St. John’s Wort for Depression
September 2000; Volume 3; 97-101
By E-P. Barrette, MD, FACP
St. john’s wort remains one of the top selling supplements with 1998 retail sales surpassing $140 million. Since St. John’s wort was last reviewed in this publication in January 1998,1 much new information concerning efficacy, adverse effects, and drug interactions has been learned. Some of these data are troubling and require reconsideration of usage.
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 St. John’s wort was reawakened in the mid-20th century. In 1984, the German Commission E published its first monograph supporting the use of this herb for "psychovegetative disturbances, depressive moods, anxiety, and/or nervous unrest."2
St. John’s wort continues to be the most widely prescribed anti-depressant in Germany, surpassing fluoxetine and other newer anti-depressants.
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 Hypericin, presumed to be the active component, varies from 0.06% to 0.75% depending on time of harvest and quality of the plants.
Mechanism of Action
Early evidence of a mechanism involving monoamine oxidase inhibition has not been seen in more recent studies. Since hypericin does not cross the blood-brain barrier, the proposed mechanism involves peripheral actions on serotonin and other receptors, modulation of corticotropin-releasing hormone levels, and other cytokines.
Recent data support hyperforin as a potential additional active component of St. John’s wort.5 Hyperforin has activity at serotonin, dopamine, and norepinephrine receptors in vitro. Since hyperforin, a phloroglucinol, and hypericin, a naphthodianthrone, are chemically unrelated and their plant content varies independently, this controversy may explain variations seen in effectiveness. Overall, no agreement exists on the active agents or the mechanism of action.
Clinical Evidence
In 1996, a meta-analysis published in BMJ supported the use of St. John’s wort for depression and generated much attention.6 The authors updated this meta-analysis in 1999 for the Cochrane library.7 All randomized trials comparing hypericum (alone or in combination with other herbal agents) to placebo or antidepressant medications in patients with depression were included.
A total of 2,291 patients were included in 27 studies. Twenty-four of 27 trials were double blind. However, six studies used a liquid preparation of hypericum, which has a distinctive taste and is difficult to blind. Standard definitions of treatment response were used. Many trials used more than one measurement, e.g., a Hamilton Depression Scale (HAM-D) score of < 10 or < 50% of the baseline score (n = 21) or "much improved" on the Clinical Global Impression Index (n = 16).
The results from 14 of the 17 trials comparing St. John’s wort to placebo were combined. St. John’s wort response rate was 56% while the placebo response rate was 25%. The pooled rate ratio confirmed a significant effect (2.47, 95% confidence interval [CI] 1.69, 3.61). Ten trials compared St. John’s wort to another active agent, either a tricyclic antidepressant (n = 8) or a benzodiazepine (n = 2). Pooling of responder rates from these trials suggested an equivalent response: mono-preparations rate ratio 1.01 (95% CI 0.87, 1.16); combination preparations rate ratio 1.52 (95% CI 0.78, 2.94). Similar results were obtained when the analysis was limited to the four trials with mono-preparations of hypericum vs. tricyclic antidepressants in patients with DSM-III defined major depression.
Since the publication of the 1999 meta-analysis, a new review and another meta-analysis have been published. The meta-analysis by Kim et al had more strict entry criteria than the Cochrane analysis.8 This meta-analysis combined the results of six studies already included in the Cochrane analysis. The rate ratio was 1.48 (95% CI 1.03, 1.92) favoring hypericum over placebo. Hypericum was equivalent to tricyclic anti- depressants. A systematic review of English language articles with rigorous criteria included eight studies.9 Gaster et al reported an increased absolute response rate from 23% to 55% with the use of hypericum compared to placebo. However, the response rates were from 6% to 18% lower when compared with tricyclic antidepressants.
Several recent trials have been published since the meta-analyses. Schrader et al enrolled 162 patients with mild-to-moderate depression (ICD-10 criteria) and compared 250 mg bid hypericum vs. placebo over six weeks.10 This randomized, double-blind trial demonstrated a 56% response rate with hypericum compared to 15% with placebo. A more recent multicenter randomized, double-blind trial compared 350 mg hypericum tid, 100 mg/d imipramine, and placebo.11 Two hundred sixty-three patients with moderate depression (ICD-10 definition with HAM-D > 17) were treated for eight weeks. Hypericum improved the mean HAM-D score significantly more than placebo (-15.4 vs. -12.1) and a similar amount to imipramine (-15.4 vs. -14.2). The improvement with imipramine when compared to placebo (67% vs. 63%) did not reach statistical significance.
The major criticisms of the trials published to date involve the treatment duration and the selection of subjects. All the trials ran from four to eight weeks with one exception of a 12-week poorly designed trial. A minority of studies used well-defined entry criteria, and most address only milder depression. The comparative trials with tricyclic antidepressants used doses lower than considered standard. Finally, the variety of commercially produced products makes comparisons difficult, because all the studies published to date were performed in Europe using European-produced supplements.
One recent trial comparing hypericum to a selective serotonin reuptake inhibitor (SSRI) has been published. This six-week trial comparing 800 mg/d hypericum to 20 mg/d fluoxetine enrolled 149 elderly subjects with mild-to-moderate depression.12 Improvement in the HAM-D score was similar with both treatments: St. John’s wort from 16.60 to 7.91, fluoxetine from 17.18 to 8.11.
Finally, only one trial has looked at severely depressed patients.13 In this six-week trial comparing twice the usual dose of St. John’s wort (600 mg tid) to imipramine (50 mg tid), the decrease in HAM-D scores was slightly greater with imipramine (26.1 to 13.4) than with St. John’s wort (25.3 to 14.4, P < 0.02).
Adverse Effects
In the Cochrane meta-analysis, dropouts and adverse effects were seen less often with hypericum than with standard antidepressants: dropouts 8.9% vs. 13.6%, any adverse effect 26.3% vs. 44.7%, respectively. A systematic review of the adverse effects of hypericum reported the total percentages of adverse effects caused by hypericum in trials comparing hypericum with tricyclic antidepressants: gastrointestinal symptoms (8.5%), dizziness/confusion (4.5%), tiredness/sedation (4.3%), and dry mouth (4.0%).14
Induction of hypomania is a known complication of antidepressant therapy. Recently, several well-described cases of hypericum-precipitated hypomania have been reported.15
In a phase 1 study of pure hypericin in HIV positive adults, phototoxicity occurred in 26 of 30 and was severe in 11 of 23.16 The dose of hypericin 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. One case of sub-acute polyneuropathy occurred on sun-exposed areas after four weeks of hypericum.17
Drug Interactions
Many drug-herb interactions have been reported. The serotonin syndrome was seen in five elderly patients who started hypericum while on stable doses of sertraline (four patients) and nefazodone (one patient).18 Similar interactions with paroxetine19 and trazodone20 have been reported.
Reports from Sweden have noted reduced international normalized ratio in patients on chronic stable warfarin and breakthrough bleeding in women on oral contraceptives after starting hypericum.21 The changes resolved with discontinuation of the supplement. Further
reports of interactions between oral contraceptives, warfarin, and theophylline were summarized by Ernst.22 Ernst also reviewed studies in healthy subjects demonstrating lower serum digoxin and phencoumarin levels with hypericum vs. placebo. These cases suggest induction of hepatic cytochrome P450 enzymes by hypericum, which then results in lower levels of the drug.
Two patients, 11 and 20 months post-cardiac transplantation, developed acute rejection three weeks after starting hypericum.23 In both cases, stable therapeutic serum cyclosporin levels became subtherapeutic after starting the supplement and returned to normal after discontinuation.
An open-labeled study measured the interaction between hypericum and indinavir, an antiretroviral agent, in eight healthy male subjects.24 The mean indinavir serum level at eight hours after dosing fell tenfold (0.493 vs. 0.048 µg/ml, P = 0.027). This report resulted in the release of a FDA health advisory on February 10, 2000.
Recent Regulation
In response to the FDA’s health advisory, the French health ministry reportedly banned the sales of all supplements and food products containing St. John’s wort in France.25 In addition, Japan, Belgium, Canada, and the UK have adopted regulations governing the labeling and sale of products containing St. John’s wort.
Formulation and Dosage
Most studies have used 300 mg tid. One study in patients with severe depression used 600 mg tid. Many European trials have used LI 160, a methanolic standardized extract. Several standardized ethanol extracts exist. Most products are formulated to contain 0.3% hypericin and provide 2.7 mg/d hypericin when 900 mg hypericum is taken. (See Table 1 for price comparison.)
| Table 1-Retail prices of SSRIs and St. John's wort | |||
| Drug/Botanical | Manufacturer | Formulation | Cost (30-day supply) |
| Prozac® (fluoxetine) | Eli Lilly and Co. | 20 mg | $68.88 |
| Paxil® (paroxetine) | SmithKline Beecham | 20 mg | $68.25 |
| Zoloft® (sertraline) | Pfizer | 50 mg | $61.12 |
| Celexa (citalopram HBr) | Forest Laboratories | 20 mg | $58.84 |
| St. John's Wort extract | Kira | 300 mg dried Hypericum perforatum special extract "LI 160" from upper parts of flower and leaves standardized to 0.3% hypericin |
$29.98 |
| Full Spectrum St. John's Wort |
GNC | 150 mg St. John's wort extract standardized to 0.3% hypericin |
$15.99 |
| St. John's Wort | Nature's Way | 300 mg St. John's wort dried extract (leaves and flowers), 100 mg rosemary leaves, 60 mg spirulina |
$14.99 |
| Centrum® Herbals St. John's Wort |
Whitehall-Robins Healthcare |
200 mg St. John's wort flowers and leaves standardized to contain 0.3% total hypericin compounds |
$5.49 |
| Source: Online mail-order firms | |||
Conclusion
Since the original meta-analyses supporting St. John’s wort, several new studies have shown a benefit in depression. Unfortunately, studies six months or longer in well-defined subjects with standardized extracts have not been published, and numerous herb-drug interactions have been described. The only comparative trial with an SSRI did not include a placebo arm and studied subjects with very mild symptoms. Fortunately, several U.S. trials, including a large NIH trial, are ongoing. Until these studies are published, exactly how to incorporate St. John’s wort into the care of depressed patients is not certain.
Recommendation
The recent cases of hypomania, serotonin syndrome, and the many drug-herb interactions that have been reported are very concerning. With the scant evidence available for moderate-to-severe depression, St. John’s wort should be avoided.
For those who elect to use hypericum in the care of their patients, careful review of this new information is well advised.
References
1. Hornig M. Hypericum (St. John’s wort) for treatment of depression. Altern Med Alert 1998;1:4-7.
2. Blumenthal M, ed. The Complete German Commission E Monographs. Boston, MA: Integrative Medicine Communications; 1998:214-215.
3. Schulz V, et al. Rational Phytotherapy: A Physicians’ Guide to Herbal Medicine. New York: Springer-Verlag; 1998:50-65.
4. Wagner H, Bladt S. Pharmaceutical quality of hypericum extracts. J Geriatr Psychiatry Neurol 1994;7(Suppl 1):S65-S68.
5. Chatterjee SS, et al. Hyperforin as a possible anti- depressant component of hypericum extracts. Life Sci 1998;63:499-510.
6. Linde K, et al. St. John’s wort for depression—an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-258.
7. Linde K, Mulrow CD. St. John’s wort for depression (Cochrane Review). In: The Cochrane Library. Oxford: Update Software; 1999: Issue 1.
8. Kim HL, et al. St. John’s wort for depression: A meta-analysis of well-defined clinical trials. J Nerv Ment Dis 1999;187:532-538.
9. Gaster B, Holroyd J. St John’s wort for depression: A systematic review. Arch Intern Med 2000;160:152-156.
10. Schrader E, et al. Hypericum treatment of mild- moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo- controlled, multicentre study. Human Psychopharmacology 1998;13:163-169.
11. Philipp M, et al. Hypericum extract versus imipramine or placebo in patients with moderate depression: Randomised multicentre study of treatment for eight weeks. BMJ 1999;319:1534-1539.
12. Harrer G, et al. Comparison of equivalence between the St. John’s wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 1999;49:289-296.
13. Vorbach EU, et al. Efficacy and tolerability of St. John’s wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997;30(Suppl 2):81-85.
14. Ernst E, et al. Adverse effects profile of the herbal antidepressant St. John’s wort (Hypericum perforatum L.) Eur J Clin Pharmacol 1998;54:589-594.
15. Moses EL, Mallinger AG. St. John’s Wort: Three cases of possible mania induction. J Clin Psychopharmacol 2000;20:115-117.
16. Gulick RM, et al. Phase 1 studies of hypericin, the active compound in St. John’s wort, as an antiretro- viral agent in HIV-infected adults. Ann Intern Med 1999;130:510-514.
17. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St. John’s wort. Lancet 1998;352:1121-1122.
18. Lantz MS, et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.
19. Gordon JB. SSRIs and St. John’s wort: Possible toxicity? Am Fam Physician 1998;57:950,953.
20. Demott K. St. John’s wort tied to serotonin syndrome. Clin Psychiatry News 1998;26:28.
21. Yue QY, et al. Safety of St. John’s wort. Lancet 2000;355:576-577.
22. Ernst E. Second thoughts about safety of St. John’s wort. Lancet 1999;354:2014-2016.
23. Ruschitzka F, et al. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000;355:548-549.
24. Piscitelli SC, et al. Indinavir concentrations and St. John’s wort. Lancet 2000;355;547-548.
25. Anderson K. Several countries issue restrictions on St. John’s wort. NNFA Today 2000;14:22.
September 2000; Volume 3; 97-101
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