title: Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy.
abstract: Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs is warranted in larger studies that will have greater power.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, United States; Department of Psychiatry, Georgetown University School of Medicine, United States. Deutscsi@evms.edu
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Deutsch
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Schwartz
authors.forename: Nina R
authors.initials: NR
authors.lastname: Schooler
authors.forename: Clayton H
authors.initials: CH
authors.lastname: Brown
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rosse
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Rosse
mesh_terms: D000328:Adult; D000368:Aged; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D003566:Cytidine Diphosphate Choline / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005702:Galantamine / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000150:complications / Q000188:drug therapy; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018697:Nootropic Agents; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine; D003566:Cytidine Diphosphate Choline
keywords: Acetylcholine; Alpha7 nicotinic receptor; Negative symptoms; Neurocognition; Positive allosteric modulator; Schizophrenia