Atypical antipsychotic medications reduce extrapyramidal side effects and improve prevention compared to older agents. However, in spite of their use many patients with schizophrenia do not achieve functional recovery. Residual symptoms, lack of motivation and cognitive deficits persist. Thus, development of novel pharmacological strategies to address residual signs and symptoms are urgent. The hypothesis of alpha-7 nicotinic acetylcholine receptor (a7 nAChR) hypofunction is based on the prevalence of smoking in schizophrenia, receptor binding data on autopsied brain, pathophysiological and familial and genetic studies. This hypothesis has stimulated both preclinical and clinical exploration of nicotinic agonists to enhance functioning of the receptor. However, the limited availability of safe and selective a7 nAChR agonists for human administration and rapid desensitization of these receptors has made clinical trials problematic. Long term administration of an agonist could have the unintended pharmacological consequence of functional """"""""antagonism"""""""" of the receptor, whose expression is already reduced.
The aim of this R34 proposal is to conduct a """"""""proof of concept"""""""" clinical trial combining galantamine and CDP-choline. We hypothesize that galantamine will prevent desensitization, allowing choline to serve as a selective agonist, rather than becoming a functional antagonist secondary to receptor desensitization. We predict that co-administration of these agents will reduce symptoms and improve memory and attention. Fifty patients with DSM-IV schizophrenia or schizoaffective disorder will be randomly assigned to either combination treatment or placebos for both in a16 week trial. All patients will be maintained on a stable regimen of risperidone for the trial duration. The dose of galantamine will be 24 mg/day;the dose of CDP-choline will be 2000 mg/day. The PANSS, CGI and nicotine will be assessed at baseline, week 4, 8, 12 and 16. Cognition will be assessed at baseline, week 8 and 16. Adverse events will be monitored weekly. The primary outcome measure is negative symptoms, all other measures are secondary outcomes. The goals of this application fit well wit the aims of the """"""""From Intervention Development to Services;Exploratory Research Grants"""""""" announcement. If the results of this pilot trial are positive, the next steps will be a definitive trial and efforts to develop medications that combine the allosteric modulatory and agonist properties of the combination in a single molecule.
| Urbano, Maria; Okwara, Leonore; Manser, Paul et al. (2014) A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol 37:69-72 |
| Deutsch, Stephen I; Schwartz, Barbara L; Schooler, Nina R et al. (2013) Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy. Schizophr Res 148:138-44 |
