What We Need To Know About Herbals and

Antidepressants

Sally K. Guthrie, Pharm.D., BCPPAssociate Professor of Pharmacy

College of Pharmacy & Dept. of Psychiatry

Differences Between Differences Between Herbs and DrugsHerbs and Drugs

DrugDrug HerbalsHerbals

Efficacy proofEfficacy proofProof of efficacy not requiredProof of efficacy not required

MonosubstanceMonosubstanceComplex compoundComplex compound

FDA-approvalFDA-approval before marketingbefore marketing

No FDA pre-approvalNo FDA pre-approvalpost-marketing notificationpost-marketing notificationfor structure-function claimsfor structure-function claims

PatentablePatentable Not patentableNot patentable

Potency standardizedPotency standardized Potency variesPotency varies

Dose Dose establishedestablished

Usually some guidelinesUsually some guidelines

St. John’s WortSt. John’s Wort

St. John’s Wort in DepressionSt. John’s Wort in Depression•““more prescribed than Prozac in Germany”more prescribed than Prozac in Germany”

•The German Government requires examination:The German Government requires examination:

macroscopicmacroscopic microscopicmicroscopic phytochemicalphytochemical

Including tests for microbial, heavy metal, pesticide, andIncluding tests for microbial, heavy metal, pesticide, andand radioactive contaminationand radioactive contamination

The German Commission E has prepared monographs The German Commission E has prepared monographs on herbal remedies; listing the parts of the plant used, on herbal remedies; listing the parts of the plant used, the uses, interactions, contraindications, side effectsthe uses, interactions, contraindications, side effectsand dosesand doses

St. John’s Wort in DepressionSt. John’s Wort in Depression

double-blind studies using LI 160/LoHyp-57double-blind studies using LI 160/LoHyp-57

2001 - 15 were placebo controlled 2001 - 15 were placebo controlled - 9 were comparisons with other - 9 were comparisons with other antidepressants - 3 with SSRIs antidepressants - 3 with SSRIs

Study duration was 4 weeks in many older studies, Study duration was 4 weeks in many older studies, short or no washout period, ?other meds?short or no washout period, ?other meds?

Overall, according to the meta-analysis published in Overall, according to the meta-analysis published in BMJ in 1996 and another in 2001; SJW is more effectiveBMJ in 1996 and another in 2001; SJW is more effectivethan placebo and “as” effective as the comparators…than placebo and “as” effective as the comparators…

Linde et al. BMJ 313 (1996) 253-8.Linde et al. BMJ 313 (1996) 253-8.Volz H -P. Pharmacopsychiat 30 (1997) Suppl. 72-76.Volz H -P. Pharmacopsychiat 30 (1997) Suppl. 72-76.Wheatley D. Pharmacopsychiat 30 (1997) Suppl. 77-80.Wheatley D. Pharmacopsychiat 30 (1997) Suppl. 77-80.Harrer et al. Arzneim-Forsch, 1999, 49:289-96Harrer et al. Arzneim-Forsch, 1999, 49:289-96

Whiskey et al. Int Clin Psychopharmacol, 2001, 16:239-52Whiskey et al. Int Clin Psychopharmacol, 2001, 16:239-52

St. John’s Wort in DepressionSt. John’s Wort in Depression

St. John’s Wort in St. John’s Wort in DepressionDepression

First large multicenter U.S. trial - 11 academic centersFirst large multicenter U.S. trial - 11 academic centers

N = 98 N = 98 St. Johns WortSt. Johns Wort - LI 160 (82% completers) - LI 160 (82% completers)N = 102N = 102 placeboplacebo (85% completers) (85% completers)Baseline measures comparableBaseline measures comparableBaseline depression severity comparableBaseline depression severity comparable8 week treatment period8 week treatment periodDose = 300 mg TID SJW x 4 weeksDose = 300 mg TID SJW x 4 weeks could be increased to 1200 mg/day at week 4could be increased to 1200 mg/day at week 4

No concomitant drugs except zolpidem x 3 weeksNo concomitant drugs except zolpidem x 3 weeks

Shelton et al. JAMA 285:1978-86, 2001Shelton et al. JAMA 285:1978-86, 2001

Results : no significant difference from placeboResults : no significant difference from placebo

Shelton et al. JAMA 285:1978-86, 2001Shelton et al. JAMA 285:1978-86, 2001

16

Comparison with Sertraline, Hypericum, & Placebo

LI 160: n = 113, HAMD 23.1 ± 2.7, 300 mg TID (up to 1200), std. hypericinSertraline: n = 109, HAMD 22.5 ± 2.5, 50 mg/day (up to 100) Placebo: n = 116, HAMD 22.7 ± 2.7

Outcomes HAMD, partial response ≥ 50% HAMD, or CGI of 1 or 2; full response HAMD ≤ 8

Double-blind, randomized, placebo-controlled, 8 week study in adult outpatients from 12 sites in the U.S.

Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14

Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14

Comparison with Sertraline and PlaceboComparison with Sertraline and Placebo

Study Week

0

2

4

6

8

10

12

14

16

18

20

22

24

26

HA

MD

To

tal S

core

0 1 2 3 4 5 6 7 8

Comparison with Sertraline and Placebo

Sertraline

placebo

Hypericum

Adverse Events in Sertaline, Hypericum, Adverse Events in Sertaline, Hypericum, and Placebo Groupsand Placebo Groups

Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14

Event, No (%)

Hypericum(n = 122)

Placebo(n = 116)

Sertraline(n = 111)

HypericumV. Placebo

SertralineV. Placebo

Diarrhea 23 (21) 22 (19) 42 (38) 0.81 0.003

Nausea 21 (19) 24 (21) 41 (37) 0.78 0.02

Anorgasmia 28 (25) 16 (14) 35 (32) 0.04 0.002

Forgetfuness 28 (25) 26 (22) 13 (12) 0.75 0.04

Frequenturination

30 (27) 13 (11) 23 (21) 0.003 0.06

Sweating 20 (18) 14 (12) 32 (29) 0.21 0.003

Swelling 21 (19) 9 (8) 9 (8) 0.02 0.90

Adverse events that Differed Adverse events that Differed Significantly by TreatmentSignificantly by Treatment P valueP value

Double-Blind Comparison of SJW with Placebo26 Clinical Centers in France

Six week study comparing plb. with 300 mg TID of WS 550 (standardized to hypericin0.12% - 0.28% and hyperforin 3% - 6%)

Hyericum: n = 186, HAMD 21.9 ± 1.7

Placebo: n = 189, HAMD 21.9 ± 1.7

Results at 6 wks: -9.9 ± 6.8 hypericum v. -8.1 ± 7.1 on HAMD, P = 0.03

Lecrubier, Y, et al. Am J Psychiatry, 2002; 159:1361-6

5-HT

reuptake pump

1a 2

3

SSRIs

serotonergic terminal

1d

postsynaptic neuron

MonoamineOxidase

St. John’s Wort in DepressionSt. John’s Wort in Depression

Inhibition of Monoamine Oxidase? Inhibition of Monoamine Oxidase? Not likely with blood levels achieved in humansNot likely with blood levels achieved in humans

Serotonin Reuptake Inhibtion?Serotonin Reuptake Inhibtion? Doesn’t block serotonin neuronal membrane transporter Doesn’t block serotonin neuronal membrane transporter

Increased availability of serotonin dopamine and Increased availability of serotonin dopamine and NE?NE?Hyperforin appears to block vescicular transport: but not Hyperforin appears to block vescicular transport: but not much hyperforin crosses into the brain??much hyperforin crosses into the brain??

St. John’s Wort, Drug Interactions

Drug Finding Consequence

cyclosporin plasma levels organ rejection

amitriptyline AUC ? antidepressant effect

digoxin AUC, tr &peak ? efficacy

indinavir AUC, peak ? antiretroviral effect

nevirapine plasma levels ? antiretroviral effect

oral. contracept. ------- Intermenstrual bleeding

theophylline plasma levels ? bronchodilator effect

warfarin ------- anticoagulant effect

Ioannides C. Xenobiotica, 2002,32:451-78

More......More......St. John’s WortSt. John’s Wort

a comment from the Botanical.com netsitea comment from the Botanical.com netsite

““Yes! Yes! Yes! Happy! Happy! Happy!”Yes! Yes! Yes! Happy! Happy! Happy!”

Most effective antidepressants have the abilityMost effective antidepressants have the abilityto switch a bipolar (manic depressive) patientto switch a bipolar (manic depressive) patientfrom a depression into a maniafrom a depression into a maniaSchneck, J Clin Psychiatry 1998;59:189 (let)Schneck, J Clin Psychiatry 1998;59:189 (let)O’Breasail & Argouarch, Can J Psychiatry 1998;43 :747 (let)O’Breasail & Argouarch, Can J Psychiatry 1998;43 :747 (let)Nierenberg, Biol Psychiatry 1999;46:1707Nierenberg, Biol Psychiatry 1999;46:1707

Content of Saint John’s Wort

Productlabel

hypericinassay

hypericin (%)assay

hyperforin (%)

Hyperfin* (powder) 0.3% 0.29 ± 0.01 1.89 ± 0.12

PNC (capsule) 0.15 0.12 ± 0.02 0.20 ± 0.003

Shurfine (caplet) 0.3 0.17 ± 0.04 0.29 ± 0 .006

Shopko (capsule) 0.2 0.26 ± 0.07 0.05 ± 0.005

Nature’s Balance(caplet)

---- 0.03 ± 0.02 0.01 ± 0

DeLosReyes CC, Koda RT. Am J Health-Syst Pharm, 2002; 59:545-7

*manuf. in Germany

Unresolved Unresolved IssuesIssues

What is/are the What is/are the active ingredientsactive ingredients?? at least seven groups of bioactive compoundsat least seven groups of bioactive compounds proportions vary with growing conditionsproportions vary with growing conditions Hypericin? Hyperforin?Hypericin? Hyperforin?

What is the appropriate What is the appropriate dosedose??

Is the quality of St. John’s Wort Is the quality of St. John’s Wort equivalentequivalent amongst amongstproducts? Is it equivalent to the German LI 160?products? Is it equivalent to the German LI 160?

Optimal Optimal storagestorage/preparation conditions unknown; /preparation conditions unknown; neither hyperforin nor hypericin show good neither hyperforin nor hypericin show good thermal and photostabilitythermal and photostability

SummarySummary

Efficacy of SJW in depression still not resolvedEfficacy of SJW in depression still not resolved

Lack of information regarding mechanism of action, Lack of information regarding mechanism of action, and efficacy/toxicity associated with and efficacy/toxicity associated with chronic long-term usechronic long-term use

Lack of any regulations regarding Lack of any regulations regarding standardization of “supplements” in the U. S.standardization of “supplements” in the U. S.

Stability, potency, reproducibility of products Stability, potency, reproducibility of products produced in the U.S. not overseen except byproduced in the U.S. not overseen except bymanufacturersmanufacturers