Wort (Hypericum Perforatum L.) PJ Nathan

Home , Adhyperforin, Hypericum, Hypericum perforatum, Sigma receptor

MECHANISMS OF DRUG ACTION The experimental and clinical pharmacology of St John’s Wort (Hypericum perforatum L.) PJ Nathan

Brain Sciences Institute, Swinburne University of Technology, 400 Burwood Road, Hawthorn 3122, Victoria, Australia

Hypericum (St John’s Wort) is a plant that has been used for centuries as a medicinal herb. Pre-clinical animals studies suggest that hypericum is effective in three major biochemical systems relevant for antidepressant activity, namely the inhibition of the synaptic re-uptake system for serotonin (5-HT), noradrenaline (NA) and dopamine (DA). It is the only antidepressant capable of inhibiting the re-uptake of 5-HT, NA and DA with similar potencies. The potencies for monoamine re-inhibition and chronic changes in receptors are also consistent with changes seen with known antidepressants. Behavioral studies suggest that hypericum is active in pre-clinical animal models of depression with comparable effects to known antidepressants. Supporting the pre-clinical pharmacology and efficacy, many clinical studies have shown that hypericum has superior efficacy compared to placebo and comparable efficacy to standard antidepressants in the treatment of mild-to-moderate depression. The advantage of hypericum over other antidepressants may result from its favorable side-effect profile. Although pre-clinical and short-term clinical studies demonstrate antidepressant activity, the lack of long-term use and efficacy, and the heterogeneity of patients, interventions, extract preparations from previous clinical studies suggests that more careful and controlled studies are needed to determine the long-term efficacy of hypericum in mild-to-moderate depression. Keywords: pharmacology; hypericum; St John’s Wort; mechanism; antidepressant; mild-moderate depression; clinical efficacy; herbal remedies

Introduction About hypericum Hypericum perforatum belongs to the Guttiferae fam- St John’s Wort refers to the plant Hypericum perfor- ily. The genus Hypericum encompasses approximately atum, and has been used for centuries as a medicinal 400 species of which Hypericum perforatum itself is herb for anti-inflammatory, sedative, analgesic, divided into four subspecies that are distinguished by diuretic, antimalarial, antidepressant and vulnerary the size of their septals.8 Hypericum perforatum is action. Traditional indications have included trauma, found in many areas of the world including Europe, burns, rheumatism, hemorrhoids, neuralgia, gastroent- Asia, North America and North Africa. The name St eritis, snakebite, ulcers, contusions, sprain, diarrhea, John’s Wort comes from the fact it flowers around St menorrhagia, hysteria and depression.1,2 Its efficacy in John’s day. The crude drug, called herba hyperici, con- depression has been supported in recent times with sists of the upper aerial parts of the plant, which are implication for its use in the treatment of mild-to- harvested before or during the flowering period. moderate depression.3–5 Today, hypericum extracts are among the most widely used antidepressants in Ger- Chemical constituents of hypericum many, with more than 3.7 million prescriptions in The commercially available products of St John’s Wort 19976 and a market share of more than 25% of all anti- contain hypericum dry extracts, the pharmacological depressant prescriptions in 1997.7 While evidence sug- agent prepared from the upper aerial parts of the plant gests that hypericum has antidepressant potential, the with either 60% ethanol or 80% methanol. These exact mechanism for the antidepressant effect remains extracts differ to varying degrees in the content of six to be resolved. The aim of this article is to illustrate major natural product groups: naphthodianthrones some of the possible mechanisms that may underlie (hypericin and pseudohypericin), acylphloroglucinols hypericum’s antidepressant action and review its clini- (hyperforin and adhyperforin), flavonol glycosides cal efficacy in the treatment of mild-to-moderate (quercetin, quercitrin, isoquercitrin, rutin, hyperoside, depression. kampferol, leteolin, myricetin), biflavones (13,118-biapigenin, 13Ј,118-biapigenin (amentoflavon), proanthocyan-

idins (procycanidin B2) and phenyl propanes Dr PJ Nathan, Brain Sciences Institute, Swinburne University of 9,10 Technology, 400 Burwood Rd, Hawthorn 3122, Victoria, (chlorogenic acid and caffeic acid). Flavonol glyco- Australia. E-mail: pnathanȰbsi.swin.edu.au sides, biflavones, proanthcyanidins, and phenylpro- Received 29 January 1999; revised and accepted 19 March 1999 panes, as biogenetically related compounds, together The pharmacology of St John’s Wort PJ Nathan 334 represent the main constituents in the dry crude drug 2 ␮gml−1. While tricyclics (TCAs) such as amitripty- of St John’s Wort.9 line and imipramine, and serotonin and noradrenaline As hypericum contains numerous compounds with re-uptake inhibitors (SNRIs) such as duloxetine and biological activity it is currently not known if one milnacipran inhibit the synaptic uptake of 5-HT and chemical or a combination produces the antidepressant NA with about equal affinity, no other compound effect. However, hypericum possesses a unique phar- shows similar potency for all three uptake systems. A macology in that it displays the pharmacology of many recent study has shown that the bioactive substance antidepressants in the one drug. This may be related responsible for inhibiting synaptic re-uptake of to the multiple bioactive compounds present in hyper- monoamines is a constituent of hypericum called hy- icum. perforin. This compound potently inhibited uptake of all three monoamines in the concentration range of 80– Experimental pharmacology of hypericum 200 nmol L−1.18 Hyperforin was also present in the The monoamine hypothesis of depression postulates alcoholic extract previously tested (LI-160) by Rolli et that symptoms of depression arise from the deficit in al16 and Muller et al.17 The hyperforin present in the the availability of one or another of three biogenic alcoholic extract (LI 160) was also shown to inhibit the monoamines serotonin (5-HT), noradrenaline (NA) synaptic uptake of 5-HT, NA and DA in a similar con- and/or dopamine (DA).11 Most antidepressant drugs centration range (24–150 nmol L−1) (Table 2).18 In con- exert their pharmacological actions by increasing the trast hypericin, a major constituent of hypericum, that concentrations of 5-HT, NA or DA through: (1) the inhi- was originally thought to be important for antidepress- bition of the synaptic uptake of these transmitters; or ant action, had no effect on synaptic uptake of (2) inhibiting the metabolism of these transmitters by monoamines.18 Hypericum’s potency on monoamine monoamine oxidase type A (MAO-A) enzymes; or (3) re-uptake inhibition is remarkable as previous studies by blocking pre-synaptic inhibitory receptors such as by the same authors have shown that classical antide- ␣ 12 2-adrenoceptors. The final mechanism in the antidepressants such as imipramine were also active in these −1 pressant effect is the changes in neurotransmitter systems with IC50 values around 20 nmol L for the 5- receptor function, which in turn triggers various HT and NA uptake systems.17 Comparable potencies second messenger pathways. Receptor function is were also found in the literature for other antidepress- expressed as either changes in receptor number or the ants (Table 2). functional activity of the receptor (ie changes in second More recently Neary and Bu21 reported the first study messenger levels). An increase in receptor number or on the effects of hypericum on 5-HT and NA transport functional activity is commonly termed upregulation in intact neuronal cells. In this study it was shown that whereas a decrease in receptor number or functional hypericum inhibited transport of 5-HT by 50%, which activity is termed downregulation. Some of the com- was approximately 70% of that observed with paroxet- mon changes in neurotransmitter receptor changes fol- ine and fluoxetine, whereas for noradrenaline the main lowing chronic antidepressant or electro-convulsive effect was a 4.5-fold reduction in the apparent affinity therapy (ECT) treatment are shown on Table 1. of noradrenaline for its uptake site.21 Taken together these findings suggest that hypericum is effective in Effects on monoamine re-uptake three major biochemical systems relevant for antide- Recent reports by Rolli et al16 and Muller et al17 pressant activity, namely the inhibition of the synaptic showed that a clinically used hypericum extract (LI re-uptake system for 5-HT, NA and DA. 160) like conventional antidepressants, concentration An important consideration is the relevance of these dependently and potently inhibited the synaptic re- pharmacological effects seen in animals to the thera-

uptake of 5-HT, NA and DA with an IC50 around peutic doses used in clinical studies for the treatment

Table 1 Common changes in neurotransmitter receptor Table 2 Comparison of the potencies of hyperforin in function in the rat brain following chronic antidepressants hypericum (LI-160) and various other antidepressants for the synaptic re-uptake of 5-HT, NA and DA. Data summarised (AD) or ECT. Receptor function denotes changes in receptor 18–20 number or functional activity. Data summarised from refer- from ences11,13–15 −1 Antidepressant IC50 (nmol L ) ␣ 2-adrenoceptors Decreased ␣ 5-HT uptake NA uptake DA uptake 1-adrenoceptors Increased (after AD) ␤-adrenoceptors Decreased

5-HT2-receptors (post- Decreased (after AD) Hypericum (LI- 67 123 24 synaptic) Increased (after ECT) 160)

5-HT1A (autoreceptors) Decreased (for SSRIs and (hyperforin) MAOIs) Imipramine 20 21 17 000

5-HT1A (post-synaptic) Increased (ECT, TCAs) Amitriptyline 39 24 5300 Ͼ GABAB receptors Increased Milnacipran 203 100 1000 Dopamine (autoreceptors) Decreased Venlafaxine 210 610 Ͼ1000 The pharmacology of St John’s Wort PJ Nathan 335 of depression. The therapeutic dose of antidepressants the commercially available hypericum extract, in rats, used is usually 10–20 times less than the doses used upregulated post-synaptic 5-HT1A receptors with no in animal studies. For example the standard dose of changes in receptor affinity. In contrast to most antide- −1 imipramine (20 mg kg ) most researchers use for phar- pressants, which downregulate 5-HT2 receptors after macological studies in animals is about 10 times the chronic administration,12,42,43 hypericum has been 17,22 22,37 clinical dose in man. Similarly, the dose of hyper- shown to upregulate 5-HT2 receptors. A similar icum used by most studies is 10–20 times the average upregulation of 5-HT2 receptors has also been shown clinical dose used for mild-to-moderate depression.3 with repeated treatments with ECT, one of the most However, under these conditions most of the pharma- effective therapies for depression.12 cological effects observed with antidepressants are Recent evidence also suggests the hypericin has consistent. Furthermore, various pharmacological modest affinity for sigma receptors.43 The activity of changes evident from animal studies have been reliably hypericin at sigma receptors is a novel finding and rep- used in the past to predict clinical antidepressant effi- resents potential new insight into the pharmacological cacy.22 action of hypericum. An association between sigma receptors and antidepressant action has been postu- Effects of monoamine oxidase A activity lated on: (1) the demonstration that several antide- Initial reports suggested that hypericin, the major con- pressants such as selective serotonin reuptake inhibi- stituent of hypericum acts as an inhibitor of MAO-A tors (SSRIs) and MAOIs have moderate affinity for activity.23 However this finding has not been confirmed sigma receptors;44–47 (2) some sigma receptor ligands, by subsequent studies.24–26 Quercetin and Quercitrin, despite lacking affinity for serotonergic or norad- both flavonoide aglykone constituents of hypericum renergic receptors or transporter sites, exhibit antide- extract have also been shown to inhibit MAO-A,27 pressant profile in animal models;48 and (3) chronic although a therapeutic action of these compounds treatment with certain SSRIs and TCAs downregulate remains questionable because of their low plasma lev- sigma receptors in brain regions associated with emo- els. Supporting the negative findings, studies by Muller tion such as the limbic regions.49 17 et al showed that the IC50 values of hypericum as an Hypericum has also been shown to affect several inhibitor of MAO-A or MAO-B activity exceeded synaptic mechanisms of gamma-aminobutyric acid ␮ −1 50 100 gml (100 times higher than the IC50 for inhi- (GABA)ergic and glutamatergic neurotransmission, bition of monoamine re-uptake), making it unlikely with moderate affinities for GABAA, GABAB and N- that both these mechanisms are involved in the antide- methyl-d-aspartate (NMDA) receptors.51 Both NMDA pressant action of hypericum. However the effect of receptors and GABA receptors have been implicated in hypericum on MAO-A and MAO-B inhibition may be depression,52,53 and affinities for these receptors may dose-related as a study by Kako et al28 suggests that also contribute to the overall antidepressant effect of extremely high doses of hypericum are needed to hypericum. actively inhibit MAO. Behavioral pharmacology in animals Effects on receptors The forced swim test (FCT) in rats is a well established ␤ The downregulation of 1-adrenoceptors has been com- behavioral animal model for the evaluation of antide- monly used as a biological marker of antidepressant pressant drugs that correlates well with their clinical efficacy. This pharmacological effect is one of the most efficacy.54 In this model hypericum has been shown to consistent findings after chronic administration of anti- have antidepressant effects with an optimal dose range depressants.29 A recent study showed that chronic of 250–500 mg kg−1.55,56 More recently antidepressant ␤ administration of hypericum downregulates 1-adreno- activity of hypericum was also observed in the learned ceptors in the frontal cortex, with no change in recep- helplessness test, which is also used in detecting tor affinity.17 This finding is similar to binding studies, potential antidepressants.57 The efficacy of the hyper- both in vivo and in vitro showing that chronic but not icum extract in these two models was correlated with acute, treatment with antidepressants drugs and ECT their hyperforin contents,56–58 suggesting that the hy- ␤ 29–32 downregulates 1-adrenoceptors in rat forebrain. perforin content may be the active constituent in hyp- Data from previous studies also suggest that adaptive ericum extracts responsible for antidepressant activity. changes in the 5-HT system may also play a pivotal This also supports recent evidence that hyperforin is role in the therapeutic effect of antidepressants. It has also the major bio-active substance responsible for been shown that long-term TCA and repeated ECT lead inhibiting synaptic re-uptake of monoamines.18 to an enhanced 5-HT neurotransmission through a pro- gressive sensitisation and upregulation of the post- Clinical pharmacology and efficacy in mild synaptic 5-HT1A receptors in the dorsal hippocam- depression pus.33–39 These findings have been further supported by Every new antidepressant that is implicated for the Haddjeri et al40 showing that long-term antidepressant treatment of depression needs to be evaluated in terms treatments result in a tonic activation of forebrain 5- of its efficacy and potential side-effect profile. In order

HT1A receptors. A similar mechanism has also been for St John’s Wort to be considered an effective antide- shown for hypericum. Teufel-Mayer and Gleitz41 pressant, evidence for its superior efficacy in compari- showed that chronic but not acute administration of son to placebo and at least equal efficacy in comparison The pharmacology of St John’s Wort PJ Nathan 336 to conventional treatment must be demonstrated. Sev- NA and DA) with comparable potencies to known anti- eral placebo-controlled studies have shown a superior depressants. Hypericum is also the only antidepressant efficacy of hypericum extracts compared to placebo in known that inhibits the uptake of all three monoamines mild-to-moderate depression.59–62 The overall signifi- with similar potencies. At a receptor level, chronic ␤ cant superiority of St John’s Wort over placebo was treatment with hypericum downregulates 1-adreno- also confirmed by a recent meta-analysis.3 The ceptors (similar to most antidepressants and ECT),

responder rates for persons receiving hypericum prep- upregulates post-synaptic 5-HT1A receptors (similar to 3 arations and placebo were 56% and 25% respectively. TCAs and ECT) and upregulates 5-HT2 receptors A number of recent studies have also shown equival- (similar to ECT). Moderate affinities for Sigma, NMDA ent efficacy of hypericum extracts compared to TCAs and GABA receptors have also been shown suggesting such as maprotiline, imipramine and amitriptyline in additional mechanisms for antidepressant effect. It has mild-to-moderate depression.63–66 The responder rates also been shown that most effects of hypericum in bio- in these studies were 50% for hypericum compared to chemical models of antidepressant activity can be 52% with standard antidepressants.3 explained by the major constituent hyperforin. Pre- The clinical efficacy demonstrated for most of these clinical behavioral studies suggest that hypericum is studies should be interpreted with caution because of active in animal models of depression, with compara- a number of methodological weaknesses. The most sig- ble potencies to standard antidepressants. Clinical nificant shortcoming is the relatively short duration of studies show superior efficacy of hypericum compared the trials. Most studies were conducted over 6–8 to placebo and comparable efficacy to conventional weeks, which means that data on the efficacy of hyper- antidepressants in the treatment of mild-to-moderate icum over a longer period of time is fragmentary. Sec- depression. The benefit of hypericum over other anti- ondly, comparisons with newer antidepressants such depressants may result from its favorable clinical side- as SSRIs or serotonin and noradrenaline re-uptake effect profile. inhibitors (SNRIs) are lacking. Thirdly, the different trials vary with regard to classification of types of References depression used to characterise patients. There is no consistent documentation on the exact diagnosis and 1 Upton R. St John’s Wort Monograph. Herbalgram. Am Herb Pharm- aco 1997; 40: 3–38. severity of illness. Finally, the types of hypericum 2 Snow JM. Hypericum perforatum L. (Hyperiaceae). J Bot Med 1996; preparation and the amount of different constituents 2: 16–21. varied in different trials. Most tested preparations were 3 Linde K, Ramirez G, Mulrow C. St John’s Wort in depression — standardised for hypericin content, but the amount an overview and meta-analysis of randomised clinical trials. BMJ 1996; 313: 253–258. varied from trial to trial (ie from 0.75 mg to 2.7 mg per 4 Ernst E. St John’s Wort as an antidepressive therapy. Fortschr Med day). A recent study also suggests that hyperforin con- 1995; 113: 354–355. tent is more important for clinical efficacy and pharma- 5 De Smet PA, Molen WA. St John’s Wort as an antidepressant. BMJ cological action.67 As hyperforin levels varied between 1996; 313: 153–157. hypericum preparations (between 0.5–6%), the phar- 6 IMS. IMS Verordnungsindex Pharma III/97. IMS GmbH, Ger- many, 1997. macological constituent responsible for the antide- 7 Muller WE, Kasper S. Editorial. Pharmacopsychiatry 1997; 30: S71. pressant effect may have varied from study to study. 8 Schutt H, Schulz V. Hypericum. In: Haensel R, Keller K, Rimpler The different preparations also varied in the amount of H (eds). Hagers Handbuch der Pharmazeutischen. Praxis: Berlin, total hypericum extract (ranged from 350–900 mg per 1993, pp 474–495. 9 Nahrstedt A, Butterweck V. Biologically active and other constitu- day). Hence the content of potentially active constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry ents also would have varied between studies. Future 1997; 30 Suppl 2: S129–S134. studies with well defined hypericum preparations and 10 Erdelmeier CAJ. Hyperforin, possibly the major non-nitrogenous well defined patient groups are needed for careful secondary metabolite of Hypericum perforatum L. Pharmacopsych- examination of the clinical efficacy of hypericum. iatry 1998; 31: 2–6. 11 Leonard BE. Neurotransmitter receptors, endocrine responses and An advantage hypericum has over other antidepress- the biological substrates of depression: a review. Human Psycho- ants is its favorable side-effect profile. Hypericum has pharmacol 1986; 1: 3–21. been shown to be well tolerated in patients with the 12 Leonard BE. Mechanism of action of antidepressants. CNS Drugs incidence of adverse reactions similar to that of pla- 1995; 4: 1–12. 68 13 Charney DS, Southwick SM, Delgado PL. Current status of the cebo. The most common adverse effects reported are receptor sensitivity hypothesis of antidepressant action. In: gastrointestinal symptoms (8.5%), dizziness/confusion Amsterdam JD (ed). Pharmacotherapy of Depression. Marcel (4.5%) and tiredness/sedation (4.3%). However, the Dekker: New York, 1990, pp 13–30. observed adverse effects are after short-term therapy 14 Leonard BE. Effect of antidepressants on neurotransmission: a com- and more long-term studies are desirable. mon mechanism of action? In: Osborne NN (ed.) Current Aspects of the Neurosciences. Macmillan: Basingstoke, 1992, pp 205–238. 15 Leonard BE. Comparative pharmacology of new antidepressants. Conclusion J Clin Psychiat 1993; 54: 3–15. 16 Rolli M, Schafer C, Muller WE. Effects of hypericum extract LI 160 St John’s Wort (hypericum) has a unique pharmacology on neurotransmitter receptor binding and synaptosomal uptake systems. Pharmacopsychiatry 1995; 28: 207–210. in that it displays the pharmacology of many different 17 Muller WE, Rolli M, Schafer C. Effects of hypericum extract LI 160 classes of antidepressants. The likely mechanism of in biochemical models of antidepressant activity. Pharmacopsychi- action is the inhibition of monoamine re-uptake (5-HT, atry 1997; 30 Suppl 2: 102–107. The pharmacology of St John’s Wort PJ Nathan 337 18 Muller WE, Singer A, Wonnemann M. Hyperforin represents the 41 Teufel-Mayer R, Gleitz RJ. Effects of long-term administration of neurotransmitter reuptake inhibiting constituent of hypericum hypericum extracts on the affinity and density of the central sero-

extract. Pharmacopsychiatry 1998; 31 Suppl 1: 16–21. tonergic 5-HT1A and 5-HT2A receptors. Pharmacopsychiatry 1997; 19 Hyttel J. Pharmacological characterization of selective serotonin 30 Suppl 2: 113–116. reuptake inhibitors (SSRIs). Int Clin Psychopharmacol 1994; 9: 42 Stolz JF, Marsden CA, Middlemiss DM. Effect of chronic antide- 19–26. pressant treatment and subsequent withdrawal on 3H-5-HT and 20 Briley M, Moret C. Antidepressant properties of specific serotonin- 3H-spipirone binding in rat frontal cortex and serotonin receptor noradrenaline re-uptake inhibitors. In: Skolnick P (ed). Antide- mediated behavior. Psychopharmacology 1983; 80: 150–155. pressants: New Pharmacological Strategies. Human Press: Totowa, 43 Nelson DR, Thomas DR, Johnson AM. Pharmacological effects of NJ, 1998, pp 35–51. paroxetine after repeated administration to animals. Acta Psychiatr 21 Neary JT, Bu Y. Hypericum LI-160 inhibits uptake of serotonin and Scand Suppl 1989; 350: 21–23. noradrenaline in astrocytes. Brain Res 1999; 816: 358–363. 44 Raffa RB. Screen of receptor and re-uptake-site activity of hypercin 22 Leonard BE. From animals to man: advantages, problems and pit- component of St John’s Wort reveals sigma receptor binding. Phar- falls of animal models in psychopharmacology. In: Hindmarch I, macol Lett 1998; 62: 265–270. Stoneir PD (eds). Human Psychopharmacology: Measures and 45 Klein M, Musacchio JM. High affinity dextromethorphan binding Methods. John Wiley & Sons: London, 1989, pp 23–66. sites in guinea pig brain. Effect of sigma ligands and other agents. 23 Suzuki O, Katsumata Y, Oya M. Inhibition of monoamine oxidase J Pharmacol Exp Ther 1989; 251: 207–215. by hypercin. Planta Med 1984; 50: 272–274. 46 Schmidt A, Lebel L, Koe BK, Seeger T, Heym J. Sertraline potently 24 Demisch L, Holzl J, Gollnik B. Indentification of selective MAO- displaces (+)-[3H]3-PPP binding to sigma sites in rat brain. Eur type-A inhibitors in Hypericum perforatum L. Pharmacopsychiatry J Pharmacol 1989; 165: 335–336. 1989; 22: 194–196. 47 Itzhak Y, Kassim CO. Clorgyline displays high affinity for sigma 25 Bladt S, Wagner H. Inhibition of MAO by fractions and constituents binding sites in C57BL/6 mouse brain. Eur J Pharmacol 1990; 176: of hypericum extract. J Geriat Psychiat 1988; 154: 125–134. 107–108. 26 Cott J. Medical plants and dietary supplements: sources for innov- 48 Rao TS, Cler JA, Mick SJ, Ragan DM, Lanthorn TH, Contreras PC ative treatments or adjusts? Psychopharmacol Bull 1995; 31: 131– et al. Opipramol, a potent sigma ligand, is an anti-ischemic agent: 137. neurochemical evidence for an interaction with the N-methyl-d- 27 Sparenberg BL, Demisch J, Holzl J. Untersuchungen u¨ ber die anti- aspartate receptor complex in vivo by cerebellar cGMP measure- depressiven Wirkstoffe von Johanniskraut. Pharm Ztg Wiss 1993; ments. Neuropharmacology 1990; 29: 1199–1204. 138: 239–254. 49 Matsuno K, Kobayashi T, Tanaka MK, Mita S. Sigma 1 receptor 28 Kako MD, al-Sultan II, Saleem AN. Studies of sheep experimentally subtype is involved in the relief of behavioral despair in the mouse poisoned with Hypericum perforatum. Vet Hum Toxicol 1993; 35: forced swimming test. Eur J Pharmacol 1996; 312: 267–271. 298–300. 50 Shirayama Y, Nishikawa T, Umino A, Takahashi K. p-Chlorophen- 29 Vertulani J, Sulser F. Action of various antidepressants treatments ylalanine-reversible reduction of sigma binding sites by chronic reduces reactivity of noradrenergic cyclic AMP-generation system imipramine treatment in rat brain. Eur J Pharmacol 1993; 237: in limbic forebrain. Nature 1975; 257: 495–496. ␤ ␤ 117–126. 30 Beer M, Hacker S, Poat J. Independent regulation of 1 and 2 adrenoceptors. Br J Pharmacol 1987; 92: 827–834. 51 Wonnemann M, Schafer C, Muller WE. Effects of hypericum 31 Heal DJ, Bristow LM, Hurst EM. Sex-related differences in central extracts on glutaminergic and GABAergic receptor systems. Pharm- adrenergic function and responsiveness to repeated administration acopsychiatry 1997; 30 Suppl 2: 237–240. of desipramine and electroconvulsive shock. Br J Pharmacol 1989; 52 Cott JM. In vitro binding and enzyme inhibition by hypericum 97: 111–118. extract. Pharmacopsychiatry 1997; 30 Suppl 2: 108–112. d 32 Hosada K, Duman RS. Regulation of beta 1-adrenergic receptor 53 Heresco-Levy U, Javitt DC. The role of N-methyl- -aspartate mRNA and ligand binding by antidepressant treatment and norepi- (NMDA) receptor-mediated neurotransmission in the pathophysiol- nephrine depletion in rat frontal cortex. J Neurochem 1993; 60: ogy and therapeutics of psychiatric syndromes. Eur Neuropsycho- 1335–1343. pharmacol 1998; 8: 141–152. 33 de Montigny C, Aghajanian GK. Tricyclic antidepressants: long 54 Shiah IS, Yatham IN. GABA function in mood disorders: an update term treatment increases responsivity of rat forebrain neurons to and critical review. Life Sci 1998; 63: 1289–1303. serotonin. Science 1978; 202: 1303–1306. 55 Willner P. The validity of animal models of depression. Psycho- 34 de Montigny C. Electroconvulsive treatments enhance responsive- pharmacology 1985; 83: 1–16. ness of forebrain neurons to serotonin. J Pharmacol Exp Ther 1984; 56 Butterweck V, Wall A, Lieflander-Wulf U et al. Effects of the total 228: 230–234. extract and fractions of Hypericum perforatum in animal assays 35 Welner SA, de Montigny C, Desroches J, Desjardins P, Surani- of antidepressant activity. Pharmacopsychiatry 1997; 30 Suppl 2: 117–124. Cadotte BE. Autoradiographic quantification of serotonin1A receptors in rat brain following antidepressant drug treatment. Synapse 57 Bhattacharya SK, Chakarabarti A, Chattergee SS. Activity profiles 1989; 4: 347–352. of two hyperforin-containing hypericum extracts in behavioral 36 Nowak G, Dulinski J. Effect of repeated treatment with electrocon- models. Pharmacopsychiatry 1998; 31 Suppl 1: 22–29. vulsive shock (ECS) on serotonin receptor density and turnover in 58 Chattergee SS, Bhattacharya SK, Wonnenmann M. Hyperforin as a the rat cerebral cortex. Pharmacol Biochem Behav 1991; 38: 691– possible antidepressant component of hypericum extracts. Life Sci 694. 1998; 63: 499–510. 37 Stockmeier CA, Wingenfeld P, Gudelski GA. Effects of repeated 59 Sommer H, Harrer G. Placebo-controlled double blind study exam-

electroconvulsive shock on serotonin1A receptor binding and recep- ining the effectiveness of a hypericum preparation in 105 mildly tor mediated hypothermia in the rat. Neuropharmacology 1992; 31: depressed patients. J Ger Psych & Nerol 1994; 7: 9–11. 1089–1094. 60 Hubner WD, Lande S, Podzuweit H. Hypericum treatment of mild 38 Burnet PWJ, Michelson D, Smith MA. The effect of chronic imipra- depressions with somatic symptoms. J Gert Psychiat Neurol 1994;

mine administration on the densities of 5-HT1A and 5-HT2 receptors 7: 12–14. and the abundance of 5-HT receptors and transporter mRNA in the 61 Hansgen KD, Vesper J, Plouch M. Multicenter double blind study cortex, hippocampus and dorsal raphe of three strains of rat. Brain examining the antidepressant effectiveness of the hypericum Res 1994; 638: 311–313. extract LI 160. J Ger Psychiat & Neurol 1994; 7: 15–18. 39 Blier P, De Montigny C, Chaput Y. A role for the serotonin system 62 Scrader E, Meier B, Brattstrom A. Hypericum treatment of mild- in the mechanism of action of antidepressant treatment: pre-clini- moderate depression in a placebo-controlled study. A prospective, cal evidence. J Clin Psychiatry 1990; 51 Suppl 4: 14–20. double blind, randomised, placebo controlled, multicentre study. 40 Haddjeri H, Blier P, de Montigny C. Long term antidepressant treat- Human Psychopharmacol 1998; 13: 163–169.

ments result in tonic activation of forebrain 5-HT1A receptors. 63 Vorbach EU, Hubner WD, Arnold KH. Effectiveness and tolerance J Neurosci 1998; 18: 10150–10156. of the hypericum extract LI 160 in comparison with imipramine: The pharmacology of St John’s Wort PJ Nathan 338 randomised double blind study with 135 out patients. J Geriat Psy- 66 Weatley D. LI 160, an extract of St John’s Wort, versus amytripty- chiat Neurol 1994; 7(Suppl 1): S19–S23. line in mildly to moderately depressed out patients — a controlled 64 Vorbach EU, Arnold KH, Hubner WD. Effectiveness and tolerance 6-week clinical trial. Pharmacopsychiatry 1997; 30 Suppl 2: 77–80. of the hypericum extract LI 160 versus imipramine in patients with 67 Laakmann G, Schule C, Bagha T et al. St John’s Wort in mild to severe depressive episodes according to ICD-10. Pharmacopsychia- moderate depression: the relevance of hyperforin for the clinical try 1997; 30 Suppl 2: 81–85. efﬁcacy. Pharmacopscyhiatry 1998; 31 Suppl 1: 54–59. 65 Harrer G, Hubner WD, Podzuweit H. Effectiveness and tolerance of 68 Ernst E, Rand JI, Barnes J, Stevinson C. Adverse effects proﬁle of the hypericum extract LI 160 compared to maprotiline: a multi- the herbal antidepressant St John’s Wort (Hypericum perforatum centre double-blind study. J Geriatr Psychiatr Neurol 1994; 7: L.). Eur J Clin Pharmacol 1998; 54: 589–594. S24–S28.