It looks as though a small protein discovered in horses' brains 75 years
ago, and since dubbed substance P, may play a role in depression and
posttraumatic stress disorder (PTSD).
Thomas Geracioti, M.D., a professor of psychiatry at the University of
Cincinnati, and his colleagues compared the levels of substance P in
cerebrospinal fluid taken from 40 nonmedicated subjects with major depression
with that from 47 healthy comparison subjects.
The levels of substance P from the depressed subjects, they found, were
much higher than those from the controls (see chart).
The researchers then measured the levels of substance P in cerebrospinal
fluid taken from eight nonmedicated subjects with PTSD and from eight healthy
matched subjects. The levels of the PTSD subjects were significantly higher
than those of the controls.
"These results suggest that elevated central nervous system substance
P concentrations are involved in both major depression and PTSD,"
Geracioti and his group concluded in their report in the April American
Journal of Psychiatry.
Moreover, the researchers exposed seven combat veterans with chronic PTSD
and not on any medications to two stimuli. One was footage from the Vietnam
War, which was presumably upsetting to the subjects; the other was a film
instructing viewers how to oil paint, which presumably did not arouse the
The investigators measured the subjects' cerebrospinal levels of substance
P during each of the two viewings and then
comparedFIG1 the levels.
When the subjects viewed the war footage, their levels of substance P shot
up, which was not the case when they looked at the painting-instruction film.
So substance P responds dramatically to psychological stress in PTSD subjects,
and this response may be one of the mechanisms by which psychological trauma
unleashes PTSD symptoms, the researchers suggested.
Finally, the study results suggest that if substance P is complicit in
depression and PTSD, then chemical compounds that counter substance P might be
able to attenuate these two mental illnesses.
Indeed, Geracioti told Psychiatric News, many drug companies are
developing substance P antagonists, and a few—notably GlaxoSmithKline,
Hoffmann-LaRoche, Merck, and Pfizer—are testing some of these
antagonists in depressed subjects to see whether the antagonists might improve
Furthermore, Geracioti said, psychiatrist Dennis Charney, M.D., of Mount
Sinai School of Medicine, recently launched a trial funded by the National
Institute of Mental Health to see whether a particular substance P antagonist
might help subjects with PTSD.
He and his group, Geracioti added, will also be testing a substance P
antagonist in PTSD subjects once they reach an agreement with the drug company
that makes it.
"Since available treatments for PTSD are typically of limited
efficacy," Geracioti explained, "I have high hopes for the use of
substance P antagonists in the treatment of the illness."
As a matter of fact, Geracioti pointed out, one substance P antagonist is
already on the market. It is made by Merck, with the generic name aprepitant
and the brand name Emend. It is approved by the Food and Drug Administration
for use against chemotherapy-induced nausea and vomiting, in combination with
"It is intriguing," said Geracioti, "that patients with
PTSD sometimes describe having experienced nausea, or even frank vomiting, as
part of a traumatic exposure."
So could aprepitant help PTSD patients? Maybe. But as Geracioti clarified,
even when it is used as indicated it is supposed to be used only for three
days and "is very expensive."
The study was funded by the VA Merit Review and Research Advisory Group,
National Alliance for Research on Schizophrenia and Depression, National
Institute of Mental Health, and Merck.
"Elevated Cerebrospinal Fluid Substance P Concentrations in
Posttraumatic Stress Disorder and Major Depression" is posted at<http:ajp.psychiatryonline.org>
under the April issue. ▪