Rationale: Medication nonadherence is the highest determinant of relapse in schizophrenia. Interventions that help patients remain on medication for extended periods could substantially improve clinical outcomes. Significance: The revised R01 renewal application will advance the development of an implantable long-term risperidone delivery system to improve medication adherence in schizophrenia. Achieving this goal could improve the health and quality of life for millions of people with schizophrenia and their families. Progress: We completed both Aims during the previous period by performing in vitro-in vivo correlation (IVIVC) modeling for sterile, biodegradable implants. In the previous 2-year funding period, we developed a long-term risperidone delivery system using the biodegradable polymer poly-lactide-co-glycolide (PLGA). First, we determined in vitro risperidone release from multiple types of implants by varying lactide to glycolide ratios. We then determined in vivo serum risperidone concentration from a New Hypothesis: We propose that the benefits of long term delivery systems extend beyond a safety net against relapse. Preliminary data suggest that steady state infusion of antipsychotic medication from implants could provide consistent modulation of dopaminergic tone intermittent oral administration allowing the brain to remodel in a stable therapeutic environment. Studies in this application would test this hypothesis using animal models of antipsychotic efficacy and side effects. Proposed Studies: The current application would determine how constant risperidone infusion from implants affects behavioral (Aim 1), biochemical (Aim 2) and molecular (Aim 3) measures of efficacy and side effects comparison to three times daily oral administration in rodents.
Medication nonadherence is the highest cause of relapse in schizophrenia. Interventions that help patients remain on medicine would substantially improve quality of life for millions of patients and their families. We will advance the development of an implantable long-term antipsychotic delivery system to improve medication adherence in schizophrenia. We will also determine how constant infusion of antipsychotic medication from implants improves behavior and brain function in comparison to oral administration rodents.
|Carlson, G C; Lin, R E; Chen, Y et al. (2016) Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience 322:408-15|
|White, R S; Siegel, S J (2016) Cellular and circuit models of increased resting-state network gamma activity in schizophrenia. Neuroscience 321:66-76|
|Tatard-Leitman, Valerie M; Jutzeler, Catherine R; Suh, Jimmy et al. (2015) Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability. Biol Psychiatry 77:556-68|
|Dodman, K; Featherstone, R E; Bang, J et al. (2015) Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice. Drug Alcohol Depend 156:14-20|
|Featherstone, R E; Nagy, L R; Hahn, C G et al. (2014) Juvenile exposure to ketamine causes delayed emergence of EEG abnormalities during adulthood in mice. Drug Alcohol Depend 134:123-7|
|Billingslea, Eddie N; Tatard-Leitman, Valerie M; Anguiano, Jaynie et al. (2014) Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits. Neuropsychopharmacology 39:1603-13|
|Siegel, Steven J (2013) Capacity, confidentiality and consequences: balancing responsible medical care with mental health law. Curr Psychiatry Rep 15:380|
|Siegel, Steven J; Talpos, John C; Geyer, Mark A (2013) Animal models and measures of perceptual processing in schizophrenia. Neurosci Biobehav Rev 37:2092-8|
|Gandal, M J; Anderson, R L; Billingslea, E N et al. (2012) Mice with reduced NMDA receptor expression: more consistent with autism than schizophrenia? Genes Brain Behav 11:740-50|
|Gandal, Michael J; Edgar, J Christopher; Klook, Kerstin et al. (2012) Gamma synchrony: towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology 62:1504-18|
Showing the most recent 10 out of 14 publications