Effect of chronic oral treatment with risperidone or quetiapine on cognitive performance and neurotrophin-related signaling molecules in rats

Abstract

Antipsychotic (APs) drugs are among the top selling pharmaceuticals in the world and they have a variety of important therapeutic applications for neuropsychiatric disorders. However, there are a number of controversies related to this class of agents and many of the relevant questions are difficult to prospectively address in the clinical trial environment. For example, there have been multiple clinical trials for pro-cognitive agents in schizophrenia that have failed; however, the question of how chronic prior treatment with APs might influence the response to a pro-cognitive agent was not addressed. Moreover, there is clinical evidence that chronic treatment with some APs may lead to impairments in cognition, however, this issue and the potential molecular mechanisms of the deleterious effects have been not been prospectively addressed. Accordingly, the purpose of the work described in this dissertation was to prospectively address each of these issues in animals (specifically rats) were environmental conditions can be rigorously controlled. In each of the manuscripts included in this dissertation, two of the most commonly prescribed APs, risperidone and quetiapine were evaluated. In the work conducted in Manuscript 1, we established a therapeutic relevant dosing approach for rats (oral administration in drinking water) and reinforced the argument that these two APs are not pro-cognitive agents. Moreover, we determined that alpha-7 nicotinic acetylcholine receptor (nAChR) ligand like tropisetron has potential as an adjunctive medication in schizophrenia since the pro-cognitive effect was maintained in the presence of chronic AP treatment. In Manuscript 2, we concluded that chronic treatment with risperidone or quetiapine in rats can lead to impairments in a domain of cognition (recognition memory) that is commonly altered in neuropsychiatric disorders. Moreover, the negative effects of the APs appeared to be exacerbated over time. In Manuscript 3, we concluded that risperidone and quetiapine when administered chronically to rats have the potential to adversely affect neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function. These data would suggest that the extensive prescribing of these APs across multiple conditions in patients ranging in age from the very young to the very old should be carefully reexamined. Key Words: antipsychotic, cognition, brain volume, schizophrenia, neurotrophin