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.

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.

In accordance with Kupfer's model of acute therapy and subsequent prophylactic treatment of unipolar depression, 13 our study included a six week acute phase after which responders undergo four months of prophylactic continuation treatment (to prevent relapse or recurrence, or both).

Hypericum extract WS 5570 at a dose of 300 mg three times a day has been shown to be more effective than placebo in patients with mild to moderate major depression treated for six weeks. 9 Paroxetine, on the other hand, is a potent selective serotonin reuptake inhibitor with proved efficacy in patients with depression of any severity 10 and has a more favourable safety profile than tricyclic antidepressants. 11 In major depression, daily doses between 20 mg and 50 mg have been recommended 12 and are commonly used in clinical trials and in daily practice.

In clinical practice, hypericum extract is better tolerated than synthetic antidepressants. 7 It may be particularly helpful in severe depression with its high risk of chronicity. 8 We compared the efficacy and safety of hypericum extract with paroxetine in patients with moderate to severe depression.

Extract of Hypericum perforatum (St John's wort) is more effective than placebo in the treatment of mild to moderate major depression 1 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. 4 That study, however, was not sufficiently powered to demonstrate non-inferiority of the herbal extract.

Methods

Protocol, design, and objectives This double blind, double dummy, randomised phase III trial examined the efficacy of hypericum extract WS 5570 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, during which they received three coated tablets of hypericum placebo per day plus one paroxetine placebo capsule in the morning. After that, we randomised those still meeting the selection criteria to six weeks of double blind treatment with hypericum extract or paroxetine. Those who responded to treatment (that is, their total score on the 17 item Hamilton depression scale decreased by 50%) were invited to participate in a four month double blind maintenance phase (reported elsewhere). All patients provided written informed consent. We did not use a placebo control group because we considered it unethical to treat severely depressed patients with placebo for six weeks.

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 (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) 296.22, 296.23, 296.32, 296.33) persisting for two weeks to a year. At screening and baseline all participants had to have a total score ≥ 22 points on the 17 item Hamilton depression scale and ≥ 2 points for the item “depressive mood.” The diagnosis of depression was based on the mini-international neuropsychiatric interview.14 There were no restrictions regarding ethnic group. 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 (defined by a score ≥ 4 for item 10 of the Montgomery-Åsberg depression rating scale), who had previously attempted suicide, or who had not responded to more than one adequate treatment (equivalent to 150 mg/day amitriptyline for ≥ 6 weeks) in the present episode. Participants were not allowed to take other psychotropic medication and psychotherapy during the study (in case of previous antidepressant medication an appropriate wash out period of five half lives had to be observed).

Interventions and blinding We used hypericum extract WS 5570 (Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany), a hydroalcoholic extract from herba hyperici (drug to extract ratio 3-7:1) with standardised contents of 3-6% hyperforin and 0.12-0.28% hypericin. 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. High and low dose tablets or capsules were indistinguishable in all aspects of their outward appearance. For each drug an identically matched placebo was available (the success of blinding was evaluated by examining the drugs before distribution). During the six weeks of randomised treatment patients allocated to hypericum always took three coated tablets of hypericum/day plus one paroxetine placebo capsule in the morning whereas those in the paroxetine group took one capsule of paroxetine in the morning and three coated tablets of hypericum placebo/day. Initially this corresponded to 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 of treatment compared with baseline we increased the treatment to three doses of 600 mg/day hypericum or one dose of 40 mg/day paroxetine. The doses for paroxetine were based on published recommendations.12

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. We based assessments of safety and tolerability on spontaneous reports of adverse events, a semistructured interview exploring known side effects of the investigational treatments, physical examinations, and routine laboratory measurements. To assure uniform diagnostic and rating standards, all assessments were performed by psychiatrists and psychologists who had participated in training before patients were included.

Random sequence generation, allocation concealment, implementation Patients who still met the selection criteria at baseline were randomised at a ratio of 1:1 to hypericum or paroxetine. Randomisation was performed in blocks stratified by trial centre. A biometrician otherwise not involved in the trial generated the code using a validated computer program. The study drugs were dispensed to the centres in numbered containers. On inclusion of a patient into randomised treatment the local investigator allocated each participant the lowest available number. The block size was withheld from the investigators.