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Treating Depression with St. John’s Wort: Therapeutic Breakthrough or Hidden Hazard? Elisa Bailey, Alissa Basehoar, Jeannie Kim, Rozine Lindamood, Lauren Pearson, Justin Siegfried, Tiffany VanDervortClass of 2013 – School of Pharmacy – Virginia Commonwealth University Drug-Drug Interactions (Continued) Abstract Pharmacokinetics/Pharmacodynamics Treating Depression with St. John’s Wort (Continued) Depression is a prevalent disease affecting millions of people world-wide and alternative herbal medications are now being used more frequently as a result of lesser side effects. A comparison of St. John’s Wort, Hypericum perforatum, to seven other prescription medications showed similar efficacy with fewer adverse drug reactions. Hyperforin has been shown to be an uptake inhibitor of 5-hydroxytryptamine, dopamine, noradrenaline (norepinephrine), GABA and l-glutamate in synaptosomal preparations. A systematic review of current evidence concluded that Hypericum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants; however, a case report exists of an overdose of St. John's Wort in a patient requiring management in the intensive care unit. Overall, St. John’s Wort has a lot of evidence regarding drug interactions. This is an important piece of information, and with this, it is easier to make St. John’s Wort recommendations for those using it to treat depression. A comparison of the number of subjects reporting any adverse drug reaction (ADR) and the number of ADRs requiring discontinuation of treatment between SJW and standard antidepressants indicated that remarkably fewer events were reported for SJW. This result greatly favors SJW in terms of safety for treating depression. Pharmacokinetic data is available for several of the compounds present in St. John’s Wort, which may be considered responsible for its antidepressant action. The following table summarizes some of the pharmacokinetic values for these compounds. In February 2000, the FDA issued a public health advisory regarding the drug interaction between SJW and indinavir. Indinavir is a HIV-1 protease inhibitor that is metabolized by CYP3A4. In one study, it was shown that SJW reduced the area under the curve of indinavir by a mean of 57% (Piscitelli et. al). The mean concentration-time profiles of indinavir alone and SJW are shown in the accompanying figure. tmax is the time necessary to reach peak absorption, t1/2 is the time required for 50% elimination, and NR stands for not reported. Hyperforin is the only compound listed that has been shown to cross the blood brain barrier in animal studies. Hyperforin is believed to be responsible for St. John’s Wort’s ability to non-selectively block neurotransmitter reuptake. It is also believed to be responsible for the many drug-drug interactions because it activates human pregnane X receptor, leading to increased drug metabolism by cytochrome P450 3A4. Hyperforin was also shown to increase the activity of CYP 1A2 and 2C9. There is also limited evidence that hyperforin induces the P-glycoprotein efflux transporter. The two napthodiantrones present in St. John’s Wort are hypericin and pseudohypericin. Both of these compounds have low bioavailability due to their low water solubility. Hypericin treatment led to decreased plasma levels of adrenocorticotropic hormone and cortisol. High doses of hypericin can cause photosensitization to UV light, called hypericism. The main flavonoids found in hypericum perforatum are the monoglycosides: quercitrin, isoquercitin, and hyperoside; and the diglycoside rutin. The flavonoids undergo extensive Phase II metabolism in the intestinal wall releasing the aglycoside, quercetin. Quercetin exhibits a double peak plasma profile with the first peak appearing after 1.5 hours and the second, lower peak, after 9 hours. Studies show that flavonoids present in St. John’s Wort weakly inhibit monoamine oxidase. Introduction Depression is a common disease state that affects millions and often is under-diagnosed and under-treated on a global scale. The prevalence of the disease and the lack of diagnosis signify that there should be increased awareness of the symptoms associated with the disease and initiatives that can incorporate screenings for patients to properly diagnose depression. The World Health Organization has prompted initiatives in order to raise awareness of the disease and symptoms, which include feeling sad or worthless, loss of appetite, sleeplessness, and thoughts of suicide. From a pharmacologic perspective, depression can be caused from an imbalance of serotonin, noradrenaline (norepinephrine), and dopamine neurotransmitters. The first line drug treatments currently available include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. These types of antidepressants are helpful in managing the disease; however, unfavorable side effects and problems with medication adherence have resulted and alternative herbal medications have been implemented to treat the disease. St. John's Wort is the most influential and marketed herbal supplement for the treatment of depression. The plant is a member of the Hypericaceae family and is used to treat depressive disorders in many countries. The main active ingredient extracted from Hypericum perforatum is hypericin. The Hypericum perforatum extracts are proposed to have other significant constituents that could also be responsible for its pharmacologic effects. These constituents include thodiantrhons, flavonoids, bi-flavonoids, xanthons, and phloroglucinol derivatives. Conclusions Depression is a serious disease that affects a significant portion of the population. While there are several prescription medications available to treat depression, many suffer from severe adverse effects. Furthermore, seeking psychiatric evaluation and taking prescription antidepressants carries with it an undesirable stigma that may be severe enough to preclude some patients from seeking help. Therefore, an herbal remedy available over the counter to treat depression has great potential for helping thousands of patients. St. John’s Wort has long been known for its potential antidepressant effects. However, its efficacy and safety have been controversial. In this study, St. John’s Wort was found to be highly effective in treating major depressive disorders in comparison to placebo. The mechanism of action has been found to be due to the inhibition of monoamine oxidase and substance-P effects. Furthermore, many contradicting studies have been published that compare St. John’s Wort to prescription medications. In this study the efficacy of St. John’s Wort for treating depression compared with several other prescription medications indicated that the herbal preparation has similar effects. Perhaps more importantly, St. John’s Wort was found to have significantly fewer reports of adverse drug effects as compared to prescription antidepressants, especially those which were bad enough to force the termination of treatment. Unfortunately, St. John’s Wort suffers from its high tendency for drug-drug interactions. Given these results, we can conclude that St. John’s Wort may be a viable option for treating depression for those who do not prefer prescription medications, especially if the patient is not currently taking other medications with which St. John’s Wort may interfere. Toxicity/Side Effects A systematic review of current evidence concluded that Hypericum perforatum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants. The commonly experienced side effects are listed below: ,[object Object]

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