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Nordic Journal of Psychiatry

ISSN: 0803-9488 (Print) 1502-4725 (Online) Journal homepage: https://www.tandfonline.com/loi/ipsc20

Neutrophil/lymphocyte ratio, monocyte/

lymphocyte ratio, and mean platelet volume as

systemic inflammatory markers in different states

of bipolar disorder

Ikbal Inanli, Memduha Aydin, Ali Metehan Çaliskan & Ibrahim Eren

To cite this article: Ikbal Inanli, Memduha Aydin, Ali Metehan Çaliskan & Ibrahim Eren (2019) Neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, and mean platelet volume as systemic inflammatory markers in different states of bipolar disorder, Nordic Journal of Psychiatry, 73:6, 372-379, DOI: 10.1080/08039488.2019.1640789

To link to this article: https://doi.org/10.1080/08039488.2019.1640789

Published online: 13 Jul 2019.

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ARTICLE

Neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, and mean platelet

volume as systemic inflammatory markers in different states of bipolar disorder

Ikbal Inanlia , Memduha Aydinb , Ali Metehan C¸aliskana and Ibrahim Erena

a

Clinic of Psychiatry, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey;bFaculty of Medicine, Clinic of Psychiatry, Selcuk University, Konya, Turkey

ABSTRACT

Background: Currently, increasing evidence supports the hypothesis that alterations in the immune-inflammatory system are critical for the pathophysiology of bipolar disorder (BD). Neutrophil/ lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and mean platelet volume (MPV) have recently been investigated as inexpensive and simple inflamma-tory markers.

Aims: The aim of this study is to compare NLR, PLR, MLR, and MPV in depressive, manic, and euthymic patients with BD and healthy controls, and to evaluate whether values of NLR, PLR, MLR, and MPV are possible state or trait biomarkers in BD.

Methods: This retrospective study was conducted with 341 patients with BD (100 patients in a depressive state, 141 patients in a manic state, and 100 patients in a euthymic state) and 114 healthy controls.

Results: We found that patients with BD in manic states had higher levels of MPV, NLR, and MLR, and patients with BD in depressive states had higher levels of MPV than the controls. Moreover, MPV pre-dicted all states of BD, while NLR and MLR prepre-dicted the manic state of BD.

Conclusions: NLR, MLR, and MPV obtained from simple and inexpensive blood tests were significantly higher in patients with BD than in healthy controls, which each imply low-grade inflammation. MPV may serve as a possible trait biomarker of BD, while NLR and MLR may both serve as possible state biomarkers of the manic state.

ARTICLE HISTORY

Received 16 January 2019 Revised 26 May 2019 Accepted 29 June 2019

KEYWORDS

Bipolar disorder; neutrophil/ lymphocyte ratio; platelet/ lymphocyte ratio;

monocyte/lymphocyte ratio; mean platelet volume

Introduction

Bipolar disorder (BD) is a mood disorder characterized by manic and depressive episodes and it affects 1% of world population and causes disability [1]. A complete understand-ing of the pathophysiological processes of BD remains unclear, although there is increasing evidence of the role of inflammatory systems. Inflammation and immune system alterations have been appointed as the mechanisms contri-buting to the underlying neurobiology of BD [2–4]. Increased C-reactive protein (CRP) concentrations, alterations of serum and cerebrospinal fluid cytokines, activated lymphocyte cell subsets, altered absolute neutrophil counts, platelet counts, and altered ratios of inflammatory cells have been shown as increased inflammatory responses in patients with BD [3,5–12]. Several studies have found pro-inflammatory cyto-kines to be elevated during states of depression, mania, and euthymia, indicative of a chronic, low-grade inflammatory condition. Furthermore, several inflammatory medical co-morbidities, including diabetes mellitus, obesity, etc., have been associated with increased rates of BD [4].

Neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), and mean

platelet volume (MPV) have been investigated as cost effect-ive and easily obtainable circulating clinical markers of chronic, low-grade inflammation in many diseases [2,5,13,14]. A few studies have investigated the relationship between BD, NLR, PLR, and MLR, and they reported that those values had altered frequently in patients with BD as compared with healthy controls. For example, higher NLR, PLR, and MLR val-ues, higher platelet and lower lymphocyte numbers have been found in BD diagnosed patients [14]. Higher MLR and PLR values have been reported in the euthymic and manic states in patients with BD when compared to the controls [2]. A meta-analysis reported that inflammatory activation occurs in mood disorders; NLR and PLR may be useful to detect this activation [15]. Some studies have evaluated the clinical and prognostic value of NLR and PLR in patients with BD. Melo et al. investigated the impact of NLR and PLR on future mood episodes and psychiatric hospitalizations and found that higher NLR and PRL was associated with more episodes and hospitalizations [5]. Ivkovic et al. reported a positive correlation between suicidal behavior in BD and NLR, however, only in the patients with a positive family his-tory of suicide attempts [16]. Aykut et al. proposed a

CONTACT Ikbal Inanli ikbalcivi@yahoo.com Konya Egitim ve Aras¸tırma Hastanesi Psikiyatri Klinigi, Turgut €Ozal Cad. No: 14/D, Yazır Mah., Selc¸uklu/

Konya, Turkey

ß 2019 The Nordic Psychiatric Association

2019, VOL. 73, NO. 6, 372–379

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negative correlation between NLR and attention in cognitive tests in patients with BD [1].

The MPV is a readily available marker of platelet activation in the assessment of prothrombotic and pro-inflammatory processes in several diseases [17]. The relationship between mood disorders and platelet activity has been reported by several studies [3,18,19]. MPV has been found to be elevated in patients with manic episodes [3]. Mayda et al. revealed decreased MPV levels while others reported increased MPV levels, and they attributed this diversity to the level of inflammation [19].

Despite the increasing evidence of the role of systemic inflammation in pathophysiology of BD, there have been insufficient studies investigating simple and easily measured potential biomarkers to aid in the diagnosis of BD. The aim of this study is to compare NLR, PLR, MLR, and MPV as sim-ple inflammatory markers in depressive, manic, and euthymic patients with BD and healthy controls, and to evaluate whether plasma values of NLR, PLR, MLR, and MPV were associated with BD state or trait markers.

Methods Samples

This retrospective study was performed on 341 inpatients and outpatients with BD who were admitted to the Psychiatry Clinic between 1 April 2013 and 1 September 2018. All the data were retrieved from each patient’s hospital record stored in our hospital’s electronic database of medical records. These records include sociodemographic features such as gender, year and month of birth, marital status, and clinical features such as date of diagnosis, diagnosis at the time of hospitalization using DSM-IV-TR criteria, medical serv-ices provided or drugs prescribed, inpatient or outpatient status, comorbid diseases, and laboratory test results. This study was conducted according to the revised version of the Declaration of Helsinki. The local ethics committee approved the study.

Inclusion criteria for the BD group were the following (1) 18 years and older and (2) met the diagnostic criteria for BD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR). The control group con-sisted of 114 healthy individuals who were recruited from the local community. They were age and gender-matched with the patient group, and had no personal history of any psychiatric disorders and suicide attempts. Exclusion criteria for the all participants were the following (1) Having an auto-immune disease, acute infection, severe systemic disease, epilepsy, diabetes mellitus, hypertension, antiplatelet-anti-coagulant drug use, bone marrow disease/myelodysplastic syndrome or other kind of cardiovascular disease, as well as endocrinological, hepatic, renal, pulmonary, or neurological diseases; (2) Mental retardation or neurodevelopment disor-ders, traumatic brain injuries, or pregnancy; (3) History of dependence or abuse of alcohol and other kinds of substan-ces related disorders; (4) Body mass index (BMI) greater than 30 kg/m2. Laboratory data from basic hemogram tests and biochemical analyses were obtained from previous hospital

records of patients with BD. After the collection of venous blood into a container containing the anticoagulant ethyle-nediaminetetraacetic acid (EDTA), the Sysmex-XN 1000 auto-mated blood cell analyzer (Sysmex, Kobe, Japan) was used to analyze hemograms. Neutrophil/lymphocyte, platelet/ lymphocyte, and MLRs were calculated. Based on the data obtained from hospital records and according to DSM-IV-TR criteria, the patients were divided into three groups: depres-sive, manic, or euthymic.

Statistics

Statistical analysis was performed using SPSS version 15.0 software (SPSS, Chicago, IL). Simple descriptive statistics (mean ± standard deviation) were generated for continuous variables. For discrete variables, the number of patients and percentages are given. Normality of distribution was tested with the Shapiro–Wilk test. Variables that did not follow nor-mal distribution were analyzed using the Kruskal–Wallis test or the Mann–Whitney two-sample rank-sum test, otherwise a one-way ANOVA and t-test were used. The Chi-square test was used to compare categorical data. Differences between groups were then determined by Bonferroni’s post hoc ana-lysis. Associations were tested by Spearman’s correlation coefficient. For the multivariate analysis, the possible factors identified with univariate analyses were further entered into the logistic regression analysis to determine independent predictors of patients. Hosmer–Lemeshow goodness of fit statistics was used to assess model fit. Odds ratios (OR) with 95% confidence intervals were calculated using logistic regression. Ap value less than .05 was considered statistically significant.

Results

In this study, 341 patients and 114 healthy controls were included. There were no differences between all the patients and the controls in terms of age, gender, BMI, and smoking. However, patients with BD in depressive states had signifi-cantly higher ages and BMI than the controls (p¼.015 and p¼.001, respectively). The mean ages of the patients and the control group participants were 36.0 ± 8.8 years and 36.2 ± 12.3 years, respectively. One hundred eighty-three patients (53.7%) and 64 of the controls (56.1%) were female (Table 1). Among the patients with BD, 100 (29.5%) were in a depressive state, 141 (41%) were in a manic state and 100 (29.5%) were in a euthymic state. There were 115 (35.3%) patients with BD who were drug-naive, 31 (6.8%) were treated with mood stabilizers only, 21 (4.6%) were treated with atypical antipsychotics only, and 174 (38.2%) were treated with mood stabilizers plus atypical antipsychotics. One hundred and thirteen (33%) of the patients with BD were on lithium treatment, 61 (18%) were on treatment, and 15 (4%) were on other mood stabilizers including lamotri-gine, carbamazepine, etc. The clinical profile of the patients is indicated inTable 1.

The MPV values of patients with BD in depressive and manic states were significantly greater than controls (p¼.011)

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(Figure 1). The median neutrophil and monocyte counts, and MLR values of patients with BD in a manic state were signifi-cantly higher than those of all the other groups (p¼.001, p¼.002, and p¼.001, respectively) (Figure 2). The median WBC count and NLR value of patients with BD in a manic state were significantly higher than those of the controls (p¼.006, p¼.037, respectively) (Figure 3, Table 2). The

biochemical blood profiles of the patients and controls are indicated inTable 3.

Multiple logistic regression analysis was performed to determine the association of mood states with selected varia-bles as predictors. The two different models were applied because of the multicollinearity between dependent varia-bles including NLR and MLR. The MPV value was a

Table 1. Characteristics of patients with BD and healthy controls.

Bipolar disorder

Controls

p Value Post hoc Depressive (D)n ¼ 100 Mean ± SD,n (%) Manic (M)n ¼ 141 Mean ± SD,n (%) Euthymic (E)n ¼ 100 Mean ± SD,n (%) n ¼ 114 Mean ± SDn (%) Age 39.9 ± 13.6 34.5 ± 11.7 35.2 ± 11.1 36 ± 8.8 .015 D> M Gender Female 54 (54%) 72 (51%) 57 (57%) 64 (56%) .922 – Male 46 (46%) 69 (49%) 43 (43%) 50 (44%) – – Marital status Single 38 (40.4%) 58 (41.7%) 43 (44.8%) – .140 – Married 38 (40.4%) 48 (36.6%) 45 (46.9%) – – – Other 18 (19.1%) 23 (17.8%) 8 (16.3%) – – – Years of schooling 8.7 ± 3.7 8.7 ± 3.7 9.4 ± 4.1 – .289 –

Age of first mood episode 25.8 ± 10.4 24.5 ± 9 24.5 ± 9.3 – .402 –

Drugs Mood stabilizer 2 (9.1%) 10 (12.8%) 19 (9.1%) – – – Antipsychotic 9 (9%) 6 (4.2%) 6 (6.5%) – – – Other 56 (56%) 48 (33.6%) 70 (70%) – – – None 33 (33.7%) 79 (55.2%) 5 (5%) – – – Mood stabilizer Lithium 22 (32.4%) 33 (23.1%) 58 (61.3%) – – – Valproic acid 18 (26.5%) 21 (14.7%) 22 (23.2%) – – – Other 6 (8.8%) 1 (0.7%) 8 (8.4%) – – – None 22 (32.4%) 6 (4.2%) 7 (7.4%) – – – Seasonality 37 (37.4%) 47 (34.1%) 32 (33%) – .558 – Rapid cycling 5 (5.1%) 11 (8%) 4 (4%) – .598 –

Remission between episodes 52 (51.5%) 85 (62%) 29 (70%) – .010 E> D, M

Presence of mental illnesses in families 46 (47.4%) 65 (47.4%) 53 (47%) – .171 –

Presence of bipolar disorder in families 22 (22%) 33 (23.4%) 21 (21%) – .800 –

Number of manic episodes 3.7 ± 2.6 4.5 ± 4.1 3.2 ± 2.7 – .616 –

Number of depressive episodes 5.3 ± 3.8 3.1 ± 3.5 3.6 ± 2.6 – .001 E> D, M

Number of hospitalization 3.1 ± 2.5 3.2 ± 2.6 2.04 ± 1.9 – .001 D, M> E

Number of suicide attempt 61 (62.2%) 43 (31.4%) 20 (21%) – .001 D> M, E

Smoking 47 (47%) 66 (48.2%) 37 (37%) 38 (33.3%) .771 –

BMI 26.5 ± 2.5 26.1 ± 3.4 26.8 ± 2.5 25.5 ± 2.9 .065 –

BMI: body mass index

grups euthymic manik depressive controls MPV 13,00 12,00 11,00 10,00 9,00 8,00

Figure 1. Box plot for MPV values of groups.

grups manik euthymic depressive controls MLR 0,60 0,50 0,40 0,30 0,20 0,10 0,00

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statistically significant predictor for BD and depressive, manic, and euthymic states of BD (p¼.002, p¼.008, p¼.006, and p¼.043, respectively). The NLR and MLR values were statistically significant predictors for BD and the manic state of BD (p¼.018, p¼.001, p¼.004, and p¼.001, respectively). Age was a statistically significant predictor for the depressive state (p¼.006) (Table 4).

Discussion

This study demonstrated that inflammation markers includ-ing MPV, NLR, and MPV values of patients with BD were altered compared to healthy controls. We found that patients with BD in manic states had higher levels of WBC, MPV, NLR, and MLR, and patients with BD in depressive states had higher levels of MPV than the controls. Furthermore, MPV predicted all mood states of BD, while NLR and MLR pre-dicted the manic state of BD. Our results support the associ-ation of BD with low-grade inflammassoci-ation and suggest that NLR and MLR may be potential state biomarkers for BD in manic states, while MPV may be a potential trait biomarker for BD in all states.

There is growing evidence that inflammation is involved in the pathophysiology of BD and many studies have investi-gated inflammation pathways and their mediators that are involved in mood disorders. Consistent with previous litera-ture, patients with BD have marked low-grade inflammation which can be measured in standardized laboratory settings. Changes in levels of NLR, MLR, PLR, and MPV are associated with the presence of inflammation and positive results related to these have been reported in all states of BD including euthymia [15,19,20]. A recent meta-analysis reported that people with BD had significantly higher NLR than HC; however, only in studies including subjects in a manic state and in any mood state was NLR significantly higher for patients with BD as compared with controls,

grups euthymic manik depressive controls NLR 5,00 4,00 3,00 2,00 1,00 0,00

Figure 3. Box plot for NLR values of groups.

Table 2. Comparison of blood count parameters between patients with BD and healthy controls. Bipolar disorder

Controls

p Value Post hoc Depressive (D)n ¼ 100 Mean ± SD,n (%) Manic (M)n ¼ 100 Mean ± SD,n (%) Euthymic (E)n ¼ 141 Mean ± SD,n (%) n ¼ 114 Mean ± SD, n (%) WBCs (103/ml) 7.5 ± 1.8 8 ± 2.1 7.7 ± 1.9 7.1 ± 1.7 .006 M> C Hemoglobin (g/dl) 14 ± 1.5 14.1 ± 1.6 13.9 ± 1.5 14.2 ± 1.6 .734 – Platelets (103/ml) 256 ± 92.9 260 ± 65.4 256 ± 71.3 257 ± 65.3 .695 – MPV (fl) 10.5 ± 0.9 10.5 ± 0.9 10.3 ± 0.8 10.1 ± 0.8 .011 D, M> C Lymphocytes (103/ml) 2.6 ± 0.8 2.4 ± 0.6 2.4 ± 0.5 2.4 ± 0.5 .344 – Monocytes (103/ml) 0.6 ± 0.2 0.7 ± 0.3 0.6 ± 0.1 0.5 ± 0.1 .001 M> D, E, C Neutrophils (103/ml) 4.2 ± 1.6 4.6 ± 1.6 4 ± 1 3.8 ± 1.2 .002 M> D, E, C NLR 1.7 ± 0.5 2 ± 0.7 1.7 ± 0.3 1.6 ± 0.5 .037 M> C PLR 104.6 ± 42.9 113.3 ± 41.2 109.6 ± 33.5 111.7 ± 34.4 .173 – MLR 0.2 ± 0.1 0.3 ± 0.1 0.2 ± 0.1 0.2 ± 0.1 .001 M> D, E, C

WBC: white blood cell; MPV: mean platelet volume; NLR: neutrophil/lymphocyte ratio; PLR: platelet/lymphocyte ratio; MLR: monocyte/lymphocyte ratio

Table 3. Comparison of biochemical blood profiles between patients with BD and healthy controls. Bipolar disorder

Controls

p Value Post hoc Depressive (D)n ¼ 100 Mean ± SD,n (%) Manic (M)n ¼ 100 Mean ± SD,n (%) Euthymic (E)n ¼ 141 Mean ± SD,n (%) n ¼ 114 Mean ± SD,n (%)

Fasting plasma glucose 85.6 ± 15.6 85.7 ± 12.2 89.5 ± 9.7 87.4 ± 9.8 .013 E> M, D

Urea 24.9 ± 8.4 23.9 ± 8.2 22.7 ± 7.8 24 ± 9 .277 – Creatinine 0.8 ± 0.6 0.8 ± 0.2 0.8 ± 0.1 0.8 ± 0.6 .986 – AST 22.1 ± 10.3 25.5 ± 13.6 19.8 ± 6.6 20.6 ± 6.3 .005 M> E, C ALT 21.1 ± 12.1 20.8 ± 12 18.2 ± 9.7 19.1 ± 9.4 .352 – Total cholesterol 174.9 ± 28.1 164.9 ± 29 165.8 ± 24 172.9 ± 28.3 .001 D> M, E < D Triglyceride 124 ± 48.4 108.8 ± 37.8 115.2 ± 43.5 118.3 ± 44.7 .228 – HDL-C 45 ± 14.9 42 ± 9.9 44 ± 8.9 47.9 ± 12.5 .001 E> M LDL-C 104.3 ± 24.9 95.7 ± 25.5 92.7 ± 23 102.9 ± 19.3 .001 C> M, E TSH 1.8 ± 1.1 2.2 ± 1.2 2.4 ± 1.4 2.2 ± 1 .006 M, E, C> D Vitamin B12 353.9 ± 138 337.9 ± 152.2 325.4 ± 111 323.3 ± 106.3 .510 –

AST: aspartate aminotransferase; ALT: alanine aminotransferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; TSH: thyroid-stimulating hormone NORDIC JOURNAL OF PSYCHIATRY 375

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whereas the effect was not significant among studies includ-ing only euthymic patients [15]. In one of our previous stud-ies, we evaluated BD patients in all mood states and found that NLR in manic, depressed, and euthymic states of BD was significantly higher compared to HC [20]. Another study has also demonstrated that NLR was higher in patients in both euthymic and manic/hypomanic states of BD compared to controls, although there was no difference in the depressed state [21]. Kalelioglu et al. reported that NLR was found to be higher in both manic and euthymic patients compared to the control group [2]. In a study evaluating the manic state only, increased NLR levels in patients with BD were observed during manic episodes [19].

A few studies have evaluated the clinical value of NLR and PLR in BD. Mert and Terzi reported that NLR, MPV, and PLR values of the patients with BD were higher than those of the healthy controls [3]. Melo et al. reported that higher NLR and PRL were also associated with more episodes and hospitalizations after 18 months and only higher NLR was related to more manic episodes [5]. Another study found NLR to be a significant positive predictor of suicidal risk in euthymic patients with BD, but its effects were moderated by family history of suicide attempts such that NLR was a positive predictor only in the patients with positive family history of suicide attempts [16].

It has been indicated that NLR reflects the balance between innate (neutrophils) and adaptive (lymphocytes)

immune responses [22]. Neutrophils represent the first line of immune defense and exhibiting phagocytic and apoptotic effects through the secretion of various inflammatory media-tors such as cytokines may cause cellular DNA damage. In contrast, lymphocytes are specific inflammatory mediators, with a regulatory or protective function; lymphopenia reflects poor general health and physiologic stress [5,15]. Thus, NLR, being an integrated reflection of two different immune path-ways, is more predictive than either parameters alone, and NLR may be useful to detect the inflammatory response and the following cytokine cascade notably associated with BD [15]. In the majority of studies, NLR was found to be higher in patients with BD, and it was more consistent especially in manic states. In this study, NLR was higher in patients with BD in manic states, and we believe that NLR may be a pre-dictive factor for BD especially in manic states.

The MLR can be derived from white blood cell count and is a low-cost, effective, and readily available new marker. In recent years, the use of this value has increased in psychi-atric studies. €Ozdin et al. reported that NLR, PLR, and MLR values were higher in patients with BD who were hospital-ized due to a manic episode compared to the control sub-jects, and they noticed that there may be an increased inflammatory response in the body during the manic episode [14]. We found that patients with BD in manic states had sig-nificantly higher levels of MLR than the controls. Although there are no other studies evaluating the relationship

Table 4. Logistic regression models investigating the association between patients with BD and MPV, NLR, PLR, and MLR.

Age Gender MPV NLR PLR MLR Total patients Model 1 OR 1.003 1.035 1.496 1.613 0.996 – %95c 0.984–1.022 0.659–1.626 1.155–1.939 1.086–2.396 0.990–1.003 – p .766 .881 .002 .018 .250 – Model 2 OR 1.003 0.985 1.521 – 0.997 1.494 %95c 0.984–1.022 0.624–1.556 1.157–1.898 – 0.991–1.003 1.151–1.940 p .786 .950 .003 – 0.372 .004 Depressive patients Model 1 OR 1.037 1.205 1.552 .986 .995 – %95c 1.011–1.064 0.669–2.710 1.119–2.153 0.738–2.106 0.986–1.004 – p .006 .535 .008 .411 .303 – Model 2 OR 1.037 1.193 1.571 0.996 – 1.134 %95c 1.011–1.064 0.662–2.149 1.136–2.172 0.998–1.004 – 0.824–1.561 p .006 .557 .006 .440 – .440 Manic patients Model 1 OR 0.987 1.256 1.550 2.079 0.989 – %95c 0.962–1.012 0.724–2.178 1.134–2.118 1.344–3.217 0.989–1.006 – p .293 .418 .006 .001 .623 – Model 2 OR 0.985 1.186 1.593 1.001 – 1.928 %95c 0.960–1.010 0.677–2.077 1.164–2.180 0.993–1.008 – 1.405–2.644 p .245 .552 .004 .881 – .001 Euthymic patients Model 1 OR 0.992 1.037 1.410 1.317 0.998 – %95c 0.964–1.020 0.571–1.882 1.010–1.968 0.677–2.561 0.989–1.007 – p .557 .906 .043 .417 .672 – Model 2 OR 0.991 0.948 1.406 – 0.998 1.374 %95c 0.964–1.019 0.515–1.744 1.004-1.970 – 0.998–1.006 0.977–1.933 p .507 .917 .047 – .552 .068

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between BD in different mood states and MLR in the litera-ture, there are studies showing increased MLR especially in patients with schizophrenia [14,23]. One study demonstrated that levels of monocytes are elevated in patients with psychi-atric disorders such as BD and schizophrenia, due to an enhanced expression of immune genes and an overproduc-tion of monocytes/macrophage related cytokines [10]. Pro-inflammatory cytokines secreted by activated monocytes/ macrophages could underlie the link between the MLR and mood symptoms [24]. This theory states that chronically acti-vated monocytes/macrophage produce cytokines and inflam-matory compounds impacting brain development and predisposing the brain in such way that genetic and environ-mental influences are able to precipitate the symptoms of mood [10]. Padmos et al. reported that monocytes of a large proportion of patients with BD have an inflammatory gene expression related to the actual mood status of the patients [25]. We demonstrated that MLR values of patients with BD in manic states were higher than both controls and patients with BD in depressive and euthymic states, and we also found that MLR can be a predictive factor for the manic state. Although there are a limited number of studies evalu-ating the relationship between MLR and mood states in BD, we believe that our results are consistent with the results of monocyte-related inflammatory gene expression studies in patients with BD. Further studies are needed in this area.

The relationship between platelet parameters and mental disorders has long been recognized. Studies show that patients with various mental disorders have altered platelet activation and platelet count, but there are contradictory and inconclusive results [18,26,27]. MPV is a readily available marker of platelet activation in the assessment of prothrom-botic and pro-inflammatory potentials in several clinical con-ditions [17]. Wysokinski and Szczepocka found that there was

a negative correlation between platelet count and age in all groups in the study of patients with schizophrenia, BD, and unipolar depression, and they found a positive correlation between age and MPV in patients with schizophrenia [18]. Mert and Terzi found that the MPV values of patients with BD in manic states were higher than those of the healthy participants, and they put forward that these findings sup-port the hypothesis that inflammatory activation occurs in BD during manic episodes [3]. Another study reported that increased NLR and decreased MPV levels may reflect inflam-mation in manic patients, and they explained that decreased MPV levels are observed in high-grade inflammatory dis-eases, such as active rheumatoid arthritis, etc. [19].

There have been several studies investigating the relation-ship between MPV and unipolar depression. In a large com-munity-based population, higher MPV was reported in depressed patients compared to individuals without depres-sion and MPV levels decreased after 8 weeks of antidepres-sant treatment [26]. Uc¸ar et al. reported that NLR and MPV tend to be higher in adolescents with unipolar depression compared to healthy controls [28]. Cai et al. found that MPV, NLR, and PLR were significantly higher in unipolar depression patients than in healthy controls, and they emphasized that MPV may also serve as a biomarker of the inflammatory state

of depression [27]. In this study, patients with BD in manic and depressive states had higher levels of MPV than the con-trols. Our results support the notion that inflammation may play a role in the mixed pathophysiology of BD, and add-itionally they lend support for MPV as an inflammation marker that may also serve as a trait biomarker of BD.

MPV is not only a measure of platelet activation but also a strong predictor for inflammation states and for the future prognosis [29]. Several hormonal and immune agents influ-ence the maturation of thrombopoietic cells and the release of platelets into circulation. It seems that the size of circulat-ing platelets is dependent on the intensity of systemic inflammation and on the course of anti-inflammatory treat-ment. MPV is a reflection of both proinflammatory and pro-thrombotic conditions, where thrombopoietin and numerous inflammatory cytokines (e.g. IL-1, IL-6, and TNF alpha) regu-late thrombopoiesis [17]. To our knowledge, this study is the first to evaluate the levels of MPV in depressive, manic, and euthymic patients with BD, and it is consistent with the literature.

Platelets are a specific first line inflammatory marker that regulates parameters such as endothelial permeability and recruitment of neutrophils and macrophages, and PLR may predict the inflammatory response in mood disorders [15]. Also, some studies have reported that the PLR may be better than the NLR for determining the severity of inflammation [30]. There are few studies examining PLR levels in bipolar patients, and the results are inconsistent [1–3,14]. A meta-analysis reported higher PLR values in patients with BD when compared to controls [15]. However, we did not find a difference between patients with BD and controls in terms of PLR values. Further investigation in this area would be appropriate.

Limitations

This study has some important limitations. First, this is a retrospective study, so no causal relationship can be drawn between NLR, PLR, MLR and MPV, and BD. Second, parame-ters associated with disease severity could not be evaluated because there were no severity rating scales available in patients’ hospital records. The severity of the illness, as indi-cated by the number of hospitalizations or the number of episodes (manic or depressive), may also affect inflammatory parameters. Third, the fact that psychotropic drugs have not been evaluated, which have been reported to affect pro-inflammatory parameters, makes it difficult to define a clear result. Fourth, the fact that sleep-related features, such as sleep time and sleep quality, have not been evaluated and may affect inflammatory markers is also an important limita-tion. Fifth, although the two groups were matched for smok-ing status and BMI, a lack of assessment of uncontrollable factors, such as genetic characteristics, life style, and nutrition pattern of the participants are possible limitations.

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Conclusions

Our study showed that the NLR, MLR, and MPV obtained from simple and inexpensive blood tests were significantly higher in patients with BD than healthy controls, and it implies that low-grade inflammation probably plays an important role in the pathophysiology of BD. MPV may serve as a possible trait biomarker of BD, while NLR and MLR may both serve as possible state biomarkers of the manic state. Moreover, the presence of inflammation seems to be more noticeable in the manic state. The best approach to deter-mine if the inflammatory response in BD is a trait or state biomarker would be to plan longitudinal studies assessing the same patients in mood states and remission using psy-chometric instruments such as severity scales.

Disclosure statement

None of the authors has any conflict of interest to disclose.

Notes on contributors

Ikbal Inanli, Clinic of Psychiatry, Konya Research and Training Hospital, University of Health Sciences, Konya, Turkey

Memduha Aydin, Department of Psychiatry, Faculty of Medicine, Selcuk University, Konya, Turkey

Ali Metehan Caliskan, Clinic of Psychiatry, Konya Research and Training Hospital, University of Health Sciences, Konya, Turkey

Ibrahim Eren, Clinic of Psychiatry, Konya Research and Training Hospital, University of Health Sciences, Konya, Turkey

ORCID

Ikbal Inanli http://orcid.org/0000-0002-5848-703X

Memduha Aydin https://orcid.org/0000-0001-7679-6568

Ali Metehan C¸aliskan https://orcid.org/0000-0002-7347-7200

Ibrahim Eren https://orcid.org/0000-0003-1626-7810

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Şekil

Table 1. Characteristics of patients with BD and healthy controls.
Table 2. Comparison of blood count parameters between patients with BD and healthy controls.
Table 4. Logistic regression models investigating the association between patients with BD and MPV, NLR, PLR, and MLR.

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