KupferFrank-Placebo in Clinical Trials for Depresson.pdf

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EDITORIAL

Editorials represent the opinions

of the authors and T

OURNAL

and not those of

the American Medical Association.

Placebo in Clinical Trials for Depression

Complexity and Necessity

David J. Kupfer, MD

Ellen Frank, PhD

simmering debate about the ethical issues sur-

rounding placebo administration in random-

ized clinical trials has reached new levels of

intensity. The report of the National Bioethics Advisory Com-

mission included specific recommendations for studies in-

volving more than minimal risk, including the use of pla-

cebo controls in clinical trials.

At a time of increased interest

in drug discovery in medicine and the potential need for de-

finitive randomized clinical trials, the controversy over the

ethical issues places an appropriate burden on the scien-

tific community to justify the use of placebo controls.

2,3

One

argument is that placebo administration is not appropriate

if effective treatment for a condition exists and that assess-

ment of efficacy can be conducted with active controls. An-

other view is that placebo controls may be necessary to de-

termine the assay sensitivity of a trial and are ethical if patients

provide informed consent and are not harmed.

Treatment of depression, a well-recognized and world-

wide public health problem,

represents a special opportu-

nity to highlight several key issues in the “placebo contro-

versy” and to demonstrate why for the foreseeable future

placebo-controlled trials will be necessary. While the treat-

ment of depression has been marked by major successes with

the introduction of new classes of antidepressants and their

“uptake” by clinicians and patients,

newer antidepressants

will continue to be developed. These new products may tar-

get specific subtypes of depression, may provide more com-

plete recovery and sustained remission, and may have re-

duced adverse effects and faster onset of action. These products

will require proof of efficacy and Food and Drug Adminis-

tration approval. A better understanding of the many alter-

native or complementary treatments for depression, such as

nonprescription herbal compounds, also contributes to the

need to determine when placebo controls are appropriate.

Two articles in this issue of T

OURNAL

, one from the

Hypericum Depression Trial Study Group

and another from

Walsh et al

on placebo response, focus attention on the key

issues. The first report examines the efficacy of St John’s wort

See also pp 1807 and 1840.

ITHIN THE LAST SEVERAL YEARS

THE LONG

(Hypericum

perforatum)

in major depressive disorder (MDD)

in a 3-arm clinical trial.

This study provides an opportu-

nity to comment on the role of placebo and whether pla-

cebo efficacy rates “interfere” with the establishment of the

efficacy of new treatments. The second report addresses the

problems of placebo in depression trials using a 20-year per-

spective. Walsh and colleagues

describe how placebo char-

acteristics and clinical response levels have changed.

The current study

on the use of St John’s wort in the treat-

ment of MDD is the second one within a year

to conclude

that St John’s wort is not effective. These trials were con-

ducted because, even though St John’s wort is widely used

for the treatment of major depression and depressive symp-

toms, its efficacy has not been clearly established, despite

more than 20 randomized trials, most of which are consid-

ered to have had serious methodological flaws.

9-11

Both of

the recent trials were multicenter randomized, double-

blind, placebo-controlled trials with a standardized extract

of St John’s wort. The previous 8-week trial by Shelton et

showed no significant difference between St John’s wort

extract and placebo on any of the depression outcome mea-

sures. Response rates in the intention-to-treat analysis were

also not significantly different (26.5% for St John’s wort vs

18.6% for placebo). The second study,

reported in this is-

sue, also included a large multicenter population of outpa-

tients with MDD, but differed in that a selective serotonin

reuptake inhibitor (SSRI), sertraline, was included as an ac-

tive control in addition to testing St John’s wort extract (hy-

pericum) and placebo. From this 8-week clinical trial, the

authors conclude that neither sertraline nor hypericum was

significantly different from placebo on the 2 primary out-

come measures, the Hamilton Depression Scale (HAM-D)

and the Clinical Global Impression Scale (CGI-I). The over-

all response rates (including partial and full response) were

38.1% for hypericum, 43.1% for placebo, and 48.6% for ser-

traline.

As the authors point out, their study represents an ex-

cellent example of why it is critical to include both placebo

and active comparators in trials of agents for which effi-

cacy is unproven. Without a placebo control, one might pre-

Author Affiliations:

Department of Psychiatry, University of Pittsburgh Medical

School, Western Psychiatric Institute and Clinic, Pittsburgh, Pa.

Corresponding Author and Reprints:

David J. Kupfer, MD, Department of Psy-

chiatry, University of Pittsburgh Medical School, Western Psychiatric Institute and

Clinic, 3811 O’Hara St, Pittsburgh, PA 15213 (e-mail: kupferdj@msx.upmc.edu).

(Reprinted) JAMA,

April 10, 2002—Vol 287, No. 14

1853

EDITORIAL

maturely conclude that hypericum has efficacy compa-

rable to an SSRI, in this case, sertraline. However, without

sertraline as the active comparator, the conclusion, as in the

previously published trial, would be that St John’s wort ex-

tract is not efficacious in MDD. Before drawing conclu-

sions, the low assay sensitivity of this new trial must be ac-

knowledged. It is likely that the study was underpowered

given the assumption of a 20% drug-placebo difference in

full response rates. In addition, while relatively high doses

of hypericum (1500-1800 mg/d) were permitted, the maxi-

mum acute dose of sertraline (100 mg/d) almost certainly

contributed to its low effect size and failure to separate out

from placebo or hypericum. The overall placebo response

was high compared with the previous hypericum vs pla-

cebo study,

demonstrating the variability in placebo re-

sponse from trial to trial. A recent review of placebo con-

trols in depression trials

made a series of recommendations

to enhance documentation of treatment vs placebo effi-

cacy, including greater emphasis on effect size, rather than

significance levels alone.

Walsh and colleagues

have approached the placebo re-

sponse issue for major depression studies in a careful re-

view of controlled trials between 1981 and 2000 in which

outpatients with MDD were randomly assigned to medica-

tion or placebo. In the 75 trials meeting this criterion, the

mean (SD) proportion of patients in the placebo group who

responded was 29.7% (8.3%). Since many investigations in-

volved more than 1 active antidepressant, the greater re-

sponse with an active drug in such trials was used to cal-

culate the overall active treatment response rate (50.0%

[9.0%]). The average effect size across studies for maxi-

mum proportion responding to a medication was 0.43 (0.22).

The authors conclude that the response to placebo is highly

variable, substantial, and has increased significantly in re-

cent years as shown by the high positive correlation with

the year of publication. While the response rate for anti-

depressant medication has also increased in the last 20

years, the association between response rate and year of

publication was more statistically robust for placebo than

for active medication. Walsh et al note that the change in

placebo response rate does not appear to be directly ex-

plained by changes in study characteristics such as patient

age, placebo lead-in, or minimum required HAM-D score.

It is difficult to disagree with their contention that since the

average rate of response has changed over time, the use of

a historical standard as a valid benchmark of efficacy rates

would be a poor choice.

Both of these reports, from different perspectives, point

to the continuing set of problems inherent in clinical trials

for major depression. Based on an extensive consensus de-

velopment panel process convened in September 1999, and

on summaries of presentations at that conference, includ-

ing those by Lavori

and Rush,

a National Depressive and

Manic-Depressive Association Consensus Statement on the

use of placebo in clinical trials of mood disorders

con-

1854

JAMA,

April 10, 2002—Vol 287, No. 14

(Reprinted)

cluded that placebo has a definite role in mood disorder stud-

ies and that findings of equivalence between a new drug and

standard treatment are not evidence of efficacy unless the

new drug is also significantly more effective than placebo.

Since this report expresses the consensus of an interdisci-

plinary group of clinical researchers, biostatisticians, bio-

ethicists, and consumers, it is likely that the use of placebo-

controlled trials in developing interventions will continue.

It is also noteworthy that all the stakeholders are now much

more sensitized to the necessity of seeking newer strate-

gies for shorter durations in drug-placebo trials to mini-

mize risks, as well as to the need for alternate research de-

signs, when appropriate.

Taken together, the 2 reports in this issue of T

OURNAL

return full circle to the placebo response and understanding

its mechanisms of action

and highlight the perplexing com-

plexity of the placebo and its ability to cause “mischief” in

scientific inquiry. This may be nature’s way of providing clues

to fundamental aspects of the healing process, even as ad-

vances in medicine and the discovery of new therapies take

place. It is important to learn from, rather than dismiss, the

variability of the therapeutic response.

REFERENCES

Research Involving Persons With Mental Disorders That May Affect Decision-

Making Capacity.

Rockville, Md: National Bioethics Advisory Commission; De-

cember 1998. Available at: http://bioethics.georgetown.edu/nbuc/capacity

/TOC.htm. Accessed February 28, 2002.

Rothman KJ, Michels KB. The continuing unethical use of placebo controls.

N Engl J Med.

1994;331:394-398.

Charney DS. The use of placebos in randomized clinical trials of mood disor-

ders.

Biol Psychiatry.

2000;47:687-688.

Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the

evaluation of new treatments, part I: ethical and scientific issues.

Ann Intern Med.

2000;133:455-463.

Murray JL, Lopez AD, eds.

The Global Burden Of Disease: A Comprehensive

Assessment of Mortality and Disability From Diseases, Injuries, and Risk Factors

in 1990 and Projected to 2020.

Geneva, Switzerland: World Health Organiza-

tion; 1998.

Olfson M, Marcus SC, Druss BN, Elinson L, Tanielian T, Pincus HA. National

trends in the outpatient treatment of depression.

JAMA.

2002;287:203-209.

Hypericum Depression Trial Study Group. Effect of

Hypericum perforatum

(St John’s wort) in major depressive disorder: a randomized controlled trial.

JAMA.

2002;287:1807-1814.

Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of

major depression: variable, substantial, and growing.

JAMA.

2002;287:1840-

1847.

Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort in

major depression: a randomized controlled trial.

JAMA.

2001;285:1978-1986.

10.

Linde K, Ramirez T, Mulrow CD, et al. St. John’s wort for depression: an

overview and meta-analysis of randomized clinical trails.

BMJ.

1996;313:253-

258.

11.

Linde K, Mulrow CD. St. John’s wort for depression [Cochrane Database of

Systematic Reviews]. Oxford, England: Cochrane Library, Update Software; 2000;

issue 2.

12.

Schatzberg AF, Kraemer HC. Use of placebo control groups in evaluating

efficacy of treatment of unipolar major depression.

Biol Psychiatry.

2000;47:

736-744.

13.

Lavori PW. Placebo control groups in randomized treatment trials: a statisti-

cian’s perspective.

Biol Psychiatry.

2000;47:717-723.

14.

Rush AJ. The use of placebos in unipolar major depression: the current status.

Biol Psychiatry.

2000;47:745-747.

15.

Charney DS, Nemeroff CB, Lewis L, et al. National Depressive and Manic-

Depressive Association Consensus Statement on the use of placebo in clinical

trials of mood disorders.

Arch Gen Psychiatry.

2002;59:262-270.

16.

Lasagna L. Placebos and controlled trials under attack.

Eur J Clin Pharmacol.

1979;15:373-374.

LETTERS

lates and 19 (79%) of the 24 antibiotic-resistant isolates in all

bioassays, while preconsumption urine (average pH 6.2) failed

to prevent adhesion in any of the samples. Antiadhesion ac-

tivity was evident in the urine within 2 hours and persisted for

up to 10 hours following cranberry juice cocktail ingestion. The

extracted proanthocyanidins inhibited adhesion of all isolates

at concentrations ranging from 6 to 375 µg/mL, demonstrat-

ing potent in vitro antiadhesion activity against these antibiotic-

resistant strains.

Conclusions.

These data suggest that consumption of cran-

berry juice cocktail may offer protection against both sensi-

tive and resistant strains of P-fimbriated

E coli

by a mecha-

nism that is not likely to increase selective pressures associated

with antibiotic resistance. In light of the evidence that antibi-

otic usage is a contributing factor in development of trimeth-

oprim-sulfamethoxazole–resistant uropathogenic

E coli,

fur-

ther trials are warranted to explore the use of cranberry juice

as an alternative strategy to prevent UTIs and potentially re-

duce the rate of antibiotic resistance.

Amy B. Howell, PhD

Marucci Center for Blueberry and Cranberry Research

Rutgers University

Chatsworth, NJ

Betsy Foxman, PhD

Department of Epidemiology

University of Michigan School of Public Health

Ann Arbor

Funding/Support:

Isolate collection was supported by National Institutes of Health

grant R01 DK35368, and bacterial antiadhesion work was supported by Ocean

Spray Cranberries, Inc. Ocean Spray provided monetary support only and did not

participate in the design, analysis, or interpretation of the data.

Manges AR, Johnson JR, Foxman B, O’Bryan TT, Fullerton KE, Riley LW. Wide-

spread distribution of urinary tract infections caused by a multidrug-resistant

Esch-

erichia coli

clonal group.

N Engl J Med.

2001;345:1007-1013.

Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduc-

tion of bacteriuria and pyruria after ingestion of cranberry juice.

JAMA.

1994;271:

751-754.

Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Ran-

domised trial of cranberry-lingonberry juice and

Lactobacillus

GG drink for the

prevention of urinary tract infections in women.

BMJ.

2001;322:1571-1573.

Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of adherence of

P-fimbriated

Escherichia coli

to uroepithelial-cell surfaces by proanthocyanidin ex-

tracts from cranberries.

N Engl J Med.

1998;339:1085-1086.

Brown PD, Freeman A, Foxman B. Prevalence and predictors of trimethoprim-

sulfamethoxazole resistance among uropathogenic

Escherichia coli

in Michigan.

Clin Infect Dis.

2002;34:1061-1066.

CORRECTION

Incorrect Wording:

There was incorrect wording in the Editorial entitled “Pla-

cebo in Clinical Trials for Depression: Complexity and Necessity” published in the

April 10, 2002, issue of T

OURNAL

(2002;287:1853-1854). The last 3 sentences

in the fourth paragraph should read as follows: From this 8-week clinical trial, the

authors conclude that neither sertraline nor hypericum was significantly different

from placebo on either of the primary outcome measures: change in total Hamil-

ton Depression Scale (HAM-D) score and full response defined by combined cut-

off scores on both the HAM-D and the Clinical Global Impression Scale (CGI-I).

However, sertraline was significantly better than placebo (P=.02) on the CGI-I

alone, which was a secondary outcome measure in this study. The overall re-

sponse rates (including partial and full response) were 38.1% for hypericum, 43.1%

for placebo, and 48.6% for sertraline.

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(Reprinted) JAMA,

June 19, 2002—Vol 287, No. 23

3083

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