Post hoc analysis of a comparative study - Hypericum as an effective antidepressant.

Numerous studies show that medicines based on St. John’s wort (Hypericum perforatum) are effective against depressive mood. The evidence base includes not only placebo comparisons, but also reference-controlled comparative studies. For example, a hyperforin-rich Hypericum preparation approved for use by health insurers was compared with the SSRI paroxetine, with the phytotherapeutic performing very well or even proving superior in reducing depressive symptoms in a subgroup analysis.

Already Paracelsus used St. John’s wort to treat depression, melancholy and overexcitability and also in modern evidence-based medicine this medicinal plant is part of the treatment spectrum. For example, last year the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments Taskforce (CANMAT) issued a clinical guideline for the use of medicinal plants (“phytoceuticals”) and food supplements (“nutraceuticals”) in the treatment of mental disorders [1]. In it, St. John’s wort was assigned a level of evidence A. An herbal antidepressant based on St. John’s wort (Hypericum perforatum) that can be used in adults with mild to moderate depressive disorders** is ^{Hyperiplant®}(^WS® 5570) [2].

** Other indications of this phyotherapeutic include depressed mood, lack of drive, mood lability, imbalance, nervous restlessness and tension states, and associated sleep disorders.

^WS® 5570 vs. paroxetine: original study

The evidence base on the efficacy of Hypericum in the treatment of depressive disorders has been successively expanded over the last two decades, and several secondary analyses and post-hoc analyses are available [3]. In a 2016 subgroup analysis published in the International Journal of Psychiatry in Clinical Practice [5], data from a double-blind, randomized phase III trial by Szegedi et al. 2005 used [4]. In the original study by Szegedi and colleagues, ^WS® 5570 was shown to be equivalent to paroxetine in the treatment of depressive disorders [4]. Namely, 251 patients with moderate or severe depression according to DSM IV received treatment with ^WS® 5570 (3 × 300 mg/d) or paroxetine (20 mg/d) for 6 weeks, followed by 16 weeks of maintenance therapy. Change in HAM-D total score was used as the primary end point. After 2 weeks, initial non-responders received a dose increase. The responder rate was higher under ^WS® 5570 than under paroxetine and the HAM-D manifested an advantage of >3 ^points$ in favor of the phytotherapeutic. In addition, ^WS® 5570 proved to be better tolerated compared to the SSRI.

^$ >3 points advantage in ^WS®5570 = clinical relevance criterion.

Results of the subgroup analysis

In the subgroup analysis published in 2016, the focus was on the effects of ^WS® 5570 on the subpopulation of patients with moderate depression [5]. The latter was defined as HAM-D ^score& between 22 and 25 at baseline. Data from the first and second parts of the original study (data collection before and after the interim analysis, respectively) were pooled. A total of 64 patients with moderate major depressive disorder were included, distributed between the two study arms as follows: ^WS® 5570 3 × 300 mg/d (n = 31) vs. paroxetine 20 mg/d (n = 33). Baseline HAM-D values were 23.1 in the hypericum group and 22.9 in the paroxetine group. This and the other patient characteristics at baseline are shown in Table 1 [5]. To compare the efficacy of the two study arms, HAM-D scores were analyzed during the active treatment phase (from baseline to weeks 7, 14, 28, and 42) by performing two-sided t tests. The proportion of study participants who responded to therapy or whose depressive disorder remitted was assessed using two-sided chi-square (χ2) tests. Changes in HAM-D scores over the course of the study are shown in Table 2 [5]. Significant improvements were observed in both groups during the six-week acute therapy. The mean reduction in HAM-D score at the measurement time points after Day 7 was significantly higher in the ^WS®5570 study arm than under paroxetine. This finding is an indication that ^WS® 5570 is superior to paroxetine in reducing the intensity of depressive symptoms, the authors summarize [5].

^& HAM-D=Hamilton Depression Rating Scale

A reduction in HAMD score of at least 50% (criterion for “response”) was achieved by 87.1% of patients on ^WS® 5570 versus 60.6% in the paroxetine group (Fig. 1) [5]. This difference between treatment groups proved to be statistically significant (p=0.017, chi-square (χ 2) test, two-sided). A reduction in the HAM-D score of at least 7 points after six weeks of treatment was considered remission. This was achieved by 71% in the paroxetine group and 42.4% of the paroxetine group (p=0.001, chi-square (χ 2) test, two-sided).

Hypericum also convinced in terms of tolerability

An antidepressant used over several weeks or months should not only be effective but also well tolerated. The results of the subgroup analysis attest the Hypericum preparation ^WS® 5570 a favorable safety profile [5]. During the treatment period, 6 of 31 patients in the Hypericum group reported a total of 15 suspected adverse drug-related (ADR) events, whereas in the paroxetine group, this affected 20 of the 33 study participants (a total of 61 ADRs). In the Hypericum group, gastrointestinal complaints, general disturbances of well-being, and disturbances of the nervous system each accounted for 3 events in 3 patients. In contrast, in the paroxetine group, 22 adverse events were reported in the gastrointestinal tract in 21 patients, and nervous system dysfunction occurred in 16 patients. Data suggest that ^WS® 5570 can be used for long-term treatment or relapse prevention after acute therapy without increasing the incidence of adverse side effects [4,9,10]. This is evident, among other things, from a study by Anghelescu et al. in which therapy with ^WS® 5570 was continued for a further 16 weeks after acute treatment [9].

What is known about the ingredients and their mechanisms of action?

Hypericum extract contains over 150 constituents, including hypericin, flavonoids, xanthones, and hyperforin [3]. It is believed that the antidepressant activity can be attributed mainly to hypericin and hyperforin. The mechanism of action is postulated to be reuptake inhibition of neurotransmitters in the central nervous system. In vitro studies show that hyperforin is a potent reuptake inhibitor of serotonin, dopamine, norepinephrine, GABA, and L-glutamate from the synaptic cleft [6,8]. Unlike synthetic antidepressants, which block 5-HT receptors, hyperforin appears to inhibit serotonin reuptake by increasing intracellular concentrations of sodium and calcium [7]. The sodium gradient between the nerve cell and the synaptic cleft decreases and the reuptake of monoaminergic neurotransmitters is reduced. ^WS® 5570 is generally better tolerated than synthetic antidepressants, but it is important to clarify potential drug interactions before treatment. Due to the enzyme induction of CYP3A4, interactions with HIV drugs, cytostatics and immunosuppressants in particular are possible. However, the interaction potential of oral contraceptives and anticoagulants should not be ignored either. With these points in mind, ^WS® 5570 is an evidence-based antidepressant that can be beneficially used for both acute and long-term treatment of mild to moderate depressive disorders.

Literature:

Sarris J, et al: Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry 2022; 23(6): 424-455.
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Seifritz E, Hatzinger M, Holsboer-Trachsler E: Efficacy of Hypericum extract ^WS® 5570 compared with paroxetine in patients with a moderate major depressive episode – a subgroup analysis. Int J Psychiatry Clin Pract 2016; 20(3): 126-132.
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Anghelescu IG, et al: Comparison of Hypericum extract WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study. Pharmacopsychiatry 2006; 39(6): 213-219.
Kasper S, et al: Better tolerability of St. John’s wort extract WS 5570 compared to treatment with SSRIs: a reanalysis of data from controlled clinical trials in acute major depression. Int Clin Psychopharmacol 2010; 25(4): 204-213.