- Neuroscience Education Institute

Transcription

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.
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
Pre-Poll Question 1
Do you specifically ask patients about their use
of herbal and supplemental treatments?
1. Yes, all patients
2. Yes, some patients
3. No
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.
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.
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/DietarySupplementsHealthProfessional/. Accessed April 2013.
Most Common Non-vitamin, Non-mineral
Supplements (Adults, General Use)
Adult Use in Last 30 Days
40%
35%
30%
25%
20%
15%
10%
5%
0%
NCCAM. http://nccam.nih.gov/news/2008/121008.htm. Accessed April 2013.
Most Common Non-vitamin, Non-mineral
Supplements (Children, General Use)
Child Use in Last 30 Days
40%
35%
30%
25%
20%
15%
10%
5%
0%
NCCAM. http://nccam.nih.gov/news/2008/121008.htm. Accessed April 2013.
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?
ST. JOHN'S WORT
(HYPERICUM)
Antidepressant Mechanism
of St. John's Wort
7 groups of active compounds
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 Lglutamate 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.
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
imatinib
↓
3A4
P-glycoprotein
Drug failure
Borrelli F, Izzo AA. AAPS J 2009;11(4):710-27.
Drug
Effect on levels
Mechanism
HORMONE THERAPIES
oral
contraceptives
↓
3A4
Intermenstrual bleeding
Reduced efficacy
ANTICOAGULANTS
warfarin
↓
3A4
phenprocoumon
↓
3A4
Reduced efficacy
rivaroxaban
↓
3A4
P-glycoprotein
Reduced efficacy
apixaban
↓
3A4
P-glycoprotein
Reduced efficacy
Drug
Effect on levels
Mechanism
ANTIHYPERLIPIDEMICS
simvastatin
↓
3A4
P-glycoprotein
Reduced efficacy
atorvastatin
↓
3A4
Reduced efficacy
ANESTHETIC
fentanyl,
propofol,
sevoflurane in O2,
nitrous oxide
Unknown
Delayed emergence
Drug
Effect on levels
Mechanism
BENZODIAZEPINES
alprazolam
↓
3A4
Reduced efficacy
midazolam
↓
3A4
quazepam
↓
3A4, 2C19
Reduced efficacy
SEROTONERGIC DRUGS
amitriptyline
↓
3A4
P-glycoprotein
SRI
Additive
Serotonin syndrome
MAOI
Additive
Serotonin syndrome
OPIOID WITHDRAWAL
methadone
↓
3A4
Withdrawal syndrome
Drug
Effect on levels
Mechanism
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
ANTIPLATELET
clopidogrel
↓
3A4
Enhanced actions
(prodrug)
Drug
Effect on levels
Mechanism
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
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%, 300-mg tablet
hyperforin 3–6%
600-mg tablet
Schwabe
WS 5572
Perika®
Hypericin 0.12–0.28%, 300-mg tablet
hyperforin 3–6%
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
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;
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
Other cautions
• With immunosuppressants
• With anti-HIV drugs
• With other drugs
metabolized by 3A4,
P-glycoprotein, 1A2
• With anticancer drugs
• With SSRIs or MAOIs
• With digoxin
• With anticoagulants
• For 2–3 weeks before
surgery
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.
SAMe: Methylation
and Neurotransmitter Synthesis
methionine
methionine
synthase
SAMe
B12
SAH
H
synthesis of gene products
homocysteine
H
MTHF
H
Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22;
Miller AL. Alternative Med Rev 2008;13(3):216-26.
CH3
H
Gene Expression
RNA
gene
product
activated gene
Gene Silencing: Methylation
H
CH3
H
MTHF
H
SAMe
Me
DNMT
H
SAMe = S-adenosylmethionine
DNMT = DNA methyltransferase
Gene Silencing: Methylation
H
CH3
H
MTHF
H
H
SAMe
Me
DNMT
Me Me
Me Me
RNA
gene
product
silenced gene
Evidence of Safety and Efficacy
of SAMe: Mild to Moderate Depression
Study
Treatment
Duration p-value Effect size
Agnoli et al. SAMe 15 mg IM TID (n=20)
1976
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
Two additional studies did not provide p-value for comparison. NC: not calculable.
Carpenter D. Alternative Med Rev 2011;16(1):17-39.
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
SAMe 200 mg IM daily (n=30)
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 SAMe 150 mg IM daily (n=10)
al. 1982
Placebo (n=10)
15 days
p<0.05
NC
Carney et al.
1986
2 weeks
NS; trend
favoring placebo
0.36
Placebo (n=16)
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
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
Papakostas GI et al. Am J Psychiatry 2010;167:942-8.
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.
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
Other cautions2
• Patients with bipolar
disorder
• Patients with diabetes or
hypoglycemia; patients
taking any other
substances that affect
blood sugar
• Patients with Parkinson's
disease
• Patients with HIV
– 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.
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.
Omega-3 Fatty Acids:
Summary
BENEFITS
depression
 General health benefits*
 Unlikely to have drug
interactions
RISKS
 Some possible negative
health effects (e.g.,
increased risk of
bleeding), but generally
considered safe
 Some evidence of
efficacy in children and
adolescents
*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.
Folate and Related Compounds:
Methylation and Neurotransmitter Synthesis
methionine
folic acid
(supplement)
methionine
synthase
SAMe
dihydrofolate
(food)
B12
SAH
H
synthesis of gene products
homocysteine
CH3
MTHF
H
Papakostas GI. J Clin Psychiatry 2009;70(suppl 5):18-22;
Miller AL. Alternative Med Rev 2008;13(3):216-26.
H
H
L-methylfolate
H
MTHFR
CH 3
MTHF
folate
H
BH
H
biopterin
H
tyrosine hydroxylase
BH
BH
BH
BH
DA
tyrosine
NE
L-methylfolate
H
MTHFR
CH 3
MTHF
folate
H
BH
H
biopterin
H
tryptophan hydroxylase
BH
BH
BH
5HT
tryptophan
MTHFR Polymorphisms and
Neurotransmitter Synthesis
BH
BH
HH
CH
3
biopterin
biopterin
H
H
MTHF
MTHF
MTHFR
MTHFR
folate
CH 3
H
H
H
H
BH
BH
DA
DA
NE
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
MTHFRCOMT
interaction
MTHFR T allele + COMT Val/Val: dopamine is
degraded at an even higher rate
Peerbooms OL et al. Brain Behav Immun 2011;25(8):1530-43.
Evidence of Efficacy
Study
Design
Supplement Outcome
Coppen et
al. 1986
12-mo DB randomized PBOcontrolled. 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 PBOcontrolled. 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 PBOcontrolled. 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 81% response rate
monotherapy
Passeri et
al. 1993
8-wk DB controlled. N=96 patients
w/ depression and dementia
MTHF 50 mg Significant
or trazodone improvement in both
100 mg
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.
Summary
BENEFITS
depression
 General health benefits
RISKS
 Can mask anemia due to
B12 deficiency*
 Insufficient data for:
 Folic acid is Pregnancy
Category A at
recommended doses
*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
L-methylfolate
Folic Acid
Product
Active
ingredient
Daily
dose
Age
Daily upper
tolerability limits
Deplin
l-methylfolate
7.5–15
mg
Birth to 6 months
N/A*
7–12 months
N/A*
3.83 mg
2.4 mg
2.5 mg
1–3 years
300 mcg
4–8 years
400 mcg
9–13 years
600 mcg
14–18 years**
800 mcg
19+ years**
1000 mcg
DeltaFolate l-methylfolate
Complex
folinic acid
folacin
EnLyte
DeltaFolate
3.83 mg
complex + iron, 2.4 mg
B vitamins
2.5 mg
*Breast milk, formula, and food should be the only sources of folate for infants
**Includes pregnancy
Accessed May 2013.
MELATONIN
Melatonin
melatonin
retinoSCN
hypothalamic
tract
pineal
gland
Stahl SM. Stahl's essential psychopharmacology. 4th ed. 2013.
Phase Delay in Depression due to Reduced
Melatonin
melatonin
retinoSCN
hypothalamic
tract
"phase delay"
pineal
gland
Depression
Healthy Control
7am
11pm 7am
11pm 7am
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, placebocontrolled 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.
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.
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, QuickActing 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, placebocontrolled, 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
Practical Use of Vitamin D:
Dietary Reference Intakes
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.
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.
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/ReportAdverse
Event/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.
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
Post-Poll Question 1
Will you specifically ask patients about their use
of herbal and supplemental treatments?
1. Yes, all patients
2. Yes, some patients
3. No
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

- Neuroscience Education Institute

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