018 - Risperidone Administration in the Neonatal Period Induces Inflammation and Impairs Brain Development

Publication Number: 18.6386

Riddhi Patel, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Balaji G. Vijayakumar, Johns Hopkins School of Medicine, Chesterfield, MO, United States; Hawley Helmbrecht, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Fabiola B. Santiago, Johns Hopkins University School of Medicine, Rio Grande, Puerto Rico, United States; Isabel M. Torio, Johns Hopkins University School of Medicine, Andover, MA, United States; Shenandoah Robinson, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Raul Chavez-Valdez, Johns hopkins university school of medicine, Catonsville, MD, United States; Eric M. Chin, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Background: Administration of antipsychotics such as Risperidone (RSP) for neonates in the NICU is increasing without adequate understanding of the short- and long-term implications on the developing neural and immune systems. We hypothesized that RSP administration in the neonatal period would perturb the establishment and maturation of neural networks and enhance pro-inflammatory milieu, with long-term consequences to brain function.

Objective: Study the effects of RSP administration on neural connectivity, brain function, and peripheral immune system in perinatal brain injury using established preclinical model.

Design/Methods: At embryonic day 18, Chorioamnionitis (CHORIO) was induced in pregnant Sprague Dawley rats. Shams had laparotomy with equivalent anesthesia duration. From postnatal day 1 (P1) to P7 (Preterm) and P11-P17 (Term), pups of both sexes in the CHORIO group were randomized to receive RSP (0.5-3.0 mg/kg/day) or vehicle (n=6-11/group for all regimens). Magnetic resonance imaging was done at P40 to assess neural connectivity. Open Field behavior was tested and quantified with Any-maze software. DigiGait was used to study gait patterns. Serum cytokines were measured with mesoscale discovery. Statistical difference was determined with two-way analysis of variance (ANOVA) with Bonferroni’s correction for multiple pairwise comparisons.

Results: Following CHORIO, young adult rat pups have decreased fractional anisotropy (FA) and globally diminished functional connectivity (p < 0.05). CHORIO pups administered risperidone (RSP) in either preterm or term periods had additional microstructural injury and profoundly reduced FA (p < 0.01). RSP administered in the preterm period yielded large, global increases in functional connectivity in the thalamus and association areas (p < 0.001). In contrast, RSP administration at term induced large focal increases in sensorimotor, corticocortical, and cortical basal ganglia connections concomitant with abnormal connectivity in the amygdala (p < 0.001 for all). CHORIO pups administered RSP were profoundly ataxic and hypoactive (p < 0.001). They were uncoordinated, traveled less distance, and spent less time mobile. These results were concomitant with increased IFN, IL-6, IL-4, and IL-10 serum levels (p < 0.0001 for all) compared to vehicle treated CHORIO and sham pups.

Conclusion(s): RSP significantly changed brain structure and function and increased systemic biomarkers of inflammation. These results suggest impaired neurodevelopment and peripheral immune dysregulation and provide a basis for further scrutiny to ensure safe and appropriate use of antipsychotics in neonates.