A systematic review comparing the functional neuroanatomy of patients with depression who respond to placebo to those who recover spontaneously: Is there a biological basis for the placebo effect in depression?

Background: Functional neuroimaging research indicates that depression, and treatment, are associated with neurobiological changes. Changes associated with natural recovery or the placebo effect are unknown. The aim of this study is to assess whether the placebo effect in depression is associated with specific functional neuroimaging changes. Method: Systematic review of functional neuroimaging studies containing unipolar depressed patients. Subjects were either: in a placebo group, undergoing pre- and post-treatment scans and clinical ratings; or were treatment-free, and underwent two sets of scans and ratings. Results: Of placebo group studies, 2 of 4 showed no specific changes; the others showed increased frontal activity on recovery. Of treatment-free studies, only 2 out 5 had sufficient relevance; both showed increased anterior cingulate activity on recovery, one showed increased left DLPFC activity. Limitations: Methodological problems affected most of the studies found: low sample sizes, high inter-subject variability, and lack of design and data description for the question being asked in this review. There are limitations in comparing studies that differ in: subject type, neuroimaging technique, target site, trial design, and results. The fact that this systematic review was conducted by only one rater increases likelihood of bias. Conclusions: Recovery from depression in placebo groups correlates with changes in frontal and cingulate cortical activity, although these may also be found in recovery without treatment. It is also speculated that antidepressant treatment delay relates to 'counterbalancing' of an advantageous placebo effect with a disadvantageous initial drug effect. (c) 2006 Elsevier B.V. All rights reserved.