Schizophrenia affects around 1 in 300 people globally and is one of the leading causes of disability worldwide (Foley EM, 2023, The Mental Elf). This debilitating condition significantly reduces life expectancy by 15-25 years compared to the general population (da Roza et al., 2023; Hjorthøj et al., 2017). Symptoms experienced by individuals with schizophrenia can vary widely and encompass manifestations such as delusions, hallucinations, emotional dysfunction, impaired social functioning, and memory difficulties (Howes et al., 2023). This clinical heterogeneity underscores the urgent need to move beyond a ‘one-size-fits-all’ approach toward more personalised, targeted interventions.
While antipsychotic medications work well for many people and help reduce hallucinations and delusions, it is estimated that around one-third of individuals with schizophrenia do not respond to these conventional anti-dopamine drugs (Diniz et al., 2023). Additionally, antipsychotics show suboptimal efficacy in treating symptoms such as social withdrawal, lack of motivation, or cognitive problems – key drivers of long-term functional impairment (McGinty and Upthegrove, 2020). Advancing our understanding of the mechanisms underlying schizophrenia and its symptom heterogeneity is essential for identifying novel targets for personalised treatment strategies.
Mounting evidence suggests that low-grade inflammation may play a role in the development and persistence of psychosis (Griffiths et al., 2022; Foley EM, 2023, The Mental Elf). Inflammatory markers like cytokines, such as interleukin (IL)-6, are often elevated in patients, particularly early in the disease course (Halstead et al., 2023). However, attempts to treat schizophrenia with anti-inflammatory drugs have so far shown disappointing results (Jeppesen et al., 2020).
A recent systematic review and meta-analysis by Dudeck and colleagues (2025) in JAMA Psychiatry pooled data from over 40,000 individuals to examine differences in blood immune cells – white blood cells (WBC) such as neutrophils, monocytes, and lymphocytes – between people with schizophrenia and controls without any psychiatric condition (Dudeck et al., 2025). Immune cells are specialized cells part of our immune system helping to defend our body against pathogens or tissue damage, with dysfunction often associated with diseases. For a more detailed explanation on immune cells and their different subtypes, read my previous Mental Elf blog on immune cells in depression.
Could studying the immune system more precisely help unlock new treatments for schizophrenia? Dudeck and colleagues (2025) findings may offer new clues into the biology of schizophrenia and the role of the immune system.
Methods
Dudeck et al. (2025) conducted a systematic review and meta-analysis of 64 studies (60 cross-sectional/case-control studies and 4 longitudinal studies) comparing immune cells in the blood between individuals with schizophrenia and controls without a psychiatric condition. The authors searched four major databases – PubMed, Scopus, Web of Science, and Cochrane Library – with the last search in Jan 2024 and included over 40,000 participants. Following PRISMA and MOOSE guidelines, they applied random-effects models to calculate pooled effect sizes. Importantly, they focused on absolute cell counts rather than ratios, and contacted original authors to retrieve missing data, enhancing transparency and reducing publication bias. Study quality was assessed using the Newcastle-Ottawa Scale.
The primary outcome was differences in specific immune cell counts between the two groups.
Results
Dudeck et al. (2025) analysed data from over 26,000 individuals with schizophrenia and more than 16,000 controls. The included studies were published from 1972 to 2024, with an age range of 23 to 51 years. Chronic schizophrenia was assessed in 43 studies, first-episode schizophrenia in 18 studies, and both chronic and first-episode schizophrenia in 3 studies.
Their headline finding?
- Two types of immune cells – neutrophils and monocytes – were significantly elevated in people with schizophrenia.
Neutrophils, a key part of the innate immune system, were moderately elevated in patients compared to controls (Hedges’ g = 0.69), while monocytes also showed a meaningful increase (g = 0.49). These differences were more pronounced in people experiencing their first episode of psychosis than in those with chronic illness, suggesting that immune changes may be especially relevant early in the disease course.
Crucially, these elevations were strongest in individuals not taking antipsychotic medication. Among unmedicated or antipsychotic-naïve participants, neutrophils and monocytes were significantly higher than in those receiving treatment. This implies that inflammation may subside with antipsychotic use – or alternatively, that inflammation is a feature of acute psychosis rather than a stable trait.
The study also included longitudinal data from a subset of participants. After successful treatment of acute psychosis, neutrophil levels decreased, while eosinophil levels increased, suggesting a shift in immune profile with clinical improvement. Interestingly, there were no consistent differences in lymphocytes, eosinophils, or basophils between patients and controls in cross-sectional analyses.
The researchers also explored moderators of these effects, including age, body mass index (BMI), smoking status, illness duration, and symptom severity. Elevations in neutrophil and monocyte counts were not fully explained by these factors, though higher monocytes were associated with BMI in unmedicated patients – highlighting the need to account for metabolic comorbidities in future studies.
Overall, the findings support the hypothesis that immune activation, particularly that which involves neutrophils and monocytes, plays a role in schizophrenia – especially during early or untreated stages of illness.
Neutrophils and monocytes were significantly elevated during the early and untreated stages of schizophrenia, supporting evidence of immune dysfunction.
Conclusions
This large-scale meta-analysis by Dudeck et al. (2025) offers additional support for the immune hypothesis of schizophrenia, particularly implicating immune cells such as neutrophils and monocytes. These elevations were more pronounced in unmedicated and first-episode patients, and appeared to normalise with treatment, suggesting a dynamic relationship between immune activation and illness state.
As the authors conclude:
Our findings… may pave the way for innovative treatment strategies based on immunological and inflammatory pathways and help revolutionize the treatment landscape for schizophrenia.
While not definitive, this study provides a compelling rationale to re-examine immune-targeted approaches with greater precision.
“Our findings … may pave the way for innovative treatment strategies based on immunological and inflammatory pathways and help revolutionize the treatment landscape for schizophrenia”.
Strengths and limitations
With over 40,000 participants across 64 studies, it is the largest and most thorough synthesis to date of immune cells in schizophrenia. The authors followed PRISMA and MOOSE guidelines, used robust random-effects models, and reached out to original study authors to retrieve missing data. They also focused on absolute cell counts, rather than ratios, which provides a more direct and interpretable assessment of immune involvement.
Another strength is the subgroup and moderator analyses. By splitting data by medication status, illness stage (first-episode vs chronic), and comorbidities, the authors provide important nuance. The finding that immune cell elevations are stronger in unmedicated, early-stage patients suggests that inflammation may be state-dependent and perhaps therapeutically modifiable.
However, limitations should be noted. First, and the one I find the most important, is that most current studies (including this meta-analysis) rely on broad white blood cell counts, which are blunt tools for dissecting the complexity of the immune system. Only measuring immune cell counts offer limited insight into the functional state or activation profile of immune cells. For instance, within the innate immune system, my colleagues and I have previously reported elevated neutrophil extracellular traps (NETs) in individuals with early schizophrenia, suggesting a hyperactivated or dysregulated neutrophil response rather than a simple increase in cell number (Corsi-Zuelli et al., 2022).
In addition, the lack of difference in lymphocytes between patients and controls may simply reflect the fact that total lymphocyte count provides a non-specific measure, as it aggregates many cell types which each have their own distinct roles in the immune system. Other important limitations include:
- Heterogeneity across studies was high, reflecting substantial variation in populations, methodologies, and outcome definitions.
- Residual confounding remains a concern. Although smoking, BMI, and symptom severity were considered, other factors – like stress, diet, infections, or trauma history – may also affect immune cell counts.
- There was evidence of publication bias for neutrophil findings.
- Longitudinal data were limited (only 4 studies).
- Studies using more refined immune profiling techniques, such as flow cytometry, were excluded, even though these methods may offer critical insight into functional immune alterations.
This is the largest and most thorough synthesis to date of immune cells in schizophrenia, but more work is needed trace their activity over time using more refined immune profiling.
Implications for practice
This meta-analysis by Dudeck et al. (2025) reinforces the growing consensus that immune dysfunction plays a role in schizophrenia, particularly early in the illness and in unmedicated patients. But what does this mean for clinical practice?
From a clinical standpoint, these findings are not a call to start prescribing anti-inflammatory drugs, especially given the disappointing results from previous trials using broad immunomodulators. Instead, they suggest a need to refine how and when we target the immune system – perhaps focusing on early stages of psychosis or treatment-resistant individuals and the need to use more precise immune phenotyping to guide intervention.
This is where research into immune cell subtypes and functions becomes critical. Data on absolute numbers or percentages of white blood cells are insufficient to measure immune cell dysfunction or immune cells’ ability to release or inhibit cytokines. Therefore, more sophisticated techniques, such as flow cytometry (high-dimensional or spectral cytometry) – which are still few in psychosis and centered on chronic stages (Corsi-Zuelli et al., 2021) – and single-cell RNA sequencing (scRNA-seq) will allow a fine-grained identification of functional immune subsets. These tools could help uncover which immune cells are truly involved in symptom persistence or treatment resistance, and whether they differ across subtypes of schizophrenia.
In vitro studies will be essential to evaluate the functional capacity of immune cells in schizophrenia, moving beyond descriptive phenotyping to assess how these cells behave under stimulation or stress. In parallel, neuroimaging techniques could provide valuable insights into the relationship between circulating immune alterations and changes in the brain, including glial activity, neurotransmitter dynamics, and regional brain structure or function. Ultimately, integrating immune and inflammatory markers into routine clinical assessments may support the stratification of patients and pave the way for more personalised, mechanism-based interventions in schizophrenia.
On a more personal note, as someone involved in immunopsychiatric research, I find these results both validating and motivating. Families are often left searching for answers when traditional treatments fall short. Studies like this remind us that schizophrenia is not just a disorder of the mind – it’s shaped by the body too. Understanding these complex interactions offers hope not only for new treatments, but also for reducing stigma and shifting how we think about severe mental illness.
It is time to refine how and when we target the immune system for the study and treatment of schizophrenia.
Statement of interests
None.
Links
Primary paper
Dudeck, L., Nussbaumer, M., Nickl-Jockschat, T., Guest, P.C., Dobrowolny, H., Meyer-Lotz, G., Zhao, Z., Jacobs, R., Schiltz, K., Fernandes, B.S., Steiner, J., 2025. Differences in Blood Leukocyte Subpopulations in Schizophrenia: A Systematic Review and Meta-Analysis. JAMA Psychiatry 82. https://doi.org/10.1001/JAMAPSYCHIATRY.2024.4941.
Other references
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