1. 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

2. Differences Between Herbs and Drugs DrugHerbals Efficacy proof Proof of efficacy not required Monosubstance Complex compound FDA-approval before marketing before marketing No FDA pre-approval post-marketing notification for structure-function claims Patentable Not patentable Potency standardized Potency varies Dose established Usually some guidelines

3. St. John’s Wort

4. St. 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: macroscopic macroscopic microscopic microscopic phytochemical 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

5. St. John’s Wort in Depression double-blind studies using LI 160/LoHyp-57 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, short or no washout period, ?other meds?

6. 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… 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 Whiskey et al. Int Clin Psychopharmacol, 2001, 16:239-52 St. John’s Wort in Depression

7. 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 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

8. Results : no significant difference from placebo Shelton et al. JAMA 285:1978-86, 2001 16

9. Comparison with Sertraline, Hypericum, & Placebo 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 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. 287:1807-14

10. Comparison with Sertraline and Placebo Study Week

11. Adverse Events in Sertaline, Hypericum, and Placebo Groups Hypericum Depression Trial Study Group, JAMA, 2002. 287:1807-14 Event, No (%) Hypericum (n = 122) Placebo (n = 116) Sertraline (n = 111) Hypericum V. Placebo Sertraline V. Placebo Diarrhea 23 (21)22 (19)42 (38)0.810.003 Nausea 21 (19)24 (21)41 (37)0.780.02 Anorgasmia 28 (25)16 (14)35 (32)0.040.002 Forgetfuness 28 (25)26 (22)13 (12)0.750.04 Frequent urination 30 (27)13 (11)23 (21)0.0030.06 Sweating 20 (18)14 (12)32 (29)0.210.003 Swelling 21 (19)9 (8) 0.020.90 Adverse events that Differed Significantly by Treatment P value

12. 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

13. 5-HT reuptake pump  1a  2  3 SSRIs serotonergic terminal  1d postsynaptic neuron Monoamine Oxidase

14. 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 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??

15. St. John’s Wort, Drug Interactions DrugFindingConsequence 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

16. 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

17. Content of Saint John’s Wort Product label hypericin assay hypericin (%) assay hyperforin (%) Hyperfin* (powder) 0.3%0.29 ± 0.011.89 ± 0.12 PNC (capsule) 0.150.12 ± 0.020.20 ± 0.003 Shurfine (caplet)0.30.17 ± 0.040.29 ± 0.006 Shopko (capsule)0.20.26 ± 0.070.05 ± 0.005 Nature’s Balance (caplet) ----0.03 ± 0.020.01 ± 0 DeLosReyes CC, Koda RT. Am J Health-Syst Pharm, 2002; 59:545-7 *manuf. in Germany

18. Unresolved Issues What is/are the active ingredients? at least seven groups of bioactive compounds at least seven groups of bioactive compounds proportions vary with growing conditions proportions vary with growing conditions Hypericin? Hyperforin? 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; Optimal storage/preparation conditions unknown; neither hyperforin nor hypericin show good neither hyperforin nor hypericin show good thermal and photostability thermal and photostability

19. 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