St. John’s Wort for the Treatment of Depression: An Update
St. John’s Wort for the Treatment of Depression: An Update
By E-P. Barrette, MD, FACP
Since last reviewed in this newsletter,1 several long-awaited trials of St. John’s wort (SJW), an herbal therapy for depression, have been published. The growing literature on the efficacy, adverse effects, and drug interactions of SJW has greatly expanded. In spite of this, much controversy still exists and SJW remains one of the top selling supplements.
History
St. John’s wort was used by the ancient Greeks and by 19th century European physicians for mood disorders in addition to other conditions. Interest in herbal SJW was rekindled in the mid-20th century. In 1984 the Commission E of Germany published its first monograph supporting the use of this herb for "psychovegetative disturbances, depressive moods, anxiety, and/or nervous unrest."2
In Europe, SJW remains among the most commonly used anti-depressant and continues to outsell fluoxetine (Prozac) widely. In the United States, annual sales of SJW have been estimated to exceed $400 million.
Botany and Chemistry
St. John’s wort (Hypericum perforatum) is a perennial shrub that grows well in dry sunny areas. Its bright yellow star-shaped flowers can be seen along many highways in the United States. The flowering parts are harvested, dried, and extracted with alcohol for the medicinal supplement. A group of purple naphthodianthrones comprise the supplement’s principal ingredients. This group includes hypericin, pseudohypericin, protohypericin, protopseudohypericin, and cyclopseudohypericin.3 Other components of the extract include quercetin, quercitrin, rutin, campherol, lureolin, and hyperforin.4
The amount of hypericin, originally thought to be the active component, found in SJW varies from 0.06% to 0.75%, depending on the time of harvest and the quality of the plants.
Mechanism of Action
Early theories of a mechanism involving hypericin and MAO inhibition have been discounted. Notably, hypericin does not cross the blood-brain barrier. Extracts have been standardized to the hypericin content. Consequently, other content, such as hyperforin content, has varied and usually was not measured (or reported on the label). This variation may explain some of the differences seen in the trials.
Recent data support hyperforin as a potential active component of SJW,5 and evidence from validated animal models of depression support hyperforin.6 Hyperforin inhibits the uptake of serotonin, dopamine, norepinephrine, GABA (gamma-aminobutyric acid), and L-glutamate receptors in vitro. This broad range of affected receptors suggests a mechanism different than that of the selective serotonin reuptake inhibitors. Hyperforin, a phloroglucinol, and hypericin, a naphthodianthrone, are chemically unrelated and their plant content varies independently.
Early Clinical Evidence
In 1996, a meta-analysis published in the British Medical Journal supported the use of SJW for depression and generated much attention.7 This meta-analysis was updated for the Cochrane library in 1999.8 A total of 2,291 patients were included in 27 studies. Twenty-four of 27 trials were double-blind studies. Standard definitions of treatment response were used, e.g., Hamilton Depression Scale (HAMD) score of less than 10 or less than 50% of the baseline score or "much improved" on the Clinical Global Impression Index.
The results from 14 of the 17 trials comparing SJW to placebo were combined. SJW response rate was 56% while the response rate for placebo was 25%. The pooled rate ratio confirmed a significant effect (2.47, 95% confidence interval [CI] 1.69-3.61). Eight trials compared SJW to a tricyclic antidepressant. Pooling of responder rates from these trials suggested an equivalent response (i.e., no significant difference between SJW and tricyclic antidepressants).
These early trials have been criticized for poorly defined entry criteria resulting in heterogeneous populations, inadequate blinding, use of nonstandard outcome scores, use of combination products or low doses of SJW, small enrollment size, short duration of follow-up, and low doses of tricyclic antidepressants. In addition, the variety of commercially produced products with different extraction processes lessens the generalizability of these studies.
Recent Trials Comparing SJW to Placebo or Tricyclic Antidepressants
Since the publication of the Linde meta-analysis,7 three multicenter trials in Germany have showed a benefit of SJW over placebo (see Table 1 below).
Schrader et al enrolled 162 patients with mild-to-moderate depression (ICD-10 criteria) and compared 250 mg bid SJW vs. placebo over six weeks.9 This trial demonstrated a 56% response rate with SJW compared to 15% with placebo. For the main outcome, change in HAMD score, placebo showed essentially no change.
In the first published three-arm study, 263 subjects were randomized to SJW (350 mg tid), imipramine (100 mg/d), or placebo for eight weeks.10 Subjects with moderate depression (ICD-10 definition with HAMD > 17) were enrolled by general practitioners. SJW improved the mean HAMD score significantly more than placebo (-15.4 vs. -12.1) and to a similar extent as imipramine (-15.4 vs. -14.2). The trial had a high placebo response and only a trend to improvement of imipramine compared to placebo. The dose of SJW was higher than usual and the dose of imipramine was lower than recommended.
In an equivalence study, 324 subjects were randomized to SJW (250 mg bid) or imipramine (75 mg bid) for six weeks.11 Both treatments equally improved HAMD scores significantly over time (P = 0.20).
A recent French trial randomized 375 subjects to SJW (300 mg tid) or placebo for six weeks.12 This trial used DSM-IV criteria and baseline HAMD score was 21.9. SJW improved HAMD scores more than placebo (P = 0.037), and responder rates were higher with SJW (52.5% vs. 42.3%, P < 0.05). A subgroup analysis of less depressed vs. more depressed subjects showed that those with higher HAMD scores (22, i.e., more depressed) improved significantly while those with HAMD scores of 17-21 did not differ from placebo. This contradicts all the earlier German trials, which demonstrated benefit for SJW in mildly depressed subjects.
Clinical Studies—Negative U.S. Trials
In two U.S. trials, SJW failed to show a benefit over placebo. The Shelton trial compared SJW (300 mg tid) to placebo for eight weeks in 200 subjects.13 Although there was significant improvement over eight weeks in both arms, SJW was not better than placebo in primary outcomes. A criticism of this trial is that the enrolled subjects had chronic depression (duration of the current depressive disorder 2.3-2.7 years). However, those with a history of failing to respond to an antidepressant in the current episode or failing more than one trial of anti-depressants in the past were excluded.
The Duke trial compared SJW (300 mg tid titrated up to 1,500 mg/d), sertraline (50-100 mg/d), and placebo in 340 subjects over eight weeks.14 In the primary analysis, neither SJW nor sertraline improved depression scores more than placebo. In a secondary endpoint, sertraline was better than placebo.
Why these two U.S. trials were negative and more than 25 randomized controlled trials in Germany have shown positive benefits remains controversial. The U.S. trials were performed at academic sites while the German studies generally used community physician practices. Most German trials enrolled patients with mild-to-moderate depression but few used DSM-IV criteria. The U.S. trials trained all raters extensively and tested for reliability (e.g., scoring videotaped vignettes). The U.S. trials used a higher cut-off for the depression scores, potentially enrolling more depressed subjects. Yet the Philipp trial, which showed a benefit of SJW over placebo, had subjects with a similar baseline HAMD score (22.6) to the U.S. trials.10 Whether these or other systematic differences can explain the dichotomy of the results remains to be seen.
Trials of SJW vs. SSRIs
The several trials comparing SJW with fluoxetine or sertraline suggest these treatments to be equivalent (see Table 2 below). However, none of these trials included a placebo arm. The one U.S. trial was small and included a heterogeneous group of patients.15 The other trials included patients with mild depression. In one trial of elderly patients, the baseline HAMD scores were lower than in most trials, suggesting these subjects had very mild depression.16
Adverse Effects
A systematic review in 1998 of the adverse effects of SJW collected data from published trials and drug monitoring agencies in several European countries. Generally, SJW was well tolerated with mild side effects, most commonly gastrointestinal symptoms, dizziness/confusion, tiredness/sedation, and dry mouth.17
Photosensitivity has been seen in animals grazing on SJW. Hypericin has been confirmed as the cause of photosensitivity. In a Phase I study of pure hypericin in HIV-positive adults, phototoxicity occurred in 26 of 30 subjects and was severe in 11 of 23 subjects.18 The hypericin dose ranged from 0.25 mg/kg IV twice weekly to 0.5 mg/kg PO daily. In a 70-kg individual, the lower dose approximates 5 mg/d of hypericin. Lower doses were used in a Phase I study of oral pure hypericin in hepatitis C patients.19 Phototoxic reactions were still seen in five of 12 subjects receiving 0.05 mg/kg/d and in six of seven subjects receiving 0.10 mg/kg/d (equivalent to 3.5 mg/d and 7.0 mg/d in a 70-kg subject, respectively). One case of subacute polyneuropathy occurred on sun-exposed areas after four weeks of hypericum.20
Induction of hypomania and mania are known complications of antidepressant therapy. Well-described cases of hypericum precipitating hypomania and mania have been reported.21-24 There exists a report of cardiovascular collapse during anesthesia in a healthy 23-year-old woman who had been taking SJW for six months.25
Drug Interactions
The serotonin syndrome (mental status changes, tremor, autonomic instability, gastrointestinal upset, headache, myalgias, and motor restlessness) was seen in five elderly patients who started SJW while on stable doses of sertraline (four patients) and nefazodone (one patient).26 A similar interaction in younger patients with paroxetine has been reported.27 Reports of a serotonin-like syndrome in those taking SJW alone also have been seen.28
The growing reports of significant drug drug interactions with SJW have generated much concern (see Table 3 below). In all cases, SJW reduced the level of the second drug. Reports have noted reduced international normalized ratios in patients on chronic stable warfarin and breakthrough bleeding in women on oral contraceptives after starting SJW.29 The changes resolved with discontinuation of the supplement.
Further reports of interactions between oral contraceptives, warfarin, digoxin, and theophylline were summarized by Ernst.30 These cases suggest that SJW causes the induction of hepatic cytochrome P450 enzymes, which results in more rapid clearing of the drug. Human studies now confirm selective induction of the cytochrome P450 3A4 activity by SJW.31 Hyperforin activates the pregnane X receptor, which activates hepatic cytochrome 3A4 activity. In addition, evidence suggests that SJW also induces the intestinal transport protein P-glycoprotein, which may further lower plasma levels of drugs.
The risk of rejection in transplant patients due to lowered levels of cyclosporin when combined with SJW is well documented. An early report of two cardiac transplant patients who developed rejection after starting hypericum32 has been followed by multiple reports involving kidney, cardiac, liver, and pancreas transplants.
St. John’s wort will lower the level of antiretroviral medications used for HIV infection. An open-labeled study measured the interaction between hypericum and indinavir, a protease inhibitor (PI), in eight healthy male subjects.33 The mean indinavir serum level at eight hours after dosing fell 10-fold (0.493 vs. 0.048 mg/mL, P = 0.027). This report resulted in the release of an FDA health advisory letter in February 2000. Clearance of nevirapine, a nonnucleoside reverse transcriptor inhibitor (NNRTI), was increased when taken with SJW.34 Other PIs and NNRTIs may be similarly affected.
Dosage and Formulation
Most studies have used 300 mg given three times a day. But doses have ranged from 500 to 1,800 mg daily. Several standardized ethanol and methanol extracts exist. Most products were formulated to contain 0.3% hypericin providing 2.7 mg/d hypericin when 900 mg hypericum is taken. With the recent evidence supporting hyperforin as the active agent, some manufacturers are standardizing to this ingredient (usually 2-5%).
The continuing problem of standardization and purity was seen in a study of eight SJW products purchased in Germany (two are available in the United States).35 The products were found to contain "widely differing amounts" of hypericin and hyperforin. Some even demonstrated pronounced interbatch variability.
Conclusion
Since the original meta-analyses supporting SJW, some new studies continue to show a benefit in the treatment of depression. Concerns with generalizability of these trials remain. Also, the two U.S. trials in well-defined patients with major depression did not show a benefit with SJW. Unfortunately, no studies six months or longer in well-defined subjects with standardized extracts have been published to determine long-term efficacy. Numerous herb-drug interactions and adverse events have been reported. The only comparative trial with an SSRI, which included a placebo control arm, did not show benefit.
Recommendation
Scant evidence is available to support SJW use in moderate-to-severe depression; SJW should be avoided in these patients. Although many trials show a benefit in patients with milder depression, concerns about the methodology and generalizability of these trials remain. For those who elect to use SJW in the care of their patients, careful review of this new information, including that of drug-drug interaction, is well advised.
Dr. Barrette is Assistant Professor in Medicine, Case Western Reserve University, School of Medicine, MetroHealth Medical Center, Cleveland, OH.
References
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