Clinical bottom line
Emerging evidence implicates neuroinflammation as a key contributor to the pathophysiology of schizophrenia, with microglial activation, endogenous retroviral elements, and neuroactive steroids playing pivotal roles. Positron emission tomography (PET) imaging advances have enabled in vivo visualization of neuroinflammatory processes, supporting their association with symptom severity and disease progression. While anti-inflammatory and immunomodulatory therapies remain investigational, understanding neuroinflammation’s mechanistic underpinnings offers promising avenues for novel therapeutics. Clinicians should consider neuroinflammation as a potential target in refractory schizophrenia, although routine clinical application awaits further validation (Ferrando et al., 2025; de Jesus et al., 2026).
What the evidence shows
Ferrando et al. (2025) review PET imaging modalities targeting translocator protein (TSPO) and other markers of microglial activation, demonstrating increased neuroinflammation in schizophrenia patients compared to controls. These imaging biomarkers correlate with cognitive deficits and negative symptoms, suggesting clinical relevance.
De Jesus et al. (2026) provide an immunological perspective, detailing microglial phenotypes and their dual roles in neuroprotection and neurotoxicity. They emphasize microglial dysregulation as a driver of synaptic pruning abnormalities implicated in schizophrenia.
Zhang et al. (2025) explore the role of human endogenous retroviruses (HERVs) in schizophrenia, showing that HERV expression may trigger neuroinflammatory cascades and alter neuronal function, representing a novel molecular mechanism.
Pinna et al. (2025) discuss neuroactive steroids’ modulation of neuroinflammation and neurotransmission, highlighting therapeutic potential of steroid-based agents to restore neurochemical balance.
Xu et al. (2015) summarize pharmacological evidence supporting anti-inflammatory agents, such as minocycline and NSAIDs, as adjunctive treatments that may ameliorate symptoms by targeting neuroinflammation.
Ebrahimi et al. (2021) review noncoding RNAs as regulators of neuroinflammatory pathways, offering insights into epigenetic mechanisms and potential biomarkers.
Caveats and uncertainty
Most neuroinflammation studies in schizophrenia are associative; causality remains to be definitively established.
Heterogeneity in patient populations, disease stages, and imaging techniques complicates interpretation.
Therapeutic trials targeting neuroinflammation have yielded mixed results, with limited large-scale randomized controlled data.
Longitudinal studies are needed to clarify neuroinflammation’s role in disease onset versus progression.
Biomarker standardization and accessibility remain challenges for clinical translation.
How this may change practice
Recognition of neuroinflammation’s role may prompt integration of neuroimaging biomarkers in research and, eventually, clinical stratification.
Adjunctive anti-inflammatory or immunomodulatory therapies could be considered in treatment-resistant cases pending further evidence.
Personalized medicine approaches targeting neuroimmune pathways may emerge, guided by molecular and imaging biomarkers.
Collaboration between psychiatry, neurology, and immunology specialists will be essential for advancing care.
Ongoing research should inform clinical guidelines and identify patient subgroups most likely to benefit from neuroinflammation-targeted interventions.