Psychiatr News July 18, 2008
Volume 43, Number 14, page 24
© 2008 American Psychiatric Association
Experimental Schizophrenia Drug Shows Encouraging Results
Joan Arehart-Treichel
A small study of patients with schizophrenia taking an alpha-7 receptor
agonist (DMXB-A) found a lessening of negative symptoms in those taking the
experimental compound. Subjects also reported better organized thinking and
behavior.
For a few years now, Robert Freedman, M.D., chair of psychiatry at the
University of Colorado Health Sciences Center, and colleagues have been
undertaking a valiant quest to find a drug that improves cognition and
eradicates negative symptoms in individuals with schizophrenia—something
that available medications for schizophrenia generally fail to do.
Specifically Freedman and his team have been trying to determine whether
drugs that soup up the action of the alpha 7 nicotinic acetylcholine receptors
in the brain—the so-called alpha 7 receptor agonists—might be the
answer.
Two years ago, they reported very preliminary, but heartening results for
an alpha 7 receptor agonist called DMXB-A. Eleven subjects with schizophrenia
were found to experience significantly better cognition a day after receiving
DMXB-A than a day after getting a placebo. Improvement in attention was
especially notable. Results were published in the June 2006 Archives of
General Psychiatry (Psychiatric News, July 21, 2006).
Now Freedman and his group report more encouraging results regarding
DMXB-A. The results, which first appeared online in AJP in Advance on
April 1, will be published in the August print edition of the American
Journal of Psychiatry. Freedman is editor in chief of the journal.
This time, 29 subjects with schizophrenia were studied. They were assessed
for cognitive abilities with the MATRICS Consensus Cognitive Battery
(MATRICS), for negative symptoms with the Scale for Assessment of Negative
Symptoms (SANS), and for clinical effects with the Brief Psychiatric Rating
Scale (BPRS). After that, they received daily, for four weeks each, a 75 mg
dose of DMXB-A, a 150 mg dose of DMXB-A, or a placebo in this three-arm,
double-blind, crossover phase 2 trial. Throughout the study, they also
continued to take whatever dopamine-antagonist antipsychotic drugs they had
already been taking.
At the end of each four-week arm, the researchers used the same instruments
as at baseline to evaluate the subjects' cognition, negative symptoms, and
clinical effects. After that, the researchers compared the subjects'
cognition, negative symptoms, and clinical effects at baseline with their
cognition, negative symptoms, and clinical effects after getting 75 mg of
DMXB-A daily, 150 mg of DMXB-A daily, or a placebo daily. Finally, the
researchers compared all of the subjects' outcomes while on 75 mg of DMXB-A
daily, 150 mg of DMXB-A daily, or a placebo daily.
Subjects showed no significant improvement in cognition on the MATRICS test
after receiving either 75 mg or 150 mg of DMXB-A daily than they had after
getting a placebo daily. The reason why no significant improvement was found,
the investigators suspected, may have been because the subjects' cognition
tended to improve with testing throughout the three arms of the study. So they
decided to examine cognitive outcome for subjects only in the first arm of the
study to see whether they could find any significant differences. And they
could: subjects on either 75 mg of DMXB-A daily or on 150 mg of DMXB-A daily
showed significant improvement in attention over baseline and in working
memory over baseline, whereas subjects on a daily placebo did not.
Moreover, when the researchers examined negative-symptom outcomes and
clinical-effects outcomes for all three arms of the study, they found a
significant lessening of negative symptoms and a trend toward improvement in
clinical effects when subjects received 150 mg of DMXB-A daily versus a
placebo daily. Improvements were most notable on two negative
symptoms—anhedonia (inability to experience pleasure from normally
pleasurable life events) and alogia (difficulty in conversing fluently). Also,
numerous subjects reported that they were markedly more organized in their
thinking and behavior than they had been before getting DMXB-A.
"The results, although still preliminary, are important for two
reasons," Freedman told Psychiatric News. "First, when a
new intervention enhances the brain performance of patients with schizophrenia
beyond what it is currently, the results are encouraging for patients and
their families, and they tell psychiatrists that their patients' brain
deficits are not immutable. Second, the results suggest that... this specific
intervention... should be further developed."
Ann Olincy, M.D., associate professor of psychiatry at the University of
Colorado Health Sciences Center and one of the study investigators, was
"a bit disappointed" by the three-arm cognition test results, she
told Psychiatric News. But on the whole, she said, she was gratified
by the results, "primarily because they replicated our results from the
phase 1 study with findings of enhanced attention, though with a longer
duration of dosing... [and because] patients reported they wanted to continue
the drug after the trial because it helped them function."
Freedman's team also plans to explore the possible value of some other
alpha-7 receptor agonists besides DMXB-A in enhancing cognition and/or in
abolishing negative symptoms, he said.
The study was funded by the VA Biomedical Laboratory and Clinical Science
Research and Development Service, the National Association for Research in
Schizophrenia and Affective Disorders, and the Institute for Children's Mental
Disorders.
"Initial Phase 2 Trial of a Nicotinic Agonist in
Schizophrenia" is posted at
<http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.07071135v1>.
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