Effective alternative to standard antidepressants

The efficacy of St. John’s wort extracts for mild to moderate depression has been demonstrated in studies. A subgroup analysis compared response to hypericum extract WS 5570 with response to paroxetine.

Depression is one of the most common diseases worldwide. To mitigate their consequences, it is important that patients receive effective, but also cost-effective therapies. The first generation of antidepressants were the TCAs (tricyclic antidepressants), which had strong anticholinergic side effects and were therefore largely superseded by the SSRIs (selective serotonin reuptake inhibitors). However, adverse reactions also occur with SSRIs, mainly headache, migraine, and gastrointestinal discomfort.

Main active ingredients of Hypericum identified

Similarly, extracts of St. John’s wort (Hypericum perforatum) have been used clinically for decades for mood disorders and are recommended by international guidelines [1]. Recent study results show efficacy and good tolerability in the treatment of major depression with mild to moderate symptoms [2–8].

More than 150 active and interacting constituents have been identified in Hypericum whole extracts, with mainly hyperforin, hypericin, flavonoids and bi-flavonoids contributing to the pharmacological effect [2]. However, the mechanisms of action of the numerous components have not yet been fully elucidated. Whereas it was previously assumed that hypericin was the main active ingredient, more recent studies show that it is mainly the phloroglucin derivative hyperforin that has an antidepressant effect [9,10]. Hypericin and hyperforin differ in their pharmacogenetic effects and are present in the plant in different concentrations.

It is now known that hyperforin is a potent reuptake inhibitor of serotonin, dopamine, norepinephrine, GABA and L-glutamate. According to recent studies, the antidepressant effect may arise by hyperforin affecting the sodium gradient, leading to inhibition of transmitter reuptake [9,11]. To obtain the full pharmacological effect of Hypericum, the interaction of hyperforin, hypericin, and as yet undefined flavonoids is important [9,10].

Safety profile similar to placebo

Double-blind randomized studies are available on Hypericum extract ^WS® 5570, which is standardized to hyperforin as well as hypericin, demonstrating its efficacy. ^WS® 5570 is particularly effective on core symptoms and is more effective than placebo and, as shown in non-inferiority studies, at least as effective as standard antidepressants (TCAs, SSRIs) [7, 11-14]. The safety profile of ^WS® 5570 is similar to placebo and it is better tolerated than standard antidepressants, although mild gastrointestinal disturbances and skin irritation may occur.

Another double-blind randomized non-inferiority trial by Szegedi et al. [15] compared the efficacy of hyperium extract ^WS® 5570 with paroxetine, an agent from the SSRI group. The authors conclude that ^WS® 5570 is at least as effective as paroxetine in treating moderate to severe depression (HAMD scale: ≥22). In addition, significantly higher response rates were observed with ^WS® 5570 than with paroxetine, and more of the patients treated with ^WS® 5570 were symptom-free after six weeks of acute treatment.

After a single-blind placebo run-in period of three to seven days, patients received either 3×300 mg ^WS® 5570 or 20 mg paroxetine per day for six weeks. The change in score on the HAMD scale was an indicator of treatment efficacy. Efficacy was assessed at 7, 14, 28, and 42 days (Fig. 1).

Additional gain through better response and remission results

Recently, a subgroup analysis on Szegedi’s study has now been published [16]. The subgroup studied was that of moderately depressed patients and the purpose was to test the hypothesis of whether ^WS® 5570 is an effective therapy in patients with moderate depression. The results confirm those of Szegedi. It was found that when treated for six weeks with ^WS® 5570, the decrease on the HAMD scale was significantly higher than when treated with paroxetine. Furthermore, the authors conclude that there is an additional gain with ^WS® 5570 due to better response and remission data compared to paroxetine (Fig. 2) . Previous studies in which patients were treated with differently formulated Hypericum extracts were able to demonstrate non-inferiority in terms of response rate. However, only ^WS® 5570 showed superiority over synthetic antidepressants in remission rates. [17-21].

Take-Home Messages

The efficacy and tolerability of Hypericum extracts in mild to moderate depression have been demonstrated in numerous studies. However, the effectiveness of St. John’s wort extracts may vary depending on their composition. Now a new subgroup analysis is available comparing the therapeutic response to the Hypericum extract ^WS® 5570 with the response to paroxetine, an agent from the SSRI group.

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