Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity. Support was provided by a grant from the National Institutes of Health; National Center for Complementary and Alternative Medicine.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu
Herbal preparations for depression are often preferred over pharmaceutical drugs because they are available without prescription to patients as over-the-counter “natural” treatments, which they can use on their own. Moreover, because they are “natural,” these preparations are commonly assumed to be safe. St. John’s wort (SJW), one of the best-known and best-selling herbal therapies for depression, is obtained from the flowering tops of the perennial plant Hypericum perforatum. Similar to many anti-depressant drugs, SJW may affect monoamine oxidase activity and neurotransmitter reuptake and release (Nierenberg, Mischoulon, & DeCecco, 2002). Although available around the world, it is the most commonly used antidepressant therapy in Germany. Typical dosages are 900 mg to 1,800 mg per day, given in divided doses. Common side effects are nausea, constipation, dry mouth, headache, restlessness, tiredness, and dizziness. Photosensitivity can occur.
SJW for Major Depression
The earlier clinical trials in mild to moderate depression found SJW as effective as tricyclic antidepressant drugs and more effective than placebo (Linde & Mulrow, 2004). Most of these studies have been criticized for various methodological problems. Among the recent larger and better-designed studies, only two of four found SJW effective for major depression. Two European studies, enrolling patients with mildly to moderately severe major depression, found SJW to have a significant benefit (Kasper, Anghelescu, Szegedi, Dienel, & Kieser, 2006; Lecrubier, Clerc, Didi, & Kieser, 2002). By contrast, in two U.S. studies involving patients with more severe major depression, no significant benefit was found for SJW (Hypericum Depression Trial Study Group, 2002; Shelton et al., 2001). In an analysis of 29 randomized controlled trials of SJW for major depression, the available evidence suggested that SJW is superior to placebo, is similarly effective compared with conventional antidepressant drugs, and tends to have fewer side effects compared with antidepressant agents (Linde, Berner, & Kriston, 2008). The authors of this meta-analysis noted a large degree of heterogeneity among the placebo-controlled studies and that trials from German-speaking countries reported more favorable findings.
SJW for Minor Depression
Antidepressant studies with SJW have focused almost exclusively on patients with major depressive disorder, and the findings from these investigations have suggested that SJW may be more effective for mild major depression compared with severe major depression. On the basis of these findings, a 12-week efficacy and safety study comparing SJW, the selective serotonin reuptake inhibitor (SSRI) antidepressant citalopram (Celexa®), and placebo as treatment for minor depressive disorder was conducted at Massachusetts General Hospital in Boston, Cedars-Sinai Medical Center in Los Angeles, and the University of Pittsburgh (Howland et al., 2008; Nierenberg et al., 2010).
In this study, 29 participants were randomized to SJW, 27 to citalopram, and 25 to placebo. At baseline, the three groups did not differ with respect to most measures of symptom severity, quality of life, or psychological well-being. The main efficacy and safety outcomes from this study have not yet been published, but the three treatment conditions were equally effective in decreasing the symptoms of minor depression, improving quality of life, and improving well-being.
A structured interview for assessing adverse effects was used in the study. At baseline, prior to any type of compound being dispensed, nearly 60% of all participants endorsed symptoms that would be characterized as an adverse event. The mean number of symptoms endorsed at baseline were 5.7 for participants randomized to SJW, 4.7 for those randomized to placebo, and 4 for those randomized to citalopram. During the course of this study, 84.6% of the SJW group, 100% of the citalopram group, and 91.3% of the placebo group reported the development of or an exacerbation of adverse events. Thus, the vast majority of participants in this trial reported the presence of compound-induced adverse effects. Among the participants, 34.6% and 39.1% of the SJW and placebo group, respectively, reported clinically distressing side effects, while 60% of the citalopram group reported such effects. The adverse event profile of SJW was generally fairly benign, although participants taking SJW endorsed significantly more gastrointestinal and sleep problems than the placebo group. There were no differences in the reported reasons for discontinuation among the three groups, although 4 participants in the citalopram group discontinued due to side effects versus 2 in the placebo cohort and none in the SJW cohort.
This study was the first to directly compare a commonly used natural product with a commonly used SSRI antidepressant drug in patients with minor depression, a condition that is highly prevalent in nonpsychiatric primary care settings. Patients with minor depression may be treated by primary care practitioners with SSRI drugs, but these patients may also be likely to pursue self-treatment with nonprescription products such as SJW. The findings from this study suggest that neither SJW nor citalopram had a significant clinical or statistical effect when compared with placebo treatment for minor depression, although there were differences in tolerability, and SJW was not entirely benign.
SJW During Pregnancy and Breastfeeding
Depression is common in women in their childbearing years. With a significant proportion of unplanned pregnancies, exposure to SJW during pregnancy is expected to occur. Moretti, Maxson, Hanna, and Koren (2009) conducted a study to determine whether exposure to SJW in pregnancy was associated with major fetal malformations. The investigators prospectively collected and followed participants taking SJW and compared them with a matched group of pregnant women taking other medications for depression and to a group of healthy women who were not exposed to any known teratogens. For this study, follow-up information was collected on 54 SJW-exposed pregnancies and 108 pregnancies in the two comparator groups. The rates of major fetal malformations were similar among the three groups, with 5%, 4%, and 0% in the SJW, depression medication group, and healthy control group, respectively. These rates were not different than the 3% to 5% risk expected in the general population. The live birth and prematurity rates were also not different among the three groups. Although further large-scale studies are still needed, this first study on the effects of SJW in human pregnancy does provide some evidence of fetal safety.
The first report on SJW excretion into human milk showed that only one active component of SJW was detectable in breast milk, but no SJW components were detectable in the infant’s plasma (Klier, Schäfer, Schmid-Siegel, Lenz, & Mannel, 2002). In this case study, a mother with postnatal depression was taking a SJW preparation three times per day. Four breast milk samples during an 18-hour period were analyzed to measure the concentration of hypericin and hyperforin (two main active components of SJW). Hyperforin was excreted into breast milk at a low-level concentration, whereas hyperforin and hypericin were below the lower limit of quantification in the infant’s plasma. No side effects were observed in the mother or infant.
In another study, Klier et al. (2006) assessed 5 mothers who were taking a SJW preparation three times daily and their breastfed infants. During an 18-hour period, 36 breast milk samples were collected. Plasma samples from 5 mothers and 2 infants were analyzed for hyperforin concentrations. Hyperforin was found to be excreted into breast milk at low concentration levels, but it was at the limit of quantification in the two infants’ plasma samples. The milk-plasma ratios were very low (ranging from 0.04 to 0.13). The relative infant doses of 0.9% to 2.5% indicate that infant exposure to hyperforin through milk is comparable to the levels reported in most studies assessing antidepressant or neuroleptic drugs. No side effects were observed in the mothers or infants.
Lee, Minhas, Matsuda, Lam, and Ito (2003) investigated the safety of SJW in a group of nursing mothers and their infants. In this prospective, observational, cohort study, 33 breastfeeding women receiving SJW who contacted a teratogen/toxicant counseling service regarding the safety of SJW during breastfeeding were followed between May 1999 and April 2001. These women were compared with 101 women matched for disease and with 33 control-group healthy women matched for age and number of times they had given birth. Information collected included maternal and neonatal demographics, breastfeeding duration, use of SJW, maternal and infant adverse events, infant weight during the first year of life, and whether or not the mother experienced a decrease in lactation. No statistically significant differences were found in maternal or infant demographics or maternal adverse events. Only 1 infant in the disease-matched group and 1 infant in the non-disease control group were reported to be colicky. By contrast, there were two cases of “colic,” two of “drowsiness,” and one of “lethargy” in the SJW group. Three of these women in the SJW group consulted their physician, but specific medical treatment was not required. No significant difference was observed in the frequency of maternal report of decreased milk production among the groups, nor was a difference found in infant weight during the first year of life.
SJW Drug Interactions
Because SJW may affect monoamine oxidase activity and neurotransmitter reuptake and release, it should not be combined with antidepressant drugs or with other medications that would ordinarily be contraindicated with the use of monoamine oxidase inhibitor drugs (Nierenberg et al., 2002). SJW decreases some drug concentrations by inhibiting their absorption (e.g., iron, digoxin [Lanoxin®], cyclosporine [Sand-immune®]) or by increasing the activity of metabolic enzymes in the liver (e.g., warfarin [Coumadin®], theophylline [Theo-Dur®, Uniphyl®], oral contraceptives, HIV protease inhibitors).
A systematic literature search has concluded that there is sufficient evidence from interaction studies and case reports to suggest that SJW may induce the cytochrome P450 (CYP) 3A4 enzyme system and the P-glycoprotein drug transporter in a clinically relevant manner, thereby reducing the efficacy of co-administered medications (Mannel, 2004). The drugs most prominently affected by concomitant use with SJW are metabolized via both CYP3A4 and P-glycoprotein pathways, including HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, the immunosuppressant drugs cyclosporine and tacrolimus (Prograf®, Protopic®), and the antineoplastic agents irinotecan (Camptosar®) and imatinib mesylate (Gleevec®). The efficacy of hormonal contraceptives may be impaired, as reflected by case reports of irregular bleeding and unwanted pregnancies in women taking SJW. Drugs with a narrow therapeutic index should be monitored more closely when SJW is added, discontinued, or when the dosage is changed.
Many people, including older adults, children, and pregnant women, use herbal therapies such as SJW without consulting a health care professional (Crowe & Lyons, 2004; McKenzie & Keller, 2003; Nordeng & Havnen, 2005). As part of their direct care role, nurses should be familiar with the use of SJW, including its clinical efficacy, side effects, possible toxicity, and potential drug interactions.
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