Trial Studies Effects of St. John's Wort and Sertraline on Depression

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Reviewed: van Gurp G, Meterissian G, Haiek L, McCusker J, Bellavance F. St. John's wort or sertraline? Randomized controlled trial in primary care. Canadian Family Physician 2002;48:905-912.

Clinical studies examining the effects of St. John's wort (Hypericum perforation L., Clusiaceae) as a treatment for depression have had many criticisms, including using low doses of a comparison drug (i.e., a conventional pharmaceutical antidepressant drug used as an active control for comparison purposes), relatively short durations (some trials treat patients for less than 4 weeks, while most are from 4-6 weeks), and imprecisely classifying psychiatric disorders. The goal of this paper was to avoid some of these potential shortcomings by evaluating the severity of depressive symptoms in patients with major depression (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for a longer period of time. Patients were treated for 12 weeks with St. John's wort (SJW) or sertraline, a commonly used antidepressant, in a primary care setting. A primary care setting was chosen because depressive disorders are among the most common illnesses seen by primary care physicians. Sertraline, commonly known as Zoloft® (Pfizer, Inc.), was used for comparison because it is currently the most prescribed antidepressant drug.

The prospective, randomized, double-blind clinical trial included patients with major depression who had a Hamilton Rating Scale for Depression (Ham-D) score of greater than or equal to 16 using DSM-IV criteria. (The severity of depression in patients in the 2 previously published trials on SJW conducted in the U.S. was 16.7 according to the Ham-D scores.) The Ham-D is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and co-morbid anxiety symptoms. (Vegetative symptoms refer to sleeping and eating patterns, sexual arousal and activity, etc.) The Hamilton scale is the standard depression outcome measure used in clinical trials presented to the U.S. Food and Drug Administration by pharmaceutical companies for approval of new drug applications for antidepressants. Patients in this trial took one capsule 3 times daily of either sertraline (50 mg total dose) or SJW (extract imported from Germany, supplied as 300 mg capsules by Swiss Herbal Remedies Company, Richmond Hill, Ontario, presumably standardized to 0.3% hypericin, although the paper states "Hypericum content of 0.3%"). Total daily dose was 150 mg sertraline, 900 mg SJW. The dose for either treatment was allowed to be increased to 2 capsules 3 times daily (300 mg sertraline total dose or 1,800 mg SJW total dose per day), if the treatment was clinically insufficient at 4 weeks. For blinding purposes, all opaque capsules looked identical. Patients were evaluated at the beginning of the trial and at 2, 4, 8, and 12 weeks. Physicians administered the Ham-D, and the patients rated themselves with the Beck Depression Inventory (BDI). The BDI is a self-administered 21-item questionnaire used to assist the clinician to assess the intensity of depression in clinical and normal patients.

The study started with 87 patients; however, only 29 SJW and 28 sertraline patients completed the trial, showing a high "dropout" rate, which usually reduces the validity of the trial's outcome. (Normally, a one-third dropout rate would invalidate a trial; in this study, a total of 57 or 65% completed the study, meaning that over one-third dropped out). Mean Ham-D and BDI scores declined similarly by 12 weeks in both study groups. Scores declined to about half the mean baseline score. Nine patients in each group increased their daily dose to 6 capsules. At 2 and 4 weeks, the mean number of side effects was significantly higher in the sertraline group (P < 0.05). Both groups had similar numbers of patients reporting sleep disturbances — the most common side effect. There was one serious side effect: a patient taking 1,800 mg SJW required hospitalization after developing an acute manic reaction. Five other cases of manic episodes associated with the use of SJW have been reported in the medical literature.

Overall, the data shows that the severity of symptoms in patients with mild-to-moderate depression was similar whether they were treated with SJW or sertraline. The authors conclude that the favorable side effect profile and similar efficacy to sertraline indicates that SJW can be a first treatment option for mild-to-moderate depression in primary care settings.

However, the weaknesses of the trial design and the data produced do not permit the authors to conclude that the two treatments had equivalent effectiveness. A much larger sample size would be needed to make that claim. It should be noted that the use of "positive controls" (i.e., the sertraline/Zoloft group) is considered the more ethical standard in current clinical trial design rather than using a placebo that would usually produce a negative outcome, and which is used in most FDA clinical trials. In this way none of the subjects is denied treatment and the experimental treatment (in this case the SJW) is tested for its equivalency to the established positive control. Other weaknesses of this trial are that some subjects were recruited through advertising, so the study may not be representative of depressed patients in primary care settings, and Ham-D ratings were not confirmed by a mental health specialist.

PHOTO (COLOR): St. John's wort Hypericum perforatum.

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By Heather S. Oliff, PhD

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