title: Assessment of adverse effects of neurotropic drugs in monkeys with the "drug effects on the nervous system" (DENS) scale.
abstract: Research into therapeutics for neuropsychiatric disorders is increasingly focusing on drugs with new mechanisms of action, and such agents are often assessed in preclinical studies using nonhuman primates. However, researchers lack a standardised method to compare different drugs for common adverse effects on the nervous system. We have developed a new scale for this purpose, named "Drug Effects on the Nervous System" (DENS), and tested its utility in an analysis of the second-generation antipsychotic risperidone in monkeys. The behavioural effects of risperidone over a ten-fold clinically relevant exposure range were rated with the DENS scale and compared with a standard motor disability scale for primates. The ratings were correlated with projected D2 and 5-HT2A receptor occupancies over time. The DENS scale detected dose-dependent side effects of risperidone in addition to the motor effects detected with the motor disability scale, including cognitive, sensorimotor and autonomic functions. A consistent temporal association between the DENS scale changes and the projected D2 receptor occupancy was observed, and the DENS scale ratings demonstrated high inter-rater reliability. These results demonstrate the usefulness of the DENS scale as a highly sensitive, reliable and accurate method to identify common adverse effects of risperidone and potentially other neurotropics for translational studies in primates.
authors: Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors: Subramaniam
authors: S
authors: Uthayathas
authors: Christopher L
authors: CL
authors: Shaffer
authors: Frank S
authors: FS
authors: Menniti
authors: Christopher J
authors: CJ
authors: Schmidt
authors: Stella M
authors: SM
authors: Papa
mesh_terms: D000465:Algorithms; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D001341:Autonomic Nervous System / Q000187:drug effects; D001480:Basal Ganglia Diseases / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D005260:Female; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009420:Nervous System / Q000187:drug effects*; D015588:Observer Variation; D011619:Psychotropic Drugs / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D011955:Receptors, Drug / Q000378:metabolism; D012015:Reference Standards; D018967:Risperidone / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D011619:Psychotropic Drugs; D011955:Receptors, Drug; D018967:Risperidone