Brain findings associated with risperidone in rhesus monkeys: magnetic resonance imaging and pathology perspectives

Abstract

Brain changes associated with risperidone, a dopamine-2/serotonin-2 receptor antagonist, have been documented in rats and humans, but not in nonhuman primates. This study characterized brain changes associated with risperidone in nonhuman primates. Rhesus monkeys were orally administered risperidone in a dose-escalation paradigm up to a maximum tolerated dose of 0.5 mg/kg/day for 3 weeks, or 3 months followed by a 3-month recovery period. Transient and fully reversible neurological signs consistent with risperidone pharmacology were observed. The results of a magnetic resonance imaging evaluation after 3 months of treatment and at the end of the 3-month recovery period showed no meaningful changes in the brain. There were no risperidone-related brain weight changes or gross findings. Histomorphological evaluation of brain sections stained with hematoxylin and eosin, ionized calcium binding adaptor molecule 1 (Iba1), and luxol fast blue/cresyl violet double staining showed no notable differences between control and risperidone groups. However, evaluation of the brain after glial fibrillary acidic protein (GFAP) immunohistochemical staining revealed increased staining in the cell bodies and processes of astrocytes in the putamen without apparent alterations in numbers or distribution. The increase in GFAP staining was present after 3 weeks and 3 months of treatment, but no increase in staining was observed after the 3-month recovery period, demonstrating the reversibility of this finding. The reversible increase in GFAP expression was likely an adaptive, non-adverse response of astrocytes, associated with the pharmacology of risperidone. These observations are valuable considerations in the nonclinical risk assessment of new drug candidates for psychiatric disorders.

Investigation of Risperidone Treatment Associated With Enhanced Brain Activity in Patients Who Stutter

“…monkeys, and humans (Toro et al, 2006;Bernstein et al, 2014;Fernandez et al, 2019). In rhesus monkeys, the effect of risperidone was restricted to the striatum as histological staining showed reversible increase in staining in the cell bodies as well as processes of putamen astrocytes (Fernandez et al, 2019). Another dopamine receptor blocker, haloperidol, was shown to block D2 receptors on astrocytes.…”

Association of Risperidone With Gastric Cancer: Triangulation Method From Cell Study, Animal Study, and Cohort Study

“…Interestingly, a recent study reported that rhesus monkeys orally receiving risperidone in a dose-escalation method up to the dose of 0.5 mg/kg/day for 21 days reveal no risperidone-related brain weight changes or gross findings by magnetic resonance imaging (MRI). Although glial fibrillary acidic protein (GFAP) was detected in the brain of these monkeys after 21 days and 12 weeks, no increased GFAP staining was observed after the 12-week recovery period, suggesting this reversible increase of GFAP is likely an adaptive, non-adverse response of astrocytes ( Fernandez et al, 2019 ). In this study, the effective risperidone dose for xenograft tumor experiments is similar to those reported in the study of rhesus monkeys ( Fernandez et al, 2019 ).…”

“…Although glial fibrillary acidic protein (GFAP) was detected in the brain of these monkeys after 21 days and 12 weeks, no increased GFAP staining was observed after the 12-week recovery period, suggesting this reversible increase of GFAP is likely an adaptive, non-adverse response of astrocytes ( Fernandez et al, 2019 ). In this study, the effective risperidone dose for xenograft tumor experiments is similar to those reported in the study of rhesus monkeys ( Fernandez et al, 2019 ). Therefore, this finding may suggest a possibility that higher-dose of risperidone can be used in treatments of gastric cancer.…”