Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.
BACKGROUND
The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia.


OBJECTIVE
To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors.


METHODS
Randomized, double-blind crossover trial of 2 drug doses and 1 placebo.


METHODS
General clinical research center.


METHODS
Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count.


METHODS
Administration of DMXB-A.


METHODS
Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating.


RESULTS
Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well.


CONCLUSIONS
An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.
Olincy
Ann
A
Department of Veterans Affairs Schizophrenia Research Center, Denver, Colorado, USA.
Harris
Josette G
JG
Johnson
Lynn L
LL
Pender
Vicki
V
Kongs
Susan
S
Allensworth
Diana
D
Ellis
Jamey
J
Zerbe
Gary O
GO
Leonard
Sherry
S
Stevens
Karen E
KE
Stevens
James O
JO
Martin
Laura
L
Adler
Lawrence E
LE
Soti
Ferenc
F
Kem
William R
WR
Freedman
Robert
R
D000328:Adult; D001597:Benzylidene Compounds / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D012720:Severity of Illness Index
D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D010919:Placebos; D011725:Pyridines; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine