A comparative study of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in bipolar mania and schizophrenia

INTRODUCTION

Bipolar disorder (BD) and schizophrenia were considered in the psychotic spectrum by the psychiatric classification system until the 19th century.¹ Later, Kraepelin differentiated dementia praecox and manic-depressive disorder, setting it as a milestone in psychiatric diagnostic classification.² Nowadays, a continuity model has been established linking mania and psychosis and thereafter between BD and schizophrenia, which was in contrast to the conventional approach.³ Besides this, few studies suggested that BD and schizophrenia were extensions of each other on a neurodevelopmental basis.⁴

The role of immunological disturbance in schizophrenia and bipolar illness has also been highlighted by some etiological studies.^5–7 Some studies reported alteration of peripheral inflammatory markers like cytokines, acute phase proteins, and lymphocyte cell activation in BD patients. ^5,8–12 Jilma found increased neutrophils and decreased lymphocytes in general immune response to endotoxemia.¹³ Thereafter, Zahorec developed the neutrophil/lymphocyte ratio (NLR) as a parameter that reflects the systemic inflammation and stress intensity in critically ill patients,¹⁴ thus suggesting that these markers also contribute to the development of psychiatric disorders, particularly BD, and schizophrenia.

Various studies proposed the role of NLR value as a poor prognostic sign in some medical illnesses like pancreatitis, malignancy, and coronary heart disease.^15–17 Later on, scholars tried to find out its role in psychiatric illness as well. Many studies that have been done on patients with BD and schizophrenia tried to find out levels of NLR and PLR.^18–31 Better treatment response has been suggested in patients suffering from schizophrenia who had normal initial neutrophil and lymphocyte numbers and poor response in those who had lower lymphocyte and higher neutrophil count.³²

Based on our current understanding and available information, we found that only a single study tried to ascertain the difference between schizophrenia and BD with respect to NLR and PLR. This study demonstrated a significantly higher NLR level in schizophrenia than BD (mania) patients.²⁰ In India, no study has been done on this subject so far. Therefore, we planned to conduct this study in a tertiary care center in India.

The main objective of this study was to assess and compare the levels of NLR and PLR among bipolar mania patients, schizophrenia patients, and healthy controls in order to find out a potential biomarker for these disorders. Our a priori hypothesis for this study was that the NLR and PLR values are higher among the subjects with mania and schizophrenia in comparison to healthy controls.

MATERIAL AND METHODS

The study was conducted as a cross-sectional and observational research in the Department of Psychiatry at a tertiary care hospital in North India. Ethical permission was taken from the ethics committee of the institute. The enrolment criteria were male or female participants aged greater than 18 years, who expressed a willingness to participate in the research and gave their written consent. The exclusion criteria for bipolar mania and schizophrenia groups included having any pre-existing chronic medical conditions and treatments, substance use including heavy smoking (>15 cigarettes per day),²¹ clinical evidence related to active infections, as well as active or chronic inflammatory or autoimmune diseases among the participants, obesity (body mass index (BMI) >30 kg/m²), taking immunosuppressive or anti-inflammatory medications, and the presence of clinically significant abnormalities during the baseline assessment (such as tachycardia, tachypnea, or fever) or abnormality in a laboratory test (e.g. anemia, leukocytosis, leukopenia, and thrombocytosis).²¹ The exclusion criteria for healthy controls included any pre-existing psychiatric illness and treatment and parameters that were applicable to the bipolar and schizophrenia groups. The sample size for the study was determined based on a desired study power of 80% and a significance level (a-error) of 0.05, assuming a standard deviation of 1.0 as per the results of the reference article.²⁰ For a minimum detectable difference in means of 0.5 (NLR), 80 subjects were required as the sample size in each group. The patients who met both the inclusion as well as exclusion criteria were included in the study until the intended sample size was reached.

A total of 80 consecutive patients diagnosed with bipolar mania and 80 consecutive patients diagnosed with schizophrenia, according to the ICD-10 “(International Classification of Disease 10th Revision)”, were recruited. The diagnosis of each patient was confirmed by two senior psychiatrists who were not part of the study. In addition, 80 healthy controls, preferably individuals accompanying the patients, were also included in the study. Psychiatric illnesses were ruled out in the healthy control group using the “ICD-10 symptom checklist for mental disorders.”³³ Individuals who willingly participated in the study, provided written consent and met the inclusion criteria. Blood samples were collected from the antecubital vein of all subjects using vacutainer tubes containing ethylenediamine tetraacetic acid (EDTA) as an anticoagulant. The samples were collected in the morning hours (9 am–11 am) after overnight fasting and were sent to the laboratory for complete blood count (CBC) by a three-part blood cell counter manufactured by Sysmex (XP-100). Among CBC parameters, we included neutrophil, lymphocyte, and platelet counts for our study as they are involved in the inflammatory process. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Similarly, the PLR (platelet to lymphocyte ratio) was determined by dividing the absolute platelet count by the absolute lymphocyte count.

RESULTS

DISCUSSION

The study findings reveal a significant increase in the value of neutrophils and NLR in both bipolar mania and schizophrenia groups compared to the control group. These results show an association of BD and schizophrenia with inflammatory parameters. Most of the studies that have been done so far are consistent on a higher NLR level in schizophrenia and BD while inconclusive over the neutrophil levels.^18–31

BD and schizophrenia groups do not differ significantly when considering lymphocytes, neutrophil count, and NLR as a parameter of inflammation in the study. As per our knowledge, there is only a single study available till now that compared these markers in BD and schizophrenia. It showed a contradictory result of significantly higher NLR level in schizophrenia than BD (mania) patients.²⁰

The NLR serves as an indicator of the balance between the innate immune response (neutrophils) and the adaptive immune response (lymphocytes).³⁴ Neutrophils, as the first line of defense, play a role in phagocytosis and apoptosis, releasing various inflammatory mediators like cytokines, which can lead to cellular DNA damage.³⁵ Lymphocytes play a crucial role in the immune system as they have protective and regulatory functions. Lymphopenia, which refers to a decrease in lymphocyte count, can be an indicator suggesting compromised overall health and physiological stress.^36,37 Considering that NLR represents an integrated parameter of these two immune pathways, it has the potential to be more predictive as a biomarker for BD during manic states and schizophrenia than using either parameter alone.³⁴ Therefore, NLR could serve as a valuable indicator and biomarker for these psychiatric conditions.

Indeed, the relationship between mental disorders and platelet parameters has been acknowledged for a considerable time. The PLR has shown promise in predicting the inflammatory response in affective disorders. Platelets serve as specific first-line inflammatory markers and play a role in regulating various parameters, including neutrophil and macrophage recruitment as well as endothelial permeability.²⁶ A meta-analysis has reported that patients with BD exhibit higher PLR values compared to controls.²⁶ Indeed, platelets are known to contain significant amounts of glutamate and serotonin within their dense granules. Serotonin and glutamate are neurotransmitters that play crucial roles in various physiological processes, including mood regulation.³⁸ In this study, no significant differences were observed in PLR values and platelet count among the groups being compared. Similarly, a study done by Ozdin et al. didn’t find any significant difference in the PLR level between BD and schizophrenia groups.²⁰ The findings regarding platelet count and activation in psychiatric disorders have been contradictory and inconclusive in various studies.^{18–19,24,29–31,39,40} Considering the inconsistent findings, it is important to acknowledge that PLR may not be a consistent and reliable marker for BD and schizophrenia.

In the study, the age distribution, BMI, and distribution of gender in all the groups (bipolar mania, schizophrenia, and control groups) were compared, and no significant differences were found among these variables. This suggests that the study groups were well-matched in terms of age, BMI, and gender distribution, which reduces the potential confounding effects of these factors on the study results.

Our study has the following limitations: Since this study is conducted in a cross-sectional manner, it is not possible to establish causal relationships. Other indicators of inflammation like cytokines, interferon-gamma, C-reactive proteins, acute phase proteins, and lymphocyte cell activation have not been studied. The patients were on different psychotropic drugs, which can influence blood cell count. Any lifestyle factors or levels of psychological distress were not assessed, which may affect NLR levels.

CONCLUSION

The NLR has emerged as a promising indicator, and it reflects a state of low-grade inflammation in both schizophrenia and bipolar mania. BD and schizophrenia have been considered as part of one continuum, proven by the fact that no significant differences were observed in the levels of neutrophils, lymphocytes, platelets, NLR, and PLR between these disorders. These markers can help in the prognosis and treatment of at least a subsection of patients and also are inexpensive and easy to assess.

More such studies are required in the future to definitively establish the role of inflammatory markers in psychiatric illnesses. The longitudinal study is required to ascertain whether the markers are state- or trait-specific markers. This will open the gate for new treatment strategies.