for certain bacterial conditions [73,74], but it would be a
mistake to generalize from this to argue that antibiotics
are not effective for life threatening illnesses, just because
it is unethical for them to be studied in these clinical
situations. Many common drugs used in general medicine
have effect sizes much smaller than antidepressants.
One could make a similar criticism of the trials most
medical treatments and conclude that their efficacy
amounts to a myth constructed from 100,000 trials. Surgery
is widely used with little support from randomized
placebo-controlled trails. It is true that half-dozen psychiatrists
have written articles critical of the efficacy of
antidepressants and that, historically, mainstream physicians
have been wrong about some clinical beliefs. Nevertheless,
antidepressants are now the mainstay of
biological treatment of depressed patients throughout the
world and have been so for about the last 50 years. Ioannidis’s
recommendations to not use the psychotherapeutic
(as inferred from his statement) or pharmacological
treatments, or the combination of both treatments, are
based on speculations that do not provide a firm basis for
abandoning both psychotherapy and pharmacotherapy.
How Small and Effect Size is Too Small for a Drug
to be Used
Ioannidis does not state what amount of drug-placebo
difference he would consider clinically significant, but he
rejects the drug-placebo differences observed in clinical
trials (12-35% depending on type of depression as summarized
in Table 1) as not clinically significant. We argue
that even 1% of patients who experience substantial clinical
improvement represent a benefit, which is particularly
meaningful to those individuals. Benefits can accumulate
over time, and depression is frequently a recurrent disease.
To illustrate the ethical aspect of this issue, we use
a hypothetical example of anti-cancer drug treatment
where the underlying cancer has a death rate of 10% per
year and drug treatment reduces this by 1% per year.
This one percent lives-saved would add up and increase
the percentage of total survivors. Should we offer the
patients this 1% chance of survival? This 1% benefit
would accrue year after year to as much as a 10% cure
over a person’s life span. How small an effect size should
be regarded as clinically insignificant?
Perspectives from the Philosophy of Science and
Logic
Empirical science cannot prove anything with absolute
certainty. Some label the reasoning that if something can
occur, it will occur, and does occur all the time, the fallacy
of “appeal to probability.” Ioannidis offers no actual
evidence that they do reduce antidepressant efficacy to
zero; these are just speculations and yet, he concluded
that the opposite of the empirical evidence is true. The
erroneous logic is that, if you can criticize the evidence,
then you can conclude that the opposite of what the evidence
shows must be true. This has certain characteristics
in common with the Creationist attack on evolution.
Creationists argue that evolution cannot completely
explain everything; therefore, the opposite of evolution
(i.e. intelligent design) is true.
Practical and Ethical Constraints on Ethical
Clinical Trials
There are IRBs and ethical constraints as well as practical
limitations to clinical trials, deserving comment in a journal
on ethics and philosophy. Ioannidis calls for large,
long-term studies (by implication over 5 years) and asks
that some of these “should include suicide, and major life
events” such as “loss of job.” The trials of 50,000 patients
for drug plus presumably another 50,000 ill individuals
receiving only placebo would result in a trial that the
IRBs would not approve. This fictional trial could never
be conducted and completed and would represent too
great a health risk for the placebo group. Physicians
would not generally refer symptomatic depressed patients
for whom antidepressants were clinically indicated to
such a trial, and not enough patients would volunteer,
absent a considerable monetary payment. Moreover,
patients randomized to placebo might still withdraw prematurely,
due to lack of efficacy of placebo, and thus produce
erroneously skewed results. Our argument is not
that such a study would yield more information about
these outcomes, but rather it cannot be done for ethical
and practical reasons. We feel funding should be directed
to identifying which patients should receive medication,
and many a host of other questions.
Philosophy of Ethics
The patient voluntarily visits a physician to seek help.
The physician may diagnosis “depression,” determine
that an antidepressant is indicated for that particular
patient and then recommend it, based on that patient’s
history, current status, and other clinical factors. We consider
the recommendation of treatment using the four
ethical principles of the Belmont Report, refined by Beauchamp
and Childers [75] of: (1) beneficence, (2) non-malfeasance,
(3) autonomy and (4) justice. Beneficence, the
antidepressants’ benefit (or the lack thereof), the main
focus and our disagreement, is straightforward. Ioannidis
does not dwell on the side effects of the antidepressants,
but, most of the antidepressants currently used do have
clinically significant side effects. Physicians must work
with the patient to determine if the benefits of the drug
are worth the particular side effects the patient may be
exposed to or experience. We agree on avoiding malfeasance
from known and unknown drugs’ adverse effects.
Ioannidis makes no statement about the possible harm
Davis et al. Philosophy, Ethics, and Humanities in Medicine 2011, 6:8