Transcript 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
Drug
Dose established
Herbals
Usually some guidelines
Proof of efficacy not required
Efficacy proof
Complex compound
Monosubstance
FDA-approval
before marketing
No FDA pre-approval
post-marketing notification
for structure-function claims
Patentable
Not patentable
Potency standardized
Potency varies
St. John’s Wort
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 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?
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
Depression
First large multicenter U.S. trial - 11 academic centers
N = 98 St. Johns Wort - LI 160 (82% completers)
N = 102 placebo (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
Results : no significant difference from placebo
28
26
Hamilton Depression
Scale Score
24
22
20
18
16
16
14
12
10
8
P lacebo
6
4
St. John's W ort
2
Study Week
Shelton et al. JAMA 285:1978-86, 2001
8
7
6
5
4
3
2
1
0
0
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%
or CGI of 1 or 2; full response HAMD ≤ 8
HAMD,
Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14
Comparison with Sertraline and Placebo
Comparison with Sertraline and Placebo
26
24
HAMD Total Score
22
20
18
16
14
12
10
Hypericum
8
6
placebo
4
Sertraline
2
8
7
6
5
4
3
2
1
0
0
Study Week
Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14
Adverse Events in Sertaline, Hypericum,
and Placebo Groups
Adverse events that Differed
Significantly by Treatment
P value
Event,
No (%)
Hypericum
(n = 122)
Placebo Sertraline
(n = 116) (n = 111)
Hypericum Sertraline
V. Placebo V. 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
Frequent
urination
Sweating
30 (27)
13 (11)
23 (21)
0.003
0.06
20 (18)
14 (12)
32 (29)
0.21
0.003
Swelling
21 (19)
9 (8)
9 (8)
0.02
0.90
Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14
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
serotonergic
terminal
Monoamine
Oxidase
5-HT
SSRIs
reuptake
pump
1d
3
1a
2
postsynaptic
neuron
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??
Ioannides C. Xenobiotica, 2002,32:451-78
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.
------ plasma levels
Intermenstrual bleeding
theophylline
warfarin
-------
?  bronchodilator effect
 anticoagulant effect
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
Content of Saint John’s Wort
Product
label
hypericin
assay
assay
hypericin (%) 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
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
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