Initial phase 2 trial of a nicotinic agonist in schizophrenia.
OBJECTIVE
Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.


METHODS
Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.


RESULTS
There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.


CONCLUSIONS
DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
Freedman
Robert
R
Department of Psychiatry, Denver VA Medical Center and University of Colorado, Denver, CO 80262, USA. Robert.Freedman@UCHSC.edu
Olincy
Ann
A
Buchanan
Robert W
RW
Harris
Josette G
JG
Gold
James M
JM
Johnson
Lynn
L
Allensworth
Diana
D
Guzman-Bonilla
Alejandrina
A
Clement
Bettye
B
Ball
M Patricia
MP
Kutnick
Jay
J
Pender
Vicki
V
Martin
Laura F
LF
Stevens
Karen E
KE
Wagner
Brandie D
BD
Zerbe
Gary O
GO
Soti
Ferenc
F
Kem
William R
WR
D000328:Adult; D001288:Attention / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010054:Brief Psychiatric Rating Scale; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011950:Receptors, Cholinergic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology; D012720:Severity of Illness Index
D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine