We examined this issue in a pool of 16 studies assembled by psychiatrists John Kane and Jeffrey Lieberman in 1984. These studies all compare a standard drug, such as imipramine or amitriptyline, to a newer drug and a placebo. They use clearer diagnostic definitions of depression than did the older studies and also adopt currently accepted standards for dosage levels and treatment duration. When we examined the data, we discovered that the advantage of drug over placebo was modest. Twenty-one percent more of the patients receiving a drug improved as compared to those on placebo. Actually, most of the studies showed no difference in the percentage of patients significantly improved by drugs. There was no indication that these studies, using more careful methodology, achieved better outcomes than older studies.
Finally, it is crucial to recognize that several studies have established that there is a high rate of relapse among those who have responded positively to an anti-depressant but then are taken off treatment. The relapse rate may be 60 percent or more during the first year after treatment cessation. Many studies also show that any benefits of antidepressants wane in a few months, even while the drugs are still being taken. This highlights the complexity of evaluating antidepressants. They may be effective initially, but lose all value over a longer period.
Are Drug Trials Biased?
As we burrowed deeper into the antidepressant literature, we learned that there are also crucial problems in the methodology used to evaluate psychotropic drugs. Most central is the question of whether this methodology properly shields drug trials from bias. Studies have shown that the more open to bias a drug trial is, the greater the apparent superiority of the drug over placebo. So questions about the trustworthiness of a given drug-testing procedure invite skepticism about the results.
The question of potential bias first came to our attention in studies comparing inactive placebos to active drugs. In the classic double-blind design, neither patient nor researcher knows who is receiving drug or placebo. We were struck by the fact that the presumed protection provided by the double-blind design was undermined by the use of placebos that simply do not arouse as many body sensations as do active drugs. Research shows that patients learn to discriminate between drug and placebo largely from body sensations and symptoms.
A substance like imipramine, one of the most frequently studied antidepressants, usually causes clearly defined sensations, such as dry mouth, tremor, sweating, constipation. Inactive placebos used in studies of antidepressants also apparently initiate some body sensations, but they are fewer, more inconsistent, and less intense as indicated by the fact that they are less often cited by patients as a source of discomfort causing them to drop out of treatment.
Vivid differences between the body sensations of drug and placebo groups could signal to patients as to whether they are receiving an active or inactive agent. Further, they could supply discriminating cues to those responsible for the patients's day-to-day treatment. Nurses, for example, might adopt different attitudes toward patients they identify as being "on" versus "off" active treatment—and consequently communicate contrasting expectations.
The Body Of Evidence
This is more than theoretical. Researchers have reported that in a double-blind study of imipramine, it was possible by means of side effects to identify a significant number of the patients taking the active drug. Those patients receiving a placebo have fewer signals (from self and others) indicating they are being actively treated and should be improving. By the same token, patients taking an active drug receive multiple signals that may well amplify potential placebo effects linked to the therapeutic context. Indeed, a doctor's strong belief in the power of the active drug enhances the apparent therapeutic power of the drug or placebo.
Is it possible that a large proportion of the difference in effectiveness often reported between antidepressants and placebos can be explained as a function of body sensation discrepancies? It is conceivable, and fortunately there are research findings that shed light on the matter.
Consider an analysis by New Zealand psychologist Richard Thomson. He reviewed double-blind, placebo-controlled studies of antidepressants completed between 1958 and 1972. Sixty-eight had employed an inert placebo and seven an active one (atropine) that produced a variety of body sensations. The antidepressant had a superior therapeutic effect in 59 percent of the studies using inert placebo—but in only one study (14 percent) using the active placebo. The active placebo eliminated any therapeutic advantage for the antidepressants, apparently because it convinced patients they were getting real medication.
How Blind Is Double-Blind?
Our concerns about the effects of inactive placebos on the double-blind design led us to ask just how blind the double-blind really is. By the 1950s reports were already surfacing that for psychoactive drugs, the double-blind design is not as scientifically objective as originally assumed. In 1993 we searched the world literature and found 31 reports in which patients and researchers involved in studies were asked to guess who was receiving the active psychotropic drug and who the placebo. In 28 instances the guesses were significantly better than chance—and at times they were surprisingly accurate. In one double-blind study that called for administering either imipramine, phenelzine, or placebo to depressed patients, 78 percent of patients and 87 percent of psychiatrists correctly distinguished drug from placebo.
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