What We Need To Know About Herbals and Antidepressants

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 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

3. St. John’s Wort

4. 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

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 antidepressants - 3 with SSRIs Study duration was 4 weeks in many older studies, short or no washout period, ?other meds?

6. 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

7. 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

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

9. 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

10. 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

11. 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

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

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

15. 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

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 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

18. 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

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