Quetiapine exhibits low oral bioavailability and limited blood–brain barrier (BBB) penetration, restricting its therapeutic efficacy in central nervous system (CNS) disorders. This systematic review and meta-analysis examined whether nanoparticle-based delivery systems improve systemic exposure, brain targeting, and functional outcomes in rodent models of schizophrenia. Plasma Cmax was the only harmonized outcome eligible for quantitative pooling, whereas Brain Cmax was synthesized descriptively due to inconsistent reporting. Following PRISMA 2020 guidelines, five databases were searched through June 2025. Seventeen in vivo studies met eligibility criteria. Six provided harmonized Plasma Cmax data (ng/mL, mean ± SD) suitable for quantitative pooling using random-effects models. All other pharmacokinetic outcomes—including Brain Cmax, brain AUC, bioavailability, and brain/plasma ratios—were synthesized descriptively due to inconsistent reporting. A REML-based meta-regression evaluated whether administration route (oral, intranasal, intravenous) moderated Plasma Cmax effect sizes. Risk of bias was assessed using SYRCLE, and certainty of evidence with GRADE. Across studies, nanoformulations such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), albumin nanoparticles, intranasal microemulsions, and lipid-core nanocapsules consistently enhanced systemic and central exposure compared with conventional quetiapine. Meta-analysis showed a large, significant improvement in Plasma Cmax (SMD = 6.93; 95% CI: 3.41–10.45; p < 0.001), despite high heterogeneity (I2 = 96.1%). Meta-regression indicated that route of administration explained ~ 21% of between-study variance but did not significantly affect effect size (p = 0.281). Descriptive synthesis demonstrated consistent increases in Brain Cmax, brain AUC, early brain uptake, and brain/plasma ratios, particularly for lipid-based and intranasal nanosystems. Behavioral findings (improved PPI, reduced immobility, normalized locomotion) aligned with enhanced CNS exposure. GRADE rated Plasma Cmax as moderate certainty; all other outcomes were low to very low due to methodological variability and small sample sizes. Nanoformulated quetiapine markedly improves pharmacokinetic performance in preclinical schizophrenia models, with strong and consistent gains in both systemic exposure and CNS targeting. Lipid-based and intranasal nanoformulations show the greatest promise for enhancing brain delivery. Standardized reporting of brain PK metrics (especially Brain Cmax and AUC), harmonized sampling schedules, and rigorously powered designs will be essential for future translational advancement of nano-enabled quetiapine.
Özcan et al. (Tue,) studied this question.