Consistent with the hypothesis of this meta-analysis, patients with MDD randomized to wait-list control conditions experienced symptomatic improvement. The magnitude of this improvement corresponds to a medium effect size of approximately 0.5, which was significantly different from zero (p < 0.001). Left untreated, patients with MDD may expect an improvement on average of approximately 4 HRSD points based upon the passage of time alone.
For the purpose of comparison, prior meta-analyses of medication and placebo response in antidepressant clinical trials have reported standardized effect sizes of approximately 1.5 for medication conditions and 1.2 for placebo conditions (Kirsch and Sapirstein 1998
). Thus, patients in wait-list control conditions experience approximately 33% of the improvement occurring with medication treatment and 40% of the improvement seen with placebo administration. What causes this improvement in wait-list control conditions cannot be conclusively determined, particularly since it is unknown whether most patients improved a small amount or whether a subgroup of patients experienced remission while most others did not improve. Prior naturalistic studies and retrospective analyses would suggest that much of the change observed in the wait-list control group subjects is likely due to fluctuation in illness severity and spontaneous remission, but regression to the mean likely accounts for a portion of the change as well.
By the same token, these data indicate that 60% of the placebo response typically observed in antidepressant clinical trials is not due to the passage of time alone, but rather results from true placebo effects as well as other non-specific factors, such as demand characteristics, patient response biases, and rater bias (Kienle and Kienle 1997
). These findings lend partial support to recent efforts aimed at identifying the active physiologic mechanisms of placebo effects in psychiatric disorders such as MDD (National Institutes of Health 2011
). To the extent that placebo effects, rather than non-specific factors like spontaneous remission, are responsible for most of the change occurring in the placebo groups of RCTs, optimizing placebo effects in clinical treatment may be a means of providing relief to the approximately 120 million people worldwide suffering from MDD (WHO 2004
). Currently, many patients receiving maximal treatment will not experience sustained remission of their depression (Rush et al 2006
These results must be interpreted with several limitations in mind. The first pertains to whether participation in a wait-list control condition influences the natural course of depression. On the one hand, some investigators have reported that the diagnostic assessments and symptom measurements that are administered to patients in wait-list control conditions are therapeutic (Endicott and Endicott 1963
). Patients in research studies are provided with diagnoses that conceptualize and explain their symptoms, psycho-education about the causes and course of depression, and medical work up and monitoring, all of which may influence their reported symptoms (Fava et al 2003
). On the other hand, critics of the use of wait-list control groups in psychotherapy studies have raised the possibility that assignment to such a group is disappointing or demoralizing to patients who were hoping to receive treatment. Such a “nocebo” effect of being assigned to a wait-list control might result in the symptom change in such conditions representing an underestimate of the actual spontaneous remission of depression.
Secondly, it is possible that patients seeking out and choosing to participate in psychotherapy research studies differ in important ways from patients choosing to enroll in antidepressant clinical trials. If such differences obtained, they might confound the extension of the results found in this meta-analysis to the placebo and medication groups in antidepressant RCTs. An evaluation of the clinical and demographic characteristics of the patients enrolled in the studies making up our sample did not reveal obvious differences compared to the patients typically enrolling in antidepressant RCTs, but it is difficult to definitively rule out this possibility on the bases of retrospective analyses.
In summary, spontaneous improvement is an important contributor to change in prospective clinical studies of MDD, but it is unlikely to account for the magnitude of placebo response typically observed in antidepressant RCTs. Efforts to determine physiologic mechanisms of placebo effects in the treatment of MDD should continue in order to develop strategies for maximizing placebo effects in clinical contexts and minimizing them in the drug development setting.