COMMENTARY

Methodologic Issues in the Clinical
Trial Study of Depression
Doug Berger, M.D., Ph.D.
Japan Pharmaceutical Consultant
www.japanpsychiatrist.com/DrugDev.html
A recent study by Kirsch et al. entitled,
Initial Severity and AntidepressantBenefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration published by the Public Libraryof Science (PLoS Med February 26,2008) caused a stir in the mass media
who chimed in with sound bites like, “Antidepressants don’t work much better
than placebos for many depressed patients.” This study obtained data on allclinical trials submitted to the FDA forthe licensing of four new-generation antidepressants for which full datasets wereavailable (fluoxetine, venlafaxine,nefazodone, and paroxetine) and used meta-analytic
techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug-placebo difference scores.
While the study is a poignant reminder of the difficultyof proving statistical efficacy for antidepressants, its message that antidepressants do not work much better thanplacebo except for the most severely depressed patients
will leave many patients with significant depressive symptoms without proper medical care.
This is a summary of the major findings of this study:
1. Efficacy reaches clinical significance for only the mostextremely depressed patients, and this is due to a decrease in the response to placebo rather than an increasein the response to medication.
2. A substantial response to placebo was seen in moderately depressed groups and in groups with very severe levels of depression. It decreased somewhat, but
was still substantial, in groups with the most-severe levels of depression.
3. Given these data, there seems little evidence to support the prescription of antidepressant medication to any
but the most severely depressed patients.
How can we interpret these findings in light of ourbelieving in the incredible power of these drugs to help
depression? The reason is that clinical practice, especially for depression, is not practiced like a clinical trial,
and that for a number of methodologic reasons, the pharmacodynamics of depression are not easy to study in aclinical trial. The result is that only modest improvement
may be seen in the active treatment, and the results ofPage 18

trials of some antidepressants that later
obtain market approval are negative.
First, let me enumerate some of the differences between a clinical trial and clinical practice:
1. There are few exclusion criteria, inclusion criteria are wider, co-morbid andcomplex patients are treated.
2. Flexible dosing and multiple medications are employed.
3. In clinical practice, one treats an individual patient, treatments are not based
solely on the results of a clinical trial. Many
depressed patients clearly remit when adrug is given and relapse when a drug isremoved. Also, it is common for patients to respond
only to certain types of drugs, e.g., serotonin promoting
drugs but not norepinephrine promoting drugs or viceversa.
Next, we need to review why the study of efficacy ofdepression is so difficult:
1. Symptoms of depression are not an easily measurable and clearly reactive pharmacodynamic parameter(The action of antidepressants on depression is not as
easily measurable as the action of reserpine on bloodpressure).
2. Depression is difficult to treat. Close to 50% ofsubjects, whether on active or placebo will not havemuch response in a clinical trial. This shows that placebo itself is not exactly a favorable treatment for depression.
3. Depression assessment is subjective, and while there
has been much criticism of the use of the Hamilton Depression Rating Scale (HDRS) for a clinical trial, thisscale is still seen by the regulatory agencies to be thesine qua non for depression assessment. The Montgomery-Asberg Depression Rating Scale (MADRS) isthought by many experts be an improvement over theHDRS, however, the Kirsch et at. study did not analyze
MADRS data, and in general depression rating scales
may not be as insightful as a good clinical interview.
4. Many patients will receive sleep medications evenon placebo, and this may improve some of the symptoms that are assessed making it seem like the depression has also lifted.
PHARMA JAPAN 2083/March 24, 2008

COMMENTARY
5. Many symptoms rated as part of depression may
improve in a therapeutic environment with no drug
(hopelessness, low self-esteem), and this may cloud theissue of whether the depression itself had responded asmany patients with mild depression respond to a drug
or not.
6. The sponsors of the study need to have some response endpoint that they can measure within a 6-8 week
time-frame of the study so that “responder” is usually
defined as a 50% reduction on the HDRS. So even if
you are a responder on placebo, you may still have significant depressive symptoms left over. In other words,
many subjects on both sides are “responders”. If they
have mild non-melancholic depression their depression
is not really being treated but they feel better. Even if
they have major depression with melancholia, the symptoms that can get better do, but the depression is notbetter; e.g., 50% reduction should not be consideredresponse.
7. Entry of subjects with only mild symptoms of depression is one of the biggest problems in a clinical trial(Fig 1.). Melancholic depression, or a morbid-type of
depression is the most likely type of depression to respond only to active medication. The study sites are
motivated to rapidly enter as many subjects as possible,
thus many mild (non-melancholic) cases are entered.
Non-melancholic patients have enough symptoms ofdepression to score above the cut-off on the HDRS,
but they do not have the loss of appetite, worthlessness,and loss of ability to enjoy life like the melancholic cases,
and are more likely to have a number of symptoms that
improve in a therapeutic environment under placebo
treatment and be coded as a “responder”. Psychotic
depression should also not be entered in the study as
they require an antipsychotic in addition to an antidepressant –this is usually not a problem in a clinical trial.
Fig 1.
Spread of symptoms widens but
is inversely proportional to number of patients.
Psychotic Depression
Melancholic Depression
Non-Melancholic Depression

Depressive Mood Disorder Axis

8. Drug companies want to do the studies efficiently
and at low cost and will set the number of subjects at
the lowest number needed based on previous data in
PHARMA JAPAN 2083/March 24, 2008

order to obtain the estimated statistical power. Becauseof the methodologic difficulties inherent in the nature ofdepression studies as described here, this number may
not be enough to get wide significance vs placebo.
9. The meta-analysis assumes that all studies were of
the same quality, that all the protocols and subject numbers were adequate, that proper and consistent orientation of the sites was comparable, etc. It is well known
that inter-site variability in the discrimination of subjects
and in the quality of the study is often large in depression studies.
While the conclusion of the Kirsch study may not bevalid for the real world of depression treatment, what
can we take home from this study to help the medicalcare and clinical trial construct for depression treatment?
First, we need to improve the methods for clinical trials of depression and the knowledge of these difficulties
at the regulatory agency level. We need to show theagencies what makes sense, and work with the experts
in the fields, and large pharma needs to take the lead increating sounder-trials.
Next, I think the response of the industry must be morethan a sound bite that sounds like a “sorry you arewrong” message. One large pharma company, for example, was reported to say that the authors of the study
had “failed to acknowledge” the very positive benefitsof SSRIs and their conclusions were “at odds with thevery positive benefits seen in actual clinical practice”. I
think we must use these opportunities to educate themedia and the consumer with a message that describes
the complexities involved. For example, “Antidepressants have shown efficacy in depression in spite of thehurdles of studying this complex illness in a clinical trial–and we can provide you with the details, suicide rates
decrease in societies in proportion to use of antidepressants, and the medical community has studied and proventhe ability of antidepressants to greatly improve the qualityof life of millions of persons with this debilitating illness”,
is perhaps a more well-rounded initial comment.
Finally, both the industry and the medical professionneed to make clear and concise responses to these kindsof reports. There should be a response that is written inclear wordage for the lay person, and submitted to themajor media organs. A technical response for the professional should also be prepared which should be submitted to a major medical journal. An initial summary
response should be placed on the internet on a newwebsite dedicated to this response so that is comes up
on a search term (ie., “antidepressants don’t work”),
and the lay and professional responses placed there later
after publication. We should never just say, “of course
antidepressants work”, we must explain why. The patients who need the care, and the medical professionals
and industry teams who put in the sweat to deliver thiscare deserve this much.
Page 19