By Carmen Tamayo, MD
Depression is a serious medical illness that affects a person’s mood, thoughts, physical health, and behavior.1 Depressive disorders, including major depression and dysthymia, are disabling illnesses and affect nearly 19 million Americans each year. In the United States, it is estimated that one in five individuals is affected by a mood disorder in his or her lifetime.2 The World Health Organization estimates that worldwide 9.5% of women and 5.8% of men will experience a depressive episode in any given year.3 The lifetime risk for major depressive disorders (MDD) ranges from 10% to 25% for women and from 5% to 12% for men.
History
St. John’s wort (Hypericum perforatum), a bushy, low-growing plant covered with yellow flowers, has a 2,000-year history of use as a medicinal herb. St. John’s wort (SJW) is used widely in the treatment of mild-to-moderate depression in Europe and has become increasingly popular in the United States.
Mechanism of Action
SJW’s mechanism of action is not understood fully. The plant contains many biologically active components including hyperforin and adhyperforin (phloroglucinols); hypericin and pseudohypericin (naphthodianthrones); flavonoids; xanthones; oligomeric procyanidines; and amino acids.4 Treatment with SJW seems to disinhibit the hypothalamus-pituitary-adrenocortical-system in healthy subjects and patients with depression. Furthermore, it decreases intra- cerebral corticosteroids, which may have an effect in associated depression symptoms. This effect has been proved in studies of patients with atypical depressive features, somatization, and fatigue and for whom SJW appears to be especially effective.5
Clinical Trials
In recent years, SJW has undergone extensive scientific investigation.6,7 Its effectiveness has been shown in studies comparing it with placebo and common antidepressants. However, it is not clear if SJW is as effective as newly developed standard antidepressive agents. In the past 20 years, a number of clinical trials, meta- analyses, and systematic reviews with both positive and negative results have been published in the literature. Table 1 summarizes systematic reviews and meta-analyses of SJW for depression published between 2000 and 2004. A recent review article found SJW to be more effective than placebo and equally as effective as tricyclic antidepressants in the short-term management (1-3 months) of mild-to-moderate depression.8
Clinical trials of SJW conducted in the past five years have shown contentious results. It is important to note that there are major differences in the methodology of these trials (e.g., patient selection, endpoints, SJW doses, and selection of control group). It also is important to note that depression studies typically have a significant placebo response. In fact, failure of established antidepressants to show superiority against placebo occurs in up to 35% of trials.9 Many factors seem to contribute to this such as: failure in rating the degree of depression at the initiation of the study, short disease duration, lack of established inclusion criteria, lack of patient compliance with the treatment, lack of experienced investigators, use of concomitant medications, and short study duration.
Two of the most recently published trials have been the object of controversy10,11 because of methodological issues and publication bias. The first study, sponsored by the National Institutes of Health, compared SJW with a placebo in 200 outpatients from 11 U.S. academic centers.12 Participants completed a one-week, single-blind run-in of placebo, then were randomly assigned to receive either SJW extract (n = 98; 900 mg/d for four weeks, increased to 1,200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for eight weeks. Although the study was rigorous and met reasonable expectations for a wellconducted pharmaceutical study, the selected population included only patients with major depression (not mild or moderate). This study did not include a referenced agent or active conventional antidepressant arm. Response was defined as a Hamilton Rating Scale for Depression (HAM-D) score of >12 and a Clinical Global Impressions (CGI) score of 1 or 2. The rate of change in HAM-D scores over the course of the trial for the intention-to-treat sample revealed no significant difference between treatments (P = 0.16). The number of SJW patients who reached remission (14/98; 14.3%) was significantly higher than placebo (5/102; 4.9%). However, this likely was influenced by very low remission rates in both groups. In a subgroup analysis of patients with less severe initial depression, there was no difference in rate of change in the HAM-D scores between the SJW (n = 60) and placebo groups (n = 50).
The second study, sponsored by Pfizer, compared SJW (LI 160 extract), placebo, and sertraline (Zoloft®, a selective serotonin reuptake inhibitor [SSRI]).13 This study, which also evaluated patients (n = 340) with severe rather than mild-to-moderate MDD, yielded negative results both for the SSRI and SJW as neither SJW nor sertraline (50-100 mg/d) could be differentiated from placebo. The main outcome measure was change in the HAM-D total score from baseline to eight weeks and rates of full responses. The study may have been too brief, only eight weeks at doses of 900-1,500 mg/d of SJW, and the administered doses too low, as only 54% of patients in the SJW group and 36% in the sertraline group received the maximum permitted dosage to detect full therapeutic effects of SJW or sertraline. In addition, it may not have been powered adequately to detect between-group differences, taking into account the potential improvements in the placebo group.
Several placebo-controlled studies suggest that SJW is more effective than placebo. The largest of these trials treated 375 outpatients with mild-to-moderate depression with SJW (WS 5570) 300 mg tid for six weeks.14 Median difference in change in HAM-D score between WS 5570 and placebo was 3 points. Percentage of responders was 52.7% in the SJW group vs. 42.3% in the placebo group; the 10.4% difference was statistically significant.
In a multicenter study conducted in Germany, 72 similar patients were given 900 mg/d of SJW (WS 5572) or placebo for six weeks.15 Group differences in favor of SJW were descriptively apparent as early as day 7 of randomized treatment and were statistically significant at days 28 (P = 0.011) and 42 (P < 0.001). In this study both percentage of responders and > 50% reduction in HAM-D were significantly better for the SJW group. Between baseline and treatment end, the HAM-D total score decreased from 19.7 ± 3.4 to 8.9 ± 4.3 points in the SJW group and from 20.1 ± 2.6 to 14.4 ± 6.8 points in the placebo group (mean ± SD). Good tolerability was observed in both groups with no adverse effects reported. Comparable group differences in favor of WS 5572 were found for von Zerssen’s Depression Scale (self-rating), CGI, and a global patient’s self-assessment.
A slightly higher dose (up to 1,450 mg/d) was administered to 150 outpatients with moderate depression or dysthymia during a six-week period.16 This dose was compared with SJW 900 mg/d and placebo. There was a significant reduction in HAM-D score and Beck Depression Inventory (BDI) in all three groups compared to baseline (P < 0.05).
A double-blind RCT comparing SJW (900-1,800 mg/d) with sertraline (50-100 mg/d) was conducted in 87 patients who had major depression and had been seen by community-based offices of 12 family physicians.17 In this study there were no major differences in changes of HAM-D and BDI but significantly more side effects were observed in the sertraline group.
In a seven-week pilot study, SJW (LI 160) was administered to 30 patients with major single or recurrent depression.18 Both SJW and sertraline were administered in escalating doses (600 mg/d of SJW for one week, followed by 900 mg/d for six weeks) vs. sertraline (50 mg/d for one week, followed by 75 mg/d for six weeks). Results suggested that both treatments were therapeutically equivalent (HAM-D scores for patients on both therapies significantly improved [P < 0.05]). However, clinical response (> 50% reduction in HAM-D) did not differ between the two groups.
Comparisons of SJW with fluoxetine hydrocloride (Prozac) and tricyclic antidepressants (imipramine) suggest that SJW is therapeutically equivalent to these widely used drugs. A study of 240 patients with mild-to- moderate depression compared 500 mg/d of SJW (ZE 117) vs. fluoxetine 20-40 mg/d.19 The mean HAM-D at endpoint decreased to 11.54 for those taking SJW and to 12.20 for fluoxetine (P < 0.09). Mean CGI (severity) was significantly (P < 0.03) superior for SJW, as was the responder rate (P = 0.005) More adverse events were observed for fluoxetine (23%) than SJW (8%), so the main difference between the two treatments was safety.
In a later study, Behnke et al treated 72 patients with mild-to-moderate depression for six weeks with SJW (Calmigen extract) or fluoxetine. Significant decreases (P < 0.001) were observed in the HAM-D score (50% in the SJW group, 58% in the fluoxetine group) as well as von Zerssen’s Depression Scale (42% in the SJW group, 52% in the fluoxetine group).20Assessments by physicians and patients indicated considerable improvement with no differences between treatments. Again in this study SJW was better tolerated than fluoxetine. The authors concluded that the SJW used in this study is therapeutically equivalent to fluoxetine and therefore is a rational alternative to synthetic antidepressants.
One study that included 324 patients with mild or moderate single or recurrent depressive disorder found SJW (ZE 117, 500 mg/d) to have a better safety profile when compared to imipramine (75 mg bid).21 However, no significant difference between the two groups on HAM-D or CGI scores was observed. The imipramine group scored significantly better in the anxiety-somatization subscale. Both treatments were equivalent, but SJW was better tolerated.
A randomized, double-blind, crossover safety/efficacy trial, designed and sponsored by the National Institute of Mental Health, the National Center for Complementary and Alternative Medicine, and the Office of Dietary Supplements, currently is being conducted to evaluate the efficacy of SJW and citalopram (Celexa®) compared to placebo in patients with mild-to-moderate depression. For more information, see article on page 80.
Use During Pregnancy and Breastfeeding
There is limited evidence for the efficacy of SJW in pregnant and breastfeeding women. Although no clinical trials evaluating SJW use in pregnancy were found, a recent case report indicated SJW did not have adverse effects in breastfeeding women.22 In another case report, breast milk samples were obtained from a women with postpartum depression who was taking SJW. No adverse effects on mother or infant were observed.23 One study in mice found that SJW did not significantly affect cognitive tasks performed by the offspring of mice receiving SJW before and throughout gestation.24
In a small safety study, 33 breastfeeding women taking SJW were compared with 101 breastfeeding women who were not taking SJW.25 Adverse events were observed in both groups and included colicky infants (two in SJW vs. one in the control group), two cases of drowsiness in the SJW group, and one case of lethargy in the SJW group. The differences were not significant. However, the small sample size and possible selection bias of this study prevent one from making definitive conclusions as to whether the adverse events were attributable to SJW.
Safety of SJW
There is concern that adverse effects and safety of herbal medicines are underreported.26 Nevertheless, safety and tolerability studies have revealed that SJW preparations have better safety and tolerability profiles than synthetic antidepressants27 and appear to be safe when used in recommended doses and for less than three months. However, it generally takes at least 12 weeks to get a full response from SJW.
The most common observed adverse events in clinical trials and in observational studies have been skin reactions including photosensitization, rash, and itching; gastrointestinal problems; fatigue; restlessness; head- aches; dizziness; and dry mouth.28
The safety of SJW during pregnancy and breastfeeding has not been established in randomized controlled trials. Very little information on reproductive safety exists; therefore, SJW cannot be recommended as safe therapy for pregnant and breastfeeding women.
SJW Drug Interactions
Interactions of SJW with conventional drugs has become an issue of increased awareness among consumers, health care practitioners, and industry,29 and more research is needed to determine the nature and severity of the interactions. The U.S. Food and Drug Administration issued a Public Health Advisory on Feb. 10, 2000, stating that SJW appears to affect an important metabolic pathway that is used by many drugs prescribed to treat conditions such as AIDS, heart disease, depression, seizures, certain cancers, and rejection of transplants.30
Recent reports indicate that SJW extracts may potentiate the effect of certain enzymes required for the metabolism (absorption and excretion) of drugs such as warfarin, digoxin, theophylline, cyclosporin, and oral contraceptives. This may decrease the serum concentration of these drugs and reduce their therapeutic effects.
In addition, evidence exists that SJW reduces the effect of contraconceptives and that women taking SJW and contraconceptives for an extended period experienced a major incidence of unwanted pregnancies and bleeding.31
In general SJW has been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of drugs including alprazolam, amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, irinotecan, methadone, nevirapine, simvastatin, tacro- limus, theophylline, warfarin, phenprocoumon, and oral contraceptives.32
HIV-positive or AIDS patients taking protease in- hibitors or non-nucleoside reverse transcriptase inhibitors should use caution when taking SJW.33 Patients taking photosensitizing drugs and patients with iron deficiencies should avoid SJW because the presence of tannins in SJW may inhibit iron absorption.34 Several human cases of reversible photosensitivity to SJW have been reported.
Dosage
SJW products are available in a variety of forms (tablets, capsules, liquid extract, tea). Indications and dosage vary according to the manufacturer. Studies suggest that the brands are not interchangeable. Most SJW products are standardized to 3% hypericin extract, but some products are standardized to 2-5% hyperforin. For adults, the most commonly used dose for maintenance therapy is 300-600 mg tid. In clinical trials, dosages varied from 300-1,450 mg/d.
Conclusion
There is an urgent need for better data about the efficacy of newer pharmacotherapies, including SJW, in patients with non-major depression, refractory depression, and other depressive disorders, as well as in a broad array of special populations, including pregnant or breastfeeding women, children, adolescents, and the elderly.
SJW has been reported to be more effective than placebo and as effective as tricyclic antidepressants in the short-term management of mild-to-moderate depression. Overlapping meta-analyses and systematic reviews of multiple trials over the last two decades,35-38 as well as several more recent short-term randomized trials, support this conclusion. Comparisons of SJW with newly developed SSRIs have provided limited equivalence data to date.
Overall, the evidence supporting the efficacy of SJW in mild-to-moderate major depression remains compelling while the evidence for severe major depression is unclear. In addition, there are ethical concerns with treating major depression with SJW because even if SJW should prove effective in this population, it is much more slow to show clinical effect than standard pharmaceutical options.
Dr. Tamayo is Director, Division of Complementary and Alternative Medicine, Foresight Links Corp., London and Dundas, Ontario, Canada.
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