St. John’s wort is a proven traditional therapy option

In particular, the use of standardized St. John’s wort preparations has been shown to be effective for mild to moderate depressive symptoms, both for induction therapy and relapse prophylaxis. Based on the empirical evidence, the current S3 guideline recommends for the treatment of unipolar depression. Compliance is generally good, even in individuals who have some skepticism about antidepressants.

Depressive disorders are common, leading to significant impairment of physical and psychological well-being, as well as limitations in performance and a reduced quality of life [1]. According to the WHO forecast, depression will be one of the diseases with the greatest number of disability-adjusted life years (DALYs*) by 2030 [1,2]. The 1-year prevalence of unipolar depression is estimated to be 7.7% in the central European general population [1]. The leading symptoms are listlessness, joylessness and depressed mood. Many of those affected have reservations about side effects of conventional antidepressant medications [3]. For these patients, preparations based on a standardized St. John’s wort extract may represent a valid phytotherapeutic treatment alternative.

* The Disability-adjusted Life Years (DALYs) indicator captures the sum of years of life lost to disability or premature death due to disease [2].
 

St. John’s wort, its ingredients and the importance of hyperforin

St. John’s wort (Hyperici herba) is the dried, whole or crushed shoot tips of St. John’s wort perforatum L. of the Hypericaceae family, harvested during the flowering season. St. John’s wort extracts contain over 150 constituents, including naphthodianthrones (e.g., hypericin), flavonoids, bi-flavonoids, xanthones, and phloroglucinol (e.g., hyperforin) [4]. Thanks to comprehensive clinical and pharmacological studies, the mode of action of the individual ingredients can now be viewed in a more differentiated manner. For not only could many parallels between synthetic antidepressants and St. John’s wort extracts be uncovered. It has also been demonstrated that hypericin, flavonoids, and hyperforin, in particular, act at different targets and have different relevant effects  [5].

The antidepressant effects of St. John’s wort extract in therapeutically relevant doses have now been attributed mainly to the constituent hyperforin [5]. Among others, in an empirical study, hyperforin-rich St. John’s wort extracts showed significant superiority over hyperforin-poor extracts in reducing HAMD score compared with placebo in patients with an initial HAMD total score ≥22 (12 points vs. 6.6 points) [6]. Like synthetic antidepressants, hyperforin inhibits synaptosomal uptake of serotonin, norepinephrine, and dopamine, resulting in an increase in synaptic concentrations of these neurotransmitters [5,7]. Unlike other antidepressants, hyperforin inhibits synaptosomal uptake of neurotransmitters not by competitive binding to transporter molecules but by increasing intracellular sodium concentrations. This entails a reduction of the sodium gradient from extra- to intraneuronal. Since the sodium gradient is the driving force behind sodium-contransport-mediated transmitter uptake, hyperforin also reduces the uptake of other neurotransmitters such as GABA and L-glutatmat [5]. Furthermore, hyperforin induces increased synthesis of BDFN (brain derived neurotrophic factor), a marker of neurogenesis and a central aspect of the antidepressant pharmacological cascade [5]. Effects on neuroplasticity are now considered the major mechanism of action of antidepressants.

The ingredient hypericin is considered to affect the hypothalamic-pituitary-adrenal (HPA) axis. However, it penetrates the blood-brain barrier poorly, generating little incriminating data regarding antidepressant effects to date [5].

Flavonoids also contribute to the effect of the total extract. Animal models have demonstrated antidepressant properties for some of these ingredients. In addition, they play an important role as very potent antioxidants in reducing oxidative stress. This is increased in depression [5].

WS® 5570 is effective for mild to moderate depressive disorders.

The special extract WS® 5570 is obtained from St. John’s wort and is the basis of the preparation Hyperiplant® Rx, which is approved for use in Switzerland for mild to moderate depressive disorders. Several studies support the antidepressant efficacy of WS® 5570 [8]. According to a 2017 review published in the Journal of Affective Disorders, St. John’s wort has comparable efficacy and safety to SSRIs in patients with mild to moderate depressive disorders [9]. In a study published in 2016 by Seifritz et al. WS® 5570 even resulted in greater reductions in depression scores and superior response and remission rates compared to paroxetine 20 mg in patients with moderate depression after a treatment period of six weeks [8]. Moderate depression was defined as a baseline score of 22-25 on the Hamilton Depression Rating Scale (HAM-D). Patients received 3×300 mg/d WS® 5570 and in the comparison group paroxetine 20 mg/d. Under treatment with St. John’s wort extract, a remission rate of 64.5% was achieved after 6 weeks, which is a high value after this period. Because incomplete remission is a predictor of relapse, such high remission values should be weighted particularly heavily [10,11]. Further evidence for the antidepressant effects of WS® 5570 is provided by a meta-analysis by Kasper et al. [12] for use in the context of short-term therapies, as well as several studies on long-term perspective/maintenance therapy [13,14].

Guideline-based treatment for induction and maintenance therapy.

In long-term maintenance therapy, a pronounced prophylactic effect of WS® 5570 was observed both in patients with an early onset of depression and in patients with a high degree of chronicity [15]. Complete symptom remission and relapse prevention are noted as important treatment goals in the current S3 guideline on unipolar depression [1]. To achieve this, it is recommended to continue medication after successful response until remission with subsequent transition to maintenance therapy. The criterion for remission is a cut-off value of ≤8 points in the HAMD-17-item version [1]. Particularly in long-term therapy, it is important that medication is as free of side effects as possible to maintain adherence and compliance [10,15]. Study data indicate that compliance is generally higher in patients treated with St. John’s wort than with synthetic antidepressants; accordingly, drop-out rates are lower, which has a positive impact on the sustainability of therapeutic effects [8]. The positive benefits of St. John’s wort are also acknowledged in the S3 guidelines with the following recommendation: “If pharmacotherapy is being considered for mild or moderate depressive episodes, an initial attempt at therapy can also be made with St. John’s wort, provided that the specific side effects and interactions are taken into account.”

Good compatibility convinces

The tolerability profile of St. John’s wort extract is comparable to placebo and superior compared with synthetic antidepressants. Safety concerns are predominantly limited to the risk of interaction with other drugs. It is known from studies that activation of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-GP) is induced, which are involved in the metabolism of many drugs and can lead to an influence on the plasma levels of corresponding drugs [16]. The S3 guideline indicates that patients should be educated about the potential for interaction of St. John’s wort with other medications (including oral contraceptives, anticoagulants, and antiepileptic drugs) [8].

Source: Schwabe Pharma AG 
 

Literature:

1. DGPPN: S3-Leitlinie/Nationale Versorgungs-Leitlinie Unipolare Depression; Langfassung, 2. Auflage, 2015, Version 5 AWMF-Register-Nr.: nvl-005, www.awmf.org
2. World Health Organization (WHO). The global burden of disease. 2004 Update. Geneva: 2004, www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf
3. Kasper S, et al: Efficacy and tolerability of St. John’s wort extract for the treatment of mild to moderate depression. European Neuropsychopharmacology 2010; 20 (11) 747-765.
4. Linde K, et al: St John’s wort for major depression. Cochrane Database Syst Rev 2008;CD000448.
5. Müller WE, Schubert-Zsilavecz, Friedland K. The one difference. St. John’s wort preparations in the therapy of depression. DAZ 2020; 27:70-76.
6. Laakmann G, et al: St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 1998; 31(Suppl. 1): 54-59.
7. Muller WE: Current St John’s wort research from mode of action to clinical efficacy. Pharmacol Res 2003; 47(2): 101-109.
8. Seifritz E, Hatzinger M, Holsboer-Trachsler E: Efficacy of St. John’s wort extract WSVR 5570 compared with paroxetine in patients with a moderate major depressive episode – a subgroup analysis. International Journal of Psychiatry in clinical practice 2016; 20(3): 126-132.
9. Ng QX, et al: Clinical use of St. John’s wort perforatum in depression: A meta-analysis. Journal of Affective Disorders Volume 210, 1 March 2017, Pages 211-221.
10. 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.
11. Mendlewicz J: Towards achieving remission in the treatment of depression. Dialogues Clin Neurosci 2008; 10(4): 371-375.
12. Kasper S, et al: Efficacy of St. John’s wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci 2008; 258(1): 59-63.
13. Kasper S, et al: Placebo Controlled Continuation Treatment with Hypericum Extract WS 5570 After Recovery from a Mild or Moderate Depressive Episode, Wiener Med Wochenschrift 2007; 157(13-14): 362-366.
14. Kasper S, et al: Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression – a double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol 2008; 18(11): 803-813.
15. 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.
16. Russo E, et al. : Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res 2014; 28(5): 643-655.

InFo NEUROLOGY & PSYCHIATRY 2020; 18(6): 38-39.