What we need to know about herbals and antidepressants
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What We Need To Know About Herbals and Antidepressants. Sally K. Guthrie, Pharm.D., BCPP Associate Professor of Pharmacy College of Pharmacy & Dept. of Psychiatry. Differences Between Herbs and Drugs. Drug. Herbals. Usually some guidelines. Dose established.

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What We Need To Know About Herbals and Antidepressants

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What we need to know about herbals and antidepressants

What We Need To Know About Herbals and Antidepressants

Sally K. Guthrie, Pharm.D., BCPP

Associate Professor of Pharmacy

College of Pharmacy & Dept. of Psychiatry


Differences between herbs and drugs

Differences Between Herbs and Drugs

Drug

Herbals

Usually some guidelines

Dose established

Proof of efficacy not required

Efficacy proof

Complex compound

Monosubstance

No FDA pre-approval

post-marketing notification

for structure-function claims

FDA-approval

before marketing

Patentable

Not patentable

Potency standardized

Potency varies


St john s wort

St. John’s Wort


St john s wort in depression

St. John’s Wort in Depression

  • “more prescribed than Prozac in Germany”

  • The German Government requires examination:

  • macroscopic

  • microscopic

  • phytochemical

  • Including tests for microbial, heavy metal, pesticide, and

  • and radioactive contamination

  • The German Commission E has prepared monographs

  • on herbal remedies; listing the parts of the plant used,

  • the uses, interactions, contraindications, side effects

  • and doses


St john s wort in depression1

St. John’s Wort in Depression

double-blind studies using LI 160/LoHyp-57

2001 - 15 were placebo controlled

- 9 were comparisons with other

antidepressants - 3 with SSRIs

Study duration was 4 weeks in many older studies,

short or no washout period, ?other meds?


What we need to know about herbals and antidepressants

St. John’s Wort in Depression

Overall, according to the meta-analysis published in

BMJ in 1996 and another in 2001; SJW is more effective

than placebo and “as” effective as the comparators…

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

Linde et al. BMJ 313 (1996) 253-8.

Volz H -P. Pharmacopsychiat 30 (1997) Suppl. 72-76.

Wheatley D. Pharmacopsychiat 30 (1997) Suppl. 77-80.

Harrer et al. Arzneim-Forsch, 1999, 49:289-96


St john s wort in depression2

St. John’s Wort in Depression

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

N = 98 St. Johns Wort - LI 160 (82% completers)

N = 102placebo (85% completers)

Baseline measures comparable

Baseline depression severity comparable

8 week treatment period

Dose = 300 mg TID SJW x 4 weeks

could be increased to 1200 mg/day at week 4

No concomitant drugs except zolpidem x 3 weeks

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


What we need to know about herbals and antidepressants

Results : no significant difference from placebo

16

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


What we need to know about herbals and antidepressants

Comparison with Sertraline, Hypericum, & Placebo

Double-blind, randomized, placebo-controlled, 8 week

study in adult outpatients from 12 sites in the U.S.

LI 160: n = 113, HAMD 23.1 ± 2.7, 300 mg TID

(up to 1200), std. hypericin

Sertraline: 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

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


What we need to know about herbals and antidepressants

Comparison with Sertraline and Placebo

26

24

22

20

18

16

HAMD Total Score

14

12

10

Hypericum

8

6

placebo

4

Sertraline

2

0

2

0

1

3

4

5

6

7

8

Comparison with Sertraline and Placebo

Study Week

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


What we need to know about herbals and antidepressants

Adverse Events in Sertaline, Hypericum,

and Placebo Groups

Adverse events that Differed

Significantly by Treatment

P value

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


What we need to know about herbals and antidepressants

Double-Blind Comparison of SJW with Placebo

26 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


What we need to know about herbals and antidepressants

serotonergic

terminal

Monoamine

Oxidase

5-HT

SSRIs

reuptake

pump

1d

3

1a

2

postsynaptic

neuron


St john s wort in depression3

St. John’s Wort in Depression

Inhibition of Monoamine Oxidase?

Not likely with blood levels achieved in humans

Serotonin Reuptake Inhibtion?

Doesn’t block serotonin neuronal membrane transporter

Increased availability of serotonin dopamine and NE?

Hyperforin appears to block vescicular transport: but not much hyperforin crosses into the brain??


St john s wort drug interactions

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

St. John’s Wort, Drug Interactions

Drug

Finding

Consequence

cyclosporin

 plasma levels

organ rejection

?  antidepressant effect

amitriptyline

 AUC

 AUC, tr &peak

?  efficacy

digoxin

?  antiretroviral effect

indinavir

 AUC,  peak

nevirapine

?  antiretroviral effect

 plasma levels

oral. contracept.

Intermenstrual bleeding

-------

theophylline

 plasma levels

?  bronchodilator effect

warfarin

-------

 anticoagulant effect


What we need to know about herbals and antidepressants

More......

St. John’s Wort

a comment from the Botanical.com netsite

“Yes! Yes! Yes! Happy! Happy! Happy!”

Most effective antidepressants have the ability

to switch a bipolar (manic depressive) patient

from a depression into a mania

Schneck, J Clin Psychiatry 1998;59:189 (let)

O’Breasail & Argouarch, Can J Psychiatry 1998;43 :747 (let)

Nierenberg, Biol Psychiatry 1999;46:1707


What we need to know about herbals and antidepressants

Content of Saint John’s Wort

label

hypericin

assay

hypericin (%)

assay

hyperforin (%)

Product

Hyperfin* (powder)

0.3%

0.29 ± 0.01

1.89 ± 0.12

0.15

0.12 ± 0.02

0.20 ± 0.003

PNC (capsule)

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 issues

Unresolved Issues

What is/are the active ingredients?

at least seven groups of bioactive compounds

proportions vary with growing conditions

Hypericin? Hyperforin?

What is the appropriate dose?

Is the quality of St. John’s Wort equivalent amongst

products? Is it equivalent to the German LI 160?

Optimal storage/preparation conditions unknown;

neither hyperforin nor hypericin show good

thermal and photostability


Summary

Summary

Efficacy of SJW in depression still not resolved

Lack of information regarding mechanism of action, and efficacy/toxicity associated with

chronic long-term use

Lack of any regulations regarding

standardization of “supplements” in the U. S.

Stability, potency, reproducibility of products

produced in the U.S. not overseen except by

manufacturers


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