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Placebos and Antidepressants
Behavioral Health Update
BHSI Newsletter Vol. 1, No. 4

Placebos and Antidepressants: Deceptive Conclusions about Deceptive Treatments
Paul Hill, Ph.D., L.P.

Recent research stirred controversy and made the popular press by concluding that commonly prescribed antidepressants produced results that were not meaningfully different from placebos. This was the finding of researchers who analyzed the U.S. Food and Drug Administration (FDA) database of trials used in the initial approval of popular antidepressant medications. The analysis included the efficacy data from 38 randomized, blinded, placebo-controlled studies involving 6,944 patients treated for an average of 6 weeks with one of the six most widely prescribed antidepressants approved between 1987 and 1999 : fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), venalfaxine(Effexor), nefazodone (Serzone), and citalopram (Celexa). Specifically, the authors found that approximately 80% of the antidepressant effect was duplicated by placebo. While the results showed a statistical difference favoring active antidepressants over placebo, the authors concluded that the difference was clinically insignificant. The researchers also found that improvement at the highest doses of antidepressant medication was not different from improvement at the lowest doses.

What Providers Should Know.

• The conclusion that 80% of the drug effect is accounted for by a placebo effect is misleading and inaccurate. Researchers suggest that antidepressant drug and placebo effects are not additive. Thus, the true drug effect is greater than the drug/placebo difference reflected in the FDA data. All conditions that have an effect on depression, whether they are drug treatments, psychotherapy, or placebo, must have some action on the brain. However, these actions may not be duplicated, additive, or consistent across conditions. Recent research indicates that placebo responders and anti-depressant responders have different brain changes suggesting that these two effects are indeed different and not additive.

• A true antidepressant drug response is masked in drug/placebo comparisons by a progressive increase in the placebo effect. The placebo response has dramatically increased over the last two decades from about 30% to 50%. Factors resulting in a high placebo-response rate may include an unusual amount of attention and overly encouraging behaviors of those conducting the trial that evoke high expectations for improvement, financial rewards for rapid patient enrollment in trials, and trial designs that do not include a placebo wash-out phase.

• FDA initial antidepressant clinical trials are constructed to identify effective treatments and doses but not to determine dose relatedness in a scientific manner consistent with the principles of pharmacology. The trials are intended to identify a drug response or clinically significant reduction in symptom severity. In most cases, FDA drug trials are not designed to look at remission, relapse, or recurrence. Thus, the finding from the FDA data that highest and lowest doses yielded no improvement differences is interesting, but far from conclusive.

•Antidepressants are consistently superior to placebo at preventing relapse. Relapse rates for drug continuation patients over one year are commonly around 10%, but those assigned to placebo have close to a 50% relapse rate.

•In drug/placebo comparisons, antidepressants are far superior to placebo with severe and/or chronically depressed patients. Placebo response is directly related to severity of depression: the milder the depression, the more significant the placebo response. While 50% to 70% of mildly depressed patients improve with placebo, more severe hospitalized depressed patients have placebo response rates around 20%. The FDA sample tends to fall on the mild end of the depressive spectrum. Similarly, chronic depressed patients show less placebo response than acute patients. Placebo response rates are 50% versus 13% for patients who have been depressed for 3 months and 2 years, respectively.

What Consumers Should Know.
•FDA clinical trials show that between 55% and 75% of all patients improve with antidepressant treatment. The trials also show considerable variability in response to antidepressant drugs.

•Studies show that many treatments are about equally effective in the treatment of mild depression, but that for severe or chronic depression, antidepressant medication has a clear advantage over both the psychotherapies and placebo.?
•People who take antidepressant medications are much less likely to experience a relapse in depressive symptoms.?

•Placebos are used in research to identify side effects and for comparison purposes, but they may not be a good indicator of a drug’s true effect.?

•A combination of antidepressants and psychotherapy is consistently the most effective treatment for depression.