Neuroinflammation: an unfortunate term to describe schizophrenia, 2026, Llorca-Bofí et al

[forestglip]

Neuroinflammation: an unfortunate term to describe schizophrenia

Spoiler: Authors

Llorca-Bofí, Vicent; Parellada, Eduard; Morén, Constanza; Sellgren, Carl M.; Bioque, Miquel

Abstract
Schizophrenia, a chronic psychiatric disorder, has prompted extensive research into its immunological aspects. Studies in genetics, epidemiology, and treatment have revealed immune changes associated with schizophrenia, including shifts in cytokine levels and microglial reactivity within the central nervous system (CNS).

However, the term “neuroinflammation” has been used to describe these findings despite inconsistent classical markers, potentially oversimplifying the complex role of immune mediators in neurodevelopment and brain homeostasis.

In this paper, we critically examine the limitations of applying “neuroinflammation” to describe immune changes in schizophrenia, focusing on its four classical hallmarks: elevated cytokines, microglial reactivity, peripheral immune cell infiltration, and neurodegeneration. While some alterations in these markers are reported, many findings fall within clinical norms or likely contribute to neurodevelopment, suggesting that the term “neuroinflammation” may misrepresent their role.

Instead, we propose using alternative terminology that reflects the broader spectrum of CNS immune responses, both inflammatory and non-inflammatory, and invite the scientific community to join this dialogue to refine terminology.

By reframing immune alterations in schizophrenia, we aim to promote accuracy and consistency across medical disciplines, ensuring terminology that accurately represents the underlying biology. This, in turn, will improve communication among researchers and clinicians.

Web | DOI | PDF | Molecular Psychiatry | Paywall

 

[forestglip]

The abstract seems relevant to posts from users like @Jonathan Edwards about the terms "inflammation" and "neuroinflammation" often not being used appropriately in papers.

 

[SNT Gatchaman]

It's hard to find small quotes, the entire paper looks very good and on a quick skim I suspect Jonathan could easily have been an author (we'll see if he agrees). After discussing the meanings of inflammation in the CNS context and particularly with reference to in vivo and post-mortem findings in schizophrenia, their concluding paragraphs are —

A range of terms have been applied to describe immune changes in the CNS in schizophrenia, reflecting the lack of consensus in the field. “Neuroinflammation” is often borrowed from classical CNS inflammatory disorders, while modifiers such as “low-grade” have been introduced to capture milder phenomena. Other authors prefer broader concepts such as “neuroimmune dysfunction,” “neuroimmune alterations,” or “altered neuroimmune activity.” Each of these terms has advantages and limitations, but together they illustrate the ongoing debate on how best to conceptualize these findings. In this review we argue that, although immune alterations in schizophrenia are evident, labelling them as “neuroinflammation” is misleading and risks overstating their similarity to classical inflammatory disorders.

because “neuroinflammation” lacks a formal definition, some apply it broadly to any immune involvement in the brain, which could make our critique seem semantic. Yet placing subtle immune changes in schizophrenia on the same level as the marked pathology of classical CNS immune disorders may obscure clinically relevant distinctions.

An additional and often overlooked source of heterogeneity is sex-related immune dimorphism. Females generally mount stronger innate and adaptive immune responses and show higher rates of autoimmune disease, while males are more vulnerable to severe infectious outcomes. […] Recent postmortem transcriptomic analyses support sex-specific neuroimmune signatures in schizophrenia, with a higher immune-related transcriptomic burden observed in females. These observations suggest that insufficient adjustment for sex effects may contribute to heterogeneity in immune findings and warrant systematic consideration in future research.

Ultimately, terminology matters: it shapes how findings are interpreted, how biomarkers are pursued, and how therapies are developed. Early trials with anti-inflammatory agents suggested modest benefits, but these effects were not specific to classical anti-inflammatory drugs and disappeared in larger randomized studies.

In parallel, antipsychotic medication modulates immune pathways with a variety of effects that are not completely understood, including reductions in peripheral cytokines and immune-related gene expression, as well as modulation of in vitro microglial signalling. […] Together, these findings indicate that therapeutic effects may arise from broader neuroimmune alterations rather than classical neuroinflammation.

We therefore suggest reserving “neuroinflammation” for conditions that fulfil classical inflammatory criteria and instead adopting terms such as “neuroimmune alterations” or “altered neuroimmune activity” to describe the context-dependent immune changes observed in schizophrenia. A clearer and more precise lexicon may help generate more focused hypotheses and guide the development of tailored biomarker and treatment strategies.

 

[SNT Gatchaman]

Modifying table 1 and removing the last column for relevance to schizophrenia.

Term	Typical use in literature	Advantages	Limitations
Neuroinflammation	Classical CNS inflammatory diseases with four hallmarks	Well-known, cross-disciplinary clarity	Suggests high-grade pathology; may mislead in psychiatric context
Low-grade neuroinflammation	Mild, chronic inflammation in systemic or CNS conditions	Recognizes lower magnitude	Still assumes inflammation as primary driver
Neuroimmune dysfunction	Broad immune-related CNS abnormalities	Covers inflammatory & non-inflammatory mechanisms	"Dysfunction" implies pathology, excludes adaptive roles
Neuroimmune alterations	Descriptive immune changes without causal assumptions	Neutral, flexible	"Alterations" implies pathology, may be too unspecific
Altered neuroimmune activity	Measurable changes in CNS	Avoids inflammatory/pathological	May be too unspecific