The power of a placebo is nothing new to psychiatrists, but documenting a
placebo's punch inside the brain is more novel.
More specifically, changes in a depressed person's brain before treatment
can predict, to a sizable extent, whether the individual will respond to
treatment, a new study has found.
The placebo lead-in phase is common to many efficacy studies of
antidepressant medications. Typically, subjects receive a placebo from three
to 14 days before being randomly assigned to a placebo or medication. This
initial drug-free interval allows the effects of the study drug to be
evaluated without being compromised by pre-existing medications. Aimee Hunter,
Ph.D., a research psychologist at the UCLA Semel Institute for Neuroscience
and Human Behavior, and her coworkers decided to capitalize on the placebo
lead-in phase of an antidepressant trial to learn more about a placebo's
impact on the brain and the possible influence of this impact on treatment
Fifty-one subjects diagnosed with major depression and participating in a
double-blind, placebo-controlled antidepressant trial with a placebo lead-in
phase were included in this experiment. Brain electrical activity was measured
both before and after the one-week placebo lead-in phase with a technique
developed at UCLA called quantitative EEG cordance. The technique involves
placing electrodes on a subject's scalp to pick up electrical signals, which
are then fed into a computer. The computer then measures the electrical
signals coming from the subject's brain and processes them into colorful
The subjects' level of depression was then assessed using the Hamilton
Rating Scale for Depression (HAM-D). Subjects were randomized to receive
either an antidepressant or a placebo for eight weeks; at the end of that
time, depression levels were measured once more with the HAM-D. Finally, the
scientists looked to see whether there were changes in subjects' brain
electrical activity during the placebo lead-in period, and if so, whether the
changes could be linked with their clinical outcome.
Researchers measured brain changes during the placebo lead-in period in
25 subjects who later got an antidepressant. They found significant
differences between the brain changes in the 13 who responded to an
antidepressant and the 12 who did not. The brain changes predicted, at least
to some degree, subjects' clinical outcomes.
Source: Aimee Hunter, Ph.D., et al., American Journal of
Psychiatry, August 2006
The answer was yes on both counts, and not just for those subjects getting
an antidepressant, but also for those getting a placebo, the researchers
reported in the August American Journal of Psychiatry.
In the subjects given an antidepressant, decreases in prefrontal cortex
electrical activity during the placebo lead-in period were significantly
associated with lower depression scores at the end of the eight-week treatment
period. Nineteen percent of the variance in depression scores, in fact, could
be explained by brain electrical activity that occurred during the lead-in
In the case of the subjects given a placebo, increases in right temporal
lobe electrical activity during the placebo lead-in period were significantly
linked with lower depression scores at the end of the eight-week treatment
period. Twenty percent of the variance in depression scores could be explained
by brain electrical activity that occurred during the lead-in period.
"We were surprised that 19 percent of the variance in final HAM-D
scores was predicted by brain changes occurring before start of drug,"
Hunter told Psychiatric News. "That's a fairly large
proportion, especially considering that the placebo lead-in period was only
one week long compared to eight weeks of treatment with medication. We also
were surprised to find different brain changes [that is, increases in right
temporal electrical activity] during placebo lead-in that were associated with
eventual response in the placebo group."
However, when asked why decreased prefrontal activity predicted less
depression in subjects getting an antidepressant, and why increased right
temporal activity predicted less depression in subjects getting a placebo,
Hunter said that she and her team do not know. Nor do they have an answer for
why brain electrical activity changes at all during a placebo lead-in period.
But as Ian Cook, M.D., an associate professor of psychiatry at UCLa and senior
author of the study, told Psychiatric News, "We are now
conducting a study, with NIH support, to examine some candidate
factors—for example, prior experience with treatment, beliefs about
treatment, and empathic alliance with care providers."
Meanwhile, he said, a practical implication of their study results for
clinical psychiatrists "is that the `treatment' to which our patients
respond extends beyond the molecules in our pills and capsules, and that many
other features of the overall treatment system count."
The study was funded by the National Alliance for Research in Schizophrenia
and Depression, the National Center for Complementary and Alternative
Medicine, the National Institute of Mental Health, Lilly Research
Laboratories, and Wyeth Pharmaceuticals.
"Changes in Brain Function (Quantitative EEG Cordance) During
Placebo Lead-In and Treatment Outcomes in Clinical Trials for Major
Depression" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/163/8/1426>.▪