BMJ  2005;330:503 (5 March), doi:10.1136/bmj.38356.655266.82 (published 11 February 2005)

Paper

Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine

¹ Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Psychiatry and Psychotherapy, Eschenallee 3, 14050 Berlin, Germany, ² Institute for Medical Research Management and Biometrics GmbH, Scheurlstraße 21, 90478 Nürnberg, Germany, ³ Dr Willmar Schwabe Pharmaceuticals, PO Box 410925, 76209 Karlsruhe, Germany

Abstract

Objective To investigate the efficacy of hypericum extract (St John's wort) compared with paroxetine in patients with moderate to severe major depression.

Design Randomised double blind, double dummy, reference controlled, multicentre non-inferiority trial.

Setting 21 psychiatric primary care practices in Germany.

Participants 251 adult outpatients with acute major depression with total score 22 on the 17 item Hamilton depression scale.

Interventions 900 mg/day hypericum extract WS 5570 three times a day or 20 mg paroxetine once a day for six weeks. In initial non-responders doses were increased to 1800 mg/day hypericum or 40 mg/day paroxetine after two weeks.

Main outcome measures Change in score on Hamilton depression scale from baseline to day 42 (primary outcome). Secondary measures were change in scores on Montgomery-Åsberg depression rating scale, clinical global impressions, and Beck depression inventory.

Results The Hamilton depression total score decreased by mean 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value, in the hypericum group and by 11.4 (SD 8.6) points (44.8% (SD 33.5%) of baseline value) in the paroxetine group (intention to treat analysis; similar results were observed in the per protocol analysis). The intention to treat analysis (lower one sided 97.5% confidence limit 1.5 points for the difference hypericum minus paroxetine) and the per protocol analysis (lower confidence limit 0.7 points) showed non-inferiority of hypericum and statistical superiority over paroxetine. The lower limits in both cases exceeded the pre-specified non-inferiority margin of -2.5 points and the superiority margin of 0. The incidence of adverse events was 0.035 and 0.060 events per day of exposure for hypericum and paroxetine, respectively.

Conclusions In the treatment of moderate to severe major depression, hypericum extract WS 5570 is at least as effective as paroxetine and is better tolerated.

Introduction

Extract of Hypericum perforatum (St John's wort) is more effective than placebo in the treatment of mild to moderate major depression¹ and as effective as several tricyclic antidepressants^2-5 or fluoxetine.⁶ In patients with more severe depression, however, the antidepressant efficacy of hypericum extract is disputed. In a comparison of 1800 mg/day hypericum extract (LI 160) and 150 mg/day imipramine the effect of both drugs was comparable during six weeks of acute treatment.⁷ That study, however, was not sufficiently powered to demonstrate non-inferiority of the herbal extract.

We compared the efficacy and safety of hypericum extract WS 5570 with paroxetine in patients with moderate to severe depression over a six week acute phase after which responders undergo four months of prophylactic continuation treatment (to prevent relapse or recurrence, or both).

Methods

Protocol, design, and objectives
This double blind, double dummy, randomised trial examined the efficacy of hypericum extract compared with paroxetine in the acute treatment of moderate to severe major depression. After a screening examination participants underwent a single blind placebo run-in phase of three to seven days, after which we randomised those still meeting the selection criteria to six weeks of double blind treatment with hypericum extract or paroxetine.

Participants
We recruited male and female outpatients in 21 psychiatric primary care centres in Germany. All participants were 18-70 years old and had single or recurrent moderate or severe episodes of unipolar major depression without psychotic features persisting for two weeks to a year.

We excluded anyone with a decrease in total depression score of 25% during the run-in, or with a diagnosis of schizophrenia, acute anxiety disorder, adjustment disorder, depressive disorder of any type not stated above, bipolar disorder, organic mental disorder, acute post-traumatic stress disorder, or substance abuse disorder. We also excluded patients with increased risk of suicide, who had previously attempted suicide, or who had not responded to more than one adequate treatment in the present episode. Participants were not allowed to take other psychotropic medication and psychotherapy during the study.

Interventions and blinding
We used hypericum extract WS 5570 (Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany). The coated tablets contained 300 mg or 600 mg of the extract. Paroxetine was supplied in tablets of 20 mg packed in capsules containing one or two tablets. For each drug an identically matched placebo was available.

During the six weeks of randomised treatment patients allocated to hypericum always took three doses of 300 mg/day hypericum or one dose of 20 mg/day paroxetine. For patients whose total depression score had not decreased by at least 20% after two weeks we increased treatment to three doses of 600 mg/day hypericum or one dose of 40 mg/day paroxetine.

Outcomes
We assessed efficacy and safety at screening, baseline, and at the end of the first, second, fourth, and sixth weeks. The primary outcome measure was the absolute decrease of the Hamilton total depression score between baseline and week six. Secondary outcome measures included the Montgomery-Åsberg depression rating scale, the clinical global impressions, and the Beck depression inventory.

Statistical methods
We considered that hypericum would not be relevantly inferior to paroxetine if the true decrease in total depression score (primary outcome measure) for hypericum was not more than 2.5 points⁸ smaller than for paroxetine ( = -2.5).

We reserved the option of testing for superiority after establishing non-inferiority of hypericum. The primary analysis was based on the intention to treat analysis. We also performed a per protocol analysis to demonstrate robustness of the trial result to the choice of the analysis set.⁹ For the Hamilton total score, we defined response as a decrease in total score of 50% from baseline and remission as a score 10 points at week six.

Results

Participants
Between May 2000 and July 2003, we randomised 251 patients (125 to hypericum and 126 to paroxetine). Baseline demographic and clinical measures were comparable in both groups (table 1). Mean age and average duration of the current episode, however, were higher in the hypericum group. In each group more than half of the patients had a total depression score 25 and were thus severely depressed.¹⁰

View this table: [in this window] [in a new window]   Table 1 Demographic and clinical characteristics at baseline (intention to treat analysis; figures are means (SD); medians unless stated otherwise)

 

Investigational treatment
After two weeks of randomised treatment, 69/122 patients in the hypericum group (57%) and 58/122 in the paroxetine group (48%) were switched to the higher doses. Between baseline and day 42 Hamilton total scores decreased by an average of 14.4 (SD 8.8) points (corresponding to 57% (SD 34%) of the baseline value) for hypericum and by 11.4 (SD 8.6) points (45% (SD 34%)) for paroxetine (lower one sided repeated 97.5% confidence limit for the difference hypericum-paroxetine was 1.5 points) (figure).

View larger version (27K): [in this window] [in a new window]   Total Hamilton depression scores over time (intention to treat analysis, means and 95% confidence intervals)

 

At the end of the acute treatment phase 86/122 patients (71%) in the hypericum group and 73/122 (60%) in the paroxetine group responded to treatment (P = 0.08), and 61/122 (50%) and 43/122 patients (35%) showed remission (P = 0.02). For all standardised psychiatric scales we found differences between treatment groups in favour of hypericum (table 2).

View this table: [in this window] [in a new window]   Table 2 Secondary measures (intention to treat analysis; figures are numbers (percentages) unless stated otherwise)

 

Safety and tolerability
During the acute treatment phase 69/125 patients randomised to hypericum (55%) reported 172 adverse events and 96/126 treated with paroxetine (76%) reported 269 adverse events. The incidences were 0.035 adverse events per day of exposure (0.029 at 900 mg/day and 0.039 at 1800 mg/day) for hypericum and 0.060 (0.062 at 20 mg/day and 0.059 at 40 mg/day) for paroxetine. Based on the rate ratio, the incidence of adverse events in the paroxetine group was 1.72 (95% confidence interval 1.42 to 2.10) of the rate observed for hypericum. The highest incidence was found for gastrointestinal disorders (59 events in 42 patients in the hypericum group and 106 events in 67 patients in the paroxetine group), followed by nervous system disorders (35 events in 29 patients and 61 events in 43 patients, respectively). Table 3 shows adverse events that occurred in at least 10 patients in one group. Two serious adverse events occurred in the hypericum group (psychic decompensation attributable to social problems; hypertensive crisis); both were thought to be unrelated to hypericum—that is, a cause other than the administration of hypericum was evident.

View this table: [in this window] [in a new window]   Table 3 Adverse events that occurred in at least 10 patients in one group (safety analysis set; figures are numbers (percentages) of patients)

 

Discussion

Strengths and weaknesses
Non-inferiority trials of hypericum extract against synthetic antidepressants have been criticised for using doses mostly in the lower therapeutic range of the active comparators.¹¹ Our trial included a mandatory dose increase in patients with insufficient response after two weeks of treatment. For paroxetine, 40 mg/day correspond to the established use of the drug in clinical trials and daily practice.¹² The trial's assay sensitivity is supported by the observed treatment effect for paroxetine which was in line with previously published data from trials against placebo and synthetic antidepressants.¹³ Another indicator of a pharmacological effect is that in both study groups a (single blind) dose increase in initial non-responders was followed by a substantial decrease in depression score that was comparable with the effect observed in those patients who were adequately treated with the initial (lower) dose. A placebo control could not be used in this group of predominantly severely depressed patients for ethical reasons, particularly as comedication with benzodiazepines was not permitted. For the same reason we had to refrain from including patients at high risk of suicide. As we did not actually withdraw any patient because of increased risk of suicide, however, this restriction does not adversely affect the external validity of our data.

Implications for clinicians
Our results support the use of hypericum extract WS 5570 as an alternative to standard antidepressants in moderate to severe depression, especially as it is well tolerated.⁷ As in any effective antidepressant, potential interactions with other drugs deserve clinical attention.⁷

The convincing results for hypericum extract WS 5570 observed in this trial deserve independent confirmation by other research. We are assessing efficacy in long term treatment, for which the drug can be an interesting option because of its favourable ratio between efficacy and tolerability, in the ongoing continuation phase.

What is already known on this topic Hypericum extract is effective in the acute treatment of patients with mild to moderate depression The only randomised controlled trial to date in patients with severe depression was underpowered What this study adds This double blind randomised clinical trial showed that hypericum extract WS 5570 is at least as effective as paroxetine in ameliorating the symptoms of moderately or severely depressed patients

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This is the abridged version of an article that was posted on bmj.com on 11 February 2005: http://bmj.com/cgi/doi/10.1136/bmj.38356.655266.82

We thank the investigators and patients of the study, St Klement for project management, T Konstantinowicz for the data analysis, T Utz for project assistance, and A Völp for his assistance in the preparation of the manuscript.

Contributors: See bmj.com

Funding: Dr Willmar Schwabe Pharmaceuticals, manufacturer of WS 5570.

Competing interests: AS has received consultancy fees from Dr Willmar Schwabe Pharmaceuticals. RK is head of a contract research organisation (IMEREM), which is engaged in severalclinical trials of hypericum extract for different pharmaceutical companies. AD and MK are employees of Dr Willmar Schwabe Pharmaceuticals.

Ethical approval: The protocol was approved by the participating centres' appropriate independent ethics committees.

References

1. Linde K, Mulrow CD. St John's wort for depression. Cochrane Database Syst Rev2004; (4): CD000448.
2. Harrer G, Hübner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. J Geriatric Psychiatry Neurol1994; 7(suppl 1): S24-8.[Abstract/Free Full Text]
3. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ1999; 319: 1534-8.[Abstract/Free Full Text]
4. Vorbach EU, Hübner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatric Psychiatry Neurol1994; 7(suppl 1): S19-23.[Abstract/Free Full Text]
5. Wheatley D. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients—a controlled 6-week clinical trial. Pharmacopsychiatry1997; 30(suppl 2): 77-80.
6. Harrer G, Schmidt U, Kuhn U, Biller A. Äquivalenzvergleich Johanniskrautextrakt LoHyp-57 versus Fluoxetin. Arzneimittel-Forschung1998; 49: 3-10.
7. Izzo AA. Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther2004; 42: 139-48.[ISI][Medline]
8. Montgomery SA. Clinically relevant effect sizes in depression. Eur Neuropsychopharmacology1994; 4: 283-4.[CrossRef]
9. Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. London: European Agency for the Evaluation of Medicinal Products, 2000.
10. Paykel ES. The classification of depression. Br J Clin Pharmacol1983; 15(suppl 2): 155-9S.
11. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder. JAMA2002; 287: 1807-14.[Abstract/Free Full Text]
12. Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry1992; 53(suppl): 21-6.
13. Bourin M, Chue P, Guillon Y. Paroxetine: a review. CNS Drug Rev2001; 7: 25-47.[ISI][Medline]

(Accepted 17 December 2004)

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