Predicting Stable Treatment Response in Patients with Major Depression Treated with Hypericum Extract WS® 5570/5572

Objective: Recent research with several synthetic antidepressants indicates that early improvement during the initial weeks of treatment may be a highly sensitive predictor of therapeutic success in major depression. We investigated whether early improvement is sensitive and specific in predicting sustained response and non-response to antidepressant treatment with Hypericum extract WS® 5570/5572 and whether the results reported for synthetic antidepressants apply to these Hypericum extracts as well. Methods: We analyzed original data of 3 double-blind, randomized trials including a total of 594 adult out-patients suffering from major depression according to DSM-IV criteria, who received well-characterized Hypericum extract preparations WS® 5570, WS® 5572, WS® 5573 or placebo for 6 weeks. The main outcome measure was the prediction of a sustained ≥ 50 % decrease of the Hamilton Depression Scale (HAM-D) total score versus baseline (‘sustained response’) by the presence of ≥20 % HAM-D total score improvement after 1 and 2 weeks of treatment (‘early improvement’). Results: For Hypericum extract, early improvement had a sensitivity of 87 % (95 % confidence interval [CI], 82-93 %) and a specificity of 54 % (95 % CI, 45-62 %) at day 14, and a sensitivity of 43 % (95 % CI, 35-51 %) and a specificity of 86 % (95 % CI, 80-92 %) at day 7 for predicting sustained response. After 2 weeks of treatment, 78 % (95 % CI, 69-87 %) of the patients who failed to improve did not show sustained response later during treatment. Conclusion: A substantial fraction of the patients treated with Hypericum extracts WS® 5570/5572 showed a meaningful reduction of depressive symptoms during the first two weeks of treatment (early improvement), which was found to be a sensitive predictor of sustained response. The results determined for the herbal extracts were comparable to those for effective synthetic antidepressants investigated previously.

References

• 1 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. DSM-IV. Washington, DC; American Psychiatric Association 2000
• 2 Barnes J, Anderson L A, Phillipson J D. St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties.  J Pharm Pharmacol. 2001;  53 583-600
• 3 Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression.  J Clin Psychiatry. 2000;  61 656-663
• 4 Charney D S, Berman R M, Miller H L. Treatment of depression. In Schatzberg AF, Nemeroff CB, editors The American Psychiatric Press Textbook of Psychopharmacology. 2nd ed Washington, DC; American Psychiatric Press 1998
• 5 Franke L, Schewe H -J, Uebelhack R, Müller-Oerlinghausen B. Predictors of therapeutic effects in amitriptyline treatment. 1. Plasma drug levels.  Pharmacopsychiatry. 2003;  36 134-142
• 6 Franklin M, Cowen P J. Researching the antidepressant actions of Hypericum perforatum (St. John's wort) in animals and man.  Pharmacopsychiatry. 2001;  34 (1, suppl) S29-37
• 7 Glass R M. Depression: a call for papers.  JAMA. 2002;  288 1400-1401
• 8 Hamilton M. Development of a rating scale for primary depressive illness.  Br J Soc Clin Psychol. 1967;  6 278-296
• 9 Harrison P. Herbal medicine takes root in Germany.  CMAJ. 1998;  158 637-639
• 10 Kalb R, Trautmann-Sponsel R D, Kieser M. Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial.  Pharmacopsychiatry. 2001;  34 96-103
• 11 Kasper S. Hypericum perforatum - a review of clinical studies.  Pharmacopsychiatry. 2001;  34 (1, suppl) S51-55
• 12 Kim H L, Streltzer J, Goebert D. St. John's wort for depression: a meta-analysis of well-defined clinical trials.  J Nerv Ment Dis. 1999;  187 532-538
• 13 Laakmann G, Dienel A, Kieser M. Clinical significance of hyperforin for the efficacy of Hypericum extracts on depressive disorders of different severities.  Phytomedicine. 1998;  5 435-442
• 14 Laakmann G, Jahn G, Schüle C. Hypericum-perforatum-Extrakt bei der Behandlung leichter bis mittelschwerer Depressionen. Klinische und pharmakologische Aspekte.  Nervenarzt. 2002;  73 600-612
• 15 Laakmann G, Schüle C, Baghai T, Kieser M. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy.  Pharmacopsychiatry. 1998;  31 (1, suppl) 545-549
• 16 Lecrubier Y. Clinical significance of hyperforin for the efficacy of Hypericum extracts on depressive disorders of different severities.  Eur Neuropsychopharmacol. 2001;  11 (3, suppl) 105-106
• 17 Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John's Wort Extract WS 5570 in Major Depression: A Double-Blind, Placebo-Controlled Trial.  Am J Psychiatry. 2002;  159 1361-1366
• 18 Leon A C. Measuring onset of antidepressant action in clinical trials: an overview of definitions and methodology.  J Clin Psychiatry. 2001;  62 (4, suppl) 12-16; discussion 37 - 40
• 19 Leon A C, Blier P, Culpepper L, Gorman J M, Hirschfeld R M, Nierenberg A A. et al . An ideal trial to test differential onset of antidepressant effect.  J Clin Psychiatry. 2001;  62 (4, suppl) 34-36; discussion 37 - 40
• 20 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression - an overview and meta-analysis of randomised clinical trials.  BMJ. 1996;  313 253-258
• 21 Möller H K, Müller H, Volz H P. How to assess the onset of antidepressant effect: Comparison of global ratings and findings based on depression scales.  Pharmacopsychiatry. 1996;  29 57-62
• 22 Montgomery S A. Are 2-week trials sufficient to indicate efficacy?.  Psychopharmacol Bull. 1995;  31 41-44
• 23 Müller W E, Kasper S. Clinically used antidepressant drugs.  Pharmacopsychiatry. 1997;  30 (2, suppl) 71
• 24 National Institute of Mental Health. 028 CGI. Clinical Global Impressions. In: Guy W, Bonato RR, eds Manual for the EDCEU Assessment Battery. Chevy Chase, Md; U.S. National Institute of Mental Health, Psychopharmacol Res Branch 1976 12: 12-16
• 25 Norman C, Hörn M, Hummel B, Grunze H, Walden J. Paroxetine in major depression: correlating plasma concentrations and clinical response.  Pharmacopsychiatry. 2004;  37 123-126
• 26 Quitkin F M, McGrath P J, Stewart J W, Taylor B P, Klein D F. Can the effects of antidepressants be observed in the first two weeks of treatment?.  Neuropsychopharmacology. 1996;  15 390-394
• 27 Quitkin F M, Rabkin J D, Markowitz J M, Stewart J W, Mc Grath P J, Harrison W. Use of pattern analysis to identify true drug response. A replication.  Arch Gen Psychiatry. 1987;  44 259-264
• 28 Quitkin F M, Stewart J W, McGrath P J, Nunes E, Ocepec-Welikson K, Tricamo E. et al . Further evidence that a placebo response to antidepressants can be identified.  Am J Psychiatry. 1993;  150 566-570
• 29 Quitkin F M, Stewart J W, McGrath P J, Taylor B, Beasley C, Stewart J. et al . Are there differences between women’s and men’s antidepressant responses?.  Am J Psychiatry. 2002;  159 1848-1854
• 30 Serretti A, Lilli R, Smeraldi E. Pharmacogenetics in affective disorders.  Eur J Pharmacol. 2002;  438 117-128
• 31 Stahl S M, Nierenberg A A, Gorman J M. Evidence of early onset of antidepressant effect in randomized controlled trials.  J Clin Psychiatry. 2001;  62 (4, suppl) 17-23; discussion 37 - 40
• 32 Stassen H H, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses.  Pharmacopsychiatry. 1996;  29 87-96
• 33 Stassen H H, Angst J, Delini-Stula A. Fluoxetine versus moclobemide: cross-comparison between the time courses of improvement.  Pharmacopsychiatry. 1999;  32 56-60
• 34 Stassen H H, Dahmen N, Giegling I, Nürnberg P, Rujescu D, Sander T, Toliat M R, Szegedi A. Genetic predisposition to psychotropic drug response. Poster presentation at ZNZ Symposium 2003, Zurich (17. October 2003). 
• 35 Stassen H H, Delini-Stula A, Angst J. Time course of improvement under antidepressant treatment: a survival-analytical approach.  Eur Neuropsychopharmacol. 1993;  3 127-135
• 36 Stassen H H, Kuny S, Hell D. The speech analysis approach to determining onset of improvement under antidepressants.  Eur Neuropsychopharmacol. 1998;  8 303-310
• 37 Szegedi A, Müller M J, Anghelescu I, Klawe C, Kohnen R, Benkert O. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression.  J Clin Psychiatry. 2003;  64 413-420
• 38 Tedlow J, Fava M, Uebelacker L, Nierenberg N N, Alpert J E, Rosenbaum J. Outcome definitions and predictors in depression.  Psychother Psychosom. 1998;  67 266-270
• 39 Volz H P. Controlled clinical trials of hypericum extracts in depressed patients - an overview.  Pharmacopsychiatry. 1997;  30 (2, suppl) 72-76
• 40 Wheatley D. Hypericum extract. Potential in the treatment of depression.  CNS Drugs. 1998;  9 431-440

1 All extracts were manufactured by Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany