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Jcp200056 441.447

A Double-blind, Randomized Trial of St John’s Wort, Fluoxetine, and Placebo in Major Depressive Disorder Maurizio Fava, MD,* Jonathan Alpert, MD, PhD,* Andrew A. Nierenberg, MD,* David Mischoulon, MD, PhD,* Michael W. Otto, PhD,* John Zajecka, MD,y Harald Murck, MD,z and Jerrold F. Rosenbaum, MD* icum extracts are rather complex mixtures, whose exact Objective: This study looks to compare the antidepressant efficacy compositions depend on the extraction method applied.
and safety of a standardized extract of St John’s wort with both However, both hyperforin and the naphthodianthrones hypericin and its 2-hydroxymethyl derivative, pseudohyper- Method: After a 1-week single-blind washout, patients with major icin, often referred to as total hypericin, are considered to be depressive disorder diagnosed by Structured Clinical Interview forDiagnostic and Statistical Manual of Mental Disorders, Fourth the most specific ingredients.1 However, the precise identity Edition were randomized to 12 weeks of double-blind treatment of the efficacious constituents of Hypericum extracts is not with LI-160 St John’s wort extract (900 mg/d), fluoxetine (20 mg/d), known, nor are the details of the pharmacological mecha- or placebo. The 17-item Hamilton Rating Scale for Depression (HAMD-17) was the primary efficacy measure, and analysis of co- Among the lay public and physicians in Europe, St variance was used to compare differences in end point HAMD-17 John’s wort (H. perforatum) is perceived to be effective for scores across the 3 treatment groups, treating the baseline HAMD-17 mild-to-moderate depression, with a benign profile of ad- verse drug events, including lack of sedation.1 In support of Results: One hundred thirty-five patients (57% women; mean age, this view, a meta-analysis of 23 European randomized trials 37.3 ± 11.0; mean HAMD-17, 19.7 ± 3.2) were randomized to of St John’s wort extract in 1757 outpatients with mild to double-blind treatment and were included in the intent-to-treat moderately severe depressive disorders2 showed that, in analyses. Analysis of covariance analyses showed lower mean placebo-controlled trials, St John’s wort was effective in 55% HAMD-17 scores at end point in the St John’s wort group (n = 45; of the subjects (n = 408), whereas placebo was effective in mean ± SD, 10.2 ± 6.6) compared with the fluoxetine group (n = 47; 22% of the subjects (n = 422). The same meta-analysis 13.3 ± 7.3; P < 0.03) and a trend toward a similar finding relative to showed that, in the 6 active comparator trials involving a the placebo group (n = 43; 12.6 ± 6.4; P = 0.096). There was also a single preparation of St John’s wort, a 64% response rate was trend toward higher rates of remission (HAMD-17 <8) in the St observed (n = 158), compared with the 58% response rate for John’s wort group (38%) compared with the fluoxetine group (30%) the antidepressant comparators (n = 159). On the other hand, and the placebo group (21%). Overall, St John’s wort appeared to be Shelton et al3 commented that most or perhaps all of the trials used in this meta-analysis had serious methodological flaws, Conclusion: St John’s wort was significantly more effective than such as a relatively short duration of the trial and failure to fluoxetine and showed a trend toward superiority over placebo. A use standardized diagnostic practices or symptom rating (25%) smaller than planned sample size is likely to account for the instruments, thereby undermining confidence in these results.
lack of statistical significance for the advantage (indicating a The findings of 2 large, multicenter, placebo-controlled moderate effect size, d = 0.45) of St John’s wort over placebo.
US studies of St John’s wort have been recently published.
The first study compared the efficacy and safety of a well- (J Clin Psychopharmacol 2005;25:441 – 447) 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 In Western Europe, extracts from St John’s wort (Hyper- States.3 The study enrolled 200 adult outpatients (mean age, icum perforatum) have been in therapeutic use for the 42.4 years; 67% women; 86% white) with MDD and a treatment of depressed mood for hundreds of years. Hyper- baseline 17-item Hamilton Rating Scale for Depression(HAMD-17)4 score of at least 20. After a 1-week single-blind *Depression Clinical and Research Program, Massachusetts General Hospital, run-in of placebo, patients were randomly assigned to receive Boston, MA; yDepartment of Psychiatry, Rush-Presbyterian– St Luke’sMedical Center, Chicago, IL and zLichtwer Pharma AG, Wallenroder either St John’s wort extract (n = 98; 900 mg/d for 4 weeks, Straße 8-10, D-13435 Berlin, Germany.
increased to 1200 mg/d in the absence of an adequate response Received August 4, 2003; accepted after revision May 5, 2005.
thereafter) or placebo (n = 102) for 8 weeks. The random Address correspondence and reprint requests to Maurizio Fava, MD, Depres- coefficient analyses for the primary efficacy measure sion Clinical and Research Program, Massachusetts General Hospital, 15 (HAMD-17) showed significant effects for time but not for Parkman St, ACC 812, Boston, MA 02114. E-mail: mfava@partners.org.
treatment or time-by-treatment interaction. The proportion of Copyright n 2005 by Lippincott Williams & WilkinsISSN: 0271-0749/05/2505-0441 participants achieving an a priori definition of response also did not differ significantly between groups (34% for St John’s Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 wort and 22% for placebo), but the number reaching remis- Improvement [CGI-I] scale score of 1 or 2) occurred in 32% sion (HAMD-17 score of 7 and a Clinical Global Impression of the placebo-treated patients versus 24% of the St John’s [CGI] score of 1 or 2) was significantly higher with St John’s wort – treated patients (P = 0.21) and 25% of sertraline-treated wort than with placebo (P = 0.02). However, these rates of patients (P = 0.26). Adverse effect profiles for St John’s wort remission were very low in the full intention-to-treat analysis and sertraline differed relative to placebo. Although this study (14/98 [14%] vs. 5/102 [5%], respectively). St John’s wort failed to support the efficacy of St John’s wort in moderately was safe and well tolerated, and headache was the only severe major depression, the equally poor performance of adverse event (AE) that occurred with greater frequency with sertraline in this trial underscores the variability in efficacy St John’s wort than with placebo (39/95 [41%] vs. 25/100 findings that are not uncommon among approved agents. The [25%], respectively).3 Although the authors of the study accompanying editorial by Kupfer and Frank8 pointed out that concluded that, in their study, St John’s wort was not effective the only 2 controlled studies of St John’s wort in the United for treatment of major depression,3 this conclusion is States had failed to reject the null hypothesis but had not yet premature given that it is not uncommon for studies to fail provided a definitive perspective on the potential utility of to differentiate placebo and antidepressant treatment among St John’s wort. In addition, despite the fact that the European agents that eventually achieve the 2 pivotal trials necessary for studies had suggested efficacy of St John’s wort in mild-to- Food and Drug Administration approval.5 For example, an moderate depression, both studies included only patients with analysis of 5 antidepressant agents found that, of 39 trials filed moderate to severe MDD, as a HAMD-17 score of 20 or with the Food and Drug Administration, only 14% of these higher was required for entry into these 2 studies. Accord- trials found active drug superior to placebo for all primary ingly, there is need for further study of the antidepressant and secondary outcome measures of depression, and only 44% efficacy and safety of a standardized extract of St John’s wort of studies differentiated drug from placebo on the first (H. perforatum, LI-160) relative to both placebo and fluoxe- depression item on the HAMD.6 Accordingly, it is fully within tine in a population of outpatients with mild to moderately 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 study7 which tested in MDD the efficacy andsafety of the same well-characterized H. perforatum extract (LI-160) used in the Shelton study. The study was conducted This was a 12-week, randomized, active- and placebo- in 12 academic and community psychiatric research clinics in controlled, parallel-group, double-blind study conducted in the United States. Adult outpatients (n = 340) recruited patients with a diagnosis of MDD. The study was conducted between December 1998 and June 2000 with MDD and a in 2 sites (Boston and Chicago). Upon enrollment, all baseline total score on the HAMD-17 of at least 20 were eligible patients were required to have discontinued any randomly assigned to receive St John’s wort, placebo, or previous psychoactive medication for a specified period of sertraline (as an active comparator) for 8 weeks. Based on time to qualify for entry into the single-blind placebo clinical response, the daily dose of St John’s wort could range washout period of 7 days (Table 1). Patients still meeting the from 900 to 1500 mg and that of sertraline from 50 to 100 mg.
diagnostic inclusion criterion after the washout period On the 2 primary outcome measures, neither sertraline nor St entered the 12-week, acute, double-blind therapy phase, John’s wort was significantly different from placebo. The receiving 1 of the following 3 randomized double-blind random regression parameter estimate for mean (SE) change treatments: (1) LI-160 St John’s wort extract (300 mg thrice in HAMD-17 total score from baseline to week 8 (with a a day; daily dose, 900 mg), (2) fluoxetine 20 mg every day, greater decline indicating more improvement) was À9.20 or (3) placebo. The study was planned as a single-center trial (0.67) (95% confidence interval, À10.51 to À7.89) for with an anticipated total of approximately 180 enrolled placebo vs. À8.68 (0.68) (95% confidence interval, À10.01 patients at the Depression Clinical and Research Program of to À7.35) for St John’s wort (P = 0.59) and À10.53 (0.72) the Massachusetts General Hospital in Boston from Septem- (95% confidence interval, À11.94 to À9.12) for sertraline (P = ber 1998 to September 2000. Because of difficulties in 0.18). Full response (HAMD-17 score of 8 and a CGI completing enrollment by the target date, a second site TABLE 1. Treatment Schedule—Double-dummy Technique Figures denote number of tablets/capsules per day. The schedule for the acute therapy applies also for the responders during follow-up. TID indicates thrice Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 St John’s Wort, Fluoxetine, and Placebo in MDD (Department of Psychiatry, Rush-Presbyterian – St Luke’s i. Unacceptability to discontinue or likelihood to need Medical Center, Chicago, Ill) was added to the Boston site.
medication that is prohibited as concomitant treatment Following an interim analysis of the study performed in September 2001, the sponsor (Lichtwer Pharma AG, Berlin, j. Clinical or laboratory evidence of hypothyroidism.
Germany) opted to close the study and to proceed with the k. Failure to respond during the course of current major final analyses carried out on a sample size smaller (n = 135) depressive episode to at least 2 adequate antidepressant trials, defined as 8 weeks or more of treatment witheither imipramine 150 mg or greater (or its tricyclicequivalent), phenelzine 60 mg or greater (or its monoamine oxidase inhibitor equivalent), or fluoxetine Patients were primarily recruited from general adver- 20 mg or greater (or its selective serotonin reuptake tising and clinician referrals. Meeting all criteria listed below, patients of either sex and any ethnic origin with a l. Any other condition which, in the investigator’s diagnosis of MDD were included in the study. The patients judgment, may pose a significant risk to the patient’s were required to meet the following inclusion criteria: health or may decrease the chances of obtaining reliable data to achieve the objectives of the study.
b. Current experience of a major depressive episode m. Mental condition rendering the patient unable to un- according to Diagnostic and Statistical Manual of derstand the nature, scope, and possible risks of the Mental Disorders, Fourth Edition of at least 2 weeks’ n. History or suspicion of unreliability, poor cooperation, c. A HAMD-17 total score !16 at both screen and or noncompliance with medical treatment.
d. Negative pregnancy test within 5 days before study start in women of childbearing potential (nonchild- After the placebo washout period, all patients were bearing potential was defined as postmenopause for at randomized unless they met either 1 of the following criteria least 1 year or surgical sterilization or hysterectomy at at the randomization visit: HAMD-17 less than 16 or a reduction in HAMD-17 by 25% or greater as compared with e. Use of adequate contraception in women of childbear- the screening visit. During the period of randomized treatment, double-blind conditions were maintained using f. Readiness and ability on the part of the patient to the following double-dummy schedule (see Table 1).
comply with the physician’s instructions and to fill out For each treatment group, the following daily schedule the self-report measures in connection with their 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 a. Pregnancy, lactation, or nonuse of medically accepted (St John’s wort) or 20 mg of fluoxetine.
means of contraception in women of childbearingpotential.
b. Current serious suicidal or homicidal risk (according to Hypericum extract (St John’s wort) (LI-160) and matching placebo were provided by Lichtwer Pharma, c. Serious or unstable medical illness including cardio- whereas fluoxetine and matching placebo were provided by vascular, hepatic, renal, respiratory, endocrine, neuro- the Massachusetts General Hospital research pharmacy, and fluoxetine capsules manufactured by Eli Lilly and Co were used. The Hypericum extract was standardized to between e. One or more of the following Diagnostic and Statistical 0.12% and 0.28% hypericin, and the entire study supply came Manual of Mental Disorders, Fourth Edition diagnoses: from 1 batch. The study was conducted under an investiga- organic mental disorders; substance use disorders, tional new drug application filed by Lichtwer Pharma.
including alcohol, active within the last 6 months; The frequency of visits was as follows: screen (7 – 14 schizophrenia; delusional disorder; psychotic disorders days before baseline), baseline (day 0), visit 1 (day 7 + not elsewhere classified; bipolar disorder; or antisocial 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 f. History of multiple adverse drug reactions or allergy to g. Mood-congruent or mood-incongruent psychotic features.
h. Any of the following treatments at baseline or within On enrollment, all patients were administered the the specified time frame before baseline: other psy- Structured Clinical Interview for Diagnostic and Statistical chotropic drugs, 14 days; other investigational psy- Manual of Mental Disorders, Fourth Edition Axis I dis- chotropic drug, 40 days; fluoxetine, 40 days; or any orders.9 All patients were administered at each visit the other investigational drug, 1 month.
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Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 1. The 28-item HAMD. The 28-item HAMD4 allows the assessment of the HAMD-17 scale, which is the primary The primary objective of the study was to evaluate the efficacy measure of the study. This instrument was efficacy of LI-160 compared with placebo and fluoxetine for completed by the investigators based on their assessment decreasing depressive symptoms in patients with MDD. One- of the patient’s depressive symptoms.
way analysis of covariance (ANCOVA) was used to assess 2. The CGI Severity of Illness (CGI-S) and improvement differences in HAMD-17 depression severity at end point (CGI-I) scales. The patients’ CGI10 was based on the (week 12). The covariate was the baseline HAMD-17, and investigators’ assessment of the patients depressive the final HAMD-17 served as the dependent variable. These analyses were performed on the ITT populations; the last- 3. The Beck Depression Inventory (BDI).11 This self-rated observation-carried-forward approach was used for missing instrument was completed by the patients based on their assessment of the severity of depression.
The secondary efficacy end points were (1) the proportion of remitters after 12 weeks of treatment (visit 6) At each visit, the following vital signs were monitored or end point, with remission = HAMD-17 score less than 8, as safety parameters: blood pressure and heart rate. The was assessed with pairwise Fisher exact tests; (2) the change following laboratory assessments (complete blood count, from baseline after 12 weeks of treatment (visit 6) or end chemistries, and urinalysis) were performed at screen and point in CGI-S was assessed with pairwise ANCOVA, using week 12 or end point. All laboratory values as well as all the CGI-S at baseline as the covariate; (3) the CGI-I score electrocardiographic recordings were assessed by the inves- after 12 weeks of treatment (visit 6) or end point was tigator as to whether they had to be judged as AEs. For the assessed with pairwise ANOVA; and (4) the BDI change recording of AEs, patients were required to report sponta- from baseline in the total score after 12 weeks of treatment neously any AEs as well as the time of onset and intensity of (visit 6) or end point was assessed with pairwise ANCOVA, using the BDI at baseline as the covariate. These analyseswere performed on the ITT population.
The primary efficacy measure for this study was the HAMD-17. This instrument was administered at each visit by The proportion of patients reporting AEs in the ITT the clinical study investigators. The primary efficacy end sample was compared across the 3 treatment groups using point for this study was the final HAMD-17 total score after 12 weeks of randomized treatment on end point. Secondaryefficacy measures included the CGI-S, the CGI-I, and the BDI.
The ITT population included 135 outpatients with MDD (57% women; 19% minorities; mean age, 37.3 ± 11.0 Safety analysis was performed for all patients who years; mean HAMD-17, 19.7 ± 3.2; mean CGI-S score, 4.2 ± took at least 1 dose of study medication (all-subjects-treated 0.6) who were randomized to double-blind treatment. Of group). Measures of safety included reported AEs, routine those randomized, 101 (75%) were enrolled in the Boston laboratory assessments (performed at the first pretreatment site, and 34 (25%) in the Chicago site. There was no visit and at week 8), physical examinations (performed at the significant difference in pairwise comparisons of age among first pretreatment visit and at week 8), and the patient’s vital patients randomized to St John’s wort (mean, 37.4 ± 11.7), signs, including blood pressure, heart rate, body temperature, fluoxetine (mean, 36.7 ± 9.6), or placebo (mean, 37.8 ± respiration rate, and body weight (assessed at both 12.0). Similarly, there were no significant differences in sex pretreatment visits and at all study weeks that included a 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 nosignificant differences at baseline in the mean HAMD-17, Statistical significance was set at P 0.05. Intent-to- treat (ITT) analyses were conducted. The primary ITT The rate of completion of the 12-week, double-blind, included all subjects who completed their baseline visit, were placebo-controlled phase was as follows: 60% (27/45) for deemed eligible to continue the study, and were therefore St John’s wort, 51% (24/47) for fluoxetine, and 49% (21/43) randomized to double-blind treatment.
for placebo. As shown in Table 2, St John’s wort treatmentwas associated with a significantly (P < 0.05) greater Baseline Clinical and Demographic Variables decrease in HAMD-17 scores compared with fluoxetine at all Pairwise differences among treatment groups for postbaseline visits, except visit 5 (week 8). There was also a clinical and demographic variables of the ITT sample were trend (P < 0.1) toward a significantly greater reduction in compared with analyses of variance (ANOVA) and Fisher HAMD-17 score compared with placebo at visit 1 (week 1) and visit 6/end point. There were also nonsignificantly Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 St John’s Wort, Fluoxetine, and Placebo in MDD TABLE 2. Mean HAMD-17 Scores in the ITT Sample of Outpatients With MDD (n = 135) *P < 0.05, St John’s wort versus fluoxetine (pairwise ANCOVA).
yP = 0.062, St John’s wort versus placebo (pairwise ANCOVA).
zP = 0.096, St John’s wort versus placebo (pairwise ANCOVA).
higher rates of remission (HAMD <8) in the St John’s wort originally planned. As mentioned earlier, the sponsor of the group (38%) compared with the fluoxetine group (30%) and study conducted an interim analysis with the intent of closing the study earlier partly because of the delay in achieving the Table 3 reports the results of the analyses for the target enrollment and partly because of the negative/ secondary end points. In 4 patients, the BDI at baseline was inconclusive results of the 2 prior US studies. Following missing, so the BDI score at screen was carried forward; the interim analysis, the sponsor closed the study and opted similarly, the BDI at end point was missing in 5 patients, so to proceed with the final analyses carried out on a sample the BDI from the previous visit was carried forward. There size smaller (n = 135) than originally planned (n = 180). Our was a trend toward a significantly (P < 0.1) greater reduction findings are consistent with those of a meta-analysis of 23 in CGI-S at visit 6/end point in St John’s wort – treated European randomized trials of St John’s wort extract in 1757 patients compared with fluoxetine-treated patients, and the outpatients with mild to moderately severe depressive CGI-I scores were significantly (P < 0.05) lower at visit disorders.2 The meta-analysis had shown that, in placebo- 6/end point in St John’s wort – treated patients compared with controlled trials, St John’s wort was effective in 55% of the fluoxetine-treated patients. There was also a trend (P < 0.1) subjects (n = 408), whereas placebo was effective in 22% of toward a significantly lower CGI-I score among St John’s the subjects (n = 422), and that, in the 6 active-comparator wort – treated patients compared with placebo-treated pa- trials involving a single preparation of St John’s wort, a 64% There was only 1 serious AE during the course of the study: a patient randomized on St John’s wort overdosed on TABLE 3. Mean CGI-S, CGI-I, and BDI Scores in the ITT Sample 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 inpatients 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 In our study of outpatients with mild to moderate In 4 patients, the BDI at baseline was missing; thus, the BDI score at MDD, a well-standardized H. perforatum (St John’s wort) screen was carried forward; similarly, the BDI at end point was missing in 5 extract (LI-160) was significantly more effective than patients, so the BDI from the previous visit was carried forward.
fluoxetine and showed a trend toward statistically significant *P = 0.078, St John’s wort versus fluoxetine (pairwise ANCOVA).
superiority over placebo. The main limitation of our study is P < 0.05, St John’s wort versus fluoxetine (pairwise ANOVA).
zP = 0.070, St John’s wort versus placebo (pairwise ANOVA).
that the sample size of our study (n = 135) is smaller than Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 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) GIT indicates gastrointestinal tract; URTI, upper respiratory tract infection.
*P < 0.05, Placebo versus fluoxetine and versus St John’s wort (pairwise Fisher exact test).
response rate was observed with St John’s wort (n = 158), Europe and the United States continues to suggest that St compared with the 58% response rate of the antidepressant John’s wort agents may offer antidepressant efficacy for comparators (n = 159). Our results are also consistent with some individuals with mild to moderate depression. As far those of a recently published multicenter European study12 as safety and tolerability are concerned, our findings are which showed that, among 375 outpatients with mild to consistent with those of Shelton et al; St John’s wort moderate MDD (HAMD-17 score at baseline between 18 appeared to be safe and well tolerated, and headache was the and 25), treatment with a hydroalcoholic H. perforatum most common AE in our trial (42%) and was the only AE extract was accompanied by a significantly (P = 0.04) greater that occurred with greater frequency with St John’s wort than reduction in HAMD-17 score than placebo. In this study,12 placebo in the Shelton et al study ([41%] vs. [25%], the remission rate (defined as a HAMD-17 score <7) was also significantly (P = 0.03) higher for Hypericum (24.7%) How do we explain the apparent lack of efficacy of fluoxetine in this trial? To the same extent that we used On the other hand, our findings are not consistent a fixed-dose approach to St John’s wort (900 mg/d), we also with those of the 2 placebo-controlled trials of the same H.
used a fixed-dose approach to fluoxetine (20 mg/d), and perforatum (St John’s wort) extract (LI-160) used in our data from our group suggest that a significant proportion of study. The first study3 enrolled 200 adult outpatients with patients nonresponding to 20 mg/d may go on to respond when moderate to severe MDD. Although there was no significant the dose is increased to 40 or 60 mg/d.13,14 Similarly, in a difference in outcome at the end of the 8-week treatment on recent double-blind study in MDD, where clinicians were the primary efficacy measure between St John’s wort (900 – allowed to escalate the dose greater than 20 mg/d in non- 1200 mg/d) or placebo, the number reaching remission of responders to 4 weeks of fluoxetine 20 mg/d, the final mean MDD was significantly higher with St John’s wort than with daily dose for fluoxetine was 42 mg, with 31.3% of the pa- placebo (P = 0.02), with very low overall rates in the full tients remaining at a dose of 20 mg, while 28.4% and 40.3% intention-to-treat analysis (14/98 [14%] vs. 5/102 [5%], receiving an increase to 40 and 60 mg, respectively.15 These respectively).3 The recently published multicenter study studies suggest that fluoxetine 20 mg/d, although typical- sponsored by the National Center for Complementary and ly considered an effective dose in the treatment of MDD, Alternative Medicine and by the National Institute of Mental may not be an adequate dose for a significant proportion of Health7 provided results that were somewhat inconclusive, as patients having MDD. Furthermore, the smaller (25%) than both St John’s wort (900 – 1500 mg/d) and sertraline (50 – planned sample size is likely to account for the lack of sta- 100 mg/d) were not significantly different from placebo on tistical significance for the advantage (indicating a moderate the 2 primary outcome measures. As noted earlier, negative effect size, d = 0.45) of St John’s wort over placebo.
studies for antidepressant medications are relatively common In summary, in our study of outpatients with mild to among agents meeting approval for Food and Drug moderate MDD, a well-standardized preparation of H.
Administration approval, and all studies on an agent need perforatum (St John’s wort) extract (LI-160) was signifi- to be considered when evaluating the true effect size of the cantly more effective than fluoxetine and showed a trend agent. The total evidence from the accumulated trials in toward superiority over placebo. Further studies are needed Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology  Volume 25, Number 5, October 2005 St John’s Wort, Fluoxetine, and Placebo in MDD to fully evaluate the antidepressant efficacy of St John’s 3. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort. NIMH, NCCAM, and the NIH Office of Disease wort in major depression: a randomized controlled trial. JAMA. 2001;285(15):1978 – 1986.
Prevention have jointly funded a study of St John’s wort 4. Hamilton M. A rating scale for depressions. J Neurol Neurosurg compared with citalopram and placebo for the treatment of minor depression. This study will generate information about 5. Otto MW, Nierenberg AA. Assay sensitivity, failed clinical trials, and the efficacy of St John’s wort for a milder form of depression the conduct of science. Psychother Psychosom. September– October and help to fill the gaps in our knowledge about the clinical 6. Hooper M, Amsterdam JD. Do clinical trials reflect drug potential? A use of this most important herbal product.
review of FDA evaluation of new antidepressants. Poster presented at:NCDEU 39th Annual Meeting; June 11 – 14, 1998; Boca Raton, Fla.
7. Hypericum Depression Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled The study was supported by a grant of Lichtwer trial. JAMA. 2002;287(14):1807 – 1814.
Pharma AG (Berlin, Germany) to the Massachusetts General 8. Kupfer DJ, Frank E. Placebo in clinical trials for depression: complexity Hospital. The authors thank Dr John Worthington of the and necessity. JAMA. 2002;287(14):1853– 1854.
9. First MB, Spitzer RL, Gibbon M , et al. Structured Clinical Interview for Massachusetts General Hospital Depression Clinical and DSM-IV– Axis I Disorders—Patient Edition (SCID-I/P, Version 2.0).
Research Program and Drs Marc Pfeffer, Diane London, New York: Biometrics Research Department, New York State Psy- Shelley Kramer, Alexander Altschuller, and Laurie Witts of Partners Research and Education Program (PREP) for their 10. Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rev help and support in conducting the study. The authors also Ed DHEW Publication No. (ADM) 7 – 338. National Institute of MentalHealth: Rockville, MD; 1976.
thank Lee Gresham, Megan Hughes, and Pam Roffi of the 11. Beck AT, Ward CE, Mendelson M. An inventory for measuring Massachusetts General Hospital Depression Clinical and depression. Arch Gen Psychiatry. 1961;4:561– 571.
Research Program and Courtney Vitale of Partners Re- 12. Lecubrier Y, Clerc G, Didi R, et al. Efficacy of St. John’s wort extract search and Education Program (PREP) for their technical WS 5570 in major depression: a double-blind, placebo-controlled trial.
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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.
14. Fava M, Alpert J, Nierenberg AA, et al. Double-blind study of high-dose 1. Nierenberg AA, Mischoulon D, DeCecco L. St. John’s wort: a critique fluoxetine vs. lithium or desipramine augmentation of fluoxetine in of antidepressant efficacy and possible mechanism of action. In: partial and non-responders to fluoxetine. J Clin Psychopharmacol.
Mischoulon D, Rosenbaum JF, eds. Natural Medications for Psychiatric Disorders. Philadelphia, PA: Lippincott Williams and Wilkins; 2002:3–12.
15. Fava M, Hoog SL, Judge RA, et al. Acute efficacy of fluoxetine 2. Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression— versus sertraline and paroxetine in major depressive disorder including an overview and meta-analysis of randomised clinical trials. BMJ.
effects of baseline insomnia. J Clin Psychopharmacol. April 2002;22 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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Case MDL No. 2459 Document 85 Filed 08/08/13 Page 1 of 3 UNITED STATES JUDICIAL PANEL MULTIDISTRICT LITIGATION IN RE: LIPITOR (ATORVASTATIN CALCIUM) MARKETING, SALES PRACTICES AND PRODUCTS LIABILITY LITIGATION ORDER DENYING TRANSFER Before the Panel : Pursuant to 28 U.S.C. § 1407, plaintiffs in three actions pending in the District of South Carolina move to centralize this litiga

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Graefes Arch Clin Exp Ophthalmol (2011) 249:715–721DOI 10.1007/s00417-010-1612-6Retinal functional changes measured by frequency-doublingtechnology in patients treated with hydroxychloroquineLucia Tanga & Marco Centofanti & Francesco Oddone & Mariacristina Parravano &Vincenzo Parisi & Lucia Ziccardi & Barbara Kroegler & Roberto Perricone &Gianluca ManniReceived

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