Autophagy in Schizophrenia: A Continuum From Developmental Vulnerability to Progressive Neuronal Stress? A Scoping Review.

Abstract

Background and hypothesis: Autophagy, the cell's primary degradation and recycling system, is essential for neuronal homeostasis. A structured synthesis of studies directly investigating autophagy in schizophrenia (SCZ) is lacking. This scoping review aimed to map the available evidence directly assessing autophagy processes in SCZ.

Study design: We systematically searched Medline (via Ovid), Embase, and PsycINFO from inception to February 2025. Twenty-four eligible studies-encompassing clinical cohorts, postmortem brain tissue, animal and cellular SCZ-relevant models-were thematically analyzed.

Study results: Findings indicated impaired autophagy in SCZ, implicating it in 3 main processes: (1) disrupted neurodevelopment/synaptic pruning, (2) lysosomal dysfunction/proteostasis, (3) compromised mitochondrial turnover/metabolic homeostasis. Antipsychotic treatment showed variable effects, with some agents partially restoring autophagic markers, whereas others heightened dysfunction. Transcriptomic studies identified autophagy-related gene signatures with potential diagnostic relevance. Synthesizing these findings, impaired autophagy emerged as a possible mechanistic link between early neurodevelopmental vulnerability and progressive cellular stress, which may underlie disease progression in some cases.

Conclusions: Autophagy dysfunction may contribute to both early neurodevelopmental and later progressive cellular changes in SCZ. However, much of the current evidence derives from cross-sectional studies, peripheral biomarkers or animal models, with limited direct evidence from the human central nervous system. These limitations constrain causal interpretation. Even so, autophagy represents a promising therapeutic target, with potential to support early neural development and prevent progressive cellular decline. Longitudinal, multimodal studies integrating peripheral and central autophagy markers with clinical outcomes are needed to clarify autophagy's role in SCZ pathophysiology and treatment.