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Year: 2010

A extract in the treatment of depressive symptoms in outpatients: an open study

Melzer, J ; Brignoli, R ; Keck, M E ; Saller, R

Abstract: Background: Extracts of have demonstrated in randomized trials (RCTs) to be effective in mild to moderate depressive episodes, However, as their use in dailyprac- tice may differ from that in RCTs we have conducted a study to achieve a better estimate oftherange and frequency of adverse drug reactions (ADR) and the efficacy. Patients and Methods: In an obser- vational study in Germany, adult outpatients with depressive syndrome were treated with an extract of St. John’s Wort. Study duration was 12 weeks, with control visits every 4 weeks, Besides anamnestic data, the variables assessed were: evolution of ICD-l0 derived sympscore, Global Clinical Impression scale (GCI), and toleraoility, Results: 1,778 patients from 304 centers participated in the study (mean duration of disorder 7.3 ± 18.9 months), and 1,541 patients completed it. At the last control visit the ICD-l0 sum score had dropped by 63.1 % and the proportion of patients described as ’normal to mildly ill’ (GCI-s) had increased from 21 .6% at admission to 72.4%. Regarding the GCI-i, 77% of the patients had improved ’very much’ or ’much’ at the last visit. This was consistent with their self-assessment (76%). Lower age and shorter duration of the disorder were associated with significantly better outcomes, The incidence of ADRs was 3,54% and had been decreasing continuously fram the first contra I visit onwards; serious ADRs did not occure, Conclusions: The herbai drug was weil tolerated, and no new or serious ADR were identified. In view of the limitations inherent to the study design, it can be concluded that extracts of St. John’s Wort are effective as an in the management of in daily practice.

DOI: https://doi.org/10.1159/000277628

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-32976 Journal Article Published Version

Originally published at: Melzer, J; Brignoli, R; Keck, M E; Saller, R (2010). A Hypericum extract in the treatment of depressive symptoms in outpatients: an open study. Forschende Komplementärmedizin, 17(1):7-14. DOI: https://doi.org/10.1159/000277628 Original Article . Originalarbeit Forschende Komplementärmedizin Wissenschaft. Praxis· Perspektiven Forsch Komplementmed 2010;17 :7­14 Published o nline: Fe bruary 3, 201 0 001: 10.1159/000277628

A Hypericum Extract in the Treatment of Depressive Symptoms in Outpatients: An Open Study

a C b a Jörg Melzer , b Reto Brignoli Martin E. Keck , d Reinhard Saller a Institute of Complementary Medicine, Dept. of Internal Med icine, University Hospital Zurich, b Cliena Schloessli, Private Hospital for and , Oetwil am See,

C Clinical pharmacology ­ Tradyser Inc., Rüschlikon, d Neu roscience Center, Zürich, Switzerland

Key Words Schlüsselwörter Hypericum perforatum . Herbai drugs . Phytotherapy , Hypericum perforatum ' Pflanzliche Medikamente · Antidepressant, Open­label trial· Phase 4 ' Drug toxicity Phytotherapie , Antidepressivum , Offene Studie· Phase 4 . Medikamentenverträglichkeit Summary Background: Extracts of Hypericum perforatum have demon- Zusammenfassung strated in randomized trials (RCTs) to be effective in mild to Hintergrund: In randomisierten Studien (RCT) zeigen sich Jo- moderate depressive episodes, However, as their use in daily hanniskrautextrakte in der Behandlung von Patienten mit mil- practice may differ from that in RCTs we have conducted a den bis mäßigen depressiven Episoden als wirksam. Da sich study to achieve a better estimate of the range and frequency die Anwendung in der ärztlichen Alltagspraxis jedoch von of adverse drug reactions (ADR) and the efficacy. Patients RCTs unterscheiden kann, führten wir eine Studie durch, um and Methods: In an observational study in Germany, adult Spektrum und Häufigkeit unerwünschter Arzneimittelwirkun- outpatients with depressive syndrome were treated with an gen (UAW) sowie Aspekte der Wirksamkeit besser abschätzen extract of St. John's Wort. Study duration was 12 weeks, with zu können. Patienten und Methode: In einer offenen Studie in control visits every 4 weeks, Besides anamnestic data, the Deutschland wurden erwachsene Patienten, die an einem de- variables assessed were: evolution of ICD­l0 derived symp- pressiven Syndrom litten, 12 Wochen lang (mit 4­wöchent- \Dm score, Global Clinical Impression scale (GCI) , and tolera- lichen Kontrolluntersuchungen) ambulant mit einem Johan- oility, Results: 1,778 patients from 304 centers participated in niskrautextrakt behandelt. Neben den anamnestischen Daten the study (mean duration of disorder 7.3 ± 18.9 months), and wurden folgende Variablen untersucht: ICD­l0­basierter Sym- 1,541 patients completed it. At the last control visit the ICD­l0 ptomscore, Global Clinical Impression Scale (GCI), Verträg- sum score had dropped by 63.1 % and the proportion of pa- lichkeit. Ergebnis: 1778 Patienten aus 304 Arztpraxen nahmen tients described as 'normal to mildly ill' (GCI­s) had increased an der Studie teil (durchschnittliche Krankheitsdauer 7,3 ± from 21 .6% at admission to 72.4%. Regarding the GCI­i, 77 % 18,9 Monate) und 1541 beendeten die Studie. Bei der letzten of the patients had improved 'very much' or 'much' at the last Kontrolluntersuchung war der ICD­l0­Summenscore um visit. This was consistent with their self­assessment (76%). 63,1 % gesunken. Der Anteil der Patienten, die sich als «nor- Lower age and shorter duration of the disorder were associ- mal bis leicht krank» (GCI­s) einstuften, war von 21,6% zu Be- ated with significantly better outcomes, The incidence of ginn auf 72,4% am Ende der Studie gestiegen. Bezogen auf ADRs was 3,54% and had been decreasing continuously fram die GCI­i ging es 77 % Patienten am Ende «sehr viel» oder the first contra I visit onwards; serious ADRs did not occure, «viel» besser, was mit der Selbsteinschätzung der Patienten Conclusions: The herbai drug was weil tolerated, and no new (76%) gut übereinstimmte. Ein niedrigeres Alter und eine kür- or serious ADR were identified. In view of the limitations in- zere Erkrankungsdauer waren mit einem signifikant besseren here nt to the study design, it can be concluded that extracts Outcome verbunden. Die Inzidenz von UAW betrug 3,54% of St. John's Wort are effective as an antidepressant in the und nahm von der ersten Kontrolluntersuchung an kontinuier- management of depression in daily practice. lich ab; schwerwiegende UAWs wurden nicht beobachtet. Schlussfolgerung: Das pflanzliche Medikament wurde gut vertragen; es wurden keine neuen oder schwerwiegenden UAW berichtet. Vor dem Hintergrund der Einschränkungen durch das Studiendesign kann die Intervention als wirksam in der Behandlung von Patienten mit Depressionen in der AII- tagspraxis angesehen werden.

© 2010 S. Karger G mbH. Freiburg Jörg Melze r. MD KARGER Institute of Complemenlary Medicine f.x +49 7614 52 07 14 A ccess ible o nline ('1 1: Departme nt of Internal Medicinc. U ni versit y Hospital Z urich In ()rmation@Karge r.de www.karger.com/fok Raemislrasse 100. CH·809 1 Z urich. Swil zerland w\\'w. karge­r.com Tel. +41 44255-2460. Fax -439 4 joerg.melzer@usz. ch Background The study presented here is an open, descriptive, observa• tional (case series) study with a proprietary ethanolic extract Depression is associated with significant social and functional of Hypericum perforaturn, conducted under conditions of impairments as weil as high direct and indirect health care daily practice in Germany. The scope of such studies is to ob• costs [1 , 2]. Depressive disorders have been reported to cause ta in information on prescription modalities, acceptability. even greater functional disability than diabetes, chronic lung compliance of the , achieve a bett er estimate of the disease, hypertension, or back pain [3]. Depressive disorder is frequency of adverse effects (and possibly identify rare, hith• a chronic disorder which is often characterized by relapses erto unknown adverse reactions) and get a broader picture of and recurrences. The lifetime risk of depression is 10-25% for the efficacy (e.g. inclusion of subgroups not studied in earlier women and 5-12% for men [4,5]. Furthermore, epidemiologi• trials) [12]. cal data suggest that 75-80% of patients experience recurrent depression. The rate and timing of recurrence mainly seems to depend on th e type of recovery. In patients who recovered Patients and Methods completely the rate of recurrence was much lower and the time to recurrence was much longer than in patients with re• Study Design and Variables sidual symptoms [6]. Patients with depressive disorders were treated with a herbai preparation of Hypericum perforaturn (Helarium"', Bionorica AG, Neumarkt. Ger• Recent research in a setting comparable to daily practice many) in a community-based outpatient setting in Germany. The phys i• has demonstrated that about 50% of patients respond to the cians participating in this observational multicenter study included gen• first antidepressive monotherapy but only about 30% achieve eral practitioners, internists, neurologists, and psychiatrists. The diag• remission [7] . The rate of remission can be increased to al• noses were descriptive in th e wordings of the investigators (treating phy• most 50% when a second drug is used if the initial antidepres• sician) and later coded according to ICD-10 (one main term and one descriptor term by R.B.). The ICD-derived scales were validated with the sant drug fails. With an ongoing sequential monotherapy, with HAMD 17 and its subscores and correlated weil (data presented else• a change to a third or fourth drug, remission can be improved where). Treatment was documented for adult outpatients with depressive by an additional 10% each time [5]. However, in -con• symptoms that required a pharmacological intervention. trolled trials high relapse rates of 40-60% were observed Patients with any contraindication for Hypericum, with poor tolerabil• within 6 mdnths after discontinuation of the antidepressant ity in a previous treatment with Hypericum, or who currently participated in a c1inical study were not included in the study. Hypericum dosage was treatment [8, 9]. Therefore, further treatment strategies and initiated according 10 the recommendations in the package insert, but more effective or better tolerated agents continue to be re• could subsequently be adjusted according 10 the physician's estimate re• quired in order to improve treatment outcomes in all 3 phases garding best balance of efficacy and tolerability. The length of the trial of depression management commonly accepted: (1) acute was set at 3 monlhs in order to allow sufficient time for a response to con• phase, usually 6-12 weeks; (2) continuation phase, in which solidate and for c1inical benefits 10 be evident. Data assessment was performed at 4 times: at baseline and at weeks 4, the goal of the treatment is to maintain the absence of depres• 8, and 12 (study termination), with the idea of identifying adverse drug sive symptoms for an additional 4-9 months so that the de• reactions (ADRs) and estimating change of symptoms in terms of early pressive episode can be considered completeJy resolved; and response and at study end to see the maximum achieved effect. Demo• (3) maintenance phase, i.e. often several years during which graphics (age, sex, marital and professional status) and psychiatrie hi story the goal of the treatment is to prevent the recurrence of an• (duration of current episode, current diagnosis, concomitant di seases and medication, prescribed dosage of Hypericum [Helarium® capsules or tab• other distinct depressive episode. lets]) were recorded at the baseline visit (table 1). The goal of treatment is to achieve full remission of symp• The Clinical Global Impression scale (CGI) was used to evaluate the toms, which may take up to 4 months, and to maintain remis• extent of change during treatment with Hypericum, as the CGI can be sion. To this end, according to current guideJines the antide• wide ly used in psychiatry [13]. Severity was assessed by the 7-point CGI pressant to be given should be matched to the individual pa• - severity scale (CGI-s; 1 = normal/not at all ill ; 7 =extremely ill). The description of this scale states that 'the severity of illness item requires the tient's requirements considering [10, 11]: c1inician to rate the severity of the patie nl 's illness at the time of assess• - previous treatment response to a particular drug, ment, relative to the c1inician 's past experience with patients who have - tolerability and adverse effects of a previously given drug, the same diagnosis'. - profile of side effects (e.g. sedation, weight gain), The extent of improvement was assessed by the 7-point CGI - im• - low lethality, if history or likelihood of overdose, provement scale (CGI-i; 1 = very much improved; 7 = very much wors.:) at the 2nd, 3rd, and fin al visit. The CG1-i asks the c1inician to rate ho\\ - concurrent physical illness or condition that may make the much the patient's illness has improved or worsened relative to a bas.: lin c: antidepressant more noxious or less tolerated, state. A patient's iJlness is compared to change over time and rated ..-\d• - concurrent medication that may interact with the antide• ditionally, Ihe patients also evaluated their status themselves by e mplo\• pressant drug, ing simplified ve rsions of the CGI-s and the CGI-i. - associated psychiatrie disorder that may specifically re• ICD-10 criteria were used to construct a severity rating on a sc- k from 0 = absent, to 4 = severe; that is: (1) 'depression' (mood ( aff~c ­ spond to a particular dass of antidepressant (e.g. obsessive tive) disorders, F30-F39): such as lowering of mood, loss or int Lr~, \. compulsive disorder and reuptake inhibitors), lack of energy, reduction of self-esteem; (2) '' (neurolic. sIr <• - patients' preference. related, and somatoform disorders, F40-F44, F48): such as e\ c~ , 01

8 Forsch Komplementmed 2010;17:7-14 Melzer/B rignolilKeckiSaller Table 1. Patient data at baseline and patient flow For each block, the sum score and the highest individual score were calculated. Furthermore, the patients were administered a visual ana- Patients included, 0 1778 logue scale (VAS; ranging from 'I feel very bad' to ' I feel very weil') with Sex, n (%) lower values indicating better subjective feelings. In addition, current -Male 367 (20.9%) treatments, modifications in the dosage of lhe herbai drug, as weil as - Female 1411 (79.1 %) ADRs (mentioned spontaneously or after general question, respectively), were documented at all visits. Age, years -Mean (SO) 49.76 (15.2) - Range 18-97 SI. John's Wort (Hypericumper[oralum) One of the problems encountered with herbaI extracts, even from SI. Mean (SO) time suffcring from disorder, n:t0nths 7.3± 18.9 10hn's wort, is the variation of their compounds between different prepa- rations [15]. The herbaI drug itself (i.e. the raw material) is a complex Profession, n (%) 1741 (97.9%) multicompound [16], and ­ depending on the extraction method ­ its ex- - Housewife/man 440 (24.7%) tracts may differ in quantity and qualitiy [17]. However, Hypericum ex- -Part-time 221 (12.4%) traxts possess a moderate to high potency to inhibit the reuptake of -Full-time 611 (34.4%) monoamines, serotonin, dopamine, noradrenaline, and the amino­acid - Retired 314 (17.7%) GABA and glutamate. Unlike standard reuptake in- - Unemployed 155 (8.7%) hibitors, Hypericum exerts this reuptake inhibition in a non­competitive Marital status, n (%) 1741 (97.9%) way by enhancing intracellular Na+­ion concentrations [19]. Recent stud- - Single 252 (14.2%) ies indicate that SI. 10hn's wort is capable of increasing the in­vivo -Married 1021 (57.4%) dopamine release [19], appears to increase extracellular dopamine levels - Widowed 246 (13.8%) in the brain [20] and increase plasma concentration of dihydroxypheny- - Divorced 222 (12.5%) lacetic acid (DOPAC), the main metabolite of dopamine, possibly by an Dropouts, n 237 inhibitory effect on dopamine beta­hydroxylase [21]. - Due to patients requestlwithdrawal of consent 74 For this study, the extract provided by the manufacturer, was Helar- - Termination of treatment before 3rd visit 70 ium Hypericum®, a hypericum extract with 255­285 mg dry ethanolic - Due to inefficacy 53 exlract per coated tablet, standardized to hypericin 0.3% and of a hyper- forin content of 2­3%, or Helarium­425® with 425 mg dry ethanolic ex- - Reason unknown 37 tract per capsule (DER 3.5­6:1). Helarium­425® is slandardized to hyper- - Due to advers~ effects (n) 3 icin 0.1 ­ 0.3% and has a hyperforin content of max. 6%, flavonoid/ rutoside min. 6% in the extract. Patients analyzed, n 1541

Concomitant treatments, n (%) 194 (10.91 %) - Antidepressive: tricyclic 21 (1.18%) Statistical Methods -SSRI 17 (0.96%) Statistical analysis was performed with WinST AT 2001.1 for Windows (SPSS­validated). The continuous data are presenled as means and stand- - MAO inhibitors 2(0.11%) ard devialions (SO); additionally, medians, 95% confidence intervals - Hypericum 0(0%) (CIs) as weil as ranges, and numbers (n) of patients were calculated. Cat- -NaSSA 5 (0.28%) egorical data are presented using counts (n) and percentages rounded to 1 - Antipsychotic: neuroleptics 15 (0.84%) decimal place. All p values are 2­tailed, and p < 0.05 was considered sta- - Lithium 1 (0.06%) tistically significant. Unless stated otherwise, values before versus after - : herba I 31 (1.74%) treatment were compared by means of the Student's t­test, or the x'­test - Hypnoticlsedative: benzodiazep./ 46 (2.59%) for nominal or ordinal data. The safety population, defined as subjects Imidazopyridine who received ~1 dose of any study drug and for whom post­dose data - Hormonal: HRT 10 (0.56%) were available, were used in the analysis and evaluation of the safety - Cardiac: nitrates 0(0%) variables. - Beta-blockers 3 (0.17%) The influence of demographic factors (age, duration of disorder, gen- - Analgesic: NSAID 14 (0.79%) der) and the ICD­lO derived score at admission and at the final visit were - Varia, not psychopharmaceutical 27 (1.52%) examined by multiple stepwise regression analyses. - Not pharmaceutical 2 (0.11 %)

HRT: Hormonal replacement therapy; MAO inhibitor: Monoamine oxi- dase A inhibitor; NaSSA: Noradrenergic and specific serotonergic anti- Results depressant; NSAlD: Non steroidal anti­inflammatory drug; SSRI: Selec- tive serotonin reuptake inhibitor. Demographies and Data at Admission

304 centers participated in this study with a total of 1,778 pa- anxiety and fears; (3) somatic symptoms related to anxiety/depression tients (1­17 patients per center), recruited during winter and (neurotic, stress­related, and somatoform disorders, F40­F44, F48): spring 1999. The (cumulative) number of dropouts was 38 at such as cardiovascular, or digestive, or respiratory, or muscular trou- visit 1 (after 28.1 ± 30.2 days), 115 at visit 2 (after 57.6 ± 32.7 bles; (4) somatoform disorders (F45): such as multiple somatic troubles, refuses medical diagnoses, continuous suffering due to days), and 237 patients at visit 3 (after 89.8 ± 36.6 days; table symptoms. 1). Questioned about it, 810 patients (45.6%) reported having

Hypericum for Depression in Outpatients Forsch Komplementmed 2010;17:7­14 9 Table 2. CGI-s at CGI Visit Q Visit 1 Visit 2 Visit 3 Last visit LOCF admission, at each control visit and Normal (not at all iU) 14(0,8% ) 28 (1,6%) 92 (5,2 %) 275 (15,4 %) 296 (16,6%) LOCF (LOCF vs. ad- Borderline mentally ill 88 (4,9%) 98(5,5 %) 156 (8,7%) 191 (10,7 %) 214 (12 %) mission, p < 0.001) Mildlyill 282 (15 ,8%) 405 (22,7%) 649 (36,4%) 690 (38,7%) 769 (43 ,1 %) Moderately ill 607 (34%) 650 (36,4 %) 525 (29,4%) 257 (14,4%) 310 (17 ,4%) Markedly ill 616 (34,5%) 475 (26,6%) 191 (10,7%) 86 (4,8 %) 130(7,3%) Severely iU 133 (7,5%) 63 (3,5 %) 24 (1,3%) 15 (0,8 %) 25 (1,4%) Extremely ill 6 (0,3 %) 4 (0,2%) 1(0,1 %) 0(0%) 0(0%)

N =1784 1757 (98,5%) 1740 (97,5%) 1652 (92,6%) 1527 (85,6%) 1757 (98,5%) Not assessable 11 (0,6%) 17 (1 %) 14 (0,8%) 13 (0,7%) 13 (0,7%) No da ta 21 (1 ,2%) 38(2,1%) 126 (7 ,1 %) 251 (14 ,1 %) 21 (1 ,2%)

Table 3. Patients' self-assessment at control Parameter Visit 1 Visit 2 Visit 3 Last visit LOCF visits and rating according to CGI-i (LOCF vs. admission, p < 0.001) Very much improved 61 (3.4 % ) 199 (11.2%) 51 8 (29.1%) 556 (31.3%) Much improved 350 (19.7%) 745 (41.9%) 722 (40.6 %) 795 (44.7%) Minimally improved 856 (48.1 %) 581 (32.7 %) 218 (12.3%) 272 (15.3%) No change 424 (23.8 %) 103 (5 .8%) 57 (3.2%) 87 (4.9 %) MinimaUy worse 33 (1.9 %) 15 (0.8%) 9 (0.5 %) 12 (0.7%) Much worse 13 (0.7%) 13 (0.7 %) 8(0.4%) 14 (0.8%) Very much worse 4 (0.2 %) 3 (0.2%) 1 (0.1 %) 5 (0.3%)

N =1778 1741 (97.9%) 1659 (93 .3%) 1533 (86.2%) 1741 (97.9%) No da ta 37 (2.1 %) 119 (6.7 %) 245 (13.8%) 37 (2.1%)

had similar problems before; in 1,073 patients (60.3%) an or- patients, respeetively). These eontinued to be the favored ganie eause had been excluded, whereas in 88 patients (4.9%) sehedules as the trial went on. it was eonfirmed; 1,068 patients (60.1 %) reported psyehoso- In addition to the Hyperieum treatment, 492 patients eial stress preeeding their problems, and 850 (47.8%) feit they (27.7%) reeeived supportive psyehotherapy (n = 335; 18.8%), were related to external events or eireumstanees. 64 patients speeifie psyehotherapy (n = 56; 3.1 %), gymnasties (n = 35; 2%), (3.6%) admitted an addietion in the past, and 51 patients ete. (2.9%) at the time of admission. The addietions reported At admission, 145 (8.16% ) of the patients diseontinued ranged from alcohol (n = 72, 4%), pharmaeeutieals (n = 17, their psyehotropie medieation, mostly antidepressants, anxio- 1 %), drugs (n = 5, 0.3% ) to those 'not speeified' (n = 11, lyties, and hypnoties/sedatives. During the study, 134 patients 0.6%). reeeived 194 new preseriptions, predominantly hypnoties/sed- The vast majority of the patients were diagnosed with de- atives, antidepressants, and anxiolyties. Noteworthy is the low pressive episodes (F32.0­F33.9; n = 1,481; 83.3%); other diag- proportion of patients medieated at admission , and the very noses eould be classified as neurotie, stress­related and so- limited number of eo­preseriptions whieh might refleet the matoform disorders, i.e. anxiety (F40­F48: n = 137; 7.71 %), mostly mild to moderate nature of the depressive disorders psyehovegetative syndrome (F45.3: n = 123; 6.9%), exhaus- treated. tion (F43­F43.9: n = 107; 6.0%), ete. Only 2 patients (0.1 %) were diagnosed with bipolar disorder (F31.9). Considering the highest ICD­derived subseore, depression predominated in Outcomes 892 patients (50.17 % ), while anxiety predominated in 735 (41.34%) and somatie symptoms of anxiety/depression in 151 Clinical Global Impression patients (8.49%). The proportion of patients deseribed as 'normal' to 'mildly ill' The treatments preseribed were either Helarium® tablets inereased from 21.6% at admission to 72.4% at the last visit (n = 452; 25.42%) or Helarium­425® eapsules (n = 1,319; (visit 3, last observation earried forward ­ LOCF. table 2). 74.18% ; no data: n = 7; 0.39%). The mean daily dose was Consistently, the proportion of those rated as 'moderately ill' 822.5 ± 205.4 mg dry ethanolie Hyperieum extraet at admis- or 'worse' deereased from 76.6% to 26.5%. Regarding th e sion (range 425­1,700 mg) and 754.4 ± 231.1 mg at the last CGI­i, at the last visit (LOCF) 77 % of the patients were re- visit. The most eommonly preseribed dosage sehedules were ported to have (very) mueh improved. That was eonsistent an intake twiee or three times daily (58.6% or 27.1 % of the with the patients' self­assessments aeeording to whieh 76 %

10 Forsch Komplementmed 2010;1 7:7­14 Melzer/Brignoli/Keck/Saller 25

20 ..

15 0

""~ 8 10 -- Depressivity -a- Anxiety ___ Somatic S. of anxietyldepress. - Somatoform disorder had improved (very) much (table 3). In all of these seal es the was highly significant, i.e. p < 0.001, but there were no data of improvement was progressive and largest at the end of the 33.4% of the patients. trial. Comparing the ratings at the last visit (LOCF) with those at admission, improvements were highly significant in Factors Affecting Outcome all three of these variables. Higher age, longer duration of the disorder (frequently asso• ciated with earlier episodes) and the ICD-lO derived sum [CD-lO Derived Scores score at admission were associated in stepwise regression The ICD-10 derived scores are regarded as me an va lues of analyses with a higher, i.e. worse, ICD-lO derived sum score the 4 subscores over time and as mean scores of the individual at the final visit (constant: -5.95, ± 95% CI 3.98, P = 0.003; symptoms at admission and at the last visit (patients 'on treat• age: coefficient 0.08, ± 95% CI 0.05, P < 0.001; duration: coef• ment'; fig. 1). ficient 0.08, ± 95% CI 0.05, P = 0.001; ICD sum score at ad• After 4 weeks of treatment (visit 1), the mean total sum mission: coefficient 0.27, ± 95% CI 0.08, P < 0.001). Higher score had diminished significantly by 23.6%, without major doses at admission were also associated with poorer outcomes differences between subscores (depression: -23.2%, anxiety: (p = 0.037), probably reflecting more serious conditions at the -24.9%, somatic symptoms of anxiety/depression: -21.8%, so• outset. Comparing the improvements of the highest and low• matoform disorder: -24.8%; all p < 0.001). The reduction had est quintiles of the study sampie by ICD-10 derived sum continued significantly at the 2nd control visit after approxi• scores at admission , age or duration of disorder (variable: mately 8 weeks of treatment; the total sum score had dimin• CGI-i at last visit LOCF), the ICD-10 derived sum score had ished by 46% compared to admission (depression: -46.6%, no influence on the outcome. Lower age and shorter duration anxiety: -47%, somatic symptoms of anxiety/depression: of disorder were associated significantly more often with -42.2%, somatoform disorder: -47%; all p < 0.001). At the being rated as 'very much improved'. last control visit, the mean total sum score had dropped sig• nificantly by 63.1 % with some differences between subscores, i.e. the somatic symptoms related to anxiety/depression di• Safety minished less, i.e. by 55.7% (depression: -63.6%, anxiety: -62.6%, somatoform disorder: -66.9%; all p < 0.001) (fig. 2). Patients rated the tolerance as 'very good' (n = 1,172; Comparing the mean ICD-lO derived scores at admission 65.92%), 'good' (n = 500; 28.12%) and 'moderate, poor or and at visit 3 there is a homogeneous reduction of the indi• very poor' (n = 27; 1.51 % ; assessed: n = 1,721 ; 96.79%). The vidual symptoms rated. Noteworthy is the low score of sui• frequency of ADR was 3.54% (any event counted once per cidal thoughts already at admission, which seems indicative of patient; table 4) and decreased from 2.9% at the first control the mostly mild to moderate nature of the depressive disor• visit to 1.2% at visit 2, and 1 % at visit 3. The only ADR re• ders treated. ported by >1% of the patients were gastrointestinal troubles and tiredness; followed by photosensibilization and restless• Visual Analogue Seale (VAS) ness (0.7% each). The patients were administered a V AS at each visit. The In terms of adverse events, 5 patients (0.3%) were hospital• steady and significant drop of its mean value indicates an im• ized due to psychiatrie reasons and 1 due to an aggravation of proved subjective well-being of the patients. The difference a previously known colitis ulcerosa before the first control

Hypericum for Depression in Outpatients Forsch Komplementmed 2010;17:7-14 11 lowering of mood cardiovascular troubles alteredldiminished appelile impaired social or digestive troubles professional functioning

dislurbed lack of energy sleep respiratory numbness I troubles dazzing psychomolori re du elion of retardation self-esteem and or agilalion self-confidenee vertigo muscular troubles diffieully Ideas of guill or eoneentrating worthlessness orlhinking suieidal Ihoughls (F322, severe depression) loss oflibido c cephalgia exess. anxiely and fears diffieully in eoping wilh panie anaeks anxlely and fear multiple somalle troubles

dislurbed feeling of sleep unsleadiness exeilability of refuses medleal autanomous diagnosis nel'!. system

jumplness motarie agitation

diffieully conllnuous severe pein conllnuous preoceupallon and eoncenlraling d sUffering due 10 symploms

Fig. 2. Mean ICD-10 derived symptom scores for rating of the severity of adepression, b anxiety, c somatic symptoms related to depression or anxi- ety, d somatoform di sorders re lated to depression or anxiety (. =admission and 0 =visit 3, scores 0­4).

Table 4. Summary of ADRs recorded at each ADR Visit 1 Visit2 Vis.it 3 Total visit and total Gastrointestinal troubles 16 (0.9%) 5 (0.28%) 4 (0.22%) 20 (1.12%) Tiredness 12 (0.67%) 8(0.45%) 7 (0.39%) 19 (1.07%) Photosensibilization 11 (0.62%) 3(0.17%) 2 (0.11 %) 11 (0.62%) Restlessness 9 (0.51 %) 2(0.11%) 3(0.17%) 10 (0.56%) Allergic skin reaction 2(0.1 1%) 2 (0.11 %) 1 (0.06%) 3 (0.17%) Appetite increased 2 (0.11 %) 0(0%) 0(0%) 2 (0.11%) Dizziness, beadache 1 (0.06%) 1 (0.06%) 1 (0.06%) 1 (0.06%) Constipated 1 (0.06%) 0(0%) 0(0%) 1 (0.06%) Polyuria 1 (0.06%) 0(0%) 0(0%) 1 (0.06%) Acroparesthesias 1 (0.06%) 0(0%) 0(0%) 1 (0.06%) Difficu1ty swallowing capsule 1 (0.06%) 0(0%) 0(0%) 1 (0.06%) Vertigo 0(0%) 1 (0.06%) 0(0%) 1 (0.06%)

ADRs,n 57 22 18 71 Patients with ADRs, n 52 (2.92%) 21 (1.18%) 17 (0.96%) 63 (3.54%) visit. There were no deaths reported in this study. A house­ treatment and was withdrawn from the trial . She received no wife aged 57 taking Helarium 425® was reported to have se­ other medication at the time and no other data of interest verely increased photosensitivity during the first month of were reported. Another female, aged 67years, also withdrew

12 Forsch Komplemenlmed 2010;17:7­14 Melzer/BrignolilKeck/Saller from the trial due to increased photosensitivity and a male pa• vere depression. Yet, the patient group studied here corre• tient, aged 63 years, withdrew due to a '' not speci• sponds to a community-based population generally found in fied further. outpatient settings. Furthermore, although we found that the The frequency of ADRs was similar in patients who re• duration of depression correlated negatively with the duration ceived comedication, whether psychotropic or not. However, of the disorder, this could not be analyzed in more detail due the number of these patients is relatively small (n =134). Cu• to a lack of data. Finally, the ICD-lO score used may seem taneous reactions, including increased photosensitivity, were unusual. Yet it was chosen in order to facilitate a transfer of reported more frequently in males (due to more exposure to the physicians' diagnoses in daily practice into diagnostic cat• sunlight?) whereas digestive troubles and tiredness were more egories. In order to ensure correspondence with commonly frequent among female patients. used psychometric instruments, the ICD-derived scales were validated with the HAMDn and its subscores and correlated significantly. Discussion Although St. John's wort is generally weil tolerated in clini• cal trials, increasing attention has been given to its tendency to The latest metaanalysis of RCTs found Hypericum prepara• compromise the effectivity of other (e.g., cy• tions to be superior to placebo in patients with major depres• closporine, HIV protease inhibitors, oral contraceptives, dig• sion, to be similarly effective and to have fewer side effects oxin, warfarin, and theophylline) by interactions mediated than standard antidepressants [22] . Yet, a trend for decreasing through cytochrome P450 enzymes [30] and transport protein effect sizes over time in trials of St. John's wort was seen in P-glycoproteins [31]. Thus, prescribers should beware of pos• another metaanalysis [23], suggesting that St. John's wort may sible decreases in the systemic bioavailability of conventional be less effective in treating depression than previously thought. drugs [32] especially with Hypericum extracts rich in hyper• More recent trials - which include only patients with docu• forin [33 , 34]. In the study presented here, comprising a total mented major depression or large proportions of patients who of 1,778 patients, the frequency of adverse effects was low have suffered from their current depressive episode for >2 (3.54% of the patients), decreased over time and was similar in years - may have excluded groups that are particularly respon• patients who received comedication, whether psychotropic or sive to Hypericum extract [24] . Consistent with this observa• not. There were neither serious nor unexpected ADRs. This tion, the strengths of the study presented he re is that it found a low incidence of ADRs with Helarium® is in line with formerly poorer outcome in patients with Ion ger duration of the disor• pubJished data on Hypericum preparations, especially Hyperi• der, higher age and - less consistently - a higher symptom cum preparations not enriched in hyperforin [35]. score at admission. This increases our knowledge of the factors that affect the treatment response. These finding were also ob• served in a large cohort of outpatients treated with selective Conclusions serotonin reuptake inhibitors (SSRI) [25] . Furthermore, con• sidering the highest ICD-derived subscore, depression pre• In this open observational study, the herbai preparation of vailed in half of the cases, anxiety prevailed in 41.3% of the Hypericum perforaturn was weil tolerated and no new or seri• cases and somatic symptoms of anxiety/depression were high• ous adverse effects were identified. In view of the limitations est in 8.5% of the patients. This stratification had no relevant of the study design, it may be concluded that Hypericum per• influence on the outcomes. However, these results somehow foraturn was a quite effective antidepressant for mild to mod• correspond with data on th e comorbidity of depression and erate depression. A positive treatment response was favored anxiety as well as with associations between somatic com• by a more recent onset of the disorder, lower age of the pa• plaints and depression and they could give an additional ra• tients and, possibly, less severe symptoms at baseline. tional for the use of Hypericum [26,27]. While it would be pre• mature to draw any conclusions concerning efficacy from these observation al findings, they may be of interest to genera te hy• Acknowledgements and Disclosure Statement potheses for future trials with Hypericum, because a consistent and progressive reduction of these symptoms could be seen in This study was supported by an unconditonal grant from Bionorica, Ger• many. We thank the investigators and the patients who participated in the ICD-lO derived scores (anxiety, somatoform, and somatic this study. symptoms). Yet, one has to be aware that placebo effects, the Conflicl 0/ /nteres t: The authors do not have any financial interest (eg• natural course of the disorder, and regression to the mean can uity holdings or stock options) in any corporate entity dealing with the result in high rates of good outcomes that may be misattrib• material or the subject matter of this contribution. Neither did they have uted to the specific treatment [28, 29]. within the last 3 years, status as an officer, a member of the Board, nor a member of an Advisory Committee of any entity engaged in activity re• Possible shortcomings of this study are that most of the pa• lated to the subject matter of this contribution. There is no planned, tients inves tigated had only mild to moderate depression, thus pending, or awarded patent on this work by the involved institution. the results cannot be extrapolated to patients with more se- None of the authors received speaking fees at symposia on Hypericum.

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