Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00100165.

Figure 1

Effects of DMXB-A on default network activity. Left panels indicate regions that showed reduced activity following administration of drug (collapsed across drug dose), compared to placebo administration. Right panels show areas of greater activity. Statistical maps thresholded at p < 0.05, FWE corrected. Data are shown in the radiological convention (R on L). Individual subject responses are shown in bottom panels.

Figure 2

Effects of DMXB-A dose and CHRNA7 genotype (SNP rs3087454) on default network activity in 16 patients with schizophrenia. Most common allele indicates homozygosity for this genotype.

Figure 3

Relationship between difference in BPRS (left) and SANS (right) scores and difference in default network activity from placebo to DMXB-A (collapsed across dose).