HYPERICUM PERFORATUM

See also section on "Depression"

I. Hypericum (aka "St. John's Wort")-contains at least 10 pharmacologically active consituents

1. Naphthodianthrons, e.g. hypericins, on whose content most preparations are standardized
2. Flavonoids, bioflavonoids, and xanthones

II. Data on effectiveness

1. Meta-analysis of randomized controlled (either vs. placebo or blinded vs. other antidepressants) trials in people with depressive disorders measuring outcomes on standardized depression scales or with self-reported sx (Lancet 313:253, 1996)

1. 23 trials

1. 20 trials were double-blind; 1 was single-blind; 2 were open
2. Tx periods ranged from 4-8 weeks
3. "Classification of depressive disorders was inconsistent"; most studies claiming pts had mild-mod depression
4. Used 7 different preparations of H. perforatum; total daily hypericin dose varied from 0.4-2.7mg (300-1000mg of total extract)
5. 17 used the Hamilton Depression Scale; 2 used the "Depression Status Inventory"; 2 used the "von Zerssen Adjective Mood Scale"; 2 didn't say how assessed outcomes

2. Results of H. perforatum vs. placebo trials (15 trials with 1008 pts)

1. Pooled response rates (e.g. score < 50% of baseline HDS) 55% with H. perforatum vs. 22% with placebo; stat. sig.

3. Results of H. perforatum vs. other antidepressant trials (5 trials with 579 pts)

1. Controlled with imipramine (1), amitriptyline (2), maprolitine (1); desipramine (1)
2. Two of these trials actually used a combination of H. perforatum and valerian root in the treatment groups
3. No sig. difference in response rates either in the H. perforatum alone vs. antidepressant trials or in the combination H. perforatum + valerian root vs. antidepressant trials (64% vs. 59% and 68% vs. 50%, respectively)

4. Data on adverse effects

1. Fewer dropouts in treatment vs. control groups or vs. antidepressant groups; no report on what side effects were
2. Accompanying editorial cites an open-label German study (J. Geriat. Psychiat. Neurol. 7 (suppl. 1): S34-8, 1994) which found most common side effects to be: 0.6% GI sx; 0.5% "allergic reactions" (?); 0.4% fatigue

2. Meta-analysis of 6 randomized trials, all 4-6wks in duration (J. Nerv. Ment. Dis. 187:532, 1999--JW)

1. Likelihood of clinical response sig. greater with H. perforatum than placebo (73% vs. 38%)
2. Likelihood of clinical response not sig. diff. between H. perforatum and tricyclic antidepressants (both 62%; though the latter in lower doses than commonly used to tx depression)

3. Individual trials comparing hypericum perforatum with placebo
   1. St. John's Wort 900-1200mg/d was no more effective than placebo in an 8-week randomized multicenter trial involving 200 outpts with major depression (JAMA 285:1978, 2001--JW)
   2. St. John's Wort 900-1500mg/d (0.12-0.28% hypericins; divided TID) had efficacy no different from placebo in a randomized trial of 340 pts with mod-severe depression (Hamilton Depression Scale > 19) over 24wk f/u.  Interestingly, Sertraline 50-100mg/d also was no better than placebo! (JAMA 287:1807, 2002--abst;AFP)
4. Individual trials comparing hypericum perforatum with other antidepressants
   1. 263 pts with moderate depression presenting to primary care practices randomized to hypericum extract 350mg TID, imipramine 100mg/d, or placebo. At 8wks, reduction of depressive sx in hypericum & imipramine groups were similar and both sig. better than placebo (BMJ 319:1534, 1999--JW)
   2. 324 pts with mild-mod depression randomized to hypericum vs. imipramine; at 6wks, mean decrease in scores on Hamilton Depression Scale was similar in both groups; no diff. between groups in clinician and pt ratings of global improvement; adverse effects noted in 39% of pts on hypericum and 63% of those on imipramine (BMJ 321:536, 2000--JW)
   3. In a study in 251 adults with major depression w/o psychotic features randomized to hypericum (extract WS 5570 standardized to 0.12-0.28% hypericins, 300mg TID) vs. paroxetine 20mg/d (either drug doubled at 2wks if no initial response), at 6wks, depression scores had decreased significantly more in the hypericum group; adverse effects were seen sig. less frequently in the hypericum group (55% vs. 76%) (BMJ 330:503, 2005--AFP)

II. Interactions with other drugs

1. May reduce serum levels of Protease Inhibitors
2. Decreases serum concentrations of cyclosporine
3. Decreases prothrombin time in pts on Warfarin
4. May reduce serum concentrations of Digoxin
5. Ass'd with "serotonin-syndrome"-like sx (MS changes, tremor, autonomic instability, HA, and motor restlessness) in pts on SRI's (Med. Lett. 42:56, 2000)
6. May reduce effectiveness of Combined Hormonal Contraceptives
   1. Acts as an inducer of CYP3A4, the hepatic enzyme responsible for the metabolism of estrogens and progestins found in oral contraceptives; 2 case reports of pregnancies in women on OCP's and St. John's Wort as of FDA alert 2/02)