgery

Other cautions

• With other drugs

metabolized by 3A4,

P-glycoprotein, 1A2

• With SSRIs or MAOIs


S-ADENOSYLMETHIONINE

(SAMe)


SAMe

• 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.

http://nccam.nih.gov/health/supplements/SAMe


SAH

homocysteine

methionine

SAMe methionine

synthase

H H

H H

CH3

MTHF

B12

Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22;

Miller AL. Alternative Med Rev 2008;13(3):216-26.

SAMe: Methylation

and Neurotransmitter Synthesis

synthesis of gene products


RNA

gene

product

activated gene

Gene Expression


Gene Silencing: Methylation

H H

H H

CH3

SAMe Me DNMT

= DNA methyltransferase

SAMe

DNMT

= S-adenosylmethionine

MTHF


Gene Silencing: Methylation

RNA

gene

product

silenced gene

Me Me Me Me

H H

H H

CH3

SAMe Me DNMT MTHF


Evidence of Safety and Efficacy of SAMe: Mild to Moderate Depression

Two additional studies did not provide p-value for comparison. NC: not calculable.

Carpenter D. Alternative Med Rev 2011;16(1):17-39.

Study Treatment Duration p-value Effect size

Agnoli et al.

1976

SAMe 15 mg IM TID (n=20)

Placebo (n=10)

15 days p<0.05 1.6

Fava et al.

1992

SAMe 1600 mg/day PO (n=17)

Placebo (n=21)

6 weeks NS 0.16

Thomas et

al. 1987

SAMe 200 mg/day IV bolus (n=9)

Placebo (n=11)

2 weeks NS 0.12

Salmaggi

et al. 1993


Placebo (n=40)

30 days p<0.01 0.33

De Leo et

al. 1987

SAMe 200 mg IM daily (n=20)

Placebo (n=20)

4 weeks p<0.05 0.61

Janicak et

al. 1989

SAMe 400 mg/day IV (n=7)

Imipramine 150 mg/day IV (n=3)

Placebo (n=5)

15 days p<0.02 1.46

Carrieri et

al. 1990

SAMe 1000 mg/day Placebo (n=11)

Placebo SAMe 1000 mg/day (n=10)

15 days/

15 days

p<0.05 NC


Evidence of Safety and Efficacy

of SAMe: Severe Depression


Study Treatment Duration p-value Effect

size

Kagan et al.

1990


Placebo (n=6)

3 weeks p<0.05 0.79

Caruso et al.

1987


Placebo (n=30)

3 weeks p<0.01 1.4

Delle Chiaie

et al. 1997


Placebo (n=35)

3 weeks p=0.05 0.43

Muscettola et

al. 1982


Placebo (n=10)

15 days p<0.05 NC

Carney et al.

1986


Placebo (n=16)

2 weeks NS; trend

favoring placebo

0.36

Primary outcome: HAM-D total change. NC: not calculable.


Evidence of Efficacy of SAMe:

Study Limitations

• 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

Papakostas GI et al. Am J Psychiatry 2010;167:942-8.

P=0.1

P<0.02

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

Placebo + AD: N=34

6-Week Study in Major Depressive Disorder


SAMe: Safety

• 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


2. Mayo Clinic. http://www.mayoclinic.com/health/same/NS_patient-same. Accessed May 2013.


http://www.mayoclinic.com/health/same/NS_patient-same




SAMe: Safety

• 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








SAMe:

Summary

BENEFIT

Possible benefit for mild,

moderate, and severe

depression

RISKS

May lower blood sugar

levels

Insufficient data,

particularly for:

Long-term use



Practical Use of SAMe

• 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.




Practical Use of SAMe

Do not take1

• Patients with bipolar

disorder

• Patients with Parkinson's

disease

• Patients with HIV

Other cautions2

• Patients with diabetes or

hypoglycemia; patients

taking any other

substances that affect

blood sugar

– May need to monitor serum

glucose levels

• Not recommended in first

trimester








OMEGA-3 FATTY ACIDS


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.

http://nccam.nih.gov/health/omega3


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.


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.


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.


http://www.naturalstandard.com/databases/herbssupplements/fishoil.asp?



Omega-3 Fatty Acids:

Summary

BENEFITS



depression

General health benefits*

Unlikely to have drug

interactions

Some evidence of

efficacy in children and

adolescents

RISKS

Some possible negative

health effects (e.g.,

increased risk of

bleeding), but generally

considered safe

*Not necessarily in supplement form


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.


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

NCCAM. http://nccam.nih.gov/health/omega3. Accessed May 2013; Natural Standard.

http://www.naturalstandard.com/databases/herbssupplements/fishoil.asp?. Accessed May 2013.





FOLATE


Folate and Related Compounds

• 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.


SAH

homocysteine

methionine

SAMe methionine

synthase

H H

H H

CH3

MTHF

B12

Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22;

Miller AL. Alternative Med Rev 2008;13(3):216-26.

Folate and Related Compounds: Methylation and Neurotransmitter Synthesis

synthesis of gene products

folic acid

(supplement)

dihydrofolate

(food)


DA NE

BH

tyrosine

BH BH BH BH

tyrosine hydroxylase

L-methylfolate


MTHF

H H

H H

CH 3

folate MTHFR

biopterin

BH


BH

tryptophan

BH BH BH BH

5HT

tryptophan hydroxylase

L-methylfolate


MTHF

H H

H H

CH 3

folate MTHFR

biopterin

BH


BH

BH

MTHF

H H

H H

CH 3

folate

MTHFR

biopterin

BH

MTHFR MTHF

H H

H H

CH 3

biopterin

BH

DA NE DA

MTHFR Polymorphisms and

Neurotransmitter Synthesis


MTHFR Polymorphisms, Neurotransmitter

Synthesis, and Depression

High(C/C)

Low(C/T or T/T)

IF MTHFR

activity is:

THEN

L-methylfolate is: Homocysteine is: Methylation is: NT synthesis is:

Metabolism MTHFR-

COMT

interaction

MTHFR T allele + COMT Val/Val: dopamine is

degraded at an even higher rate

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

Peerbooms OL et al. Brain Behav Immun 2011;25(8):1530-43.


Folate and Related Compounds:

Evidence of Efficacy

Study Design Supplement Outcome

Coppen et

al. 1986

12-mo DB randomized PBO-

controlled. N=75 patients on Li+

Folic acid

200 mcg

Patients with highest

folate levels had

greatest

improvement

Coppen

and Bailey

2000

10-wk DB randomized PBO-

controlled. N=127 patients with

MDD on fluoxetine 20 mg

Folic acid

500 mcg

Significant

improvement vs.

PBO in females only

Alpert et al.

2002

8-wk open-label. N=22 patients

with MDD, SSRI nonresponse

Folinic acid 31% response rate

19% remission rate

Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13.



Evidence of Efficacy Study Design Supplement Outcome

Godfrey et

al. 1990

6-mo DB randomized PBO-

controlled. N=41 patients w/ low

red cell folate (24 MDD, 17 schiz)

MTHF 15 mg Significant

improvement vs. PBO

Guaraldi et

al. 1993

6-wk open-label. N=20 elderly

depressed patients

MTHF 50 mg

monotherapy

81% response rate

Passeri et

al. 1993

8-wk DB controlled. N=96 patients

w/ depression and dementia

MTHF 50 mg

or trazodone

100 mg

Significant

improvement in both

groups

Ginsberg et

al. 2011

Retrospective analysis. N=242

MDD patients on SSRI/SNRI (95

received L-MTHF)

L-MTHF 7.5

or 15 mg

Improvement in 18.5%

of adjunct group vs.

7.01% of

monotherapy group

Papakostas

et al. 2012

2 DB randomized PBO-controlled

parallel sequential 30-day trials.

Trial 1: 148 patients w/ TRD

Trial 2: 75 patients w/ TRD

L-MTHF

7.5 mg (Trial

1) or 15 mg

(Trial 2)

Trial 1: NS

Trial 2: significant

improvement vs. PBO

Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13.



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.

http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/







Summary

BENEFITS



depression

General health benefits

Folic acid is Pregnancy

Category A at

recommended doses

RISKS

Can mask anemia due to

B12 deficiency*

Insufficient data for:


*Anemia is no longer the basis for

diagnosing B12 deficiency


Practical Use of Folate

and Related Compounds

• 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


Accessed May 2013; Willems FF et al. Br J Pharmacol 2004;141:825-30.





Practical Use of Folate

and Related Compounds

• Side effects are uncommon

*Breast milk, formula, and food should be the only sources of folate for infants

**Includes pregnancy


Accessed May 2013.

Age Daily upper

tolerability limits

Birth to 6 months N/A*

7–12 months N/A*

1–3 years 300 mcg

4–8 years 400 mcg

9–13 years 600 mcg

14–18 years** 800 mcg

19+ years** 1000 mcg

Folic Acid Product Active

ingredient

Daily

dose

Deplin l-methylfolate 7.5–15

mg

DeltaFolate

Complex

l-methylfolate

folinic acid

folacin

3.83 mg

2.4 mg

2.5 mg

EnLyte DeltaFolate

complex + iron,

B vitamins

3.83 mg

2.4 mg

2.5 mg

L-methylfolate





MELATONIN


pineal

gland

SCN retino-

hypothalamic

tract

melatonin

Stahl SM. Stahl's essential psychopharmacology. 4th ed. 2013.

Melatonin


pineal

gland

SCN retino-

hypothalamic

tract

melatonin

7am 11pm 7am 11pm 7am

Healthy Control

Depression

"phase delay"

Phase Delay in Depression due to Reduced Melatonin

Stahl SM. Stahl's essential psychopharmacology. 4th ed. 2013.


Melatonin: Evidence of Efficacy

• 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

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.

*Not available over the counter


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)

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.

*Some positive evidence in children with behavioral, developmental, and intellectual disorders

http://www.naturalstandard.com/demo/demo-pro-melatonin.asp





http://www.mayoclinic.com/health/melatonin/NS_patient-melatonin. Accessed May 2013




Melatonin:

Summary

BENEFITS

Possible benefit for

depression

Can improve sleep

RISKS

Insufficient data

Not recommended in

pregnancy due to

hormonal changes


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

Quera Salva MA et al. Curr Pharm Design 2011;17(15):1459-70.



• 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.









• 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.





VITAMIN D


Vitamin D in Depression

• 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)

Anglin RES et al. Br J Psychiatry 2013;202:100-7.


Vitamin D: Evidence of Efficacy

• 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.


Vitamin D:

Summary

BENEFIT

?

RISKS

Insufficient data

Possibility of vitamin D

toxicity


Life Stage Estimated Average

Requirement (IU/d)

Recommended Dietary

Allowance (IU/d)

Upper Level Intake (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

pregnant/lactating 400 600 4000

http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx.

Practical Use of Vitamin D:

Dietary Reference Intakes


OTHER SUPPLEMENTS


Other Supplements Used for Depression

• 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.



• 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)

Dwyer AV et al. Alternative Med Rev 2010;16(1):40-9.



• 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.



• 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)

NCCAM. http://nccam.nih.gov/health/kava?nav=gsa. Accessed May 2013.

http://nccam.nih.gov/health/kava?nav=gsa


Talking to Patients

• 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


Things Patients Should Know

• 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/ReportAdverseEvent/default.htm) and/or the manufacturer (phone number on product label)

• Natural does not equal safe

FDA. http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm050824.pdf.

Accessed April 2013.

http://www.fda.gov/Food/DietarySupplements/ReportAdverseEvent/default.htm

http://www.fda.gov/Food/DietarySupplements/ReportAdverseEvent/default.htm

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm050824.pdf


Summary

Does it work? Is it safe?

St. John's wort Probably Yes (interactions)

SAMe Maybe Yes

Omega-3 Maybe Yes

Folate Maybe (yes for

l-methylfolate)

Yes

Melatonin Insufficient data Yes (not in pregnancy)

Vitamin D Insufficient data Yes (at usual doses)


For Your Patients: Credible Sources for

Information on Herbs and Supplements

• National Center for Complementary and

Alternative Medicine

– nccam.nih.gov

• Office of Dietary Supplements

– ods.od.nih.gov

nncam.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

Post-Poll Question 1


Posttest Question 1

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


Posttest Question 2

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

using herbs and supplements to treat major depressive...

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