Examining the Link Between the Immune System and Schizophrenia

Psychiatric TimesPsychiatric Times Vol 36, Issue 11
Volume 36
Issue 11

As research continues to point to a connection between the immune system and schizophrenia, a study of innate immunity in patients with first episode psychosis and schizophrenia provides further insights into the potential mechanisms of this link.


As research continues to point to a connection between the immune system and schizophrenia, a study of innate immunity in patients with first episode psychosis and schizophrenia provides further insights into the potential mechanisms of this link.


Since prenatal and early life infections are associated with schizophrenia risk, there has been growing interest in an immune hypothesis of schizophrenia.1 For instance, a recent study found significantly increased neutrophils in patients with first-episode psychosis (FEP) compared with controls, and higher neutrophil counts were associated with greater total and positive symptoms as well as reduced total brain gray matter volume on MRI.2 Similarly, recent meta-analyses have found an increased ratio of neutrophils to lymphocytes and monocytes to lymphocytes in the blood of patients with psychosis.3,4

To further explore this notion, Steiner and colleagues5 performed a study of innate immunity in patients with FEP and unmedicated schizophrenia compared with controls. The innate immune system-which includes monocytes and granulocytes-is the first line of defense following infection.

The researchers aimed to identify if monocytes and granulocytes are increased in psychosis; whether the levels of these cells correlate with levels of the inflammatory marker C-reactive protein (CRP); whether these parameters change after six weeks of antipsychotic treatment; and if changes in immune parameters correlate with changes in psychotic symptoms.

The study included blood bank specimens (fasting samples) from 129 patients with drug-naïve FEP; 124 unmedicated (≥6 weeks) patients with schizophrenia; and 294 control participants. Illicit drug use (including cannabis) and history of immune disease or immunotherapy were exclusionary for the study. Controls were screened for personal or family history of neuropsychiatric disorders. Assessments of blood and psychopathology (using the Positive and Negative Syndrome Scale [PANSS]) were performed at baseline, and data on six-week follow-up assessments were available for 175 of the participants.

The majority of the participants were treated with either olanzapine or risperidone. Blood samples were evaluated for monocyte and granulocyte counts as well as markers of neutrophil and monocyte activation. Between-group differences were calculated by non-parametric tests. Correlation of cell counts with demographic, clinical, and blood measures were assessed by Spearman rank tests. Findings were corrected for multiple comparisons.

The study found that patients with FEP and unmedicated schizophrenia had significantly higher neutrophil and monocyte counts and CRP levels than controls at baseline, with larger effect sizes for neutrophils. About 25% of patients had neutrophil counts above the reference range. Neutrophil and monocyte counts were significantly correlated with CRP levels at baseline.

By contrast, eosinophil counts were lower in patients with small effect sizes. Both neutrophil and monocyte counts were significantly positively correlated with blood markers of neutrophil activation (Granulocyte-colony stimulating fact [G-CSF], myeloperoxidase [MPO], and neutrophil gelatinase associated lipocalin [NGAL]) and monocyte activation (soluble CD40 antigen [sCD40] and macrophage inflammatory protein-1 alpha [MIP-1α]). Neutrophil counts and CRP levels were significantly positively correlated with PANSS positive symptoms.

Following six weeks of antipsychotic treatment, neutrophil counts were significantly decreased and eosinophils were significantly increased in FEP and chronic schizophrenia samples, but there were no significant changes in monocyte counts or CRP levels in FEP. Changes in neutrophil counts and CRP levels beyond six weeks were significantly correlated with changes in PANSS total and positive symptoms.

In patients with FEP, antipsychotic dose (in chlorpromazine equivalents) was negatively correlated with the change in neutrophil counts. Neutrophil and monocyte counts were not correlated with age or illness duration, but they were influenced by cigarette smoking. Cortisol measures were associated with monocyte but not neutrophil counts.

The authors performed the largest systematic analysis of differential blood cell counts in patients with FEP. They found significantly increased neutrophil and monocyte counts during acute psychosis with in both drug-naive FEP and unmedicated schizophrenia. As neutrophil and monocyte counts only partly normalized during antipsychotic treatment, the researchers concluded that increased numbers of innate immune cells may represent a trait marker for psychosis.

They also found that neutrophil counts correlated with positive symptoms at baseline and with antipsychotic treatment, suggesting that these cells may act as a modulatory of acute disease severity. Upregulated NGAL and MIP-1α supports a potential role of bacterial infections as a triggering factor of psychosis. Strengths of the study included a large sample size and clinically well-characterized patients. Limitations include the inability to determine the potential precipitants of neutrophil and monocyte activation and absence of brain imaging data.

The bottom line

There is evidence in some patients for a transient inflammatory response during onset of acute psychosis that wanes afterwards and persists in an attenuated form. Antipsychotics may have anti-inflammatory effects. Neutrophil and monocyte counts as well as CRP levels may be useful markers of disease acuity, severity, and treatment response.

Dr Miller is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is the Schizophrenia Section Editor for Psychiatric Times.


The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.



1. Miller BJ, Goldsmith DR. Towards a schizophrenia immunophenotype: progress, potential mechanisms, and future directions. Neuropsychopharmacology. 2017;42:299-317.

2. Nunez C, Stephan-Otto C, Usall J, et al. Neutrophil count is associated with reduced gray matter and enlarged ventricles in first-episode psychosis. Schizophr Bull. 2019;45:846-858.

3. Mazza MG, Lucchi S, Rossetti A, et al. Neutrophillymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in non-affective psychosis: a meta-analysis and systematic review. World J Biol Psychiatry. 2019; doi:10.1080/15622975.2019.1583371.

4. Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2019;206:4-12.

5. Steiner J, Frodl T, Schiltz K, et al. Innate immune cells and c-reactive protein in acute first-episode psychosis and schizophrenia: relationship to psychopathology and treatment. Schizophr Bull. 2019 Aug [Epub ahead of print].

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