Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia.
BACKGROUND
3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia.


METHODS
Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the α7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia.


RESULTS
Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype.


CONCLUSIONS
The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.
Tregellas
Jason R
JR
Department of Psychiatry, Denver VA Medical Center, VISN19 MIRECC, Colorado, USA. Jason.tregellas@ucdenver.edu
Tanabe
Jody
J
Rojas
Donald C
DC
Shatti
Shireen
S
Olincy
Ann
A
Johnson
Lynn
L
Martin
Laura F
LF
Soti
Ferenc
F
Kem
William R
WR
Leonard
Sherry
S
Freedman
Robert
R
D000328:Adult; D001597:Benzylidene Compounds / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects; D001931:Brain Mapping / Q000379:methods; D003072:Cognition Disorders / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005133:Eye Movements / Q000187:drug effects; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012559:Schizophrenia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine