One particularly systematic report in the literature involved the administration of alprazolam, imipramine, and placebo over an eight-week period to groups of patients who experienced panic attacks. Halfway through the treatment and also at the end, the physicians and the patients were asked to judge independently whether each patient was receiving an active drug or a placebo. If they thought an active drug was being administered, they had to decide whether it was alprazolam or imipramine. Both physicians (with an 88 percent success rate) and patients (83 percent) substantially exceeded chance in the correctness of their judgments. Furthermore, the physicians could distinguish alprazolam from imipramine significantly better than chance. The researchers concluded that "double-blind studies of these pharmacological treatments for panic disorder are not really 'blind.'"
Yet the vast majority of psychiatric drug efficacy studies have simply assumed that the double-blind design is effective; they did not test the blindness by determining whether patients and researchers were able to differentiate drug from placebo.
We take the somewhat radical view that this means most past studies of the efficacy of psychotropic drugs are, to unknown degrees, scientifically untrustworthy. At the least, we can no longer speak with confidence about the true differences in therapeutic power between active psychotropic drugs and placebos. We must suspend judgment until future studies are completed with more adequate controls for the defects of the double-blind paradigm.
Other bothersome questions arose as we scanned the cascade of studies focused on antidepressants. Of particular concern is how unrepresentative the patients are who end up in the clinical trials. There are the usual sampling problems having to do with which persons seek treatment for their discomfort, and, in addition, volunteer as subjects for a study. But there are others. Most prominent is the relatively high proportion of patients who "drop out" before the completion of their treatment programs.
Numerous dropouts occur in response to unpleasant side effects. In many published studies, 35 percent or more of patients fail to complete the research protocol. Various procedures have been developed to deal fairly with the question of how to classify the therapeutic outcomes of dropouts, but none can vitiate the simple fact that the final sample of fully treated patients has often been drastically reduced.
There are still other filters that increase sample selectivity. For example, studies often lose sizable segments of their samples by not including patients who are too depressed to speak, much less participate in a research protocol, or who are too disorganized to participate in formal psychological testing. We also found decisions not to permit particular racial or age groups to be represented in samples or to avoid using persons below a certain educational level. Additionally, researchers typically recruit patients whose depression is not accompanied by any other type of physical or mental disorder, a situation that does not hold for the depressed in the general population.
So we end up wondering about the final survivors in the average drug trial. To what degree do they typify the average individual in real life who seeks treatment? How much can be generalized from a sample made up of the "leftovers" from multiple depleting processes? Are we left with a relatively narrow band of those most willing to conform to the rather rigid demands of the research establishment? Are the survivors those most accepting of a dependent role?
The truth is that there are probably multiple kinds of survivors, depending upon the specific local conditions prevailing where the study was carried out. We would guess that some of the striking differences in results that appear in multicenter drug studies could be traced to specific forms of sampling bias. We do not know how psychologically unique the persons are who get recruited into, and stick with, drug research enterprises. We are not the first to raise this question, but we are relatively more alarmed about the potential implications.
Researched Motivation And Outcome
We conducted an analysis that further demonstrates how drug effectiveness diminishes as the opportunity for bias in research design wanes. This analysis seized on studies in which a newer antidepressant is compared (under double-blind conditions) with an older, standard antidepressant and a placebo. In such a context the efficacy of the newer drug (which the drug company hopes to introduce) is of central interest to the researcher, and the effectiveness of the older drug of peripheral import. Therefore, if the double-blind is breached (as is likely), there would presumably be less bias to enhance the efficacy of the older drug than occurred in the original trials of that drug.
We predicted that the old drug would appear significantly less powerful in the newer studies than it had in earlier designs, where it was of central interest of the researcher. To test this hypothesis, we located 22 double-blind studies in which newer antidepressants were compared with an older antidepressant drug (usually imipramine) and a placebo. Our meta-analysis revealed, as predicted, that the efficacy rates, based on clinicians's judgments of outcome, were quite modest for the older antidepressants. In fact, they were approximately one-half to one-quarter the average size of the effects reported in earlier studies when the older drug was the only agent appraised.
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