Active placebos versus antidepressants for depression (Review)

Authors’ conclusions The more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted. P L A I N L A N G U A G E S U M M A R Y Tricyclic antidepressants compared with active placebos for depression This review examined trials which compared antidepressants with ’active’ placebos, that is placebos containing active substances which mimic side effects of antidepressants. Small differences were found in favour of antidepressants in terms of improvements in mood. This suggests that the effects of antidepressants may generally be overestimated and their placebo effects may be underestimated. 2 Active placebos versus antidepressants for depression (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. B A C K G R O U N D Since the 1970’s there has been a consensus, based predominantly on the results of clinical trials, that tricyclic antidepressants (TCAs) have a specific therapeutic effect in depression. However, an examination of the literature reveals that the evidence from such trials is not consistent. Although most reviews find that the drug is significantly superior to a placebo in a majority cases, the degree of superiority is generally not large and between 22% and 73% of studies or comparisons fail to find a significant difference (Cole 1964; Davis 1965; Klerman 1967; McNair 1974; Morris 1974; Rogers 1975). In addition, comprehensive analyses of early antidepressant research revealed that the methodology employed influenced the result. In particular, the absence of random allocation or blinding increased the apparent effect size (Smith 1969, Wechsler 1965), a finding which has been noted more recently in other areas of medicine (Schulz 1995, Schulz 1996). A further methodological concern is the possibility of bias due to unblinding effects. Greenberg 1994a have pointed out that the different physiological experiences resulting from the ingestion of an active drug and an inert placebo may lead patients and assessors to suspect the identify of medication. This may introduce bias due to different expectations of treatment. Several studies have found that drugs, including antidepressants, can be distinguished from placebo more readily than would be predicted by chance (White 1992). There are various possible explanations for this unblinding effect and its possible association with outcome. Unblinding may occur due to the therapeutic effect of the medication or may occur due to side effects but correlate with therapeutic effect. In both these circumstances the therapeutic effect would determine the outcome and how it was measured. However, another suggestion is that side effects may enhance the placebo effect in patients taking active medication (Thomson 1982). A further possibility is that the occurrence of side effects may unblind raters which may produce biased ratings. In these latter situations, outcome may be determined by factors other than the specific effect of the medication, that is results may be biased. There is some evidence that unblinding effects may be associated with outcome ratings in the absence of evidence that the drug is effective. A drug trial with problem drinkers found that perception of medication group predicted outcome rating, although there was no evidence the drug was effective (Toneatto 1992) and similar findings were reported in a trial of antipsychotic drugs ( Engelhardt 1969). In addition side effects have been shown to correlate significantly with patient and clinician outcome depression ratings in a meta-analysis of placebo controlled trials of fluoxetine (Greenberg 1994b). Some investigators have addressed this difficulty by using placebos containing active substances. Small doses of drugs with anticholinergic actions have typically been employed to mimic side effects of TCAs in placebo preparations. Thomson 1982 reviewed some of these studies and found that they were more likely to have a negative outcome than studies using inert placebos. It would be difficult to conduct a trial using an active placebo at present because many clinicians would feel it was unethical. Meta-analysis of previous active placebo controlled trials therefore provides an opportunity to investigate the efficacy of antidepressants under conditions of greater “blindness”. In addition, by combining results of several small trials with various groups of depressed patients metaanalysis should increase the power to detect an effect and balance the idiosyncracies of individual trials. Depression is the commonest psychiatric condition and antidepressant drug treatment accounted for 1.9% of all NHS drug costs in the early 1990s (Henry 1993). This proportion is likely to have increased since then due to the escalation in prescribing of the new SSRI drugs (Donoghue 1996). Antidepressants are lucrative products for the pharmaceutical industry which therefore devotes much research to the development of new agents. These new drugs are frequently expensive and represent a potentially significant and escalating drain on health service resources unless properly evaluated. Since new drugs have been evaluated by comparison with the gold standard of TCAs the results of this review also have implications for evaluation of the role of newer drugs such as the SSRIs. O B J E C T I V E S To investigate the efficacy of antidepressants when compared with ’active’ placebos for treating people with depression. An active placebo is a placebo tablet which contains a drug which is not thought to have a specific effect in the disorder being treated and which is employed to mimic the effect of taking an active substance.