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St. John’s Wort

The antidepressant effects of St. John's wort are of public health importance not only because depressive illness represents a major public health problem, but also because of the increased popularity of botanical preparations. St. John's wort extracts offer an option for an inexpensive "over-the-counter" treatment for depression. This might be an advantage to a patient unwilling to seek medical attention for a mental disorder because of the stigma attached to a psychiatric diagnosis, but it might also confound the course and treatment of a condition requiring medical expertise.

Major depressive disorder (MDD) is a common disorder with an estimated life time prevalence of 15% in the United States. Depression is the main cause of suicide: about 70% of all suicides in the U.S. are attributed to untreated depression. It has been estimated that in the year 2020 suicide will be the tenth cause of death in the U.S. Studies suggest that at any given time, approximately 2 to 3 percent of the population is hospitalized or seriously impaired by affective illness. It has been estimated that approximately three times as many women as men are treated for depression. The cost of major depressive disorder has been estimated to exceed 50 billion dollars per year to the U.S. economy. In spite of an enormous research effort by a large number of investigators worldwide, using all the tools of contemporary biology, depression remains a severe common and complex human disease of high mortality and morbidity of unknown cause.

The cardinal biologic manifestations of MDD consist of alteration in the hypothalamic functions that influence food intake, libido, circadian rhythms, and the synthesis and release of hypothalamic neurohormones. Patients with MDD, with melancholic features, typically have decreased appetite, decreased sexual interest, early morning awakening, diurnal variation in mood, and endocrine abnormalities, such as hypogonadism, hyposomatotropism, and hypercortisolism. The most consistent finding in biologic psychiatry is that patients with MDD, with melancholic features, often have hypercortisolism, of a magnitude that at times resembles that seen in Cushing's disease.

Successful treatment of MDD with currently available therapeutic agents can be achieved only in about 65-70% of patients. Although many newly developed second generation antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) have reduced the risks of side effects in comparison to tricyclics (TCAs), they have made little impact on improving the effectiveness of treatment. Thousands of studies have been conducted to address the function of various neurotransmitter systems in order to explore the biologic basis of MDD. Nevertheless, existing models, including the monoamine hypothesis, do not explain the biology of depression. The search for new molecules and biological targets for antidepressant drug discovery remains a challenge for contemporary psychiatry. Moreover, such work is needed to understand the fundamental molecular mechanisms underlying depression and to point out new directions for treatment. The investigation of the mechanisms for the reported therapeutic activity of traditional herbal products, such as St. John's wort, may uncover new mechanisms and novel treatments for MDD and other CNS disorders in addition to establishing the mechanism of action of St. John’s wort.

Extracts of the plant Hypericum perforatum (popularly known as St. John's wort), a member of the Hypericaceae family, have been used as a medicinal herb for centuries, for a range of indications including depressive disorders. Several preparations containing St. John's wort are commercially available in Europe. Hypericum extracts are among the most widely used antidepressants in Germany, with a market share of more than 25% of all antidepressant prescriptions in 1997. Hypericum extracts contain varying degrees of six major natural product groups that may contribute to their pharmacological effects [naphthodianthrones (hypericin belongs to this group), acylphloroglucinols, flavonol glycosides (hyperforin belongs to this group), biflavones, proanthocyanidins, phenylpropanes, biflavones, proanthcyanidins, and phenylpropanes].

Most of the research on Hypericum perforatum has been performed in Germany and published in European journals. Several randomized clinical studies have shown that Hypericum perforatum extracts were significantly superior to placebo and similarly effective as standard antidepressants in the treatment of mild to moderately severe depression. The advantage of Hypericum perforatum over other antidepressants seems to result from its favorable side effect profile. The safety and lack of significant side effects have been demonstrated in clinical trials; the most commonly reported side effects were gastrointestinal irritations (0.06%), allergic reactions (0.5%), tiredness (0.4%), and restlessness (0.3%). In contrast, the most common adverse reactions associated with the use of conventional drug therapy are lethargy, sleepiness, impairments in concentration and memory, disorientation, impotence, confusion, dry mouth, and weight gain.

Despite the widespread use of Hypericum, the mechanisms of its antidepressant action remain largely unknown. There are many indicators that the effects of Hypericum perforatum in the brain are consistent with changes reported with known antidepressants. Pre-clinical studies suggest that Hypericum perforatum is effective in three major biochemical systems relevant for antidepressant activity: inhibition of the synaptic re-uptake systems for serotonin, noradrenaline and dopamine; it also produces monoamine re-inhibition and long-term changes in receptors. However, there is controversy as to the exact mechanism of action for the antidepressant effects of Hypericum perforatum. Although earlier studies claimed hypericin as the active constituent and demonstrated that hypericin inhibits monoamine oxidases (MAO A and MAO B), the enzymes largely responsible for the breakdown of noradrenaline and serotonin, later studies have debated whether hypericin is in fact the active constituent responsible for Hypericum's actions. Recent studies have claimed that hyperforin is the main antidepressant component of St. John's wort. The antidepressant property of hyperforin has been attributed to its capacity to increase the extracellular levels of the monoamines, such as dopamine, noradrenaline and serotonin, and glutamate in the synaptic cleft, probably as a consequence of reuptake inhibition. Therefore, it is possible that both hypericin and hyperforin have antidepressant properties; however, it is still unclear whether those are the only compounds that contribute to the antidepressant effects of Hypericum. Little is known about the effects of long-term administration of Hypericum, and about the effects of Hypericum perforatum at the molecular level (i.e. altering gene expression).

While Hypericum perforatum has been reported to have clinically significant antidepressant effects, the mechanism of action remains unclear. Until it is clear how this botanical works, further psychiatric research will be severely limited as will any attempts to standardize botanical dietary supplement preparations for use in mood disorders. The information we will obtain from studies on St. John’s wort at the UCLA Center for Dietary Supplement Research in Botanicals will help define the mechanism of the antidepressant actions of Hypericum perforatum, and to define the bioactive and/or marker compounds. Specifically, these studies will address the current controversy over whether the hyperforin and/or hypericin fractions are responsible for the effects we observe. It is important to remember that botanical dietary supplements likely work due to a combination of ingredients, so that a classical search for a single bioactive compound is unlikely to be successful.

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