Is Elevated Neutrophil Count and Neutrophil-to-Lymphocyte Ratio a Cause or Consequence of Schizophrenia?—A Scoping Review

Abstract

Background: Several studies have found an association between elevated neutrophil count or neutrophil-to-lymphocyte ratio (NLR) in peripheral blood from patients with schizophrenia. The etiology behind this effect is unknown, and it is unclear if changes in neutrophil count and NLR may be induced by antipsychotics or if these parameters relate to the diagnosis and symptoms of schizophrenia. The purpose of this scoping review was to map research that explores this association, and to identify gaps in the current knowledge base.Method: The work was conducted in accordance with established methodological standards for scoping reviews. Studies on neutrophil count and NLR in schizophrenia were identified through search in relevant databases, and a parallel screening procedure was performed to ensure validity and reproducibility of the search. Articles that included different comparison groups, with differences in medication status (drug-naïve or drug-free vs. medicated), current disease state (relapse vs. remission), or treatment response, were included, as well as studies evaluating the association between symptomatology and neutrophil count or NLR.Results: The available literature was limited with substantial differences in aims, methods, and outcomes. In total, 13 articles were included for the synthesis of this review. Some interesting trends were identified: Neutrophil count and NLR seem to be elevated in schizophrenia patients regardless of current or past use of antipsychotic therapy. Neutrophil count and NLR correlated significantly with positive symptoms of schizophrenia. Still, these findings should be interpreted with caution due to considerable methodological differences and weaknesses in the literature, particularly concerning the blood sampling procedure.Conclusion: By including longitudinal studies and by comparing patient groups based on medication status, disease state and response, our study provides a basis for dissecting the associations between increased neutrophil count or NLR and a diagnosis of schizophrenia. Further research should investigate and quantify the apparent strong correlation between neutrophil count or NLR and positive symptoms in schizophrenia, to evaluate its clinical potential to guide diagnostics, treatment, or as a predictor of outcome. This review also exposes important methodological weaknesses in the literature on neutrophil count and NLR measurements. Standardization of blood sampling and processing is crucial to reduce bias, and factors that are known to influence leukocyte levels need to be accounted for.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

“…Increased levels of NETs were irrespective of sex, BMI, tobacco smoking, and other recreational drugs. These results extend previous findings of elevated neutrophils in schizophrenia [15][16][17][18][19][20], by mechanistically showing that these cells are in an active inflammatory state. It is becoming increasingly apparent that the release of NETs from neutrophils upon activation has a central role in both the initiation and chronicity of autoimmune and inflammatory diseases [32].…”

“…In addition, elevated NETs in our patients were not correlated with clinical variables such as duration of psychosis, psychosis age of onset, DUP, or BPRS. In two previous studies, increased blood neutrophils were associated with the severity of symptoms in FEP patients [ 16 , 80 ]. Others showed high neutrophils correlated with decreased grey matter volume and enlarged ventricles in FEP patients [ 81 ].…”

“…Instead, we observed the potential of first- and second-generation antipsychotics in inhibiting neutrophil-produced NETs induced by the stimulant PMA. Accordingly, meta-analyses show that increased neutrophil-to-lymphocyte ratio (NLR) observed in non-affective psychosis is unrelated to drug treatment [ 79 ], and that a significant decrease in neutrophil counts and NLR is observed after antipsychotic initiation [ 16 ]. Together, these results suggest that elevated neutrophils and related NETs in early schizophrenia are unlikely the result of pharmacological treatment.…”

“…Immune cell-based research could help to identify components of the immune system most relevant to the persistently reported low-grade inflammation and its impact on related neurochemical and behavioural changes [13,14]. In schizophrenia, meta-analyses show that total white blood cell counts are significantly elevated in patients relative to controls; a particular increase in neutrophils is observed among drug naïve first-episode psychosis (FEP), acute relapse, and chronic patients, independent of confounding variables such as sex, age, body mass index (BMI), and smoking [15][16][17][18][19][20].…”

Altered Neutrophil-to-Lymphocyte Ratio in Patients with Non-Affective First Episode Psychosis and its Relationship with Symptom Severity and Cognitive Impairment

“…Amongst the non-affective FEP patients (schizophrenic spectrum disorder) in this cross-sectional study, we found positive correlations between symptoms severity (re ected by the PANSS factors, as well as the CGI-S) with higher NLR, but no signi cant correlations between NLR and disease onset pro le (re ected as duration of untreated psychosis (DUP)). Our study revealed no signi cant correlation between NLR and PANSS-negative symptom score, which is in parallel to ndings reported in existing review [51]. Overall it suggested the potential role of NLR as a biomarker of clinical severity in the acute episode of FEP patients.…”