Effects of Second-Generation Long-Acting Injectable Antipsychotics on Brain Structure in Schizophrenia: A Systematic Review of Neuroimaging Studies

Background/Objectives: Second-generation long-acting injectable antipsychotics (SGA-LAIs) are increasingly used to improve adherence and prevent relapse in patients suffering from schizophrenia. Beyond clinical efficacy, growing attention is being paid to their potential impact on brain structure. This systematic review aims to synthesize available evidence from neuroimaging studies investigating the effects of SGA-LAIs on grey matter (GM) and white matter (WM) in individuals with schizophrenia. Methods: A systematic search of PubMed/MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials was run from database inception to 13 August 2026, supplemented by Google Scholar, trial registries, and backward and forward citation tracking of the included studies. Eligible studies were original reports assessing the effects of SGA-LAIs on brain structure or brain function with magnetic resonance imaging (MRI) in patients with schizophrenia. Study selection followed the PRISMA 2020 statement, and data extraction focused on sample characteristics, treatment, imaging outcomes, and main findings. Risk of bias was appraised with RoB 2 and ROBINS-I. Results: Of 687 unique records screened, nine studies met the inclusion criteria. The evidence base is narrow: the nine studies correspond to only five independent samples, with six of them acquiring both a baseline and a follow-up scan and five providing a randomized comparison with oral antipsychotics, and the only molecules studied were risperidone LAI and paliperidone palmitate. Five randomized reports compared an SGA-LAI with oral antipsychotics and described better preservation of intracortical myelin and of cortical thickness with the long-acting formulation, most often in frontal regions, although the between-group difference reached statistical significance in only two of them and diffusion measures in one cohort moved in the opposite direction. Two cross-sectional functional MRI studies comparing risperidone LAI with first-generation depot medication described activation patterns closer to those of healthy controls in the LAI group, and one longitudinal resting-state study documented changes in regional homogeneity during paliperidone palmitate treatment. In some cases, structural or functional changes correlated with clinical or cognitive improvement. However, all included studies were judged to be at high or serious risk of bias, and the nine studies correspond to only five independent samples, so that the apparent convergence of findings partly reflects repeated analyses of the same participants; the limited number of studies and their methodological heterogeneity prevent firm generalizations. Conclusions: Preliminary and low-certainty evidence suggests that SGA-LAIs may be associated with better preservation of intracortical myelin and cortical thickness in schizophrenia, with convergent but weaker functional data and with diffusion findings that do not fit this reading. These results are hypothesis-generating and do not establish a neuroprotective effect. Larger and independent longitudinal studies with standardized imaging protocols and prespecified clinical endpoints are needed before any structural advantage of LAI formulations can be considered established.