Efficacy and tolerability of Hypericum extract for the ... - Livar.net

European Neuropsychopharmacology (2010) 20, 747–765 

REVIEW 

Efficacy and tolerability of Hypericum extract for the 

treatment of mild to moderate depression 

Siegfried Kasper a,1 , Filippo Caraci b,1 , Bruno Forti c , 

Filippo Drago b, ⁎, Eugenio Aguglia d 

a 

Department of General Psychiatry, Medical University of Wien, MUV, Austria 

b 

Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy 

c 

CSM, Belluno, Italy 

d 

Department of Clinical Psychiatry, University of Catania School of Medicine, Catania, Italy 

Received 13 May 2010; received in revised form 13 July 2010; accepted 20 July 2010 

KEYWORDS 

Depression; 

Hypericum; 

St. John's wort; 

Efficacy; 

Review 

1. Introduction 

Abstract 

Depression is a common condition in the general community 

and the most prevalent form of psychiatric morbidity, 

⁎ Corresponding author. Department of Experimental and Clinical 

Pharmacology, University of Catania Medical School, Viale A. Doria 6, 

95125 Catania, Italy. Tel.: +39 095 7384236; fax: +39 095 7384238. 

E-mail address: f.drago@unict.it (F. Drago). 

1 These authors equally contributed to this work. 

www.elsevier.com/locate/euroneuro 

Depression is a common condition in the community with a significant impact on affected 

individuals, their relatives and society. Many patients with depression do not seek treatment and 

are often concerned about the possible adverse effects of antidepressant drugs. Extract of 

Hypericum perforatum (St. John's wort) has long been recognized as a treatment for depression. 

Several published trials and meta-analyses have demonstrated the efficacy and tolerability of 

Hypericum extract for mild to moderate depression. Recent comparative trials of Hypericum 

extract and other antidepressants, including selective serotonin reuptake inhibitors (SSRIs), 

provide support for Hypericum extract efficacy. However, since the constituents of Hypericum 

extract differ between the individual manufacturers, the efficacy cannot be extrapolated from 

one extract to another. In this review, WS 5572, LI 160, WS 5570 and ZE 117 Hypericum extracts 

have been shown to be significantly more effective than placebo with at least similar efficacy and 

better tolerability compared to standard antidepressant drugs. 

© 2010 Elsevier B.V. and ECNP. All rights reserved. 

0924-977X/$ - see front matter © 2010 Elsevier B.V. and ECNP. All rights reserved. 

doi:10.1016/j.euroneuro.2010.07.005 

although figures depend on the population studied and 

diagnostic criteria used. Studies that employ Diagnostic and 

Statistical Manual of Mental Disorders, Fourth Edition (DSM- 

IV) criteria of major depression provide lower prevalence 

estimates than those that allow more self-reporting of 

depressive symptoms and less stringent diagnostic criteria 

(Battaglia et al., 2004; Mulsant and Ganguli, 1999; Olsen et 

al., 2004; Wilhelm et al., 2003). A large-scale survey of 5566 

individuals assessed using the modified-Mini-International 

Neuropsychiatric Interview (MINI) showed that the prevalence 

of major depression in Italy was 10.8% (Battaglia et al.,

748 S. Kasper et al. 

2004), a figure that corresponds with those from other 

epidemiological studies (Mulsant and Ganguli, 1999). However, 

the actual impact of such depressive disturbances is 

likely to be underestimated as patients may not be 

sufficiently severe to meet standard diagnostic criteria 

(Aguglia and Forti, 2001). 

One of the most important factors in treatment of mild to 

moderate depression is the tolerability of pharmacological 

therapy, since the majority of patients have to continue 

normal work activities (Sommer and Harrer, 1994). Side 

effects of psychoactive drugs, such as dependence and mood 

alterations, are often feared by patients, which is thought to 

lead to an overall low rate of acceptance of standard 

pharmacological treatment (Röder et al., 2004). Moreover, 

the presence of somatic symptoms in mild forms of 

depression may cause further problems with compliance 

because of the side effects of antidepressant therapy 

(Vorbach et al., 1994). Thus, treatment of patients with 

mild to moderate depression represents a particularly 

clinically challenging problem. 

Extracts of Hypericum perforatum, commonly called St. 

John's wort, have been used for centuries in herbal medicine 

and have been clinically studied since the early 1990s (Röder 

et al., 2004). Drugs based on Hypericum extract are widely 

employed in Europe and are gaining popularity in the United 

States (Kasper and Dienel, 2002; Lecrubier et al., 2002). 

Hypericum extract contains at least 10 active constituents 

that may contribute to its pharmacological effects (Wagner 

and Bladt, 1994). Components known, or suspected, to play a 

role in antidepressant activity include phloroglucines (e.g. 

hyperforin), naphthodianthrones (e.g. hypericin) and the 

flavonoids (e.g. quercitrin). Although the labeling of extracts 

indicates that several of the products studied should be 

pharmaceutically equivalent, dissolution under biorelevant 

conditions revealed that they have quite different release 

profilesandcannotbeconsideredswitchable(Westerhoff et 

al., 2002). Clinical evaluation and comparison of Hypericum 

extracts is problematic due to the differences in study design, 

inclusion criteria and extract used and, in many earlier 

studies, the Hypericum preparations are not adequately 

characterized. In some studies, the preparations are standardized 

by either their hypericin or hyperforin content or, 

occasionally, both. Although these individual substances alone 

have been shown to have antidepressant activity, the total 

extract appears to be more effective (Reichling et al., 2003). 

Some more recent studies use several active components or 

the whole extract to characterize a preparation. 

The mechanisms of action of Hypericum extract are not 

fully understood (Butterweck, 2003), although some authors 

have hypothesized that hyperforin is the main active principle 

responsible for the antidepressant activity (Mennini and 

Gobbi, 2004). The antidepressant activity of Hypericum 

extract has been demonstrated in different animal models 

of depression (Butterweck, 2003). Hypericum extracts can 

inhibit the synaptosomal uptake of noradrenaline, serotonin 

and GABA in a concentration-dependent manner (Butterweck, 

2003; Schrader, 2000). In particular it has been hypothesized 

that non-selective inhibition of monoamines occurs in part 

via modulation of Na + gradient membranes, with Hypericum 

extract causing sodium influx into the neuron, which finally 

leads to the release of intracellular calcium (Singer et al., 

1999; Marsh and Davies, 2002). In vivo studies have demon- 

strated that Hypericum extracts lead to a downregulation 

of β-adrenergic receptors (Butterweck, 2003), a common 

biochemical marker of antidepressant efficacy (Simbrey 

et al., 2004). Furthermore Hypericum extract is known 

to increase dopaminergic activity in the prefrontal cortex 

(Yoshitake et al., 2004). 

Stress and hypothalamic–pituitary–adrenal (HPA) axis 

abnormalities have a central role in the pathogenesis of 

depression, with an impaired negative feed-back of glucocorticoids 

on the activity of the HPA axis, which results in 

elevated cortisol levels (Krishnan and Nestler, 2008). H. 

perforatum significantly attenuated restraint stress-induced 

increases in plasma ACTH and corticosterone levels (Kumar 

et al., 2010; Grundmann et al., 2010; Butterweck and 

Schmidt, 2007). Studies in healthy male volunteers have 

found that Hypericum extracts can modulate salivary and 

serum cortisol levels (Franklin et al., 2006; Schule et al., 

2001). Further studies are needed to better understand the 

molecular mechanisms underlying the antidepressant activity 

of H. perforatum and the specific effects of the different 

Hypericum preparations. 

Much of the heterogeneity seen in Hypericum clinical trial 

data can be explained by the differences in extract 

preparation. The aim of this review is to examine clinical 

evidence related to the efficacy and tolerability of available 

Hypericum extracts for the treatment of depression of mild 

to moderate severity, and to compare the efficacy and 

tolerability of specific preparations of Hypericum extract 

with standard antidepressant drugs and allows individual 

extracts to be evaluated on a peer-extract basis. We will 

focus our attention on patients with mild to moderate 

depression which is the population most likely to benefit 

from Hypericum extract therapy due to the favourable 

tolerability profile. Relevant studies were selected from 

literature sourced using comprehensive Medline searches for 

articles on Hypericum extract from 1993 to the present using 

the following search terms: Hypericum, St. John's wort, 

Johanniskraut, Johanniskrautextrakt, and depression. Additional 

manual searches were also performed in the reference 

lists of published meta-analyses and randomized controlled 

trials identified in the literature search. Most active control 

studies in this review were designed to determine noninferiority 

with standard antidepressant treatment in terms 

of efficacy and to examine the tolerability of Hypericum 

extract in comparison to standard antidepressant drugs. 

2. Clinical evidence for efficacy and tolerability 

of Hypericum extract 

The clinical studies were selected for this review on the basis 

of the patients' baseline clinical status. Only studies of 

patients with mild to moderate depression were included. 

Mild to moderate depression is defined by a baseline 

Hamilton Depression Rating Scale (HAMD) score of 16–24 or 

mean HAMD score of 16–24 or by The Tenth Revision of the 

International Classification of Diseases and Related Health 

Problems (ICD-10), F32.0, F32.1, F33.0 and F33.1. 

Of the various extracts available, LI 160, with a hypericin 

content of 0.72–0.96 mg in a 900 mg dose, has been the most 

frequently studied. Other studies have used extracts WS 

5570, WS 5572, WS 5573, STEI300, ZE 117, psychotonin,

Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression 

esbericum, LoHyp-57, calmigen, STW3, and an unnamed 

extract from the Swiss Herbal Remedies Company, which 

have differing hypericin and hyperforin contents (Table 1). 

Clinical studies have been reviewed by the specific preparation 

of Hypericum extract used, to determine whether 

some extracts might have a greater antidepressant effect 

than others. 

2.1. Hypericum extract vs. placebo 

Numerous studies have compared the efficacy of Hypericum 

extract with placebo in patients with major depression 

(Hänsgen and Vesper, 1996; Hübner et al., 1994; Hypericum 

Depression Trial Study Group, 2002; Kalb et al., 2001; 

Table 1 Preparation details of Hypericum extracts used in clinical trials. 

Extract Daily dose (mg) Standardized 

hypericin content 

LI 160 900 (3×300) (Bjerkenstedt 

et al., 2005; Brenner et al., 

2000; Hänsgen and Vesper, 

1996; Harrer et al., 1994; 

Hubner et al., 1994; 

Hypericum Depression Trial 

Study Group, 2002; Shelton 

et al., 2001; Sommer and 

Harrer, 1994) 

WS 5570 900 (3×300) (Kasper et al., 

2004; Lecrubier et al., 2002) 

WS 5572 900 (3×300 (Kalb et al., 2001; 

Laakmann et al., 1998) or 

3×600 (Szegedi et al., 2005)) 

0.12–0.28% (Hypericum 

Depression Trial Study 

Group, 2002; Lecrubier 

et al., 2002) (0.72–0.96 mg 

in 900 mg/day dose) 

(Wheatley, 1997) 

0.12–0.28% (Lecrubier 

et al., 2002; Szegedi 

et al., 2005) 

Laakmann et al., 1998; Lecrubier et al., 2002; Lehrl and 

Woelk, 1993; Philipp et al., 1999; Schmidt and Sommer, 

1993; Schrader et al., 1998; Shelton et al., 2001; Sommer 

and Harrer, 1994; Witte et al., 1995; Kasper et al., 2006, 

2008a,b). A summary of these studies including responder 

rates is shown in Table 2. In the majority of studies, the 

responder rate is defined as the proportion of patients with a 

HAMD score of b10 at endpoint or a ≥50% reduction in HAMD 

score from baseline to endpoint. Studies comparing LI 160 

and placebo, all conducted in Germany, showed a significantly 

greater response with LI 160 vs. placebo. Two studies, 

both conducted in the US (Hypericum Depression Trial Study 

Group, 2002; Shelton et al., 2001), showed no significant 

difference between LI 160 and placebo. However, the 

greater severity of depression of the patients included in 

Standardized 

hyperforin content 

Preparation method 

Not stated Extracted by methanol 

80% w/w (drug to extract 

ratio 4–7:1) (Bjerkenstedt 

et al., 2005) 

3–6% (Lecrubier 

et al., 2002; 

Szegedi et al., 

2005) 

Not stated 5% (Laakmann 

et al., 1998) 

Extracted from Herba 

hyperici (drug to extract 

ratio 3–7:1) (Lecrubier 

et al., 2002; Szegedi 

et al., 2005) 

Not stated 

WS 5573 900 (3×300) Not stated 0.5% Not stated 

Psychotonin f 200–240 (Witte et al., 1995) Not stated Not stated Not stated 

ZE 117 500 (2×250) (Schrader, 2000; 0.2% (Woelk, 2000) or 0.5% Not stated Extracted by ethanol 50% 

Schrader et al., 1998; Woelk, (Schrader et al., 1998) 

w/w (drug to extract ratio 

2000) 

4–7:1) (Schrader, 2000; 

Woelk, 2000) 

STEI300 1050 (3 ×350) (Philipp 0.2–0.3% (Philipp et al., 2–3% (Philipp Extracted by ethanol 60% 

et al., 1999) 

1999) 

et al., 1999) w/w (Philipp et al., 1999) 

Esbericum 75–300 (1–4×75) (Shaper and Not stated Not stated Extracted by ethanol 60% 

Brummer, 2005) 


2.0–5.5:1) (Shaper and 

Brummer, 2005) 

LoHyp-57 800 (4×200) (Harrer et al., Not stated Not stated Extracted by ethanol 60% 

1999) 


5–7:1) 

Calmigen 300 (2×150) (Behnke 

et al., 2002) 

Not stated Not stated Not stated 

Unnamed extract 900 (3×300) (van Gurp 0.3% hypericin (note: the Not stated Not stated 

from Swiss et al., 2002) 

paper states “Hypericum 

Herbal 

content of 0.3%”) (van Gurp 

Remedies 

et al., 2002) 

STW3/Laif 600 612 (Gastpar et al., 2005) Not stated Not stated Not stated 

749

Table 2 Overview of design and response data from comparative studies of Hypericum extract for depression. 

Study Design Disease severity at baseline Hypericum extract (mg/day) Comparator Population 

(mg/day) 

a N Responders n/N (%) 

Hypericum Comparator 

Placebo as comparator 

(Lehrl and Woelk, 1993) DB, R HAMD mean 22.7 LI 160 (900) Placebo ITT/EP 50 4/25 (16.0) b 

2/25 (8.0) 

(Schmidt and Sommer, DB, R Mild to moderate LI 160 (dose not 

Placebo PP 60 (66.6) (26.7) 

1993) 

stated in abstract) 

(Hubner et al., 1994) DB, R, Mild: ICD-9 300.4, 

LI 160 (900) Placebo ITT 39 14/20 (70) 9/19 (47) 

SC 309.0; mean HAMD ~12 

(Sommer and Harrer, DB, R, Mild: ICD-9 300.4 and 

LI 160 (900) Placebo PP 89 

1994) 

MC 309.0; mean HAMD ~16 

c 

28/42 (67) 13/47 (28) 

(Hänsgen and Vesper, DB, R Moderate: HAMD 

LI 160 (900) Placebo EP 107 35/53 (66.0) 

1996) 

mean 20.7 

c 

12/54 (22.2) 

(Shelton et al., 2001) DB, R, Mild to moderate: HAMD LI 160 (900–1200) Placebo ITT 200 (all) 26/98 (26.5) 19/102 (18.6) 

MC 20–22 

109 (mild to 

moderate) 

20/59 (33.9) 11/50 (22) 

(Hypericum Depression DB, R, Mild, moderate and severe: LI 160 (900) Placebo EP 229 43/113 (38.1) 50/116 (43.1) 

Trial Study Group, 2002) MC HAMD ≥20, mean ~23 (77.6% 

mild to moderate, data are 

shown for the whole cohort 

since separate data for the 

mild to moderate subgroup 

were not provided) 

PP 166 39/82 (47.6) 47/84 (56) 

(Lecrubier et al., 2002) DB, R, HAMD 18–25, mean 

WS 5570 (900) Placebo ITT/EP 375 

MC HAMD 21.9 

e 

98/186 (52.7) 80/189 (42.3) 

(Laakmann et al., 1998) DB, R, Mild to moderate: mean WS 5572 (900) 

Placebo ITT 98 24/49 (49.0) 

MC HAMD ~20–21 

(WS 5572 only; not 

including the WS 

5573 group of the 

study, N=49) 

c 

16/49 (32.7) 

(Kalb et al., 2001) DB, R, Mild to moderate: mean WS 5572 (900) Placebo ITT 72 23/37 (62.1) 

MC HAMD ~20 

c 

15/35 (42.9) 

(Witte et al., 1995) DB, R Moderate: ICD-10 F32.1; Mean 

HAMD 23.6 

Psychotonin f. (200–240) Placebo EP 97 34/48 (70.8) c 

25/49 (51.0) 

(Schrader et al., 1998) DB, R, Mild to moderate: ICD-10 F32.0, ZE 117 (500) Placebo ITT 159 

MC F32.1; HAMD 16–24, mean ~20 

e 

45/80 (56.3) 12/79 (15.2) 

(Philipp et al., 1999) DB, R, Moderate: ICD-10 F32.1, F33.1 STEI 300 (1050) Placebo ITT 146 67/100 (67) 22/46 (47.8) 

MC 

EP 153 67/106 (63.2) 22/47 (46.8) 

(Kasper et al., 2006) DB, R Mild or moderate major WS 5570 (600–1200) Placebo PP 324 159/243 26/81 (31.1%) 

MC depressive episode: 

mean HAMD 22.8 

(65.4%) 

750 S. Kasper et al.

Placebo as comparator in long-term trial 

(Kasper et al., 2008b) DB, R 

MC 

Tricyclic as comparator 

(Vorbach et al., 1994) DB, R, 

MC 

(Harrer et al., 1994) DB, R, 

MC 

(Wheatley, 1997) DB, R, 

MC 

Recurrent episode of moderate 

major depression HAMD ≥20, 

mean ~23 

Depressive disorder according 

to DSM-III-R; mean HAMD ~20 

Moderate: ICD-10 F32.1; HAMD 

16–24, mean HAMD ~21 

(Bergmann et al., 1993) DB Mild to moderate: mean 

HAMD 15.6 

(Woelk, 2000) DB, R, Mild to moderate: mean 

MC HAMD 22.4 (mild N=189; 

moderate N=135) 

(Philipp et al., 1999) DB, R, Moderate: ICD-10 F32.1 

MC and F33.1 

SSRI as comparator 

(Brenner et al., 2000) DB, R Mild to moderate: HAMD ≥17, 

mean HAMD ~21 

(Hypericum Depression 

Trial Study Group, 2002) 

DB, R, 

MC 

(Harrer et al., 1999) DB, R, 

MC 

(Schrader, 2000) DB, R, 

MC 

WS 5570 (900) Placebo PP 426 Relapse rates 

51/282 (18.1%) 

LI 160 (900) Imipramine 

(75) 

LI 160 (900) Maprotiline 

(75) 

Mild to moderate: HAMD 17–24 LI 160 (900) Amitriptyline 

(75) 

Mild, moderate and severe: 

HAMD ≥20, mean ~23 (77.6% 

mild to moderate; data are 

shown for the whole cohort 

since separate data for the mild 

to moderate subgroup were not 

provided) 

Mild to moderate: ICD-10 F32.0 

and F32.1; mean HAMD ~17 

(mild N=72, moderate N=77) 

Mild to moderate: HAMD 16–24, 

mean HAMD ~20 

Esbericum (dose not stated) Amitriptyline 

(30) 

ZE 117 (500) Imipramine 

(150) 

STEI 300 (1050) Imipramine 

(100) 

LI 160 (900) Sertraline 

(75) 

LI 160 (900) Sertraline 

(50) 

LoHyp-57 (800) Fluoxetine 

(20) 

ZE 117 (500) Fluoxetine 

(20) 

Relapse rates 

37/144 (25.7%) 

ITT 135 42/67 (62.7) 37/68 (54.4) 

PP 130 54/66 (81.8) 40/64 (62.5) 

EP 102 27/51 (53) 28/51 (55) 

PP 86 27/44 (61) 28/42 (67) 

ITT 156 40/87 (46) 42/78 (53.9) 

PP 121 40/67 (59.7) 42/54 (77.8) 

EP 80 32/40 (80) c 

28/40 (70) 

EP 324 e 

68/157 (43.2) 67/167 (40.1) 

ITT 205 67/100 (67) 66/105 (62.9) 

EP 216 76/106 (71.7) 70/110 (63.6) 

ITT 28 7/13 (54) 6/15 (40) 

EP 30 7/15 (46.7) 6/15 (40) 

ITT 222 43/113 (38.1) 53/109 (48.6) 

EP 224 46/113 (40.7) 55/111 (49.5) 

PP 161 39/82 (47.6) 48/79 (61) 

ITT 149 (all) 50/70 (71.4) 57/79 (72.2) 

72 (mild) 27/33 (81.8) 30/39 (76.9) 

77 (moderate) 23/37 (62.2) 27/40 (67.5) 

EP 161 (all) 50/77 (64.9) 57/84 (67.8) 

ITT 240 f 

75/126 (60) 45/114 (40) 

(continued on next page) 


751

Table 2 (continued) 

Study Design Disease severity at baseline Hypericum extract (mg/day) Comparator 

(mg/day) 

SSRI as Comparator 

(Behnke et al., 2002) DB, R, 

MC 

(van Gurp et al., 2002) DB, R, 

MC 

(Gastpar et al., 2005) DB, R, 

MC 

(Szegedi et al., 2005) DB, R, 

MC 

Mild to moderate: mean HAMD Calmigen (300) Fluoxetine 

~20–21 

(40) 

HAMD ≥16, mean HAMD ~19 Swiss Herbal Remedies (900– Sertraline 

1800) 

(50–100) 

Moderate: ICD-10 F32.1, F33.1; STW3/Laif 600 (612) Sertraline 

HAMD 20–24, mean HAMD ~22 

(50) 

Moderate to severe: HAMD ≥22, 

mean HAMD 25.5 (44% had 

moderate depression, HAMD 

22–24 but data are shown for 

the whole cohort since separate 

data for the moderate subgroup 

were not provided) 

(Bjerkenstedt et al., 2005) DB, R, Mild to moderate major 

depressive disorder DSM-IV 

Mean HAMD ~24–25 

(Fava et al., 2005) DB, R, 

MC 

Mild to moderate major 


HAMD score (17 items) Mean 

HAMD ~22 

(Moreno et al., 2006) DB, R, Mild to moderate major 


HAMD score 14–17 

(Gastpar et al., 2006) DB, R, 

MC 

Moderate depression: ICD-10 

F32.1, F33.1 mean HAMD ~22 

WS 5570 (900–1800) Paroxetine 

(20–40) 

LI 160 (900) Fluoxetine 

(20) 

Placebo 

LI 160 (900) Fluoxetine 

(20) 

Placebo 

Hypericum extract Iperisan 

3×1 (900 mg) 

Fluoxetine 

(20) 

Placebo 

STW3-VI (900) Citalopram 

(20) 

Placebo 

Population a N Responders n/N (%) 

Hypericum Comparator 

ITT 70 16/35 (45.7) c 

EP 90 a 

20/45 (44.5) c 

21/35 (60.0) 

22/45 (48.9) 

PP 

(12 weeks) 

70/102 (68.6) 69/98 (73.5) 

24 weeks 161 68/81 (84.0) 65/80 (81.3) 

ITT 244 d 

86/122 (70.5) 73/122 (59.8) 

200 d 

ITT 163 22/54 (40.7%) Fluoxetine 

20/54 (37%) 

Placebo 

21/55 (38.1%) 

ITT 135 17/45 (37.7%) Fluoxetine 

14/47 (29.8%) 

Placebo 

9/43 (20.9%) 

ITT 66 4/20 (20%) Fluoxetine 

11/20 (55%) 

Placebo 

11/26 (42.3%) 

PP 

(12 weeks) 

388 71/131 (54.2%) Citalopram 

71/127 (55.9%) 

Placebo 

51/130 (39.2%) 

a ITT/EP/PP data are presented where available; b Data are taken from the review of Linde et al. (2005a,b); c ITT data were not reported; d PP data not reported; e The PP analysis (data not 

reported) was undertaken and yielded similar results to the ITT analysis; f The ITT analysis (data not reported) was undertaken and yielded similar results to the PP analysis. DB = double-blind; 

EP = evaluable patients (safety analysis population); HAMD = Hamilton Depression Rating Scale; ITT = intention to treat population; MC = multicenter; NS = not significant, pN0.05; PP = per 

protocol (protocol compliant) population; R = randomized. 

752 S. Kasper et al.


these studies limits the generalization of these findings; 

whereas many other well designed studies have demonstrated 

positive results for Hypericum extract in mild depression 

patients. 

Of the other placebo-controlled studies, two, using 

extract WS 5572, showed a significant response compared 

with placebo (Kalb et al., 2001; Laakmann et al., 1998) and, 

in a large study, WS 5570 extract was shown to be 

significantly more effective than placebo (Lecrubier et al., 

2002). Findings from a study comparing two Hypericum 

extracts with different concentrations of hyperforin (WS 

5572, 5% and WS 5573, 0.5%) suggest that the efficacy of 

Hypericum extract in mild to moderate depression might 

depend on the hyperforin content (Laakmann et al., 1998). 

A double-blind, randomized, placebo-controlled, multicenter 

clinical trial (Kasper et al., 2006) has demonstrated 

the superior antidepressant efficacy of WS 5570 600 mg/day 

(in one dose) and of WS 5570 1200 mg/day (in two daily 

doses) compared to placebo in the treatment of patients 

with a mild or moderate major depressive episode after 

6 weeks of treatment. Interestingly the primary outcome 

measure, the HAMD total score change vs. baseline after 

6 weeks, indicates no significative differences in efficacy 

between WS 5570 600 mg/day and 1200 mg/day, although 

the number of patients who experienced remission was 

higher in the WS 5570 1200 mg/day group than the WS 5570 

600 mg/day group. 

The antidepressant efficacy of Hypericum extracts has 

been studied in different controlled clinical trials performed 

in patients with mild or moderate, or with moderate or 

severe depression. No studies have been specifically conducted 

in mild depression patients. In view of the high 

response rate normally seen in mild depression, the efficacy 

of Hypericum extracts in this subtype of depression has been 

questioned, also considering the large and unpredictable 

response to placebo. 

Interestingly a recent sub-analysis of data from three 

different controlled clinical trials has clearly shown that St. 

John's wort extract WS 5570 has a significant beneficial 

effect during acute treatment of patients suffering from mild 

depression (Kasper et al., 2008a). A subgroup of 217 patients 

with a pre-treatment total score ≤20 points on the 17-item 

HAMD was selected for the sub-analysis from a total of more 

than 1200 patients included into these trials. The rates of 

responders (i.e., patients with a HAMD total score decrease 

≥50%) were 73%, 64%, 71%, and 37% for WS 5570 600 mg/day, 

900 mg/day and 1200 mg/day, and placebo, respectively. 

These data suggest that Hypericum extracts, compared to 

placebo, were significantly able to reduce depression 

severity in mild depressed patients. Furthermore this study 

shows that treatment with WS 5570 leads to a substantial 

increase in the probability of remission within 6 weeks of 

treatment (Kasper et al., 2008a). 

Continuing treatment with antidepressant drugs has been 

considered as the most accepted strategy to prevent relapse 

in major depression (Geddes et al., 2003). Different trials 

have investigated the efficacy of antidepressant drugs in the 

short-term treatment of an acute episode, whereas a paucity 

of methodologically adequate studies have analyzed the 

effect of such drugs during long-term prophylaxis (Fava et 

al., 2003). Interestingly recent studies have been performed 

to assess the long-term efficacy and safety of Hypericum 

753 

extracts in treatment of depression. (Kasper et al., 2004, 

2007, 2008b). 

A double-blind, randomized, placebo-controlled trial 

has also been recently conducted to analyze the prophylactic 

efficacy and safety of Hypericum extract WS 5570 

900 mg/day (3–6% hyperforin) compared to placebo in 

preventing relapse during 6 months' continuation treatment 

and 12 months' long-term maintenance treatment 

after recovery from an episode of recurrent depression 

(Kasper et al., 2004, 2008b). Patients who continued 

treatment with WS 5570 were at a 30% lower risk of relapse 

during the first six months than those in whom the 

antidepressant medication was replaced by placebo after 

recovery from the acute episode. Interestingly, the 

prophylactic effect of WS 5570 during long-term maintenance 

treatment was particularly pronounced in patients 

with an early onset and consequently with a more 

extended history of depression. Furthermore the tolerability 

of WS 5570 in long-term maintenance treatment was 

on the placebo level (Kasper et al., 2008b). 

Placebo-controlled studies showed Hypericum extracts 

to be well tolerated with no noticeable differences 

between Hypericum preparations. Typically, adverse 

events were reported at incidences similar to placebo. 

Schmidt and Sommer (1993) specifically assessed cognitive 

effects and reported that no impairment of any cognitive 

functions occurred. In an LI 160 study, no notable side 

effects were reported in either group (Sommer and Harrer, 

1994). In the ZE 117 study by Schrader et al. (1998) 

adverse events, similar in both groups, were described as 

transient, self-limiting and, in the case of ZE 117, mainly 

non-specific gastrointestinal complaints. A placebo-controlled 

study showed a greater incidence of specific 

adverse events with Hypericum extract vs. placebo 

(Hypericum Depression Trial Study Group, 2002). However, 

these events were mild in severity and thought to be due 

to spurious associations created in the analysis process. In 

an LI 160 study by Shelton et al. (2001) LI 160 was well 

tolerated; only headache was reported in more patients 

taking LI 160 than placebo: in 39/95 (41%) and 25/100 

(25%), respectively (p =0.02). 

2.2. Hypericum extract vs. tricyclic antidepressants 

A number of studies have compared Hypericum extracts with 

the older tricyclic antidepressants for depression and shown 

them to be at least as effective and better tolerated than 

tricyclics (Table 2) (Bergmann et al., 1993; Harrer et al., 

1994; Philipp et al., 1999; Vorbach et al., 1994; Wheatley, 

1997; Woelk, 2000). 

In a double-blind study comparing Hypericum extract LI 

160 was as effective as maprotiline in reducing HAMD score at 

4 weeks and the responder rates were similar (61% and 67% 

for LI 160 and maprotiline, respectively, based on the perprotocol 

analysis). A higher proportion of patients experienced 

adverse events in the maprotiline group (13 [25%] and 

18 [35%] with LI 160 and maprotiline, respectively) (Harrer 

et al., 1994). Increased tiredness, dryness of the mouth and 

cardiac complaints were more commonly reported with 

maprotiline than with LI 160. In a 6-week, double-blind study 

comparing Hypericum extract LI 160 with imipramine


(Vorbach et al., 1994), patients treated with LI 160 (N=67) 

showed a reduction in HAMD score from 20.2 to 8.8, similar to 

that seen in the imipramine-treated group (from 19.4 to 

10.7; N=68); both significant reductions from baseline 

(pb0.001). Interestingly, in a subgroup analysis of patients 

with a baseline mean HAMD score ≥21, LI 160 (N=26) was 

significantly more effective than imipramine (N=25) in terms 

of HAMD and Clinical Global Impression (CGI) severity 

reduction (pb.05). Patients receiving LI 160 had a lower 

frequency and severity of adverse effects compared with 

imipramine. 

One criticism made of the above study (Vorbach et al., 

1994) was that the interpretation of similar efficacy was not 

based on an adequately a priori planned statistical hypothesis. 

This shortcoming was addressed in another LI 160 study 

using amitriptyline as the chosen comparator (Wheatley, 

1997). Patients were randomized to receive Hypericum 

extract LI 160 (N=87) or amitriptyline (N=78). At 6 weeks, 

the responder rate was statistically similar in both treatment 

groups (p=.064; per=protocol analysis), and adverse effects 

were reported significantly less frequently among LI 160treated 

patients (37% vs. 64% for amitriptyline; p≤0.05) with 

the most common side effect in the amitriptyline group being 

dry mouth and in the LI 160 group, headache. In total, 24% of 

patients discontinued treatment in the LI 160 group, 

compared with 31% with amitriptyline; the most common 

reason for discontinuation in both groups was adverse 

events. In a comparative trial, Hypericum extract ZE 117 

was at least as effective as imipramine (Woelk, 2000); the 

reduction in mean HAMD scores in patients receiving ZE 117 

was similar to imipramine at 6 weeks (12.00 and 12.75, for ZE 

117 and imipramine, respectively). Doses were chosen to 

avoid possible criticism from using overly low doses of 

synthetic antidepressants. Interestingly, at endpoint, the 

mean score on the anxiety-somatization subscale of the 

HAMD was significantly lower in the Hypericum extract group 

(3.79) than the imipramine group (4.26) (p=.03). As with LI 

160 in the previous study, Hypericum extract ZE 117 was 

significantly better tolerated than the tricyclic comparator 

(pb0.01): adverse effects were observed in 39% of patients 

given Hypericum extract and in 63% of patients administered 

imipramine, with 3% and 16% discontinuing treatment 

because of adverse events, respectively. 

The finding that Hypericum extract had an efficacy at 

least equal to that of imipramine confirmed data from an 

earlier study using Hypericum extract STEI 300; Philipp et al. 

(1999) carried out the first trial in which Hypericum extract 

was compared with tricyclic antidepressants and placebo. 

Patients were randomized to STEI 300, imipramine or 

placebo for 6 weeks followed by 2 weeks follow-up. STEI 

300 was significantly more effective than placebo and at 

least as effective as imipramine in terms of responder rate at 

6 weeks, and significant greater improvements in quality of 

life (using the SF-36 scale) were also observed with STEI 300 

vs. placebo. No safety concerns with STEI 300 were noted, 

with the most frequent adverse effect in the imipramine 

group being dry mouth (38% [13% with placebo]) and in the 

STEI 300 group, nausea (8% [2% with placebo]). 

In a meta-analysis by Röder et al. (2004), (N=1231) the 

mean responder rates were 55.0% for Hypericum extract and 

53.9% for tricyclic antidepressants (p=.13). The responder 

rate ratio [RR], defined as the ratio of the responder rates 

observed with comparator and Hypericum extract was 0.98 

(95% CI=0.87–1.10, p=.70) (Röder et al., 2004). The number 

of adverse events was significantly lower in patients 

administered Hypericum extract than those receiving tricyclics; 

the proportion of patients reporting adverse effects 

was 49.0% vs. 28.3% for tricyclics vs. Hypericum extract, 

respectively (pb.00001). Consequently, the frequency of 

therapeutic discontinuation was 3.6 times higher in patients 

treated with tricyclics than those treated with Hypericum 

extract. 

Overall studies suggest that Hypericum extracts, when 

compared to tricyclic antidepressants, demonstrate a similar 

efficacy and a more favourable side-effects profile. 

2.3. Hypericum extract vs. SSRIs 

There have been a number of comparative studies between 

Hypericum extract and SSRIs, with recent studies incorporating 

more rigorous methodology and greater patient 

numbers than earlier trials as with the other studies 

described (Table 2) (Behnke et al., 2002; Brenner et al., 

2000; Gastpar et al., 2005; Harrer et al., 1999; Hypericum 

Depression Trial Study Group, 2002; Schrader, 2000; Szegedi 

et al., 2005; van Gurp et al., 2002; Fava et al., 2005; 

Bjerkenstedt et al., 2005; Moreno et al., 2006; Gastpar et 

al., 2006; Papakostas et al., 2007). 

Several trials have compared Hypericum extract with 

sertraline. In a small preliminary study comparing Hypericum 

extract LI 160 with sertraline in 30 outpatients with mild to 

moderate depression (Brenner et al., 2000), a clinical 

response was seen in 54% of patients receiving LI 160 and 

40% of those receiving sertraline (p=NS, ITT analysis) and 

both treatments were well tolerated. In a randomized 

controlled trial in primary care, 90 patients with major 

depression (HAMD ≥16) were randomized to treatment with 

either sertraline (50–100 mg/day) or an unnamed Hypericum 

extract containing 0.3% hypericin (900–1800 mg/day) (van 

Gurp et al., 2002). Assessments were carried out at entry and 

at weeks 2, 4, 8 and 12. At week 12, Hypericum extract 

achieved similar improvements in HAMD and Beck Depression 

Inventory (BDI) scores to sertraline (18.9–9.4 and 19.5–12.1 

for Hypericum extract vs. 19.7–11.5 and 18.4–12.0 for 

sertraline, for HAMD and BDI respectively; p=NS). During the 

early stages of treatment, significantly more adverse effects 

were reported among sertraline-treated patients than 

among those receiving Hypericum extract. The authors 

concluded that Hypericum extract has a role as a first 

treatment option for mild to moderate depression in primary 

care settings. 

In another recent study, 123 patients with moderate 

depression (ICD-10 F32.1 or F33.1, HAMD 20 to 24) were 

randomized to Hypericum extract STW3 (612 mg) and 118 

patients to sertraline (50 mg) with approximately 100 

patients in each group being treated for a period of 

12 weeks followed by 12 weeks follow-up (Gastpar et al., 

2005). At 12 weeks, reductions in HAMD scores were similar 

between groups and responder rates were 68.6% and 73.5% 

for STW3 and sertraline, respectively (p value not stated, PP 

analysis). At 24 weeks, in the 161 patients who continued on 

treatment for the 12-week follow-up (81 patients receiving 

STW3 and 80 receiving sertraline), responder rates were


84.0% in STW3 recipients and 81.3% in the sertraline group (p 

value not stated). Overall, tolerability was deemed ‘good’ or 

‘very good’ in most patients (99.2% and 94.9% of patients 

with STW3 and sertraline, respectively). Adverse events 

attributed to study medication and discontinuations due to 

adverse events were more common with sertraline than 

STW3; treatment-related adverse events occurred in 12 

[9.8%] and 16 [13.6%] patients treated with STW3 and 

sertraline, respectively, with drug-related discontinuations 

seen in 5 (4.1%) and 10 (8.5%) patients, respectively. One of 

the strengths of this study is that the sample size was 

calculated to ensure adequate power to demonstrate the 

non-inferiority of STW3 compared with sertraline. 

In the Hypericum Depression Trial; neither Hypericum 

extract (LI 160; 900–1500 mg/day) nor sertraline (50– 

100 mg/day) were shown to have significantly greater effect 

on HAMD score or significantly greater responder rate (based 

on HAMD and CGI scores) than placebo (Hypericum Depression 

Trial Study Group, 2002). However, Linde et al. (2002) 

suggest that as patients had relatively long-term chronic 

depression, this lack of efficacy vs. placebo might be due in 

part to a high proportion of the patients being treatment 

resistant (Cott and Wisner, 2002; Linde et al., 2002; 

Wheatley, 2002). Since patients significantly related to the 

treatment arm to which they had been randomized, loss of 

blinding may have been another limitation of this study. 

Other authors have suggested that unsuitable outcome 

measures (Spielmans, 2002; Volp, 2002), and overoptimistic 

effect sizes are the cause of these unexpected findings 

(Linde et al., 2002). Adverse events reported at a significantly 

greater rate with sertraline than placebo and LI 160 

were diarrhoea, nausea, anorgasmia, and sweating. However, 

the authors note that these events, inconsistent with 

Hypericum's previously reported safety profile, were all 

mild, and multiple comparisons may have produced spurious 

associations. 

Several studies have compared Hypericum extract with 

fluoxetine. A study comparing Hypericum extract LoHyp-57 

800 mg/day and fluoxetine 20 mg/day was carried out in 161 

elderly patients with mild to moderate depressive episodes 

(ICD-10 F32.0 and F32.1) (Harrer et al., 1999). Efficacy in 

terms of improvement in HAMD score and responder rate was 

similar with Hypericum extract and SSRI. LoHyp-57 was 

better tolerated than fluoxetine with a total of 12 

undesirable events considered to be possibly or probably 

related to study drug observed in the LoHyp-57-treated 

group compared with 17 in the group treated with 

fluoxetine. 

In a similar comparative, randomized study in 240 

patients, Hypericum extract ZE 117 was at least as effective 

as fluoxetine for mild to moderate depression in terms of 

HAMD score reduction, and achieved a significantly greater 

responder rate (p=.005) and significantly greater improvements 

in CGI item 1 (p=.03) than fluoxetine (Schrader, 

2000). ZE 117 had a superior tolerability profile with a 

lower global incidence of adverse effects (14% vs. 25%, 

respectively; p b.07). No patients discontinued due to 

adverse events with ZE 117. In a study comparing the 

Hypericum extract calmigen with fluoxetine (Behnke et al., 

2002), both treatments were significantly effective with no 

differences between groups in any of the efficacy or 

tolerability endpoints. Other studies have compared 

755 

Hypericum extracts with fluoxetine (Fava et al., 2005; 

Bjerkenstedt et al., 2005; Moreno et al., 2006; Papakostas 

et al., 2007). 

Bjerkenstedt et al. (2005) conducted a 4-week, multicenter, 

double-blind, randomized controlled study comparing 

LI 160 900 mg/day and fluoxetine 20 mg/day in 163 

patients affected with mild to moderate depression. 

Unfortunately both active treatments failed to prove 

superiority over placebo regarding the primary efficacy 

measure, the HAMD total score reduction from baseline to 

4 weeks of treatment. The number of responders was not 

significantly different in the three groups (Table 2). Nevertheless, 

considering the stricter criterion of remission (final 

HAMD b8) to assess treatment success, both Hypericum (24%) 

and fluoxetine (28%) were significantly superior to placebo, 

but Hypericum was significantly better tolerated than 

fluoxetine. One of the limits of this study is the duration of 

treatment (4 weeks), which seems to be too short, considering 

that separation of active drug from placebo may 

require 6 and more weeks of treatment. 

Similar results have been observed in an 8-week doubleblind 

trial in patients with mild to moderate depression, 

assessing the efficacy and safety of H. perforatum in 

comparison with fluoxetine (Moreno et al., 2006). Outcome 

was monitored using the HAMD, Montgomery-Åsberg depression 

rating scale, CGI. The mean HAMD score was low 

compared to other studies (14–17) and only 66 patients 

completed the study. The authors found no differences 

between the groups regarding mean HAMD changes and the 

lowest response to treatment in the Hypericum group, when 

compared with both placebo and fluoxetine groups. The 

number of patients included in this study does not allow 

definitive conclusions due to the statistical power of the 

sample size. 

In a 12-week, randomized, active- and placebo-controlled, 

parallel-group, double-blind study Fava et al. 

(2005) have analyzed the efficacy and safety of H. 

perforatum (LI-160 900 mg/die) relative to both placebo 

and fluoxetine (20 mg/die) in a population of 135 outpatients 

with mild to moderately severe MDD. The primary efficacy 

end point for this study was the final HAMD-17 total score 

after 12 weeks of randomized treatment on end point. The 

mean HAMD score in the three groups was 19. Interestingly 

the authors found that St. John's wort treatment was 

associated with a significantly (Pb0.05) greater decrease in 

HAMD-17 scores compared with fluoxetine and showed a 

trend toward statistically significant superiority over placebo. 

An higher rate of remission (HAMD-17b8) was observed in 

the St. John's wort group (38%) compared with the fluoxetine 

group (30%) and the placebo group (21%). There were no 

adverse events related treatment discontinuations in the 

Hypericum group and placebo-treated patients, whereas 4% 

(2/47) of the fluoxetine-treated patients dropped out 

because of side effects. Surprisingly in this study fluoxetine 

lacked of efficacy and St. John's wort treatment was not 

significantly superior to placebo. The authors suggest that 

these data may be explained with the smaller than planned 

sample size. Recruitment was stopped before planned 

sample size was reached due to decision of the sponsor. 

Larger studies are therefore needed to fully compare the 

efficacy of H. perforatum vs. fluoxetine in the treatment of 

mild to moderate depression.


One of the most discussed issues in the field of antidepressant 

trial is the relationship between timing of clinical 

improvement and resolution of depressive symptoms during 

the treatment of major depressive disorder (Papakostas 

et al., 2007). Some authors have proposed that patients 

showing a significant symptom improvement during the first 

2 weeks of treatment, might not respond to antidepressant 

drugs per se, but they might have a ‘placebo’ pattern of 

response (Stewart et al., 1998; Nierenberg et al., 2004). On 

the contrary other authors have demonstrated that a clinical 

response during the first 2 weeks of treatment can highly 

predict a greater drug vs. placebo difference in depressive 

symptoms improvement at endpoint (Stassen et al., 1998; 

Szegedi et al., 2003). 

Along this line Papakostas et al. (2007) have examined 

data from the 39 responders of the above discussed 12-week 

double-blind study (Fava et al., 2005) comparing H. 

perforatum, fluoxetine or placebo (Papakostas et al., 

2007). The authors defined an early clinical response as a 

25% decrease in 17-item HDRS after 2 weeks and found that, 

among the 39 responders, earlier clinical improvement 

predicted lower HDRS-17 scores at week 12 in the patients 

treated with either fluoxetine or Hypericum, but not in 

placebo-treated patients. The small sample size of the study 

does not allow definitive conclusions and larger studies are 

needed to demonstrate that an early clinical improvement 

during treatment can predict a greater symptom resolution 

at endpoint in depressed patients responding to Hypericum 

or fluoxetine. 

Szegedi et al. (2005) conducted a well designed, 6-week, 

multicenter, double-blind, randomized controlled study 

comparing WS 5570 900 mg/day and paroxetine 20 mg/day 

in 251 patients affected with moderate to severe depression. 

This study has been thought worthy of inclusion in this review 

because it is the only study to compare Hypericum extract 

with paroxetine and, although patients had a more severe 

form of depression than the other studies reviewed, nearly 

half (44%) had a baseline HAMD of 22–24 (moderate 

depression). To avoid criticisms of inadequate dosing doses 

were increased to 1800 mg/day WS 5570 or 40 mg/day 

paroxetine if no response was observed within 2 weeks. 

Outcome was monitored using the HAMD, Montgomery- 

Åsberg depression rating scale, CGI, and BDI. After 

2 weeks, 57% and 48% of patients in the WS 5570 and 

paroxetine groups, respectively, were switched to the higher 

doses. Between baseline and day 42, the average reduction 

in the HAMD score was 14.4 (SD 8.8) for WS 5570 and 11.4 (SD 

8.6) for paroxetine (pb.01; ITT analysis). Fig. 1 shows the 

total HAMD scores over time in the intent-to-treat population. 

WS 5570 showed a numerically greater responder rate 

compared with paroxetine, although this did not reach 

significance (70.5% vs. 59.8%; p=.08). In addition, a greater 

proportion of patients treated with paroxetine reported 

adverse events. Data show that WS 5570 was at least as 

effective as SSRI even in patients with moderate depression 

with greater tolerability, and suggest that Hypericum 

extract is a valid alternative to more frequently prescribed 

antidepressants such as SSRIs. 

Finally Gastpar et al. (2006) conducted a 6-week, large 

multicenter, double-blind, randomized placebo-controlled 

study to compare the efficacy and safety of H. perforatum 

(STW3-VI 900 mg/day) to citalopram 20 mg/day in 388 

Figure 1 Total HAMD scores over time (intention to treat 

analysis, means and 95% confidence intervals) from a trial 

comparing the Hypericum extract WS 5570 and paroxetine in 

244 patients with moderate to severe depression. On day 42 WS 

5570 was statistically superior to paroxetine (pb0.01, two-sided 

t-test) (modified from Szegedi et al. (2005) with permission). 

patients affected with moderate depression. Outcome was 

monitored using the HAMD, the von Zerssen's Adjective Mood 

scale and the CGI. The mean HAMD score in the three 

treatment groups was 22. The authors found a statistical 

significant therapeutic equivalence of Hypericum extract 

STW3-VI to citalopram and the superiority of this Hypericum 

extract over placebo. Furthermore the percentage of 

responders at the end of treatment was 54.2% in the 

Hypericum group, 55.9% in the citalopram group and 39.2% 

in the placebo group. More adverse events were observed in 

patients treated with citalopram than in other group 

treatment, thus suggesting both a non-inferiority in terms 

of clinical efficacy and a better safety and tolerability of 

Hypericum extract in comparison to citalopram (Gastpar 

et al., 2006). 

3. Evidence from meta-analyses 

Several systematic reviews and quantitative meta-analyses 

of Hypericum extract trials, compared with both placebo and 

standard antidepressants, provide a comprehensive overview 

of clinical studies involving Hypericum extract (Table 3) 

(Kim et al., 1999; Linde et al., 1996, 2005a,b, 2008; Linde 

and Knuppel, 2005; Röder et al., 2004; Volz and Laux, 2000; 

Whiskey et al., 2001; Rahimi et al., 2009). In Table 3, in all 

meta-analyses except Röder et al., the RR was defined as the 

ratio of the responder rates observed with Hypericum 

extract and comparator, whereas in Röder et al. it is 

inverted (comparator/Hypericum). 

Over time, there has been a trend towards an improved 

quality of meta-analysis relating to Hypericum extract in 

terms of studies included and the criteria used to select 

studies. Recent meta-analyses of Hypericum extract have 

sought to encompass more methodologically sound studies 

than those used in earlier meta-analyses, which has been 

made possible by improvements in the quality of individual 

clinical studies. This has led to a greater number of large 

randomized studies with rigorous criteria for major


Figure 2 Change from baseline (means and 95% confidence intervals) in the re-scaled cluster 1 (core symptoms of depression) and 

cluster 2 (mainly anxiety and insomnia-related symptoms) scores in 544 patients with mild to moderate depression treated with 

Hypericum extract for 42 days (Kasper and Dienel, 2002). Re-scaled cluster scores were calculated as the means of the scores of all 

items included in the cluster re-scaled to a 0–100 scale (where 0=all items in the cluster score 0; 100=all items in the cluster scored 

the maximum score). Negative values indicate symptom improvement. 

depression and higher baseline depression scores. Further 

evidence for the greater selectivity of included studies in 

more recent meta-analyses relates to the diagnostic criteria 

used; in Röder et al. (2004), the majority of studies included 

used ICD-9 and ICD-10 and DSM (DSM-III, III-R, and IV) criteria. 

A minimum HAMD score of 16 to 21 was stated as inclusion 

criteria in 15 studies and, in 7 studies, a maximum score of 

20, 24 or 25 was specified. One of the major limitations, 

however, is the inclusion in all meta-analyses of studies using 

different preparations of Hypericum extract. 

Linde et al. (2005a) point out that, compared with trials 

published before 1995, newer trials have larger sample sizes, 

are of longer duration, are more likely to use a placebo run-in 

phase, are more often restricted to patients who met criteria 

for major depression and tend to include patients with higher 

baseline scores on depression scales. In addition, documentation 

of methodology and daily doses are more thorough in 

the more recent trials. In their most recent meta-analysis 

Linde et al. (2008) have examined several new well-designed 

trials restricted to patients with major depression. 

Linde and Mulrow (2000) carried out a systematic review 

and meta-analysis of the efficacy and tolerability of 

Hypericum extract, which was published as a Cochrane 

review. This was an update of a systematic review carried 

out in 1996, one of the first for Hypericum extract. Only 

randomized studies were included in which Hypericum 

extract was compared to placebo or conventional antidepressants 

for the treatment of depression. Outcomes were 

measured using standardized clinical evaluation scales. 

Moreover, for inclusion, the methodology of each individual 

study required assessment by at least two independent 

observers using the evaluation scale proposed by Jadad et al. 

(1996). Of 45 studies identified, 27 met the inclusion criteria 

for a total of 2291 patients. Seventeen of the included trials 

757 

were placebo-controlled. Ten studies compared Hypericum 

extract (8 Hypericum extract alone, two in combination with 

Valeriana extract) with other antidepressants or sedatives. 

Among these various trials, diagnostic criteria were quite 

broad and included dysthymia and also patients with mild 

symptoms who did not meet criteria for major depression. 

Other potential drawbacks among these studies include a 

limited follow-up period, which for the most part did not 

exceed 4 weeks, and the use of low doses of standard 

antidepressants in comparative trials. Nonetheless, in spite 

of these negative aspects, the methodology was considered 

generally acceptable. Overall, Hypericum extracts were 

significantly superior to placebo (RR 2.47, 95% CI=1.69– 

3.61) for short-term therapy of mild or moderate depression 

and were very well tolerated. In this meta-analysis, 

Hypericum was also shown to be at least as effective as 

standard antidepressants (Hypericum extract alone, RR 1.01, 

95% CI=0.87–1.16; combined extracts, RR 1.52, 95% 

CI=0.78–2.94). However, data from this meta-analysis did 

not allow to establish whether Hypericum extract has 

equivalent clinical efficacy to other antidepressants for the 

heterogeneity of the studies, the short duration of the 

observation period and the low proportion of studies using an 

SSRI as comparator. 

In a subsequent meta-analysis by Linde et al., (2005a,b), 

published in 2005, which is an update to the 2000 systematic 

Cochrane review, only randomized, controlled, double-blind 

studies were included; of 68 possible studies identified, 37 

trials met the inclusion criteria, including 26 comparisons 

with placebo and 14 with standard synthetic antidepressants 

(13 of these provided efficacy data: 6 tricyclics, 7 SSRIs). 

Responders were defined as those who experienced objective 

improvement using the HAMD and CGI scales. The studies 

with placebo involved 3320 patients, many of whom were


Table 3 Overview of several meta-analyses of Hypericum extract. 

Review Year Inclusion 

criteria 

(Linde et al., 1996) 1996 RCT a , depressed patients, 

single or combination 

preparation, comparison 

with placebo or other 

antidepressants, all 

clinical outcome measures 

(Linde and Mulrow, 2000) 2000 RCT, depressed patients, 




antidepressants, all 

clinical outcome measures 

(Kim et al., 1999) 1999 Blinded/controlled, single 

preparation, depression 

(ICD10, DSM-IIIR, DSM-IV), 

outcomes by HAMD 

(Volz and Laux, 2000) 2000 Placebo-controlled trials 

of Hypericum or fluoxetine 

in mild depressive disorders 

(HAMD ≤24) 

(Whiskey et al., 2001) 2001 RCT, depression, single 



antidepressants, outcomes 

by HAMD 

(Kasper and Dienel, 2002) 2002 Double-blind, RCT, mild 

to moderate depression, 

comparison with placebo, 


(Röder et al., 2004) 2004 Double-blind, RCT, 

depression, single 



antidepressants 

(Linde et al., 2005a) 2005 Double-blind, RCT, included 

patients with depression, 

single preparations, 

comparison with placebo or 

other antidepressant, all 

clinical outcomes 

(Rahimi et al., 2009) 2009 Double-blind, RCT, included 

patients with depression 



with placebo or SSRI, 


Number of studies 

(total number of patients) 

15 vs. placebo (1008) 

8 vs. antidepressants/ 

sedatives (749) 


10 vs. antidepressants (1123) 


4 vs. tricyclic 

antidepressants (482) 

17 Hypericum vs. 

placebo (1739) 

9 fluoxetine vs. 

placebo (1873) 

14 vs. placebo 

9 vs. antidepressants 

Responder rate ratio* 

(95% CI) 

2.67 (1.78–4.01) 

1.1 (0.93–1.31) for 

single preparations 

1.52 (0.78–2.94) 

for combinations 

2.47 (1.69–3.61) 

for single preparations 


combination 


single preparations 


combination 

1.48 (1.03–1.92) 

1.11 (0.92–1.29) 

Responder rate ratio 

not stated 

HAMD reduction 

10.2 (51.4%) 

12.5 (55.5%) 

1.98 (1.49–2.62) 

1.00 (0.90–1.11) 

3 vs. placebo (544) 1.35 for cluster 

1 HAMD items 

1.40 for cluster 

2 HAMD items 



(2231) 



(2283) e 

13 SSRI vs. placebo (1995) 

11 Hypericum vs. SSRI (1652) 

0.66 (0.57–0.78) 

0.96 (0.85–1.08) 

1.15 (1.02–1.29) b and 

2.06 (1.65–2.59) c 

depression only 

1.71 (1.40–2.09) c and 

6.13 (3.63–10.38) d 

including other 

diagnoses 

1.01 (0.93–1.10) overall 

0.97 (0.85–1.12) vs. SSRIs 

1.03 (0.93–1.14) vs. older 

antidepressants 

1.22 (1.03–1.45) 

0.99 (0.91–1.08)


Table 3 (continued) 

Review Year Inclusion 

criteria 

(Linde et al., 2008) 2008 Double-blind, RCT, included 

only patients with major 

depression, single 

preparations, comparison 


antidepressant, all 

clinical outcomes 

affected by major depression, and were treated for more 

than 4 weeks using a mean dose of 800 mg/day Hypericum 

extract. The 14 trials using standard antidepressants as the 

comparator involved 2283 patients (Linde et al., 2005a; 

Linde and Knuppel, 2005). The proportion of responders was 

comparable in Hypericum extract-treated patients compared 

with that seen with both tricyclic antidepressants 

(RR=1.03, 95% CI =0.93–1.14) and SSRIs (RR=0.98, 95% 

CI=0.85–1.12). There was a trend towards fewer dropouts 

for any reason or due to adverse effects in patients treated 

with Hypericum extract compared with placebo and also less 

dropouts compared with those administered standard 

antidepressants. 

To avoid compromising results by inclusion of studies with 

weak methodology, Kasper and Dienel (2002) carried out a 

meta-analysis using trials that also met relatively strict 

criteria based on patient selection (diagnostic criteria), 

outcome measures used, design (double-blind, placebocontrolled), 

period of observation as well as quality of 

investigator rating. The meta-analysis included three randomized, 

double-blind, placebo-controlled studies including 

a total of 544 patients affected by mild to moderate 

depression who received Hypericum extract (3×300 mg/ 

day) or placebo. These studies all utilized standardized and 

well-defined diagnostic criteria (DSM-IV) of mild to moderate 

major depression. Primary outcome was measured using the 

total HAMD score and therapy lasted for 6 weeks. 

The objective of the meta-analysis was to evaluate the 

therapeutic profile of Hypericum extract by cluster analysis 

and determine if Hypericum extract has a selective effect on 

particular signs and symptoms of depression. Cluster analysis is 

a statistical technique that attempts to overcome potential 

shortcomings of factor analysis, particularly difficulties in 

interpretation. For the HAMD, most analyses include two 

factors, one related to core symptoms of depression (e.g. 

profound, non-reactive sadness, somatic symptoms, and 

lethargy) and another to elements such as agitation and 

anxiety. For this meta-analysis, two clusters were also 

identified. The first (HAMD items 1, 2, 3, 7, 8, 12, 13, 14, 

and 16) represented core symptoms of depression including 

somatic symptoms. The second (HAMD items 4, 5, 6, 9, 10, 11, 

15, and 17) was composed primarily of items that evaluated 

anxiety and insomnia correlated with depression. Hypericum 

Number of studies 

(total number of patients) 


17 vs. antidepressants (2810) 

Responder rate ratio* 

(95% CI) 

1.28 (1.10–1.49) in the 

nine larger trials 

1.87 (1.22–2.87) in the 

nine smaller trials 

1.02 (0.90–1.15) vs. tri- or 

tetracyclic antidepressants 

1.00 (0.90–1.11) vs. SSRIs 

*The responder rate ratio is the ratio of the responder rates observed with Hypericum and comparator (a value N1 denotes a greater effect 

with Hypericum vs. comparator) with the exception of Röder et al. (2004), where it is inverted and defined as the ratio of the responder 

rates of comparator and Hypericum (in this case a value b1 denotes a greater effect with Hypericum vs. comparator). a Or quasi-randomized 

(e.g. alteration); b five larger trials; c six smaller trials; d five smaller trials; e 13 provided quantitative data. HAMD = Hamilton Depression 

Rating Scale; RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor. 

759 

extract was found to be particularly efficient in reducing core 

symptoms of depression in a global manner with a therapeutic 

profile similar to SSRIs. Fig. 2 shows the change of the cluster 

scores vs. baseline, and demonstrates that score changes 

over time were similar for both clusters but the extent of 

score changes was more pronounced for core symptoms of 

depression (cluster 1). 

The meta-analysis by Röder et al. (2004) examined the 

available clinical data by considering only the average 

responder rate to Hypericum extract therapy, compared 

with placebo or other antidepressants. This meta-analysis 

found that, compared with newer generation antidepressants, 

the mean responder rate was highly similar in the Hypericum 

extract and antidepressant groups (51.0% vs. 48.0%, respectively) 

(Röder et al., 2004). This review also differentiated 

rates of treatment success from Hypericum extract or 

comparator therapy according to subgroups of patients, 

based on severity. Inclusion criteria for the meta-analysis 

were a double-blind, randomized design with placebo or other 

antidepressants as the comparator, diagnosis of depression 

and use of Hypericum extract alone and not in combination 

with other plant extracts. The quality of the studies was 

quantified using a scoring system derived from criteria used by 

the authors. Thirty studies satisfied both the inclusion and 

quality criteria for the meta-analysis, 12 of which had been 

previously included in the meta-analysis by Linde et al. (Linde 

et al., 2005a; Linde and Knuppel, 2005). However, the metaanalysis 

from Röder et al. (2004) contained more studies using 

SSRIs as the comparator. The results showed a significantly 

higher efficacy with Hypericum extract compared with 

placebo (N=2129, RR=0.66, 95% CI=0.57–0.78). The average 

number of patients responding to therapy was also significantly 

higher for Hypericum extract compared with placebo 

(53.3% vs. 32.7%, respectively; pb.00001, number needed to 

treat [NNT]=4.2, 95% CI=3.0–6.6). Hypericum extract also 

showed an efficacy that was similar to standard antidepressants 

(N=2231, RR=0.96, 95% CI=0.85–1.08) and the average 

number of patients responding to therapy was also similar for 

Hypericum extract and other antidepressants [52.3% vs. 

51.3%, respectively (p=.509)]. In the subgroup with mild to 

moderate depression, Hypericum extract showed significantly 

higher efficacy with respect to standard antidepressants 

(N=1166, RR=0.85, 95% CI=0.75–0.97, p=.01, NNT=14.3,


95% CI=8.3–100.0). The mean responder rate was 59.5% in the 

Hypericum extract group compared with 52.9% for standard 

antidepressants (p=.14). 

Linde et al. (2008) carried out a systematic review and 

meta-analysis on the efficacy and tolerability of Hypericum 

extract in major depression, which was published as a 

Cochrane review. Only randomized studies were included in 

which Hypericum extract was compared with placebo or 

standard antidepressants for the treatment of major 

depression. Outcomes were measured using standardized 

clinical evaluation scales. Moreover, for inclusion, the 

methodology of each individual study required assessment 

by at least two independent observers, using scales 

developed by Jadad et al. (1996). 

Of 79 studies identified, 29 met the inclusion criteria for a 

total of 5489 patients. Eighteen of the included trials were 

placebo-controlled. Seventeen studies compared Hypericum 

extract with other antidepressants. Eight new trials were 

included since the last update (Linde et al., 2005b) with a 

total of 1947 patients. The severity of depression was 

described as mild to moderate in 19 trials, and as moderate 

to severe in 9 trials. Responders were defined as those who 

experienced objective improvement using the HAMD and CGI 

scales. The studies with placebo involved 3064 patients, 

whereas the seventeen trials using standard antidepressants 

as the comparator involved 2810 patients. Patients receiving 

Hypericum extract were significantly more likely to be 

responders (RR=1.48; 95% CI=1.23–1.77), but placebocontrolled 

trials were highly heterogeneous. In the nine 

larger trials the combined response rate ratio for Hypericum 

extract compared with placebo was 1.28 (95% CI=1.10– 

1.49), whereas effects in favour of Hypericum extract were 

more pronounced in the nine smaller trials (RR=1.87 95% 

CI=1.22–2.87). 

In the meta-analysis, Hypericum was also shown to be at 

least as effective as tricyclic antidepressants (RR=1.02 95% 

CI=0.90–1.15) or SSRI (RR=1.00 95% CI=0.90–1.11). Interestingly 

patients treated with Hypericum extract were less 

likely to drop out from studies due to adverse effects than 

patients allocated to older standard antidepressants 

(OR=0.24; 95% CI=0.13–0.46) or to SSRIs (OR=0.53; 95% CI 

0.34–0.83). 

This meta-analysis examines for the first time only clinical 

trials conducted in patients with major depression and 

suggests that Hypericum extract have a modest effect over 

placebo in a similar range as standard antidepressant drugs, 

finally showing that Hypericum extracts have fewer side 

effects than standard antidepressant drugs. However it 

should be underlined that trials from German-speaking 

countries have significantly more positive results than trials 

from other countries. The reasons for the “country effect” 

are unclear and further studies are needed to investigate this 

difference. 

In a recent meta-analysis Rahimi et al. (2009) have 

examined all studies comparing the efficacy and tolerability 

of Hypericum extract and SSRIs. Only randomized and double 

blinded conducted in patients with major depressive 

disorder were included. Outcomes were measured using 

HAMD. Duration of treatment ranged between 4 and 

12 weeks in various studies. The methodological quality of 

included trials was assessed using the Jadad score. 13 eligible 

controlled clinic trials were included in the meta-analysis. 

Comparison of SSRIs with placebo yielded a significant 

relative risk (RR) of 1.22 (95% CI: 1.03–1.45) for clinical 

response, whereas a non significant RR of 0.96 (95% CI=0.71– 

1.29) was observed for remission. 

In this meta-analysis Hypericum was also shown to be at 

least as effective as SSRI. The authors, by comparing 

Hypericum extract with SSRI, found that rate of clinical 

response (RR=0.99 95% CI=0.91–1.08), remission (RR=1.10 

95% CI=0.90–1.35), and reduction of HAMD score (RR=0.32 

95% CI=−1.20–0.64), was similar between Hypericum and 

SSRIs. Lower withdrawal due to adverse events was observed 

in patients treated with Hypericum extract compared to SSRI 

(RR=0.53 95% CI=0.35–0.82). 

The results obtained from this meta-analysis demonstrate 

both a similar efficacy of Hypericum extract and SSRI and a 

better profile of tolerability for Hypericum, finally suggesting 

that Hypericum extract might be considered as an 

alternative to SSRIs in the management of mild to moderate 

depression. 

4. Tolerability with Hypericum extract: evidence 

from meta-analyses and systematic reviews 

The absence of adverse effects is an important factor in the 

treatment of patients affected by mild to moderate depression, 

given that these patients are less likely to accept drugs 

with undesirable effects than patients with more severe forms 

of depression. Poor tolerability has been shown to have a 

negative impact on compliance, with the potential for 

worsening of depressive symptoms (Keller et al., 2002). In 

general, Hypericum extracts have a favourable tolerability 

profile and are generally better tolerated than standard 

antidepressant drugs (Ernst et al., 1998; Rahimi et al., 2009). 

The meta-analysis by Röder et al. (2004) found a lower 

incidence of adverse events with Hypericum extract (24.5%) 

compared to that seen with synthetic antidepressants 

(32.8%); although this did not reach significance (p=.09), 

and a similar number of withdrawals due to adverse effects 

(p=.2). Another methodologically sound overview of the 

adverse effects of Hypericum extract comes from a 

systematic review by Knuppel and Linde (2004). Part of this 

review was performed in the context of updating the metaanalysis 

of Linde, et al. discussed above (Linde et al., 2005a; 

Linde and Knuppel, 2005). Overall, the systematic review 

examined dropout rates and adverse effects in 24 doubleblind, 

randomized trials, 17 large-scale observational studies 

as well as numerous case reports, case series and data sets 

from surveillance agencies (Knuppel and Linde, 2004). Based 

on the results of this review, the authors made several 

statements regarding the rates of adverse effects and 

dropouts in patients treated with Hypericum extract. Firstly, 

in randomized trials, rates were similar for Hypericum 

extract and placebo, lower for Hypericum extract compared 

with tricyclic antidepressants and slightly lower for Hypericum 

extract compared with SSRIs. In non-randomized 

observational studies, rates of discontinuation due to 

adverse effects among Hypericum extract-treated patients 

are low even in long-term studies and effects are generally 

mild. 

Several longer-term studies on Hypericum extract have 

also been completed, which provide an assessment of the


tolerability of this agent over a longer period of follow-up. 

Data from four large post-marketing surveillance studies 

with a total of 14, 212 patients taking various preparations of 

Hypericum extract have been published (Lemmer et al., 

1999; Rychlik et al., 2001; Schakau et al., 1996; Woelk et al., 

1994). In these studies, the overall incidence of side effects 

was 0.1–2.4% with 0.1–0.9% of patients discontinuing due to 

drug-related adverse events (Schulz, 2006). 

Linde and Knuppel (2005) published a systematic review 

of 16 large-scale, open-label observational studies on 

Hypericum extract, including an assessment of methodological 

quality, involving a total of 34,804 patients. Two studies 

were long-term (52-week) observational studies including 

the WS 5572 study (Lemmer et al., 1999) in mild to moderate 

depression reviewed by Schulz (2006), and a study of 

Hypericum extract Laif 600 in depressive disorders, published 

in abstract form (Zeller, 2000). In these two studies, 

3.4% and 5.7% of patients discontinued due to adverse 

effects. All adverse events reported with Hypericum extract 

were mild and the most common were gastrointestinal 

symptoms, light sensitivity and other skin problems. 

In a 1-year, open-label study on 313 patients with mild to 

moderate depression according to the DSM-IV scale, the 

tolerability of Hypericum extract was rated as good or very 

good after one year by both patients and physicians (Hubner 

and Arndt, 2000). At the end of the 12-month follow-up 

period, there were no significant differences between the 

initial and final parameters concerning EEG, blood pressure, 

heart rate or haematological parameters. Only 11.2% of 

cases reported undesirable events during the entire year of 

therapy, the most frequently reported adverse events being 

infections of the upper airway, headache and gastrointestinal 

disturbances. 

Acute mania was reported in one patient taking 1800 mg 

Hypericum extract in a randomized, double-blind comparison 

with sertraline (van Gurp et al., 2002). Several other 

cases of acute mania have been reported (Fahmi et al., 2002; 

Guzelcan et al., 2001; Moses and Mallinger, 2000; Nierenberg 

et al., 1999). No causal relationship between the use of the 

extract and the mania has been established but the 

propensity for affective switching, as seen with synthetic 

antidepressant use, cannot be ruled out. Hypericum extracts 

should be therefore avoided in patients with bipolar 

disorder. 

Phototoxicity has been raised as a potential adverse 

effect of Hypericum extract. In the official register of 

spontaneous events (Schulz, 2001), only 1 case per 300,000 

treated cases has been reported. Volunteer studies have 

shown a non-clinically relevant increase in photosensitivity, 

only detectable using highly sensitive photometric measurement. 

This might become relevant, but only in fair-skinned 

individuals, in those with skin disorders or after extended 

solar irradiation (Schempp et al., 2000) and most individuals 

would be highly unlikely to experience problems. Investigations 

in volunteers have also shown that the threshold dose 

for an increased risk of photosensitization is about 2–4 g/day 

of a usual commercial extract (equivalent to approximately 

5–10 mg of hypericin), considerably more than doses used in 

clinical practice (Schulz, 2001). It has been estimated that a 

Hypericum extract dose 30–50 times greater than the 

recommended daily dose taken at one time would be 

required to cause severe phototoxic reactions (Ernst et al., 

1998). Indeed, only few cases have been reported with 

respect to a serious phototoxicity reaction necessitating 

treatment cessation (Bove, 1998; Golsch et al., 1997; Lane- 

Brown, 2000). In one, a woman developed recurrent 

erythematous lesions in areas exposed to light following 

consumption of a commercial Hypericum extract for 3 years. 

The condition resolved after discontinuation of Hypericum 

extract (Golsch et al., 1997). In another case, a woman 

experienced neuropathy after taking Hypericum extract 

(Bove, 1998) and three cases of severe blistering and burns 

were reported in patients taking Hypericum extracts (either 

internally or topically) before exposure to sunlight (Lane- 

Brown, 2000). 

According to Brockmoller et al. (1997), given that 

photosensitivity is unlikely at doses of up to 1800 mg/day, 

potential phototoxic effects may only become apparent 

when Hypericum extract is taken with other drugs with 

phototoxic effects (Schulz, 2001). 

5. Compliance 

761 

Compliance with antidepressant medication is essential to 

ensure treatment response and prevent relapse and symptom 

recurrence (Keller et al., 2002). However, compliance 

with antidepressant medication is poor, with one set of 

published data indicating that between 30% and 60% of 

patients do not take their medications as prescribed 

(Demyttenaere et al., 2004), a figure which agrees broadly 

with other commonly quoted estimates of antidepressant 

non-compliance (Olivier-Martin, 1986). The rate of onset and 

poor tolerability of antidepressant drugs has a considerable 

influence on patient compliance. To illustrate the point, one 

US study that examined claims data among 2012 patients 

found that initiating treatment with a tricyclic antidepressant 

reduced the probability of antidepressant treatment 

compliance vs. SSRI plus psychotherapy (Tai-Seale et al., 

2000). In contrast, Hypericum extract is associated with a 

good tolerability profile and good compliance. In a placebocontrolled 

study of Hypericum extract (ZE 117) involving 162 

patients, an electronic counter was inserted in the medicinal 

container in order to evaluate compliance (Schrader, 2000). 

A high level of compliance was observed, with a therapeutic 

coverage of 81.7% noted. Adherence to therapy was 

attributed, at least in part, to a low number of undesirable 

effects (5 in the placebo group and 6 in the Hypericum 

extract group), generally limited to acute gastrointestinal 

complaints. Other investigators have suggested that the 

superior tolerability of Hypericum extracts relative to other 

antidepressants, particularly tricyclics, could account for 

advantages in terms of compliance (Wheatley, 1997). 

Finally a recent trial from Kasper et al. (2008b) has 

demonstrated that long-term treatment with Hypericum 

extract is not associated with any unexpected drug-specific 

risks or problems of intolerance (Kasper et al., 2008b). 

Furthermore the rates of potentially attributable events 

reported during double-blind treatment with Hypericum 

were lower than in the placebo group. Recent meta-analyses 

have also clearly demonstrated that treatment with Hypericum 

extract is associated with a lower withdrawal due to 

adverse events when compared to standard antidepressant 

drugs, thus suggesting an advantage of Hypericum extract in


terms of tolerability and compliance (Linde et al., 2008; 

Rahimi et al., 2009). 

6. Drug interactions with Hypericum extract 

Several systematic reviews have examined the published 

literature on Hypericum extract-mediated drug interactions 

(Henderson et al., 2002; Izzo, 2004; Mills et al., 2004; Whitten 

et al., 2006). Izzo (2004) published a review of the clinical 

evidence related to drug interactions with Hypericum extracts 

which pulls together many small studies and case reports. 

Interactions of clinical relevance often relate to the potential 

of Hypericum extracts for inducing cytochrome P450 enzymes 

(particularly CYP 3A4) and also increasing expression of Pglycoprotein 

(Pgp). Current evidence suggests that these 

effects can be due to hyperforin, one of the main constituents 

of Hypericum extract, which increases the expression of the 

pregnane X receptor, and then induces Pgp expression as well 

as CYP 3A4 activity (Moore et al., 2000). Moreover pharmacodynamic 

interactions have been described between Hypericum 

extract and other antidepressants (e.g. serotonin 

reuptake inhibitors such as paroxetine and sertraline) with 

the possible occurrence of a serotonin syndrome (Zhou and 

Lai, 2008). 

Izzo (2004) have reviewed the data relating to interactions 

with oral contraceptives (OCs); several cases have been 

reported in which women have had breakthrough bleeding 

while taking Hypericum extract with OCs. In two open-label 

post-marketing surveillance studies (Hall et al., 2003; 

Pfrunder et al., 2003) of concomitant OC and Hypericum 

extract use over 3 months, there was no loss of contraceptive 

control; endogenous hormone levels showed an absence of 

ovulation in all patients taking Hypericum extract throughout 

the study period. 

A systematic review was conducted by Whitten et al. 

(2006) to examine the quality and outcomes of clinical trials 

analyzing the effect of St. John's wort extracts on the 

metabolism of drugs by CYP3A. All of the 19 studies that used 

high-dose hyperforin extracts (N10 mg =day) had outcomes 

consistent with CYP3A induction, while the three studies 

using low-dose hyperforin extracts (b4 mg=day) demonstrated 

no significant effect on CYP3A (Whitten et al., 

2006). 

7. Conclusion 

Whether examined individually or combined in quantitative 

meta-analyses, the results of numerous clinical studies 

strongly support the effectiveness of some Hypericum 

extracts for the treatment of mild to moderate depression. 

Study methodology and quality of reporting have increased 

in recent years, which should make prescribers and 

patients more confident in choosing Hypericum extract 

over conventional antidepressants. Although a small 

number of comparative trials have shown Hypericum 

extract to be effective in severe depression, the majority 

do not support this view, and, therefore, weighing current 

evidence, Hypericum extract is not recommended for 

patients with severe depression. There is some evidence 

that Hypericum extract is effective in controlling symp- 

toms in patients with disorders associated with or related 

to depression such as anxiety (Muller et al., 2003), 

somatoform disorders (Muller et al., 2004; Volz et al., 

2002; Woelk, 2000), and obsessive compulsive disorder 

(Taylor and Kobak, 2000). 

Overall, current evidence appears to support the 

efficacy of Hypericum extract for the treatment of mild 

to moderate depression; meta-analyses of clinical trials 

suggest that Hypericum extract is significantly more 

effective than placebo and at least as effective as 

standard antidepressants. Those extracts which demonstrate 

efficacy in clinical trials can and should be 

recommended for the treatment of mild to moderate 

depression. Based on our review of individual clinical 

trials, WS 5572, LI 160, WS 5570 and ZE 117 Hypericum 

extracts have been shown to be significantly more 

effective than placebo with similar efficacy to standard 

antidepressants. Initial studies of extracts LoHyp-57, 

psychotonin, calmigen, Swiss Herbal Remedies, STW3, 

STEI 300 and esbericum have produced promising results 

but further clinical data are needed to confirm their 

effectiveness in mild to moderate depression. 

Considering the favourable safety profile of all extracts 

studied (equivalent to placebo and better tolerated than 

standard antidepressants), which also correlated with a 

lower frequency of dropouts in clinical studies than seen 

with standard antidepressants, Hypericum extract is a 

valid therapeutic approach in patients with mild to 

moderate depression. For these patients, for whom 

adverse effects of treatment may be difficult to accept, 

Hypericum extracts provide a high rate of pharmacological 

compliance. They provide an effective and well tolerated 

alternative to standard tricyclic and SSRI antidepressants 

and are advocated for first line therapy of mild to 

moderate depression. 

Role of the funding source 

This study was not supported by external funding. 

Contributors 

All authors have been actively involved in the construction of the 

paper from the outset and have had full editorial control over its 

content. 

Conflict of interest 

Siegfreid Kasper has received grant/research support from Eli Lilly, 

Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor 

and Servier; has served as a consultant or on advisory boards for 

AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, 

Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen, 

and Novartis; and has served on speakers' bureaus for AstraZeneca, 

Eli Lilly, Lundbeck, Schwabe, Sepracor, Servier and Janssen. 

Filippo Caraci has received grants or honoraria as a consultant 

from Eli Lilly, Janssen, and Innova Pharma. 

Bruno Forti and Eugenio Aguglia declare that they have no 

conflict of interests. 

Filippo Drago has served as a consultant or on advisory boards for 

Eli Lilly, GlaxoSmithKline, AstraZeneca, Novartis, Pfizer, SIFI, 

Amdipharm, Grunenthal.


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