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
Dr. Willmar Schwabe Pharmaceuticals
PO Box 410925
76209 Karlsruhe
Germany
Telefon: +49 721 4005 572
Fax: +49 721 4005 333
eMail: meinhard.kieser@schwabe.de