Am J Psychiatry 159:5, May 2002
The Functional Neuroanatomy of the Placebo Effect
Helen S. Mayberg, M.D.,
J. Arturo Silva, M.D.
Steven K. Brannan, M.D.
Janet L. Tekell, M.D.
Roderick K. Mahurin, Ph.D.
Scott McGinnis, B.S.
Paul A. Jerabek, Ph.D.
Administration of placebo
can result in a clinical response indistin-
guishable from that seen with active anti-
depressant treatment. Functional brain
correlates of this phenomenon have not
been fully characterized.
Changes in brain glucose me-
tabolism were measured by using positron
emission tomography in hospitalized
men with unipolar depression who were
administered placebo as part of an inpa-
tient imaging study of fluoxetine. Com-
mon and unique response effects to ad-
ministration of placebo or fluoxetine
were assessed after a 6-week, double-
Placebo response was associated
with regional metabolic increases involv-
ing the prefrontal, anterior cingulate, pre-
motor, parietal, posterior insula, and pos-
terior cingulate and metabolic decreases
involving the subgenual cingulate, para-
hippocampus, and thalamus. Regions of
change overlapped those seen in respond-
ers administered active fluoxetine. Fluoxe-
tine response, however, was associated
with additional subcortical and limbic
changes in the brainstem, striatum, ante-
rior insula, and hippocampus, sources of
efferent input to the response-specific re-
gions identified with both agents.
The common pattern of cor-
tical glucose metabolism increases and
limbic-paralimbic metabolism decreases
in placebo and fluoxetine responders sug-
gests that facilitation of these changes may
be necessary for depression remission, re-
gardless of treatment modality. Clinical im-
provement in the group receiving placebo
as part of an inpatient study is consistent
with the well-recognized effect that alter-
ing the therapeutic environment may
significantly contribute to reducing clinical
symptoms. The additional subcortical and
limbic metabolism decreases seen uniquely
in fluoxetine responders may convey addi-
tional advantage in maintaining long-term
clinical response and in relapse prevention.
(Am J Psychiatry 2002; 159:728–737)
here is little debate as to the power of the placebo ef-
fect in controlled short-term clinical trials of antidepres-
sants, as well as in other medical and surgical treatments
(1–3). Placebo response in the acute phase of antidepres-
sant trials has often been seen as an unavoidable and dis-
tracting consequence inherent in the assessment of any
given treatment intervention—whether cognitive, phar-
macological, or surgical (4–11). While continuation stud-
ies (12–16) have repeatedly demonstrated an advantage of
maintenance medication over continued placebo admin-
istration in preventing relapse and recurrence, the pres-
ence of a significant placebo effect with short-term ad-
ministration provides a unique opportunity to examine
brain mechanisms mediating clinical antidepressant re-
sponse unencumbered by nonspecific drug, lesion, or