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A Double-blind, Randomized Trial of St John's Wort, Fluoxetine, and Placebo in Major Depressive Disorder
ISSN: 0271-0749
Accession: 00004714-200510000-00007
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Author(s):Fava, Maurizio MD*; Alpert, Jonathan MD, PhD*; Nierenberg, Andrew A. MD*; Mischoulon, David MD, PhD*; Otto, Michael W. PhD*; Zajecka, John MD; Murck, Harald MD; Rosenbaum, Jerrold F. MD*
Issue:
Volume 25(5), October 2005, pp 441-447
Publication Type:
[Original Contributions]
Publisher:
© 2005 Lippincott Williams & Wilkins, Inc.
Institution(s):
*Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA; Department of Psychiatry, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL and Lichtwer Pharma AG, Wallenroder Straße 8-10, D-13435 Berlin, Germany.
Received August 4, 2003; accepted after revision May 5, 2005.
Address correspondence and reprint requests to Maurizio Fava, MD, Depression Clinical and Research Program, Massachusetts General Hospital, 15 Parkman St, ACC 812, Boston, MA 02114. E-mail: mfava@partners.org.
Table of Contents:
≪ Drug-Induced Agranulocytosis: Impact of Different Fc[gamma] Receptor Polymorphisms?
≫ Polymorphic Variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and Dopamine D2 and D3 Receptors and Their Association With Tardive Dyskinesia in Severe Mental Illness.
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Abstract
Complete Reference
Outline* Abstract
* MATERIALS AND METHODS
o Design
o Eligible Patients
o Randomization Criteria
o Medications
o Instruments and Efficacy Measures
o Safety Measures
o End Points
o Evaluation of Safety
* STATISTICAL METHODS
o Baseline Clinical and Demographic Variables
o Primary Efficacy End Point
o Secondary Efficacy End Points
o Safety
* RESULTS
* DISCUSSION
* ACKNOWLEDGMENTS
* REFERENCESGraphics
* Table 1
* Table 2
* Table 3
* Table 4Abstract
Objective: This study looks to compare the antidepressant efficacy and safety of a standardized extract of St John's wort with both placebo and fluoxetine.
Method: After a 1-week single-blind washout, patients with major depressive disorder diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomized to 12 weeks of double-blind treatment with LI-160 St John's wort extract (900 mg/d), fluoxetine (20 mg/d), or placebo. The 17-item Hamilton Rating Scale for Depression (HAMD-17) was the primary efficacy measure, and analysis of covariance was used to compare differences in end point HAMD-17 scores across the 3 treatment groups, treating the baseline HAMD-17 as the covariate.
Results: One hundred thirty-five patients (57% women; mean age, 37.3 ± 11.0; mean HAMD-17, 19.7 ± 3.2) were randomized to double-blind treatment and were included in the intent-to-treat analyses. Analysis of covariance analyses showed lower mean HAMD-17 scores at end point in the St John's wort group (n = 45; mean ± SD, 10.2 ± 6.6) compared with the fluoxetine group (n = 47; 13.3 ± 7.3; P < 0.03) and a trend toward a similar finding relative to the placebo group (n = 43; 12.6 ± 6.4; P = 0.096). There was also a trend toward higher rates of remission (HAMD-17 <8) in the St John's wort group (38%) compared with the fluoxetine group (30%) and the placebo group (21%). Overall, St John's wort appeared to be safe and well tolerated.
Conclusion: St John's wort was significantly more effective than fluoxetine and showed a trend toward superiority over placebo. A (25%) smaller than planned sample size is likely to account for the lack of statistical significance for the advantage (indicating a moderate effect size, d = 0.45) of St John's wort over placebo.
In Western Europe, extracts from St John's wort (Hypericum perforatum) have been in therapeutic use for the treatment of depressed mood for hundreds of years. Hypericum extracts are rather complex mixtures, whose exact compositions depend on the extraction method applied. However, both hyperforin and the naphthodianthrones hypericin and its 2-hydroxymethyl derivative, pseudohypericin, often referred to as total hypericin, are considered to be the most specific ingredients.1 However, the precise identity of the efficacious constituents of Hypericum extracts is not known, nor are the details of the pharmacological mechanism of antidepressant action.
Among the lay public and physicians in Europe, St John's wort (H. perforatum) is perceived to be effective for mild-to-moderate depression, with a benign profile of adverse drug events, including lack of sedation.1 In support of this view, a meta-analysis of 23 European randomized trials of St John's wort extract in 1757 outpatients with mild to moderately severe depressive disorders 2 showed that, in placebo-controlled trials, St John's wort was effective in 55% of the subjects (n = 408), whereas placebo was effective in 22% of the subjects (n = 422). The same meta-analysis showed that, in the 6 active comparator trials involving a single preparation of St John's wort, a 64% response rate was observed (n = 158), compared with the 58% response rate for the antidepressant comparators (n = 159). On the other hand, Shelton et al 3 commented that most or perhaps all of the trials used in this meta-analysis had serious methodological flaws, such as a relatively short duration of the trial and failure to use standardized diagnostic practices or symptom rating instruments, thereby undermining confidence in these results.
The findings of 2 large, multicenter, placebo-controlled US studies of St John's wort have been recently published. The first study compared the efficacy and safety of a well-characterized H. perforatum (St John's wort) extract (LI-160) with placebo in outpatients with major depressive disorder (MDD) recruited in 11 academic medical centers in the United States.3 The study enrolled 200 adult outpatients (mean age, 42.4 years; 67% women; 86% white) with MDD and a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17)4 score of at least 20. After a 1-week single-blind run-in of placebo, patients were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. The random coefficient analyses for the primary efficacy measure (HAMD-17) showed significant effects for time but not for treatment or time-by-treatment interaction. The proportion of participants achieving an a priori definition of response also did not differ significantly between groups (34% for St John's wort and 22% for placebo), but the number reaching remission (HAMD-17 score of <=7 and a Clinical Global Impression [CGI] score of 1 or 2) was significantly higher with St John's wort than with placebo (P = 0.02). However, these rates of remission were very low in the full intention-to-treat analysis (14/98 [14%] vs. 5/102 [5%], respectively). St John's wort was safe and well tolerated, and headache was the only adverse event (AE) that occurred with greater frequency with St John's wort than with placebo (39/95 [41%] vs. 25/100 [25%], respectively).3 Although the authors of the study concluded that, in their study, St John's wort was not effective for treatment of major depression,3 this conclusion is premature given that it is not uncommon for studies to fail to differentiate placebo and antidepressant treatment among agents that eventually achieve the 2 pivotal trials necessary for Food and Drug Administration approval.5 For example, an analysis of 5 antidepressant agents found that, of 39 trials filed with the Food and Drug Administration, only 14% of these trials found active drug superior to placebo for all primary and secondary outcome measures of depression, and only 44% of studies differentiated drug from placebo on the first depression item on the HAMD.6 Accordingly, it is fully within norm expectation for approved antidepressants for some studies to fail to differentiate active from placebo treatment.
Similar findings were obtained in the recently published multicenter study 7 which tested in MDD the efficacy and safety of the same well-characterized H. perforatum extract (LI-160) used in the Shelton study. The study was conducted in 12 academic and community psychiatric research clinics in the United States. Adult outpatients (n = 340) recruited between December 1998 and June 2000 with MDD and a baseline total score on the HAMD-17 of at least 20 were randomly assigned to receive St John's wort, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of St John's wort could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. On the 2 primary outcome measures, neither sertraline nor St John's wort was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAMD-17 total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval, -10.51 to -7.89) for placebo vs. -8.68 (0.68) (95% confidence interval, -10.01 to -7.35) for St John's wort (P = 0.59) and -10.53 (0.72) (95% confidence interval, -11.94 to -9.12) for sertraline (P = 0.18). Full response (HAMD-17 score of <=8 and a CGI Improvement [CGI-I] scale score of 1 or 2) occurred in 32% of the placebo-treated patients versus 24% of the St John's wort-treated patients (P = 0.21) and 25% of sertraline-treated patients (P = 0.26). Adverse effect profiles for St John's wort and sertraline differed relative to placebo. Although this study failed to support the efficacy of St John's wort in moderately severe major depression, the equally poor performance of sertraline in this trial underscores the variability in efficacy findings that are not uncommon among approved agents. The accompanying editorial by Kupfer and Frank 8 pointed out that the only 2 controlled studies of St John's wort in the United States had failed to reject the null hypothesis but had not yet provided a definitive perspective on the potential utility of St John's wort. In addition, despite the fact that the European studies had suggested efficacy of St John's wort in mild-to-moderate depression, both studies included only patients with moderate to severe MDD, as a HAMD-17 score of 20 or higher was required for entry into these 2 studies. Accordingly, there is need for further study of the antidepressant efficacy and safety of a standardized extract of St John's wort (H. perforatum, LI-160) relative to both placebo and fluoxetine in a population of outpatients with mild to moderately severe MDD.
MATERIALS AND METHODS
DesignThis was a 12-week, randomized, active- and placebo-controlled, parallel-group, double-blind study conducted in patients with a diagnosis of MDD. The study was conducted in 2 sites (Boston and Chicago). Upon enrollment, all eligible patients were required to have discontinued any previous psychoactive medication for a specified period of time to qualify for entry into the single-blind placebo washout period of 7 days (Table 1). Patients still meeting the diagnostic inclusion criterion after the washout period entered the 12-week, acute, double-blind therapy phase, receiving 1 of the following 3 randomized double-blind treatments: (1) LI-160 St John's wort extract (300 mg thrice a day; daily dose, 900 mg), (2) fluoxetine 20 mg every day, or (3) placebo. The study was planned as a single-center trial with an anticipated total of approximately 180 enrolled patients at the Depression Clinical and Research Program of the Massachusetts General Hospital in Boston from September 1998 to September 2000. Because of difficulties in completing enrollment by the target date, a second site (Department of Psychiatry, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill) was added to the Boston site. Following an interim analysis of the study performed in September 2001, the sponsor (Lichtwer Pharma AG, Berlin, Germany) opted to close the study and to proceed with the final analyses carried out on a sample size smaller (n = 135) than the one originally planned.
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[Email Jumpstart To Image] TABLE 1. Treatment Schedule-Double-dummy Technique
Eligible PatientsPatients were primarily recruited from general advertising and clinician referrals. Meeting all criteria listed below, patients of either sex and any ethnic origin with a diagnosis of MDD were included in the study. The patients were required to meet the following inclusion criteria:
a. Age, 18 to 65 years.
b. Current experience of a major depressive episode according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition of at least 2 weeks' duration.
c. A HAMD-17 total score >=16 at both screen and baseline.
d. Negative pregnancy test within 5 days before study start in women of childbearing potential (nonchildbearing potential was defined as postmenopause for at least 1 year or surgical sterilization or hysterectomy at least 3 months before study start).
e. Use of adequate contraception in women of childbearing potential.
f. Readiness and ability on the part of the patient to comply with the physician's instructions and to fill out the self-report measures in connection with their examination at the study visits.
g. Written informed consent.Exclusion criteria were the following:
a. Pregnancy, lactation, or nonuse of medically accepted means of contraception in women of childbearing potential.
b. Current serious suicidal or homicidal risk (according to investigator's judgment).
c. Serious or unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematologic disease.
d. History of seizure disorder.
e. One or more of the following Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses: organic mental disorders; substance use disorders, including alcohol, active within the last 6 months; schizophrenia; delusional disorder; psychotic disorders not elsewhere classified; bipolar disorder; or antisocial personality disorder.
f. History of multiple adverse drug reactions or allergy to the study drugs.
g. Mood-congruent or mood-incongruent psychotic features.
h. Any of the following treatments at baseline or within the specified time frame before baseline: other psychotropic drugs, 14 days; other investigational psychotropic drug, 40 days; fluoxetine, 40 days; or any other investigational drug, 1 month.
i. Unacceptability to discontinue or likelihood to need medication that is prohibited as concomitant treatment during the study.
j. Clinical or laboratory evidence of hypothyroidism.
k. Failure to respond during the course of current major depressive episode to at least 2 adequate antidepressant trials, defined as 8 weeks or more of treatment with either imipramine 150 mg or greater (or its tricyclic equivalent), phenelzine 60 mg or greater (or its monoamine oxidase inhibitor equivalent), or fluoxetine 20 mg or greater (or its selective serotonin reuptake inhibitor equivalent).
l. Any other condition which, in the investigator's judgment, may pose a significant risk to the patient's health or may decrease the chances of obtaining reliable data to achieve the objectives of the study.
m. Mental condition rendering the patient unable to understand the nature, scope, and possible risks of the study.
n. History or suspicion of unreliability, poor cooperation, or noncompliance with medical treatment.
Randomization CriteriaAfter the placebo washout period, all patients were randomized unless they met either 1 of the following criteria at the randomization visit: HAMD-17 less than 16 or a reduction in HAMD-17 by 25% or greater as compared with the screening visit. During the period of randomized treatment, double-blind conditions were maintained using the following double-dummy schedule (see Table 1).
For each treatment group, the following daily schedule was applied: morning, 1 tablet plus 1 capsule; midday, 1 tablet; and evening, 1 tablet. Patients were instructed to take study medications shortly before their meals. The total daily dose of active treatment was 900 mg of Hypericum extract (St John's wort) or 20 mg of fluoxetine.
MedicationsHypericum extract (St John's wort) (LI-160) and matching placebo were provided by Lichtwer Pharma, whereas fluoxetine and matching placebo were provided by the Massachusetts General Hospital research pharmacy, and fluoxetine capsules manufactured by Eli Lilly and Co were used. The Hypericum extract was standardized to between 0.12% and 0.28% hypericin, and the entire study supply came from 1 batch. The study was conducted under an investigational new drug application filed by Lichtwer Pharma.
The frequency of visits was as follows: screen (7-14 days before baseline), baseline (day 0), visit 1 (day 7 + 2 days), visit 2 (day 14 ± 2 days), visit 3 (day 28 ± 2 days), visit 4 (day 42 ± 2 days), visit 5 (day 56 ± 2 days), and visit 6 (day 84 ± 2 days).
Instruments and Efficacy MeasuresOn enrollment, all patients were administered the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders.9 All patients were administered at each visit the following instruments:
1. The 28-item HAMD. The 28-item HAMD 4 allows the assessment of the HAMD-17 scale, which is the primary efficacy measure of the study. This instrument was completed by the investigators based on their assessment of the patient's depressive symptoms.
2. The CGI Severity of Illness (CGI-S) and improvement (CGI-I) scales. The patients' CGI 10 was based on the investigators' assessment of the patients depressive symptoms.
3. The Beck Depression Inventory (BDI).11 This self-rated instrument was completed by the patients based on their assessment of the severity of depression.
Safety MeasuresAt each visit, the following vital signs were monitored as safety parameters: blood pressure and heart rate. The following laboratory assessments (complete blood count, chemistries, and urinalysis) were performed at screen and week 12 or end point. All laboratory values as well as all electrocardiographic recordings were assessed by the investigator as to whether they had to be judged as AEs. For the recording of AEs, patients were required to report spontaneously any AEs as well as the time of onset and intensity of these events.
End PointsThe primary efficacy measure for this study was the HAMD-17. This instrument was administered at each visit by the clinical study investigators. The primary efficacy end point for this study was the final HAMD-17 total score after 12 weeks of randomized treatment on end point. Secondary efficacy measures included the CGI-S, the CGI-I, and the BDI.
Evaluation of SafetySafety analysis was performed for all patients who took at least 1 dose of study medication (all-subjects-treated group). Measures of safety included reported AEs, routine laboratory assessments (performed at the first pretreatment visit and at week 8), physical examinations (performed at the first pretreatment visit and at week 8), and the patient's vital signs, including blood pressure, heart rate, body temperature, respiration rate, and body weight (assessed at both pretreatment visits and at all study weeks that included a clinic visit).
STATISTICAL METHODSStatistical significance was set at P <= 0.05. Intent-to-treat (ITT) analyses were conducted. The primary ITT included all subjects who completed their baseline visit, were deemed eligible to continue the study, and were therefore randomized to double-blind treatment.
Baseline Clinical and Demographic VariablesPairwise differences among treatment groups for clinical and demographic variables of the ITT sample were compared with analyses of variance (ANOVA) and Fisher exact tests.
Primary Efficacy End PointThe primary objective of the study was to evaluate the efficacy of LI-160 compared with placebo and fluoxetine for decreasing depressive symptoms in patients with MDD. One-way analysis of covariance (ANCOVA) was used to assess differences in HAMD-17 depression severity at end point (week 12). The covariate was the baseline HAMD-17, and the final HAMD-17 served as the dependent variable. These analyses were performed on the ITT populations; the last-observation-carried-forward approach was used for missing data and withdrawals.
Secondary Efficacy End PointsThe secondary efficacy end points were (1) the proportion of remitters after 12 weeks of treatment (visit 6) or end point, with remission = HAMD-17 score less than 8, was assessed with pairwise Fisher exact tests; (2) the change from baseline after 12 weeks of treatment (visit 6) or end point in CGI-S was assessed with pairwise ANCOVA, using the CGI-S at baseline as the covariate; (3) the CGI-I score after 12 weeks of treatment (visit 6) or end point was assessed with pairwise ANOVA; and (4) the BDI change from baseline in the total score after 12 weeks of treatment (visit 6) or end point was assessed with pairwise ANCOVA, using the BDI at baseline as the covariate. These analyses were performed on the ITT population.
SafetyThe proportion of patients reporting AEs in the ITT sample was compared across the 3 treatment groups using pairwise Fisher exact tests.
RESULTSThe ITT population included 135 outpatients with MDD (57% women; 19% minorities; mean age, 37.3 ± 11.0 years; mean HAMD-17, 19.7 ± 3.2; mean CGI-S score, 4.2 ± 0.6) who were randomized to double-blind treatment. Of those randomized, 101 (75%) were enrolled in the Boston site, and 34 (25%) in the Chicago site. There was no significant difference in pairwise comparisons of age among patients randomized to St John's wort (mean, 37.4 ± 11.7), fluoxetine (mean, 36.7 ± 9.6), or placebo (mean, 37.8 ± 12.0). Similarly, there were no significant differences in sex ratio among patients randomized to St John's wort (53% women), fluoxetine (53% women), or placebo (65% women). As shown in Tables 2 and 3, there were no significant differences at baseline in the mean HAMD-17, CGI-S, and BDI scores.
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[Email Jumpstart To Image] TABLE 2. Mean HAMD-17 Scores in the ITT Sample of Outpatients With MDD (n = 135)Graphic
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[Email Jumpstart To Image] TABLE 3. Mean CGI-S, CGI-I, and BDI Scores in the ITT Sample of Outpatients With MDD (n = 135)The rate of completion of the 12-week, double-blind, placebo-controlled phase was as follows: 60% (27/45) for St John's wort, 51% (24/47) for fluoxetine, and 49% (21/43) for placebo. As shown in Table 2, St John's wort treatment was associated with a significantly (P < 0.05) greater decrease in HAMD-17 scores compared with fluoxetine at all postbaseline visits, except visit 5 (week 8). There was also a trend (P < 0.1) toward a significantly greater reduction in HAMD-17 score compared with placebo at visit 1 (week 1) and visit 6/end point. There were also nonsignificantly higher rates of remission (HAMD <8) in the St John's wort group (38%) compared with the fluoxetine group (30%) and the placebo group (21%).
Table 3 reports the results of the analyses for the secondary end points. In 4 patients, the BDI at baseline was missing, so the BDI score at screen was carried forward; similarly, the BDI at end point was missing in 5 patients, so the BDI from the previous visit was carried forward. There was a trend toward a significantly (P < 0.1) greater reduction in CGI-S at visit 6/end point in St John's wort-treated patients compared with fluoxetine-treated patients, and the CGI-I scores were significantly (P < 0.05) lower at visit 6/end point in St John's wort-treated patients compared with fluoxetine-treated patients. There was also a trend (P < 0.1) toward a significantly lower CGI-I score among St John's wort-treated patients compared with placebo-treated patients at visit 6/end point.
There was only 1 serious AE during the course of the study: a patient randomized on St John's wort overdosed on heroin, was treated in the hospital, released, and then discontinued from the study. Overall, St John's wort appeared to be safe and well tolerated. There were no AE-related treatment discontinuations in the St John's wort-treated and placebo-treated patients, whereas 4% (2/47) of the fluoxetine-treated patients dropped out because of side effects. As shown in Table 4, there were no significant differences across treatment groups in rates of AEs, with the exception of skin rash, which occurred more frequently in patients on placebo than on fluoxetine or St John's wort. The most common AEs on St John's wort were headache (42%), dry mouth (22%), nausea (20%), gastrointestinal upset (20%), and sleepiness (18%).
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[Email Jumpstart To Image] TABLE 4. Most Frequent (>10% in at Least 1 of the Treatment Arms) Adverse Events in the ITT Sample of Outpatients With MDD (n = 135)
DISCUSSIONIn our study of outpatients with mild to moderate MDD, a well-standardized H. perforatum (St John's wort) extract (LI-160) was significantly more effective than fluoxetine and showed a trend toward statistically significant superiority over placebo. The main limitation of our study is that the sample size of our study (n = 135) is smaller than originally planned. As mentioned earlier, the sponsor of the study conducted an interim analysis with the intent of closing the study earlier partly because of the delay in achieving the target enrollment and partly because of the negative/inconclusive results of the 2 prior US studies. Following the interim analysis, the sponsor closed the study and opted to proceed with the final analyses carried out on a sample size smaller (n = 135) than originally planned (n = 180). Our findings are consistent with those of a meta-analysis of 23 European randomized trials of St John's wort extract in 1757 outpatients with mild to moderately severe depressive disorders.2 The meta-analysis had shown that, in placebo-controlled trials, St John's wort was effective in 55% of the subjects (n = 408), whereas placebo was effective in 22% of the subjects (n = 422), and that, in the 6 active-comparator trials involving a single preparation of St John's wort, a 64% response rate was observed with St John's wort (n = 158), compared with the 58% response rate of the antidepressant comparators (n = 159). Our results are also consistent with those of a recently published multicenter European study 12 which showed that, among 375 outpatients with mild to moderate MDD (HAMD-17 score at baseline between 18 and 25), treatment with a hydroalcoholic H. perforatum extract was accompanied by a significantly (P = 0.04) greater reduction in HAMD-17 score than placebo. In this study,12 the remission rate (defined as a HAMD-17 score <7) was also significantly (P = 0.03) higher for Hypericum (24.7%) than for placebo (15.9%).
On the other hand, our findings are not consistent with those of the 2 placebo-controlled trials of the same H. perforatum (St John's wort) extract (LI-160) used in our study. The first study 3 enrolled 200 adult outpatients with moderate to severe MDD. Although there was no significant difference in outcome at the end of the 8-week treatment on the primary efficacy measure between St John's wort (900-1200 mg/d) or placebo, the number reaching remission of MDD was significantly higher with St John's wort than with placebo (P = 0.02), with very low overall rates in the full intention-to-treat analysis (14/98 [14%] vs. 5/102 [5%], respectively).3 The recently published multicenter study sponsored by the National Center for Complementary and Alternative Medicine and by the National Institute of Mental Health 7 provided results that were somewhat inconclusive, as both St John's wort (900-1500 mg/d) and sertraline (50-100 mg/d) were not significantly different from placebo on the 2 primary outcome measures. As noted earlier, negative studies for antidepressant medications are relatively common among agents meeting approval for Food and Drug Administration approval, and all studies on an agent need to be considered when evaluating the true effect size of the agent. The total evidence from the accumulated trials in Europe and the United States continues to suggest that St John's wort agents may offer antidepressant efficacy for some individuals with mild to moderate depression. As far as safety and tolerability are concerned, our findings are consistent with those of Shelton et al; St John's wort appeared to be safe and well tolerated, and headache was the most common AE in our trial (42%) and was the only AE that occurred with greater frequency with St John's wort than placebo in the Shelton et al study ([41%] vs. [25%], respectively).3
How do we explain the apparent lack of efficacy of fluoxetine in this trial? To the same extent that we used a fixed-dose approach to St John's wort (900 mg/d), we also used a fixed-dose approach to fluoxetine (20 mg/d), and data from our group suggest that a significant proportion of patients nonresponding to 20 mg/d may go on to respond when the dose is increased to 40 or 60 mg/d.13,14 Similarly, in a recent double-blind study in MDD, where clinicians were allowed to escalate the dose greater than 20 mg/d in nonresponders to 4 weeks of fluoxetine 20 mg/d, the final mean daily dose for fluoxetine was 42 mg, with 31.3% of the patients remaining at a dose of 20 mg, while 28.4% and 40.3% receiving an increase to 40 and 60 mg, respectively.15 These studies suggest that fluoxetine 20 mg/d, although typically considered an effective dose in the treatment of MDD, may not be an adequate dose for a significant proportion of patients having MDD. Furthermore, the smaller (25%) than planned sample size is likely to account for the lack of statistical significance for the advantage (indicating a moderate effect size, d = 0.45) of St John's wort over placebo.
In summary, in our study of outpatients with mild to moderate MDD, a well-standardized preparation of H. perforatum (St John's wort) extract (LI-160) was significantly more effective than fluoxetine and showed a trend toward superiority over placebo. Further studies are needed to fully evaluate the antidepressant efficacy of St John's wort. NIMH, NCCAM, and the NIH Office of Disease Prevention have jointly funded a study of St John's wort compared with citalopram and placebo for the treatment of minor depression. This study will generate information about the efficacy of St John's wort for a milder form of depression and help to fill the gaps in our knowledge about the clinical use of this most important herbal product.
ACKNOWLEDGMENTSThe study was supported by a grant of Lichtwer Pharma AG (Berlin, Germany) to the Massachusetts General Hospital. The authors thank Dr John Worthington of the Massachusetts General Hospital Depression Clinical and Research Program and Drs Marc Pfeffer, Diane London, Shelley Kramer, Alexander Altschuller, and Laurie Witts of Partners Research and Education Program (PREP) for their help and support in conducting the study. The authors also thank Lee Gresham, Megan Hughes, and Pam Roffi of the Massachusetts General Hospital Depression Clinical and Research Program and Courtney Vitale of Partners Research and Education Program (PREP) for their technical assistance in conducting the study.
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12. Lecubrier Y, Clerc G, Didi R, et al. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am J Psychiatry. 2002;159:1361-1366. [Context Link]
13. Fava M, Rosenbaum JF, McGrath PJ, et al. A double-blind, controlled study of lithium and tricyclic augmentation of fluoxetine in treatment resistant depression. Am J Psychiatry. 1994;151:1372-1374. Bibliographic Links [Context Link]
14. Fava M, Alpert J, Nierenberg AA, et al. Double-blind study of high-dose fluoxetine vs. lithium or desipramine augmentation of fluoxetine in partial and non-responders to fluoxetine. J Clin Psychopharmacol. August 2002;22(4):379-387. [Context Link]
15. Fava M, Hoog SL, Judge RA, et al. Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia. J Clin Psychopharmacol. April 2002;22 (2):137-147. [Context Link]
Posted by llurpsienoodle on May 31, 2008, at 8:09:29
In reply to hypericum trial at mgh without tables, posted by sdb on May 31, 2008, at 7:42:17
Too bad their sample was smaller than planned, nevertheless, a very promising study. I'm interested in the modest effect size. It suggests that there is a lot of room for improvement for major depression monopharmacy.
That's probably why I take 3 AD meds. lol
Thanks for your post!
-Ll
Posted by sdb on May 31, 2008, at 13:26:55
In reply to hypericum trial at mgh without tables, posted by sdb on May 31, 2008, at 7:42:17
hypericum update:
li-160 (called Jarsin in Germany) and ws 5570 (called Neuroplant in Germany) are widely used in the US.
ZE 117 (called Remotiv in Switzerland) is an exotic extract without hyperforin. not many studies are available but promising single results are evident . it has some metabolic benefits compared to other extracts.
The newest extract is STW3-VI (called Laif in Germany) with its 900mg 1/d pill that gave good results in some studies.
The German seem to be still very actively involved in alternative medicine business.
Posted by sdb on May 31, 2008, at 16:48:53
In reply to Re: hypericum trial at mgh without tables, posted by sdb on May 31, 2008, at 13:26:55
> hypericum update:
>
> li-160 (called Jarsin in Germany) and ws 5570 (called Neuroplant in Germany) are widely used in the US.
>
> ZE 117 (called Remotiv in Switzerland) is an exotic extract without hyperforin. not many studies are available but promising single results are evident . it has some metabolic benefits compared to other extracts.
>
> The newest extract is STW3-VI (called Laif in Germany) with its 900mg 1/d pill that gave good results in some studies.
>
> The German seem to be still very actively involved in alternative medicine business.there is some data comparing extracts in efficacy of previous studies (unfortunately in German)
http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdf
Posted by sdb on May 31, 2008, at 17:27:48
In reply to Re: hypericum trial at mgh without tables, posted by sdb on May 31, 2008, at 16:48:53
> > hypericum update:
> >
> > li-160 (called Jarsin in Germany) and ws 5570 (called Neuroplant in Germany) are widely used in the US.
> >
> > ZE 117 (called Remotiv in Switzerland) is an exotic extract without hyperforin. not many studies are available but promising single results are evident . it has some metabolic benefits compared to other extracts.
> >
> > The newest extract is STW3-VI (called Laif in Germany) with its 900mg 1/d pill that gave good results in some studies.
> >
> > The German seem to be still very actively involved in alternative medicine business.
>
> there is some data comparing extracts in efficacy of previous studies (unfortunately in German)
>
> http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdf==================================================
Comparative Efficacy and Safety of a Once-Daily Dosage of Hypericum Extract STW3-VI and Citalopram in Patients with Moderate Depression: A Double-Blind, Randomised, Multicentre, Placebo-Controlled Study
M. Gastpar1, A. Singer2, K. Zeller3
1 General Psychiatric Hospital, Department of Psychiatry and Psychotherapy, University of Essen, Essen, Germany
2 EPA Euro Pharma Auftragsforschung GmbH, Kronberg, Germany
3 Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
Introduction
Patients and Methods
Selection of Patients
Study Design
Investigational Treatments
Study Objectives for Efficacy and Safety
Statistical Analysis
Results
Patient Characteristics
Results of Efficacy
Hamilton Depression Scale (HAMD)
Secondary Efficacy Parameters
Safety Evaluation
Adverse Events (AE) and Tolerability
Vital Signs
Discussion
Conclusions
References
Objective: The objective of this double-blind, randomised, placebo-controlled, multicentre clinical study was to demonstrate the non-inferiority and safety of the hypericum extract STW3-VI in a once-daily dosage regime in the treatment of moderate depression. During the 6-week treatment phase, the course of depression was documented by use of HAMD (items 1-17), the von Zerssens Adjective Mood Scale (BfS) and the CGI scales. The primary objective of this 3-arm design study was to demonstrate the non-inferiority of hypericum extract STW3-VI (900 mg) to the SSRI citalopram (20 mg) and superiority of hypericum over placebo. Methods: Outpatients (N = 388) suffering from moderate depression were enrolled. The safety and tolerability of hypericum extract in comparison to citalopram and placebo was investigated on the basis of CGI, the occurrence of adverse events and the investigation of laboratory parameters and vital signs. Results: From almost identical baseline values of 21.9 ± 1.2 points (hypericum extract), 21.8 ± 1.2 points (citalopram) and 22.0 ± 1.2 points (placebo), the HAMD score was reduced to 10.3 ± 6.4 (hypericum extract), 10.3 ± 6.4 (citalopram) and 13.0 ± 6.9 (placebo), respectively. Based on this data, the statistical significant therapeutic equivalence of hypericum extract STW3-VI to citalopram (p < 0.0001) and the superiority of this hypericum extract over placebo (p < 0.0001) was demonstrated. At the end of treatment 54.2 % (hypericum extract), 55.9 % (citalopram) and 39.2 % (placebo) of the patients were assessed as therapy responders. The secondary efficacy parameters, change in BfS, CGI and amount of therapy responders showed that the hypericum group was not statistically different from the citalopram group, and significantly superior to the placebo group. Significantly more adverse events with certain, probable or possible relation to study medication were documented in the citalopram group (hypericum: 17.2 %, citalopram: 53.2 %, placebo: 30 %). In most cases, the investigators assessed the tolerability of hypericum extract, citalopram and placebo as good or very good. Conclusion: The non-inferiority of hypericum extract as compared to citalopram and the superiority of both active compounds to placebo were demonstrated, as well as a better safety and tolerability of hypericum extract in comparison to citalopram. These results revealed that hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression.
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IntroductionDepression is one of the most frequently occurring psychiatric disorders treated by general practitioners. In recent years, the diagnosis of depression and depressive mood has continuously increased in industrial countries [16]. The first pan-European survey of depression in the European community (DEPRES I) demonstrated that 17 % of the general population suffer from depression. More than two-thirds of depressed subjects (69 %) did not receive any psychopharmacological treatment and when drug therapy was prescribed (31 %), only 25 % of these subjects were given antidepressant drugs [19]. Due to the complexity of the diagnosis and the treatment options it seems difficult to choose the appropriate medication. Therefore, general practitioners prescribe antidepressants only reluctantly, particularly because of frequent side effects. Significantly more respondents treated with a selective serotonin reuptake inhibitor (SSRI) found that their treatment made them feel more like their normal self than those treated with a tricyclic antidepressant, and fewer reported treatment-related concentration lapses, weight problems, and heavy headedness [17][41]. However, even with SSRIs, side effects frequently occurred such as sexual dysfunction, insomnia, nausea and vomiting. Up to 30 % of patients suffer from adverse reactions and discontinue treatment. Antidepressants with fewer side effects and moderate costs would be a useful supplement for the outpatient treatment of depression. Hypericum extract is such an alternative to chemically defined antidepressants such as TCAs, SSRIs and monoamine oxidase inhibitors (MAOIs). In recent years hypericum has been approved for the treatment of mild to moderate depression. In comparison to synthetic antidepressants lower rates of side effects and good compliance were observed with St. Johns Wort extracts [38].
Over the last 10 years, the antidepressive effect of hypericum extract has been demonstrated in several active- or placebo-controlled studies [13][20][27][30][34][36][37][40][42][43]. The daily dose used in these studies, administrated mainly in a 2-3 times daily dose regime, varied from 600 to 1200 mg. Due to the long elimination half-life times of the main active ingredients of Hypericum perforatum, such as hypericin, pseudohypericin and hyperforin [15][32][33], a compliance facilitating once-daily administration of hypericum extract is possible.
If hypericum extract is used according to instructions, side effects are rare. The frequency of side effects did not differ from placebo and was much lower from that of classic antidepressants. In pale skinned persons a few cases of light sensitivity of the skin (photosensitivity) were reported [4][15]. In addition, hypericum extracts interact with various drugs, most likely related to the induction of cytochrome P450 isoenzymes and/or P-glycoprotein, which may lead to a reduction in plasma concentrations and therefore in diminished therapeutic efficacy of concomitant medications. Nevertheless, clinical studies have demonstrated that hypericum extracts are safe and well tolerated.
The investigational drug of the present study was STW3-VI, a standardised extract of 900 mg of the herb Hypericum perforatum, which is registered under the trade name Laif 900® for the treatment of depression. This dosage was chosen, as the most frequently investigated daily dose of hypericum extract in the treatment of mild to moderate depressive disorders is 3 × 300 mg (corresponding to 900 mg/d). The reference drug citalopram is a potent and highly selective serotonin reuptake inhibitor [with a half-maximal inhibitor concentration (IC50) of about 1 nM]. Citalopram is one of the most effective and best-tolerated SSRIs available. The most commonly observed adverse events associated with citalopram are sweating, somnolence, nausea, tremor, dry mouth and asthenia. The antidepressant effect of citalopram is well documented by a number of controlled studies comparing its efficacy with that of placebo or standard antidepressants [1][14][28]. Therefore, citalopram is accepted as standard medication in the antidepressive therapy of outpatients.
To date no comparative study of hypericum extract and citalopram in the treatment of patients with moderate depression has been published. The purpose of this trial was to demonstrate for the first time the comparable efficacy of the hypericum extract to citalopram after short-term treatment of patients with moderate depression with a once-daily dose regimen. Additionally, the superiority of hypericum extract STW3-VI to placebo should be demonstrated. Moreover, the favourable safety and tolerability profile of hypericum extract should be shown.
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Patients and MethodsThis Phase III study was carried out in accordance with the Principles of Good Clinical Practice (GCP) for the conduct of clinical trials with drugs in humans in the EU and of the Note for Guidance on clinical investigation of medicinal products in the treatment of depression (CPMP/EWP/518/97/2002), the ICH Guidelines, and the ethical principles that have their origin in the Declaration of Helsinki. The required documents were submitted to an independent Ethics Committee and approved by positive vote.
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Selection of PatientsPrimary care physicians (general practitioners and internists) recruited the patients in the period from October 2002 to May 2003. Female and male outpatients with a moderate depressive episode and with the following inclusion criteria were included in the study: written consent after comprehensive explanation of the content, significance and scope of the clinical trial by the investigator; age: 18-70 years; females taking adequate contraceptive or without child-bearing potential; patients having depression with a score of 20-24 on the Hamilton Depression Scale (HAMD, items 1-17) [9]; and diagnosis of moderate depression (first manifestation or recurrent depressive disorder) defined by ICD-10 F32.1 or F33.1 [12] according to DSM-IV major depressive episode (296.2 × ) and recurrent major depression (296.3 × ) [5].
In addition to general exclusion criteria, the following anamnestic exclusion criteria were applicable: diagnosis of resistance to depression treatment; known schizophrenia; psychosis or dementia; depressive mood due to a serious general disease; known hypersensitivity to study medication; known photosensitivity; specific antidepressant psychotherapy during the last two months or treatment with psychoactive drugs (antidepressants, neuroleptic drugs, antidementive drugs, anxiolytic drugs etc.) during the last 3 weeks (6 weeks for fluoxetine) prior to study enrolment; and determined suicidal tendency by scores of > 2 in item 3 of HAMD scale or known attempted suicide.
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Study DesignThe study was designed as a double-blind, randomised, multicentre study to compare the efficacy and safety of hypericum extract STW3-VI to citalopram and to placebo in outpatients with moderate depression. The study period per patient was six weeks from enrolment to study end. During this time, the patients undertook four visits (including enrolment). The efficacy of the study drugs was assessed by documentation of the course of depression using rating scales, such as the Hamilton Depression Scale (HAMD), the Von Zerssens Adjective Mood Scale (BfS) [8], and the Clinical Global Impression (CGI). The investigators were experienced in the application of the studys diagnostic criteria and rating scales. Uniform standards of judgment were ensured by special rater training.
The time-points for examinations were all study visits (days 0, 7, 21 and 42). The compliance of the patients was checked and documented at the end of study by counting the returned tablets. The study course is shown in Table [1].
According to a randomisation schedule using the randomisation program IDV-Rancode 3.6, patients were chronologically randomised by the investigators to treatment groups by assigning them the lowest yet unassigned treatment number available at the trial centre.
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Table 1 Efficacy and Safety Measurements Assessed (Flow Chart)
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Investigational TreatmentsSTW3-VI is a hydroalcoholic extract from the herb Hypericum perforatum. The 900 mg extract/tablet was produced from 4 g of dry plant material, which corresponds to the maximum recommended daily dose [6][18]. Citalopram, in a dosage of 20 mg, is the recommended dosage for treatment of depression and is considered to be sufficient for outpatients [1][14][22][26]. The medications were given once daily in the morning. Due to the different visual appearance of hypericum extract and citalopram the double-dummy technique was used to guarantee complete blinding for both investigator and patient at any time in the trial.
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Study Objectives for Efficacy and SafetyThe primary objective of the study was to demonstrate the non-inferiority of hypericum extract STW3-VI to citalopram and the superiority of hypericum extract to placebo in the treatment of moderate depression as evidenced by the change in the Hamilton Depression scale score (HAMD) after a 6 week treatment period. Based on clinical considerations the pre-defined non-inferiority boundary δ between treatment groups was 3 (δ = 3 points on the Hamilton scale). As secondary parameters, the efficacy parameters BfS and CGI as well as safety and tolerability of hypericum extract STW3-VI in comparison to citalopram and placebo were investigated.
In addition, treatment success was evaluated by means of response rates. Therapy responders were defined as patients with a HAMD score of < 10 after treatment or an improvement of the initial HAMD score of at least 50 %. Patients judgement was measured with BfS scale. Tolerability was assessed by the investigators and evaluated on the basis of CGI, the occurrence of adverse events and the investigation of laboratory parameters and vital signs.
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Statistical AnalysisAppropriate descriptive univariate statistics were calculated for all observed variables. The statistical evaluation, in line with the distribution of the respective parameters, was carried out by analysis of covariance models (continuous data) with the factors, treatment and centre, as well as the covariate baseline value and with logistic regression models using the factors, treatment and centre (categorical data). Due to multiplicity (two primary objectives), the α-level was adjusted to α/2 (Bonferroni correction).
The tests for superiority were carried out on the Intention-to-treat (ITT) population, the test for non-inferiority on the Per-Protocol (PP) population.
To validate the clinical study results concerning non-inferiority, the hypothesis of superiority of citalopram over placebo was tested. The null hypothesis of equivalence was tested. This test was carried out on a two-sided α/2 level of 0.025 [the α for two-sided tests of 0.05 was divided by two (Bonferroni correction) due to the existence of two main objectives].
The hypothesis of therapeutic non-inferiority of hypericum extract to citalopram with the non-inferiority boundary δ = 3 was tested one-sided using the null hypothesis of superiority of citalopram over hypericum. The test problem was analysed with an α/2 level (type I error) of 0.0125 and the confidence interval was estimated. In cases of missing data, the LOCF approach (Last Observation Carried Forward) was applied.
For the second primary objective, the hypothesis of superiority of hypericum extract over placebo was assessed. Again, the null hypothesis of equivalence with a two-sided α of 0.025 was tested. The results were supplemented by point estimates for the treatment differences (LS means) and the corresponding one-sided 98.75 % or two-sided 97.5 % confidence intervals. To assess robustness of the test results, the analyses described were also carried out on the PP or ITT population, respectively. Analyses of the secondary efficacy parameters were based on the ITT population and used a two-sided α level of 5 %.
Accounting for an additional number of around 20 % drop-outs and non-evaluable patients because one of the two main analyses is based on the PP population, a total sample size of 390 patients had to be randomised, assuming an effect size of 0.5 between active drugs and placebo. The block size was six.
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ResultsAt 21 centres, 388 outpatients aged 18 to 74 years with moderate depression were included in the ITT population. Considering various protocol violations 312 patients could be included in the PP population. From the 388 (312) patients in the ITT (PP) population, 131 (103) patients were treated with hypericum extract, 127 (104) with citalopram and 130 (105) with placebo. Unless otherwise marked, all data and results presented are based on the ITT population. For detailed patient distribution see Fig. [1].
Abbildung in neuem Fenster zeigenFig. 1 Distribution of patients.
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Patient CharacteristicsFor all demographic variables, the p-values for comparison of the treatment groups at the beginning of treatment were above 0.05 (p = 0.2223 to 0.8030). The demographic data is summarised in Table [2]. No differences between treatment groups were found.
The first manifestation of depression had been observed, on average, 35.9 months ago. Due to the exclusion criterion (no treatment with psychoactive drugs in the three weeks prior to inclusion), a high number of patients (59 %) were not treated with antidepressant medication in the current episode. For 29.4 % of the patients, depression in the family was documented. There was no significant difference between treatment groups regarding duration of depression, medical pre-treatment and depression in the family.
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Table 2 Demographic data (ITT population)
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Results of EfficacySeitenanfang
Hamilton Depression Scale (HAMD)The improvement of the HAMD score in both active treatment groups was almost identical, with a decrease of 11.6 in the hypericum group from 21.9 ± 1.2 points (median = 22.0) at treatment start to 10.3 ± 6.4 points (median = 9.0) at the end of treatment (LOCF) and a decrease of 11.5 points in the citalopram group from 21.8 ± 1.2 points (median = 22.0) to 10.3 ± 6.4 points (median = 10.0). Placebo showed a less pronounced effect with a drop of 9.0 points from 22.0 ± 1.2 (median = 22.0) to 13.0 ± 6.9 (median = 14.0) (Table [3] and Fig. [2]). The superiority of citalopram to placebo was highly significant (p < 0.0001, ITT). The null hypothesis of equal efficacy of citalopram and placebo could be rejected. The two-sided 97.5 % confidence interval for treatment difference reached from -4.25 to -1.25 (median 2.75). The test of non-inferiority of hypericum extract STW3-VI to citalopram showed a highly significant result (PP population). The one-sided 98.75 % confidence interval for treatment difference reached from -∞ to 1.93, excluding 3, the boundary for non-inferiority. The maximum superiority of hypericum was found to be 1.47 (two-sided 97.5 % confidence interval). Finally, the question of superiority of hypericum extract to placebo was assessed (ITT population). The two-sided 97.5 % confidence interval for treatment difference reached from 1.25 to 4.22 (median 2.73). The hypothesis of equal treatment effects was rejected with a p-value of < 0.0001, i. e. the alternative hypothesis of superiority of hypericum extract over placebo was accepted.
To prove the robustness of the results, the analyses were repeated for the PP population (tests for superiority) and the ITT population (test for inferiority), respectively. The test results confirmed the results described above with the same degree of significance.
In summary, these data verified that the hypericum extract STW3-VI is not inferior to the SSRI citalopram and placebo is not as equally effective as hypericum extract.
Abbildung in neuem Fenster zeigenFig. 2 Decrease of HAMD score during the course of study (Mean ± SD, ITT population). *Data at day 42 was estimated using the LOCF approach.
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Table 3 HAMD Score during the 6 week course of study (ITT population, HAMD N = 388, BfS N = 301) values are expressed as mean (SD) and as median for HAMD. The CGI degree of severity shows the percentage of patients rated as moderately, markedly or severely ill. In the overall assessment of change in patients condition the percentage of patients rated as much and very much improved was pooled. The therapeutic effect shows the percentage of patients rated as very good
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Secondary Efficacy ParametersTreatment success (responders) was assessed by reaching a HAMD score of < 10 or an improvement of the initial HAMD score of at least 50 %. After the end of treatment, 54.2 % of the patients treated with hypericum extract and 55.9 % of the patients treated with citalopram were assessed, but only 39.2 % of the patients in the placebo group were assessed as responders (ITT population). In the logistic regression model, the overall treatment effect (differences between treatment groups) was proved to be significantly different (p = 0.0009). The pair-wise comparisons demonstrated significant superiority of hypericum extract and citalopram to placebo (p = 0.0026 and p = 0.0006, respectively), but no significant difference between the active compounds (p = 0.6252). The point estimators for the odds ratio were 0.398 and 0.343 with corresponding two-sided 95 % confidence intervals of (0.219, 0.725) and (0.187, 0.631). The response rates at the different visits were also comparable in both active treatment groups (Fig. [3]). The analysis of the PP population confirmed the results of the ITT population.
The assessment of BfS scales, which were completed independently by the patients showed a downward linear improvement with time (Table [3]). The overall difference between treatment groups regarding the last value under therapy was significant in the analysis of covariance model (p < 0.0001). In line with the other findings, the pair-wise comparisons proved the superiority of hypericum extract and citalopram to placebo (both p < 0.0001). The results of the ITT population were verified in the PP population.
Other acute phase outcomes such as the CGI scores items - severity of illness, global improvement and therapeutic effect - showed similar results. At the end of therapy the differences between the three treatment groups were statistically significant (p < 0.0001). In addition, the pair-wise comparison of hypericum extract and citalopram and of both to placebo was also significant (p < 0.001). The assessment of the PP population confirmed the ITT results. Results of CGI assessment are summarised in Table [4].
Abbildung in neuem Fenster zeigenFig. 3 HAMD score: Responder (N = 388, ITT population). *Data at day 42 was estimated using the LOCF approach.
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Table 4 CGI Score during the 6 week course of study (ITT population, N = 388). The degree of severity shows the percentage of patients rated as moderately, markedly or severely ill. In the overall assessment of change in patients condition the percentage of patients rated as much and very much improved was pooled. The therapeutic effect shows the percentage of patients rated as marked and moderate
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Safety EvaluationSeitenanfang
Adverse Events (AE) and TolerabilityAll patients receiving study medication were included in the safety analysis (ITT population, n = 388). Altogether, 58 adverse events were documented for 39 patients (29.8 %) in the hypericum group, 94 adverse events for 53 patients (41.7 %) in the citalopram group and 70 adverse events for 46 patients (35.4 %) in the placebo group. Interestingly, the greatest differences in the AE rate were observed in the system organ classes gastrointestinal disorders and nervous system disorders, which resulted in a lower incidence of AEs in the hypericum group than in the placebo group. Severe intensity of the adverse effects was documented only for 2.3 % of the AEs (hypericum and placebo: 1, citalopram: 3). Furthermore, the investigators assessment concerning the relation of AEs to study medication revealed a much lower number of AEs with a certain, probable or possible relation to study medication in the hypericum group (17.2 %) than in the other groups (53.2 % citalopram group and 30.0 % placebo group) (see Fig. [4]).
A much lower number of AEs with certain relation to study medication in the hypericum group (3.4 %) and the placebo group (5.7 %) than in the citalopram group (10.6 %) was observed.
In four patients of the hypericum group (6.9 %), in 11 patients of the citalopram group (11.7 %) and in 6 patients of the placebo group (8.6 %) the adverse events led to study discontinuation (total 21 patients, 9.5 %) (see also Table [5]).
Altogether, 6 serious adverse events (SAEs) were documented (citalopram: 2, placebo: 4). One patient in the placebo group suffered from angina pectoris, another one was hospitalised for division of an intestinal adhesion, one with appendicitis and one with general anxiety disorders. Treatment was discontinued in all of these patients. In the citalopram group, study medication was discontinued in one patient after being admitted to a hospital due to serious depression with generalised anxiety disorder. One patient was hospitalised with a lesion of the brachial plexus and intake of medication was interrupted for six days. Regarding these patients no causal relationship to study medication was seen.
In addition, no interactions of hypericum extract and citalopram with concomitant medication was documented.
In most cases, the tolerability of study medication was assessed by the investigators at study end as very good or good. Per visit, the maximum number of patients with moderate and poor tolerability of treatment was three patients (2.3 %) in the hypericum group, twelve patients in the citalopram group (9.5 %) and two patients (1.5 %) in the placebo group. After 42 days, the tolerability was rated as very good or good in all of the patients in the hypericum group, whereas moderate or poor tolerability was observed in 11 % patients in the citalopram group and in 2.3 % patients in the placebo group (ITT population).
At the final study day (day 42) these differences in global assessment of tolerability between the treatments were proved to be statistically significant in a logistic regression model. The overall p-value for treatment differences was p = 0.0022 and also the pair-wise comparisons of hypericum against citalopram and placebo reached statistical significance (p = 0.0005 and p = 0.0234, respectively).
Abbildung in neuem Fenster zeigenFig. 4 Number of adverse events nonrelated (light colour) and in relation (dark colour) to study medication (ITT population).
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Table 5 Number of adverse events by system organ class in relation to study medication (ITT population)
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Vital SignsFor assessment of safety and tolerability of study medication, blood pressure and heart rate were measured and documented at each visit. Relevant findings were not reported to either the patients or the physician or the involved study staff. In addition, evaluation of the laboratory values documented at study end showed no clinically significant changes compared to baseline values.
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DiscussionDue to the high number of prescriptions and of frequent OTC-use of hypericum in Germany for the treatment of mild to moderate depression, the question about the efficacy and safety of hypericum extract preparations has become of more interest. Hypericum extracts are potent inhibitors of the synaptosomal reuptake of the three neuronal transmitters noradrenaline, serotonin and dopamine while chemically defined antidepressants inhibit the uptake of only one or two neurotransmitters [24]. Clinical pharmacological studies in healthy volunteers investigating the effect of hypericum extract on CNS activity have shown an antidepressant effect as evidenced by increased wakefulness. The observed effects are similar to the efficacy profile of imipramine [27]. Over the last decade, the antidepressant effect of hypericum has been demonstrated in several active and placebo controlled studies in more than 3,000 patients [20][34][35][42]. However, no study investigated the once-daily administration of hypericum extract in moderate depression comparing the efficacy and safety to the highly effective SSRI citalopram and to placebo as well.
Concerning the efficacy variables investigated, no significant differences were seen between patients treated with hypericum extract STW3-VI and patients treated with citalopram in the present study. The non-inferiority of hypericum extract to citalopram and the superiority of both to placebo were demonstrated, as well as a better safety and tolerability of hypericum extract in comparison to citalopram. The mean of the HAMD score decreased from almost identical initial values at baseline (21.9 points in the hypericum group and 21.8 points in the citalopram group) to 10.3 points in both active treatment groups. For patients treated with placebo, the mean value of the HAMD score decreased from 22.0 points at baseline to 13.0 points (last value of the 6-week treatment period).
Data published over the last decade confirmed that citalopram is superior to placebo in the treatment of depression, possess similar efficacy as the tricyclic and tetracyclic antidepressants and as other SSRIs, and is safe and well tolerated in the therapeutic dose of 20 mg/day [14]. The results received in the present study confirmed recent data observed in depressed patients [10]. During treatment, a decrease in the total score on the HAMD (21 items) from a mean initial value of 21.5 ± 2.9 prior to therapy, 14.5 ± 2.9 (p < 0.001) after 4 weeks of treatment and to 9.9 ± 3.1 (p < 0.001) after 8 weeks of treatment was found. There were 9 (20.9 %) responders after 4 weeks of treatment and 28 responders (65.1 %) after 8 weeks, all of them with decrease on the HAMD (21 items) greater than 50 %.
These results are almost identical to the results of a recent active-controlled long-term study, with a once-daily dosage of 612 mg hypericum extract [7]. To summarize, in this and the present clinical trial the non-inferiority of hypericum extract to sertralin and to citalopram could be shown. These results confirm that hypericum extract is a therapeutic alternative for the treatment of moderate depression with SSRIs. Compared with the results of another recent study, which showed no significant difference in HAMD score of hypericum- and sertraline-treated patients [3], the findings of this report revealed to be an important basis for the role of hypericum extract in treating patients with depressive symptoms.
A study of the Hypericum Depression Trial Study Group [11] examined the efficacy of hypericum extract (LI 160) in comparison to the SSRI sertraline and placebo in major depressive disorder in a 3-arm clinical trial and found that neither sertraline nor hypericum extract was significantly different from placebo on the two primary outcome measures, the HAMD scale and the CGI scale. This shows the importance of a third arm with an active comparator.
However, the low assay sensitivity of this trial and the high overall placebo response must be acknowledged. In contrast to the preceding study, which could not approve the reliability of the trial because the active comparator was not superior to placebo, the reliability of this trial was shown as citalopram was superior to placebo in the present study.
The percentage of patients rated as responders was significantly higher in the active groups (55.0 % hypericum extract, 56.7 % citalopram) than in the placebo group (39.2 %, p = 0.0026 and p = 0.0006, respectively). When comparing response rates with the results of other hypericum studies with chemically defined antidepressants as comparative drug, the response rates are comparable; they range normally between 50 and 70 % after 6 weeks of treatment [20][33][42]. In a meta-analysis of placebo rates in major depressive disorder trials with chemically defined antidepressants, placebo response rates were 45.5 % (PP) and 26.9 % (ITT) [39]. Within psychiatry, and more specifically, regarding the affective disorders, responses to the use of placebo have been more frequently described and the rates recorded go from 20 to 49 % [23]. Khan et al. [17] found that only 21.1 % of antidepressant treatment arms in trials with high placebo response (> 30 % mean change from baseline) showed statistical superiority over placebo compared with 74.2 % in trials with a low placebo response (≤ 30).
Concerning tolerability and safety of treatment, hypericum revealed a favourable safety profile in comparison to citalopram. No patient in the hypericum group had an assessment of tolerability that was rated either moderate or poor on day 42 of treatment. In the present study, a total of 222 adverse events were documented for 138 (35.6 %) patients. In the investigator assessments of the relationship of the AEs to the study medication, a significant lower rate of certain, probable or possible relationships was observed in the hypericum group (17.2 %) than in the citalopram group (53.2 %). In the Placebo group 30 % related AEs occurred. A much lower number of AEs with certain relation to study medication was observed in the hypericum group (3.4 %) and the placebo group (5.7 %) than in the citalopram group (10.6 %).
This evaluation confirms the results of previous studies, that hypericum is a safe preparation with a rate of side effects not higher than placebo. According to observational studies with preparations of St. Johns Wort, an incidence of adverse events (AE) between 1 and 3 % among those treated was recorded. This is some ten times less than with synthetic antidepressants. The most common adverse events (1 per 300 000 treated cases) among the spontaneous reports in the official register, concern reactions of the skin exposed to light [35]. In addition, interactions with various drugs, most likely related to the induction of cytochrome P450 isoenzymes (especially CYP3A4) and/or P-glycoprotein were reported. Therefore, it was suggested that long-term administration of St. Johns wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP3A4 substrates such as ciclosporin A, indinavir, digoxin, warfarin and others [21].
For citalopram, well-designed short- and long-term trials demonstrate an overall safety/side effect profile consistent with other SSRIs. The more frequent adverse events (nausea, somnolence, dry mouth, increased sweating) are mainly transient, mostly mild to moderate in severity, and observed consistently across studies at rates similar to other SSRIs. Citalopram treatment did not increase risk of suicide, overdose, seizure, or arrhythmia [25]. In the study of Hovorka et al. [10] nausea was the most common adverse event of citalopram in 7 patients (16.3 %) during the first month of treatment and in 3 patients (6.9 %) during the second month of treatment. Sexual dysfunction (decrease of libido) was reported in 2 (4.7 %) male patients during the entire course of treatment.
This study also confirmed, that the long half-life times of the most important active constituents of hypericum extracts allow a once-daily dosage regimen resulting in better patient compliance. Similar results for antidepressants [44] as well as for hypericum extracts [2][7][29] were reported recently. For Laif 900®, the following half-life times were determined: hypericin 18.7 ± 4.8 h, pseudohypericin 17.2 ± 8.4 h and hyperforin 17.5 ± 4.5 h [32]. This is in accordance with the recommended once-daily use of other antidepressants having half-lives up to 24 hours such as citalopram.
It can be concluded that the present study confirms previous data in respect of safety and tolerability of hypericum extract. The incidence and character of adverse effects observed with citalopram was in the range reported from other studies as well as the placebo-response observed in this study.
The results of the study demonstrate for the first time the non-inferiority of hypericum extract STW3-VI in comparison to the SSRI citalopram in the treatment of moderate depression with a once-a-day dosage. Citalopram was shown to be as effective as older classical antidepressants in the treatment of moderate depression, while less adverse effects occurred in comparison to tricyclic and tetracyclic antidepressants. Despite this, the occurrence of the remaining side-effects due to treatment with citalopram results in a low patient compliance. Thus, the demonstrated efficacy and good tolerability make hypericum extract STW3-VI a drug of consideration in the treatment of outpatients with moderate depression and a valuable alternative to modern chemically defined antidepressants.
Seitenanfang
ConclusionsIn this double-blind, randomised, multicentre study comparing a once-daily dosage of hypericum extract STW3-VI versus the SSRI citalopram and versus placebo over 6 weeks, therapeutic efficacy and tolerability of hypericum extract STW3-VI could be demonstrated. One of the main advantages is the once-daily dosage which facilitates compliance. The clinical study proved clearly that hypericum extract is not inferior to citalopram and that both drugs are effective in the treatment of moderate depression and superior to placebo as judged by HAMD scores and scores on other rating scales. Thus, the available study confirms the results of preceding studies with hypericum extract and other chemically defined antidepressants. In addition, the favourable safety and tolerability of hypericum extract STW3-VI in comparison to citalopram was demonstrated. The demonstrated equivalent efficacy to citalopram in antidepressive therapy and the excellent tolerability revealed that hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression.
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7 Gastpar M, Singer A, Zeller K. Efficacy and Tolerability of Hypericum Extract STW3 in Long-Term Treatment with a Once-Daily Dosage in Comparison with Sertraline. Pharmacopsychiatry 2005; 38: 78-86
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11 Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. Johns Wort) in major depressive disorders. JAMA 2002; 14: 1807-1814
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13 Kasper S. Hypericum perforatum - a review of clinical studies. Pharmacopsychiatry 2001; 34 (Suppl. 1): 51-55
14 Keller MB. Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. J Clin Psychiatry 2000; 61: 896-908
15 Kerb R, Brockmoller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother 1996ep; 40: 2087-2093
16 Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S. et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8-19
17 Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis 2003; 191: 211-218
18 Kommission E. Monographie Hyperici herba (Johanniskraut) (in German). Bundesanzeiger 228 05.12.1984
19 Lepine JP, Gastpar M, Mendlewicz J, Tylee A. Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol 1997; 12: 19-29
20 Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St Johns wort for depression (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software - an overview and meta-analysis of randomised clinical trials. BMJ 1996; 313: 253-258
21 Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS. et al. Effect of St. Johns Wort on drug metabolism by induction of cytochrome P450 3A4 Enzyme. JAMA 2003; 290: 1500-1504
22 Möller HJ. et al. Psychiatrie. Stuttgart: Hippokrates Verlag 1996
23 Montejo Iglesias ML, Oca Bravo L, Soler Roibal A. Factors associated with antidepressive placebo response: a review. Actas Esp Psiquiatr 2002; 30: 246-252
24 Müller WE, Rolli M, Schäfer C, Hafner U. Effects of Hypericum Extract (LI160) in Biochemical Models of Antidepressant Activity. Pharmacopsychiatry 1997; 30: 102-107
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Schulz HU, Schürer M, Bässler D, Weiser D. Investigation of the Bioavailability of Hypericin, Pseudohypericin, Hyperforin and the Flavonoids Quercetin and Isorhamnetin Following Single and Multiple Oral Dosing of a Hypericum Extract containing Tablet. Drug Res 2005; 55: 15-22
32 Schulz HU, Schürer M, Bässler D, Weiser D. Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers. Drug Res 2005; 55: 561-568
33 Schulz V, Hänsel R, Tyler VE. 4th ed: Rational Phytotherapy. Berlin: Springer 2001, p. 64-70
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38 St. Johns Wort (Hypericumperforatum). St. Johns Wort. Quality Control, Analytic and Therapeutic Monograph. American Herbal Pharmacopoeia and Therapeutic Compendium 1997, p. 1-32
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40 Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St Johns wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 2005; 330 (7490): 503
41 Tylee A, Gastpar M, Lepine JP, Mendlewicz J. DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee. Int Clin Psychopharmacol 1999; 14: 139-151
42 Volz HP. Controlled Clinical Trials of Hypericum Extracts in Depressed Patients - an Overview. Pharmacopsychiatry 1997; 30: 72-76
43 Vorbach EU, Hübner WD, Arnoldt KH. Wirksamkeit und Verträglichkeit des Hypericum-Extraktes LI 160 im Vergleich mit Imipramin. Nervenheilkunde 1993; 12: 290-296
44 Yyldyz A, Sachs GS. Administration of antidepressants. Single versus split dosing: a meta-analysis. J Affect Disord 2001; 66: 99-206
Posted by sdb on May 31, 2008, at 17:35:24
In reply to Re: hypericum trial at mgh without tables, posted by sdb on May 31, 2008, at 16:48:53
> > hypericum update:
> >
> > li-160 (called Jarsin in Germany) and ws 5570 (called Neuroplant in Germany) are widely used in the US.
> >
> > ZE 117 (called Remotiv in Switzerland) is an exotic extract without hyperforin. not many studies are available but promising single results are evident . it has some metabolic benefits compared to other extracts.
> >
> > The newest extract is STW3-VI (called Laif in Germany) with its 900mg 1/d pill that gave good results in some studies.
> >
> > The German seem to be still very actively involved in alternative medicine business.
>
> there is some data comparing extracts in efficacy of previous studies (unfortunately in German)
>
> http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdfthe article
http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdf
is very easy to understand and gives some valuable information about all these studies hypericum/placebo, hypericum/ssri
you only need to understand the Forest-Plot, intervals, weighing and the picture is a llllittle bit clearer.
warm regards
sdb
German understanding could be useful
Posted by sdb on June 1, 2008, at 9:15:51
In reply to comparism of hypericum studies, posted by sdb on May 31, 2008, at 17:35:24
> > > hypericum update:
> > >
> > > li-160 (called Jarsin in Germany) and ws 5570 (called Neuroplant in Germany) are widely used in the US.
> > >
> > > ZE 117 (called Remotiv in Switzerland) is an exotic extract without hyperforin. not many studies are available but promising single results are evident . it has some metabolic benefits compared to other extracts.
> > >
> > > The newest extract is STW3-VI (called Laif in Germany) with its 900mg 1/d pill that gave good results in some studies.
> > >
> > > The German seem to be still very actively involved in alternative medicine business.
> >
> > there is some data comparing extracts in efficacy of previous studies (unfortunately in German)
> >
> > http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdf
>
> the article
>
> http://www.phytotherapie-komitee.de/Forschung/kfn_hyperic_281206.pdf
>
> is very easy to understand and gives some valuable information about all these studies hypericum/placebo, hypericum/ssri
>
> you only need to understand the Forest-Plot, intervals, weighing and the picture is a llllittle bit clearer.
>
> warm regards
>
> sdb
>
> German understanding could be useful1: Pharmacopsychiatry. 2006 Mar;39(2):66-75.Click here to read Links
Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study.
Gastpar M, Singer A, Zeller K.General Psychiatric Hospital, Department of Psychiatry and Psychotherapy, University of Essen, Essen, Germany. m.gastpar@uni-essen.de
OBJECTIVE: The objective of this double-blind, randomised, placebo-controlled, multicentre clinical study was to demonstrate the non-inferiority and safety of the hypericum extract STW3-VI in a once-daily dosage regime in the treatment of moderate depression. During the 6-week treatment phase, the course of depression was documented by use of HAMD (items 1-17), the von Zerssen's Adjective Mood Scale (BfS) and the CGI scales. The primary objective of this 3-arm design study was to demonstrate the non-inferiority of hypericum extract STW3-VI (900 mg) to the SSRI citalopram (20 mg) and superiority of hypericum over placebo. METHODS: Outpatients (N = 388) suffering from moderate depression were enrolled. The safety and tolerability of hypericum extract in comparison to citalopram and placebo was investigated on the basis of CGI, the occurrence of adverse events and the investigation of laboratory parameters and vital signs. RESULTS: From almost identical baseline values of 21.9 +/- 1.2 points (hypericum extract), 21.8 +/- 1.2 points (citalopram) and 22.0 +/- 1.2 points (placebo), the HAMD score was reduced to 10.3 +/- 6.4 (hypericum extract), 10.3 +/- 6.4 (citalopram) and 13.0 +/- 6.9 (placebo), respectively. Based on this data, the statistical significant therapeutic equivalence of hypericum extract STW3-VI to citalopram (p < 0.0001) and the superiority of this hypericum extract over placebo (p < 0.0001) was demonstrated. At the end of treatment 54.2 % (hypericum extract), 55.9 % (citalopram) and 39.2 % (placebo) of the patients were assessed as therapy responders. The secondary efficacy parameters, change in BfS, CGI and amount of therapy responders showed that the hypericum group was not statistically different from the citalopram group, and significantly superior to the placebo group. Significantly more adverse events with "certain", "probable" or "possible" relation to study medication were documented in the citalopram group (hypericum: 17.2 %, citalopram: 53.2 %, placebo: 30 %). In most cases, the investigators assessed the tolerability of hypericum extract, citalopram and placebo as "good" or "very good". CONCLUSION: The non-inferiority of hypericum extract as compared to citalopram and the superiority of both active compounds to placebo were demonstrated, as well as a better safety and tolerability of hypericum extract in comparison to citalopram. These results revealed that hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression.
PMID: 16555167 [PubMed - indexed for MEDLINE]
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* Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. [Adv Ther. 2004]
* [Escitalopram is more effective than citalopram for the treatment of severe major depressive disorder] [Encephale. 2004]
* Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder. [J Clin Psychiatry. 2004]
* Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. [BMJ. 2005]
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Escitalopram (Lexapro®) Escitalopram is used to treat depression and generalized anxiety disorder (GAD; excessive worry and tension that disrupts daily life and lasts for 6 months or longer). Escitalopram is in a class of antidepressants called...
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» read more ...2: Pharmacopsychiatry. 2005 Mar;38(2):78-86.Click here to read Links
Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline.
Gastpar M, Singer A, Zeller K.General Psychiatric Hospital, Dept. of Psychiatry and Psychotherapy, University of Essen, Germany. m.gastpar@uni-essen.de
OBJECTIVE: The objective of this double-blind, multi-center clinical study was to demonstrate the non-inferiority of hypericum extract versus sertraline in the treatment of moderate depression. METHODS: A total of 241 patients with a diagnosis of moderate depressive disorder (according to ICD-10 criteria) were randomized with either 50 mg sertraline or 612 mg hypericum extract (hypericum group n = 123; sertraline group n = 118). According to the study protocol, 200 patients were treated for at least 12 weeks ( n = 102 hypericum extract; n = 98 sertraline); 81 patients in the hypericum group and 80 in the sertraline group were treated after week 12 for an additional 12 weeks. Thus, most patients were treated for a period of 6 months. The primary efficacy variable was the 17-item HAMD total score at the end of the first 12-week double-blind treatment period. RESULTS: After the first 12-week treatment period, the HAMD score decreased from almost identical initial values (22.0 +/- 1.1 for hypericum and 22.1 +/- 1.1 points for sertraline) to 8.3 +/- 5.5 points (hypericum) and 8.1 +/- 5.6 points (sertraline) (mean +/- SD) in the patients treated per-protocol (PP) population. The statistical test for non-inferiority (boundary delta = 3) revealed that hypericum extract is not inferior to sertraline ( P < 0.0001). The mean difference between the treatments was 0.1995 points, with a corresponding one-sided 97.5 % confidence interval (-infinity, 1.3772). In patients who continued treatment in the follow-up phase, the HAMD score at the end of the study was 5.7 +/- 4.8 points (hypericum group) and 7.1 +/- 6.3 points (sertraline group). Comparable improvement was also found for the von Zerssen's Adjective Mood Scale (BfS) and CGI during the first and second 12-week treatment period in both treatment groups. With 68.6 % of patients in the hypericum group and 70.4 % in the sertraline group, the percentage of patients rated as responders did not differ significantly between treatment groups (12 weeks). The adverse events of 12 patients in the hypericum group (9.8 %) and of 16 patients in the sertraline group (13.6 %) were possibly related to study medication. No basic differences in the treatment groups were observed and no interaction with concomitant medication was documented. In most cases , the investigators assessed the tolerability of hypericum extract and sertraline as "good" or "very good." CONCLUSIONS: The results indicate that hypericum extract STW 3 is not inferior to sertraline and that it is a well-tolerated drug for the treatment of moderate depression. These favorable effects were achieved with a once-daily dose of 612 mg of hypericum extract given for up to 24 weeks.
PMID: 15744631 [PubMed - indexed for MEDLINE]
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* Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. [BMJ. 2005]
* Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder. [J Clin Psychiatry. 2004]
* Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. [Pharmacopsychiatry. 2001]
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Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial.
Uebelhack R, Gruenwald J, Graubaum HJ, Busch R.Charité, Humboldt University, Clinic of Psychiatry, Berlin, Germany.
In this double-blind, randomized, placebo-controlled, prospective study, the clinical efficacy and tolerability of oral Hypericum extract STW 3-VI (Laif) 900 mg once daily was compared with that of placebo. A total of 140 outpatients (94 women; 46 men) with moderate depressive disorders and a 17-item Hamilton Depression Scale (HAMD-17) score of 20 to 24 were enrolled in this study. Following a single-blind placebo run-in period of 7 days, the patients were randomized to Hypericum extract 900 mg or placebo for the 6-week treatment period. Nineteen patients have been excluded from the per protocol collective because of violations of protocol regarding the scheduling of study visits and intake of study medication. The primary endpoint for treatment efficacy was the change in total HAMD-17 score at the end of the 6-week treatment period. The HAMD-17 total score decreased significantly from baseline by approximately 11.1 +/- 4.5 points (from 22.8 +/- 1.1 to 11.8 +/- 4.4) in the Hypericum group and by approximately 3.4 +/- 3.9 points (from 22.6 +/- 1.2 to 19.2 +/- 3.8) in the placebo group (P < .001). Comparable group differences in favor of Hypericum were revealed by an additional responder analysis, the von Zerssen's Adjective Mood Scale, the Clinical Global Impressions scale, and a global efficacy assessment. Tolerability was very good in both groups; neither serious adverse events nor clinically relevant changes in safety parameters were observed, and only 2 cases demonstrated a possible connection between an adverse event and the study medication. The final safety assessment showed no differences between the Hypericum extract and placebo groups. The study provided evidence that Hypericum extract STW 3-VI in a once-daily dosing regimen may be an effective and well-tolerated option for patients with moderate depressive disorders.
PMID: 15605620 [PubMed - indexed for MEDLINE]
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li 160 has many positive studies but unfortunately a tiny amount of them could be seen as valid.
warm regards
sdb
Posted by Sigismund on June 2, 2008, at 0:44:24
In reply to Re: comparism of hypericum studies, STW3-VI, posted by sdb on June 1, 2008, at 9:15:51
Do those studies (which I have not really read) give us any reason to prefer hypericin as against hyperforin?
One problem with hypericin (I think?) here is the light sensitivity thing.
Posted by sdb on June 2, 2008, at 14:16:22
In reply to Re: comparism of hypericum studies, STW3-VI » sdb, posted by Sigismund on June 2, 2008, at 0:44:24
> Do those studies (which I have not really read) give us any reason to prefer hypericin as against hyperforin?
>
> One problem with hypericin (I think?) here is the light sensitivity thing.(1) no.
(2) as far as I know hypericin is more blamed for light sensitivity.
warm regards
sdb
Posted by sdb on June 4, 2008, at 11:30:44
In reply to Re: comparism of hypericum studies, STW3-VI }} sig, posted by sdb on June 2, 2008, at 14:16:22
> > Do those studies (which I have not really read) give us any reason to prefer hypericin as against hyperforin?
> >
> > One problem with hypericin (I think?) here is the light sensitivity thing.
>
> (1) no.
>
> (2) as far as I know hypericin is more blamed for light sensitivity.
>
> warm regards
>
> sdb
>
>here is quite much written about that:
http://www.rxlist.com/cgi/generic/stjohn_od.htm
you really have to take care of interactions.
But in general and not specifically for st. john's wort, drug (skin) - allergies can be dramatic.
Posted by sdb on June 15, 2008, at 18:11:22
In reply to Re: photosensitivity }} Sigismund, posted by sdb on June 4, 2008, at 11:30:44
i have not eaten the ultimate truth. I don't believe the psychiatrists did. what I have heard is that the hypericum stuff can be different from extract to extract. Some people may feel better
with an extract or may feel even worse. people won't believe that most things are unexplainable scientifically.If you're living in a country with a high sun radiation then it would make sense to be cautious.
some medications won't work anymore eg. cardiac meds, benzos and other things.warm regards
sdb
Posted by linkadge on June 23, 2008, at 20:50:34
In reply to Re: hypericum }} Sigismund, posted by sdb on June 15, 2008, at 18:11:22
I'm not too worried about the risks. The proven risks are minimal if you are not taking interacting drugs. Prescription meds were a lot more harsh on my system.
I have used SJW with consistent relief for fairly long periods of time. I found that the use of a standardized and reputable brand gave me nearly consistant results.
Linkadge
This is the end of the thread.
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