Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 55-56
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Update on Research of Hypericum perforatum as an Antidepressant

L. Redondo Márquez

Laboratorios Madaus, Barcelona, Spain

The therapeutic properties of Hypericum perforatum, or St. John's wort, have been known since ancient times. Nowadays, it is basically used for the treatment of mild and moderate depression and as an anxiolytic. To date, more than 400 species of the Hypericum genus have been described and more than 10 different components have been detected in the extract, which may account for its therapeutic action or adverse reactions. The main components of the Hypericum extract include, among others, hypaphorine (a phloroglucinol), hypericin (a naphthodianthrene), the extract's III-C fraction with a proven antidepressant effect, flavonoids, procyanidins, xanthones (powerful MAO-A inhibitors), phenylpropanones and amino acids, including GABA, which has an acknowledged sedative effect. The first two components have been studied most extensively and have been associated with antidepressant activity.

Most of the studies performed to date have used two Hypericum extracts, which differ primarily in their hypericin and hypaphorine content. The ratio between these two components within the extract seems to be very important, as it determines its greater or lesser efficacy as an antidepressant, its tolerability, and its potential for interacting with other drugs. Of these two extracts,
ZE 117 has particularly interesting features, as the predominant fraction corresponds to hypericin, while its hypaphorine content is only 0.2% compared with the other extracts (LI 160), whose hypaphorine content ranges between 1 and 4%. This fraction of Hypericum, due to its inhibitory effect on cytochrome P450 function, has been associated with the occurrence of drug interactions (1-3).

Pharmacokinetic studies performed with ZE 117 showed that both fractions had nonlinear kinetics, with a fast absorption of pseudohypericin (0.4-0.6 h) compared with the slower absorption of hypericin (2-2.6 h), and with a half-life of 2.7-3.2 h for pseudohypericin compared with 4.1-5.9 h for hypericin, irrespective of the dose used in both cases.

At present, there is a considerable body of clinical studies that confirm the efficacy and safety of the Hypericum extract ZE 117. It seems to be sufficiently proven that its treatment indication is mild-to-moderate depression, with a dose of 500 mg/day. The studies show that this dose can be given both in a single dose or as 250 mg twice a day, without giving rise to any detectable differences in its pharmacokinetic behavior, efficacy and tolerability (4, 5).

Among the clinical studies performed with the extract ZE 117, those that show its efficacy in mild and moderate depression are particularly interesting:

­ Double-blind, randomized, multicenter, placebo-controlled study in 162 patients treated for 6 weeks with 250 mg twice daily (1)
­ Double-blind, randomized, placebo-controlled study in 743 outpatients treated for 6 weeks with 250 mg twice daily (6)
­ Double-blind, randomized, fluoxetine-controlled (20 mg/day) study in 240 patients treated for 6 weeks with 250 mg twice daily (2, 7)
­ Double-blind, randomized, multicenter, imipramine-controlled (75 mg x 2/day) study in 324 patients treated for 6 weeks with 250 mg twice daily (8)
­ Open-label, long-term study in 117 patients treated for 52 weeks with 250 mg tablets (9)
­ Safety studies to detect the incidence of adverse reactions (10, 11)
­ Study on the incidence of interactions (12)
­ Studies on the mechanism of action (13-17)
­ Studies on its influence on the P450 cytochrome system (18, 19).

To summarize: using a certain Hypericum extract (ZE 117) with a perfectly standardized active ingredients content, it has been possible to study in detail its pharmacological and therapeutic properties and characteristics. Its efficacy and good tolerance in mild-to-moderate depression make it a genuine alternative to the classic antidepressants.

REFERENCES

1. Schrader, E, Meier, B., Brattström, A. Hypericum treatment of mild-moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo controlled, multicentre study. Human Psychopharmacol Clin Exp 1998, 13: 163-9.

2. Schrader, E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: Randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000, 15: 61-8.

3. Woelk, H. Comparison of St John's wort and imipramine for treating depression: Randomised controlled trial. BMJ 2000, 321: 536-9.

4. Böttcher et al. Eur J Clin Pharmacology 2000, 56: A10.

5. Volz, H.-P., Zeller, K. High-dose St. John´s wort extract as single dose­results of a post-marketing surveillance study including 11,296 patients. Nervenheilkunde 2000, 10: 566-9.

6. Käufeler, R., Brattström, A., Schmidlin, S., Polasek. W. 6th International Congress on Ethnopharmacology and 48th Annual Meeting of the Society for Medicial Plant Research, 2000.

7. Friede, M., Henneicke von Zepelin, H.H., Freudenstein, J. Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.0; F 32.1) with St. John's wort. Pharmacopsychiatry 2001, 34 (Suppl. 1): S38-41.

8. Käufeler, R., Meier, B., Brattström, A. Efficacy and tolerability of Ze 117 St. John's wort extract in comparison with placebo, imipramine and fluoxetine for the treatment of mild to moderate depression according to ICD-10. An overview. Pharmacopsychiatry 2001, 34 (Suppl. 1): S49-50.

9. Rechziegler, H., Beneke, M. Report No. Pharma Report PH 29620, Vol. 6 2000, 1832-2191.

10. Käufeler, R. Phytomedicine 2001.

11. Woelk, H. (In press).

12. Roots, I., Brattstöm, A. Will-Shabab, L. (In press).

13. Neary, J.T., Whittemore, S.R., Bu, Y., Mehta, H., Shi, Y.F. Biochemical mechanisms of action of Hypericum LI 160 in glial and neuronal cells: Inhibition of neurotransmitter uptake and stimulation of extracellular signal regulated protein kinase. Pharmacopsychiatry 2001, 34 (Suppl. 1): S103-7.

14. Rommelspacher, H., Siemanowitz, B., Mannel, M. Acute and chronic actions of a dry methanolic extract of Hypericum perforatum and a hyperforin-rich extract on dopaminergic and serotonergic neurones in rat nucleus accumbens. Pharmacopsychiatry 2001, 34 (Suppl. 1): S119-26.

15. Simmen, U., Higelin, J., Berger-Buter, K., Schnaffer, W., Lundstrom, K. Neurochemical studies with St. John's wort in vitro. Pharmacopsychiatry 2001, 34 (Suppl. 1): S137-42.

16. Müller, W.E., Rolli, M., Schafer, C., Hafner, U. Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1197, 30 (Suppl. 1): S102-7.

17. Fiebich, B.L., Hollig, A., Lieb, K. Inhibition of substance P-induced cytokine synthesis by St. John's wort extracts. Pharmacopsychiatry 2001, 34 (Suppl. 1): S26-8.

18. Wang, Z., Gorski,J.C., Hamman, M.A., Huang, S.M., Lesk, L.J., Hall, SD. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001, 70: 317-26.

19. Sugimoto, K., Ohmori, M., Tsuruoka, S. et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 2001, 70: 518-24.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 55-56
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com