Neutrophil-to-lymphocyte, platelet-to-lymphocyte ratios and systemic immune-inflammation index in patients with post-traumatic stress disorder

Abstract

Background

Low-grade systemic inflammation has been reported in many psychiatric diseases and is described as a non-severe state of the inflammatory response. Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder characterized by symptoms of avoidance, re-experiencing and hyperarousal that develop secondary to a serious traumatic event. The trauma itself creates psychological and biological changes in the individual, apart from PTSD. This complex situation has still not been clarified and researchers have tended to research on inflammatory processes. Systemic immune inflammation index (SII), as a new index related to inflammation, is a comprehensive value based on peripheral lymphocyte, neutrophil and platelet counts. SII has been used as a marker of subclinical inflammation and prognosis in various studies. Although the presence of inflammation in PTSD was tried to be demonstrated through cytokines, inflammatory variables such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and SII, which are low-cost and easily shown in routine examinations, have not been studied before.

Method

We compared PTSD patients with healthy controls. 160 subjects (80 PTSD and 80 controls) were enrolled for study. All patients were evaluated with Structured clinical study form for DSM-V Axis 1 disorders. Exclusion criteria were as follows: presence of PTSD symptoms shorter than one month, presence of psychiatric comorbidity, being diagnosed with psychotic disorder, bipolar disorder, autism spectrum disorder, presence of mental retardation, being under psychotropic drug treatment, presence of a neurological disease that may cause serious disability (epilepsy, cerebrovascular disease), migraine, presence of organic brain damage, smoking, alcohol and substance use disorder, presence of a chronic disease such as diabetes mellitus, hypertension, hyperlipidemia, chronic lung diseases, being in pregnancy and breastfeeding, presence of heart disease were determined as exclusion criteria. Additionally, patients with diseases that could affect the leukocyte count (hematopoietic disease, malignancy, acute infection, acute or chronic renal failure, liver failure) and medication use (chemotherapy, history of glucocorticoid use in the last three months) were not included in the study. Patients who smoked more than fifteen cigarettes per day and had a body mass index > 30 were also excluded. SII is calculated as follows; SII = platelet count x neutrophil count / lymphocyte count.

Results

Sociodemographic data were comparable among groups. Neutrophil and platelet levels of PTSD patients were significantly higher than controls although both groups’ values were in normal range. Moreover, NLR, PLR and SII were significantly higher in PTSD group.

Conclusion

We found that NLR, PLR and SII values, which are easily calculable and cost-effective markers of systemic inflammation, were significantly higher in PTSD patients than in the control group. These values may be considered to identify patients who may benefit from adjuvant anti-inflammatory pharmacological treatment on top of psychotherapeutic treatment.

Introduction

Inflammation is our immune system’s defense mechanism against infection, tissue damage and stress [1]. Low-grade systemic inflammation has been reported in many psychiatric diseases such as psychotic disorders, mood disorders and personality disorders. This condition is described as a non-severe state of the inflammatory response [2]. Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder characterized by symptoms of avoidance, re-experiencing and hyperarousal that develop secondary to a serious traumatic event [3]. Although the rate of exposure to trauma is around 70%, it has been shown that the rate of developing PTSD after exposure varies between 8 and 22% [4]. The psychological and biological differences in the development of PTSD in the traumatized individual after experiencing a trauma have attracted the attention of trauma researchers [5, 6]. However, due to the psychological and biological changes that the trauma itself creates in the individual, apart from PTSD, this complex situation has still not been clarified and researchers have tended to research on inflammatory processes [7, 8].

Blood biomarkers are the most commonly used method to study inflammatory processes in psychiatry. However, most of them are costly and difficult to use for routine examination purposes. Similar to psychiatric disorders such as schizophrenia, bipolar disorder, depressive disorder, and panic disorder, the search for biomarkers in PTSD attracts the attention of researchers [9–13]. Therefore, less costly and simpler methods were needed. For this purpose, neutrophil-lymphocyte ratio (NLR), which was initially developed as a method to evaluate inflammation in patients with poor general medical conditions, has recently started to be used to evaluate systemic inflammation in psychiatric patients [14]. In addition to NLR, platelet-lymphocyte ratio (PLR) has also been investigated as a marker of subclinical inflammation in various psychiatric disorders. In the study by Catak et al. [15], PLR was found to be significantly higher when comparing patients with bipolar disorder and schizophrenia. Similarly, in another study conducted in 2018, healthy controls and schizophrenia patients were compared and PLR was found to be significantly higher in schizophrenia patients [16]. No study evaluating NLR and PLR in PTSD patients has been found in the literature.

Systemic immune inflammation index (SII), as a new index related to inflammation, is a comprehensive value based on peripheral lymphocyte, neutrophil and platelet counts. It is calculated as follows; SII = platelet count x neutrophil count / lymphocyte count [17]. SII has been used as a marker of subclinical inflammation and prognosis in various studies [17, 18]. However, there are very few studies in the literature that evaluate the SII rate in psychiatric diseases [19] Like NLR and PLR, SII still remains uninvestigated in relationship of inflammation and PTSD. In addition, many studies have shown that proinflammatory cytokines are increased in PTSD patients [20]. Although the presence of increased inflammation in these patients was tried to be demonstrated through cytokines, inflammatory variables such as NLR, PLR and SII, which are low-cost and easily shown in routine examinations, have not been studied before. Therefore, the aim of our study is to examine inflammatory changes in PTSD patients through easily accessible biomarkers for the first time.

Method

Patient enrollment

Patients who applied to Samsun Training and Research Hospital Psychiatry Polyclinic between March and September 2023 and were diagnosed with PTSD according to DSM-5 (Diagnostic and Statistical manual of Mental Diseases, Fifth Edition) criteria were included in the study. The control group consisted of patients with no history of psychiatric or general medical illness.

Criteria for excluding participants from the research

Patients who had PTSD symptoms shorter than one month, presence of psychiatric comorbidity (obsessive compulsive disorder, anxiety disorder, substance abuse), being diagnosed with psychotic disorder, bipolar disorder, autism spectrum disorder, presence of mental retardation, being under psychotropic drug treatment, presence of a neurological disease that may cause serious disability (epilepsy, cerebrovascular disease), migraine, presence of organic brain damage, smoking, alcohol and substance use disorder, presence of a chronic disease such as diabetes mellitus, hypertension, hyperlipidemia, chronic lung diseases, being in pregnancy and breastfeeding, presence of heart disease were determined as exclusion criteria. Additionally, patients with diseases that could affect the leukocyte count (hematopoietic disease, malignancy, acute infection, acute or chronic renal failure, liver failure) and medication use (chemotherapy, history of glucocorticoid use in the last three months) were not included in the study. Patients who smoked more than fifteen cigarettes per day and had a body mass index > 30 were also excluded.

The power analysis was conducted using the G*Power v3.1.9.6 program. With a confidence level of 95% (1-α), a test power of 95% (1-β), and an effect size (f) of 0.581, the minimum number of patients to be included in the study is determined to be 76 in each group, totaling 152 patients. After the evaluation, consecutive eighty patients were enrolled in each group (160 patients in total). Age-sex matched control group patients were enrolled from a group of volunteers who were admitted to the hospital for routine health examinations for different reasons, job applications, university registrations, etc. The same exclusion criteria were applied to this group, and volunteers who were presumed to have created significant differences between the control and patient groups in terms of marital status, education degree, and economic level were excluded; the remaining 80 volunteers were included in the study.

Data collection tools

1. Sociodemographic information form

The sociodemographic information form prepared by the researcher contains items that will be used to determine the personal information of the participants and some other specified variables. Participants were asked not to give their names and to use pseudonyms.

• 2.Structured clinical study form for DSM-V Axis 1 disorders (SCID-1)

SCID-1 is a semi-structured clinical interview scale developed to make basic axis 1 diagnoses [21]. Turkish adaptation and reliability studies were carried out by Elbir and colleagues [22].

• 3.Evaluation of blood samples and calculation of indicators

In our study, the routine hemogram results of the patient at the psychiatric outpatient clinic controls were used. Since blood samples were taken under outpatient and elective conditions, attention was paid to the patients’ fasting or satiety status and the time of sample collection. Blood samples taken into tubes containing a standard amount of EDTA (BD vacutainer EDTA, BD-Plymouth, UK) were analyzed without waiting on a fixed device (Sysmex XE-2100, Kobe, Japan) that was checked regularly in the hospital central laboratory. Participants’ platelet, absolute neutrophil and absolute lymphocyte values were recorded. The NLR is calculated as the absolute neutrophil count divided by the absolute lymphocyte count, while the PLR is calculated by platelet count divided by absolute lymphocyte count. SII was calculated as described previously, platelet count x neutrophil count/lymphocyte count.

Statistical analysis

All statistical analyses were performed using the IBM SPSS Statistics for Windows (version 21.0; IBM Corp., Armonk, NY, USA). The distribution of continuous variables was tested using the Kolmogorov-Smirnov test. Accordingly, T-Test or Mann-Whitney U-Tests were used to compare the continuous variables according to the distribution of the data. Chi-square or Fisher’s exact test was used to compare categorical variables. Continuous variables were presented as mean ± SD whereas categorical variables were presented as counts and percentages.

Data availability statement

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Results

The sociodemographic characteristics of two groups were similar in terms of mean age, marital status, economic income, employment status, and degree of literacy (Table 1). Study population consisted of rather young and middle-aged participants with mean age of 37.8 ± 8.5. Female gender was dominant in both of study groups (57% vs. 66%) without significance between groups. Nearly half of all participants were employed and had a middle-degree monthly income which suggest that study population may represent the middle class of society. Heavy smokers were excluded from study and percentage of light- smoker individuals were also similar in both groups. Mean participant body mass index was also comparable and it was in normal weight range (22.0 ± 1.6 vs. 22.6 ± 2.1, p = 0.68). Patients had following factors that cause PTSD: exposure to critical accident (n = 12, 15%), exposure to natural disaster (recent major earthquake in Turkey) (n = 26, 33%), exposure to sexual abuse (n = 22, 27%), exposure to physical vandalism (n = 20, 25%). Mean duration for PTSD symptoms was 13.2 ± 5.8 months. Patients’ stress exposure duration was not questioned however no patient was exposed to PTSD-related stress factor anymore at the time of enrollment. Duration of stress exposure may play role in degree of inflammation. Nonetheless, patients’ coping capability, presence of effective psychosocial support sources, having good functionality may also contribute to process and may also have a chance alter inflammation degree positively. When blood sample results were checked, neutrophil and platelet levels of PTSD patients were significantly higher than controls although both groups’ values were in normal range (Reference ranges for neutrophils were 1.8–7.5 10⁹/L, for lymphocytes: 1.0–4.0 10⁹/L and for platelets: 140–400 10⁹/L). Moreover, NLR, PLR and SII were significantly higher in PTSD group (Table 2).

Table 1.

Sociodemographic characteristics of participants

Parameter	PTSD group (n = 80)	Control group (n = 80)	p value
Age, years	38.4 ± 7.4	37.1 ± 9.5	0.348
Female sex (n, %)	46 (57%)	53 (66%)	0.255
Working status
Employed (n, %)	39 (49%)	40 (50%)	0.874
Marital status
Single/divorced (n, %)	18 (22%)	22 (27%)	0.465
Educational degree
Middle school (n, %)	27 (34%)	26 (32%)	0.983
High school (n, %)	23 (29%)	23 (29%)
University or higher (n, %)	30 (37%)	31 (39%)
Financial status
Low income (n, %)	15 (19%)	13 (16%)	0.876
Middle income (n, %)	45 (56%)	48 (60%)
High income (n, %)	20 (25%)	19 (24%)
Smoker (n, %)	26 (32%)	33 (41%)	0.281
Body mass index	22.0 ± 1.6	22.6 ± 2.1	0.68

Table 2.

Biochemical and hematological findings of participants

Parameter	PTSD group (n = 80)	Control group (n = 80)	p value
Hb (g/L)	15.1 ± 1.4	14.8 ± 1.2	0.27
Neu (109/L)	4.6 ± 1.4	4.0 ± 0.9	0.003
Lym (109/L)	3.1 ± 0.9	3.2 ± 0.8	0.182
Plt (109/L)	304.1 ± 94.5	257.7 ± 56.9	0.001
NLR	1.5 ± 0.6	1.3 ± 0.5	0.002
PLR	106.7 ± 47.9	85.4 ± 41.2	0.003
SII (109/L)	476.6 ± 224.8	341.6 ± 195.1	0.001
Bun (mg/dl)	17.4 ± 5.0	16.4 ± 5.1	0.240
Creatinine (mg/dl)	1.2 ± 0.3	1.3 ± 0.3	0.884
AST (mg/dl)	20.9 ± 5.7	21.4 ± 5.9	0.598
ALT (mg/dl)	25.1 ± 9.1	25.7 ± 9.3	0.664

AST: aspartate transaminase, ALT: alanine transaminase, BUN: blood urea nitrogen, hb: hemoglobin, lym: lymphocyte, neu: neutrophil, NLR: neutrophil to lymphocyte ratio, PLR: plt: platelet to lymphocyte ratio, SII: Systemic immune-inflammation index; a p value <0,05 is accepted statistically significant

In terms of depressive symptoms, PTSD group showed signs of mild (n = 47, 58%) and moderate (n = 33, 42%) depressive disorder according to SCID-1. There wasn’t any patient with suicidal thoughts. When PTSD patients were divided into two (mild and moderate) according to depressive symptom severity, NLR (1.5 ± 0.6 vs. 1.6 ± 0.5, p = 0.717) PLR (108.0 ± 55.4 vs. 104.8 ± 35.2, p = 0.774) and SII (458.0 ± 255.2 vs. 503.1 ± 225.0, p = 0.381) values were comparable.

Discussion

In our study, we found that NLR, PLR and SII values, which are easily calculable and cost-effective markers of systemic low-grade inflammation, were significantly higher in PTSD patients than in the control group. We are the first to show that these predictors, which have been shown to increase in relation to systemic inflammation in many different diseases in the literature, show a significant increase in PTSD patients.

The question of how behaviors and emotions can affect immune function is an important research topic in animal and human research. Although Solomon first introduced the term psychoimmunology in 1964, it is noteworthy that there were very few human studies in this field until 1980s [23]. Psychoimmunology, as an important interdisciplinary field whose research has been focused on for the past forty years, generally examines the interaction of the nervous system with the immune system and how mental processes modulate the function of the immune system [24]. It is thought that the origins of psychoimmunology, which has an ever-expanding literature with the contributions of disciplines such as psychiatry, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, endocrinology and psychology, date back to the work of psychologist Robert Ader and immunologist Nicholas Cohen [25]. In their classical conditioning experiment on mice, Ader and Cohen presented sugar water as a conditioned stimulus along with the administration of cyclophosphamide, an immunosuppressive drug. Observation of a significant immune suppression compared to the control group when sugar water was presented alone in conditioned mice was considered one of the first evidence that the central nervous system is related to the immune system [26].

The immune system is a large and complex mechanism that works with both naturally and acquired activated cellular response and antibody cycles [27]. Main diseases that concern this system are autoimmune diseases, allergies, immune deficiencies and cancers. Pathologies involving the immune system are not limited to this, and in fact, an immune response occurs in many events that occur in the body. An immune response that can occur due to physical, biological, chemical or psychological effects is called inflammation [28].

The chemical mediators responsible for the immune response, cytokines are soluble bioactive mediators that enable communication between cells in the body, mainly between immune system cells. Since it is known that cytokine activity is closely related to behavioral changes such as psychomotor retardation, eating, sleep disorders and changes in the metabolism of monoamines such as serotonin, dopamine and norepinephrine, which are thought to play a role in the etiology of psychopathologies, examining the relationship between cytokines and common psychiatric disorders will be useful in increasing the knowledge about these disorders [29].

Cytokines, which are mostly mediators of immune activation or cell differentiation/death, are generally divided into pro-inflammatory and anti-inflammatory [27]. While the brain and other central nervous system organs are mostly unaffected by the peripheral immune response thanks to the blood-brain barrier, the occurrence of inflammation in the central nervous system is called neuroinflammation [30]. It is known that neuroinflammatory processes play a role in the etiology of many neurological diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and AIDS-related dementia [31–34]. It is also known that inflammation-related diseases play an important role in deaths all over the world [35]. Therefore, examining diseases and disorders that may be related to the immune system is important in reducing the morbidity and mortality that may arise due to them.

Studies investigating oxidative stress and inflammation in the pathogenesis of PTSD initially looked at blood antioxidant enzyme concentrations and oxidation-related gene expressions between those with and without PTSD [36]. Emerging evidence indicated the presence of increased biological oxidative stress and increased inflammation. This process has been associated with aging at the cellular level and pathological neuroprogression in neural pathways similar to chronic mental diseases [37–40]. Subsequent genetic association and DNA methylation studies and studies with blood biomarkers were found to be associated with the role of inflammatory processes in the pathogenesis of PTSD. More than twenty studies have shown elevated levels of peripheral Interleukin-6 (IL-6), Interleukin-1 beta (IL-1B), Tumor Necrosis Factor alpha (TNF-alpha) and interferon 8 in blood plasma and serum [41]. Inflammation-gene related studies on the etiology of PTSD have identified a relationship between 83 candidate genes and TNF-alpha and IL-1B genes, which indicate inflammation. These studies pointed out methylation and/or expression processes occurring in DNA [42–44].

One possible mechanism explaining the relationship between oxidation and inflammation in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is activated in trauma exposure. This activation is held responsible for stress-related primary damage to the brain. In particular, the glucocorticoid-hippocampal atrophy model assumes a neurotoxic effect of stress-triggered glucocorticoids on the brain. This effect is more evident in the hippocampus and prefrontal cortex of the brain, which are rich in glucocorticoid receptors [45]. The HPA axis interacts with immune system [46, 47]. Glucocorticoids indirectly limit inflammatory processes by inhibiting their synthesis and prevent the release of pro-inflammatory cytokines. However, in toxic situations high levels of glucocorticoids cause the expression of proinflammatory cytokines [48]. Moreover, the release of cytokines from microglia cells stimulates neural apoptosis, which has been associated with neuroprogression in PTSD [49]. One of the biomarkers that has been extensively and widely studied to indicate systemic inflammation in PTSD is C-reactive protein (CRP). C-reactive protein is found in blood and serum and is a protein released from cells that triggers inflammation. C-reactive protein is also one of the most sensitive markers among inflammatory reactants, and a positive correlation was detected in blood and serum CRP levels in studies conducted in PTSD patients [5, 50].

Although the presence of increased inflammation in PTSD patients has also been shown through cytokines [51], inflammatory variables such as NLR have never been studied before. Our study shows that NLR, an inflammation marker, is higher in PTSD patients than in the control group. White blood cell count is an inexpensive and widely used inflammatory marker. Neutrophils are the most abundant type of white blood cells and cause inflammatory cytokine secretion, since they are the first cells to respond to inflammation, especially those caused by bacterial infection, cancer, and environmental exposure. Inflammation triggered by these molecules creates oxidative stress due to cell dysfunction in various organs and is associated with increased cytosine production [52]. Neutrophil-lymphocyte ratio is a simple, reproducible and inexpensive marker of peripheral inflammation obtained by dividing the number of neutrophils by the number of lymphocytes, which indicates chronic low-grade inflammation and systemic inflammatory response, is used as an indicator of the clinical course in neuroimmune disorders. This new parameter gives us information not only about systemic inflammation but also about the patient’s stress response. While high neutrophil counts reflect inflammation, low lymphocyte counts indicate poor general health and physiological stress [53]. It is thought to be much more informative than other leukocyte parameters and frequently used markers such as IL-6, TNF-alpha and CRP [54, 55]. In addition to physical diseases [56, 57], NLR has also been investigated in psychiatric diseases such as schizophrenia, bipolar disorder and depression [58, 59]. In a study conducted with patients with resistant major depression, high levels of inflammatory and proinflammatory markers were found [60]. It was observed that stress and depression increased leukocyte and neutrophil levels while decreasing lymphocytes [61], and proinflammatory cytokine levels improved after antidepressant treatment [62] Considering all these, NLR in PTSD may be an effective and inexpensive biomarker to identify patients who may benefit from adjunctive anti-inflammatory pharmacological treatment.

In our study, the platelet-lymphocyte ratio was found to be significantly higher in the PTSD group compared to the control group. The platelet-lymphocyte ratio, obtained by dividing the platelet count by the absolute lymphocyte count, is a cost-effective and easily obtained clinical marker of peripheral inflammation [63]. Recent studies in other fields have reported that PLR is better than NLR in determining the severity of inflammation [64, 65]. Since the central nervous system is difficult to access, peripheral platelet models are widely used as indicators of 5-hydroxytryptamine metabolism and are known to reflect central serotonergic function. Therefore, platelets have been widely used in psychiatry as a peripheral model of the serotonergic system [66]. Serotonin, a neurotransmitter in the central nervous system, is an important factor in the pathophysiology of anxiety disorders, as well as playing an important role in regulating vascular tone and platelet aggression in the vascular system [67]. Platelet activation, in which serotonin and epinephrine are stimulated, is commonly seen in depression [68]. It is thought that serotonin plays a role in the pathophysiology of depression and psychiatric disorders, and accordingly, platelets also play an active role in psychiatric disorders [69]. For example, in one study, it was found that blood platelet aggregation stimulated by adenosine diphosphate in schizophrenia patients was higher than in healthy controls [70]. It has been suggested that increased platelet aggregation in patients with schizophrenia may lead to increased cardiovascular risk [71]. In a study conducted in 2015 involving 61 euthymic bipolar patients and 55 euthymic bipolar patients, NLR and PLR rates in both manic and euthymic patients were found to be significantly higher than in the control group. These findings indicate that inflammatory cells are responsible for bipolar disorder in both manic and euthymic patients, suggested that it plays a role in the pathophysiology of periods [72].

Systemic immune inflammation index shows the immunothrombosis and inflammatory status of patients with systemic immune inflammation, a new parameter calculated through inflammation markers. It is a comprehensive value based on peripheral lymphocyte, neutrophil and platelet counts. It is calculated as follows: SII = Platelet count x Neutrophil count / lymphocyte count [17]. SII has been used as a marker of subclinical inflammation and prognosis in various studies [18]. In our study, SII values of PTSD patients were found to be significantly higher than the control group. There are handful publications on SII and psychiatric diseases in the literature. In 2021, Wang et al. showed that SII was found to be high in male diabetic patients with unipolar depression [73]. In the study conducted by Zhou et al. in 2020, it was observed that major depressive disorder patients had higher SII values than the healthy control group [74]. In a study conducted on patients who had Covid-19 infection and survived, they found SII between admission and discharge. It was found that the decrease in depression was successful in predicting the depression emission of patients [75]. In the study conducted by Dionisie et al. in 2021, when they looked at SII in patients with bipolar disorder and major depressive disorder, it was shown that patients with bipolar depression and manic attack had higher SII values than those with major depressive disorder [76]. In the most recent study conducted during the writing phase of our study on this index, Wei and his colleagues examined patients with bipolar depression, manic attack and depressive episode and major depressive disorder and concluded that SII was significantly higher in bipolar depression manic attack compared to other groups [77]. In the literature, no publications examining SII in PTSD patients have been found. Considered from this perspective, our study is the first.

The idea that inflammation can be suppressed through psychological interventions via the central nervous system appears to have emerged relatively recently in the literature. Studies on this subject emphasize the mutual interaction between the central nervous system and the immune system. By better understanding the interaction between systems, it will be possible to develop or regulate treatment approaches for these disorders [78]. Post-traumatic stress disorder appears to be associated with a number of immunological changes. However, it is thought that therapeutic approaches for PTSD will help suppress inflammation. It is thought that elucidating the mutual relationship between psychiatric symptomatology and the immune system may pave the way for the reorganization of treatment modalities. In addition, it can be predicted that blood inflammatory biomarkers may be a new criterion candidate in evaluating the effectiveness of psychotherapy approaches, and pharmacotherapies may be selected based on their immunomodulation properties. In this aspect, the fact that central nervous system drugs suppress neuroinflammation, in addition to their primary mechanism of action, seems to be an important advantage for the success of pharmacotherapies.

In terms of psychotherapies, as stated by Lopresti [79], although individual behavioral therapy has anti-inflammatory effects, it would also be useful to examine whether changes in immunological parameters are specific to use of particular therapy approach.

Limitations

Our study has limitations. First of all, it is a single-center study and study population is limited to center volume whether it is a large center or not. Secondly, we only evaluated routine blood samples’ results due to ethical board restrictions and did not obtain extra examination which are beyond routine outpatient clinic assessment protocol of our hospital. So, further parameters like CRP or high-sensitive CRP and further parameters like interleukins. However, relationship between interleukins and cytokines and NLR, PLR and SII are very well studied and these are validated markers of systemic inflammation. Third, inflammation parameters may slightly differ due to gender and age. However, we suggest that it is a minor issue and would not affect our research’s inference because subject enrollment was well balanced in terms of gender. Moreover, study population consists of rather young and middle-aged individuals. Symptoms may also play a role in inflammation process. Our study population showed mild and moderate depressive symptoms. On the other hand, there wasn’t any patient with suicidal thoughts and anxiety disorder was already an exclusion criterion. This led to a relatively homogenous population with limited symptom variation. However, authors suggest that this situation spared our results from possible negative effect (which may be facilitated by suicidal thoughts and/or anxiety symptoms) on hematological parameters. Fourth and last, one of our study’s limitations is not having an interventional arm. Our study was planned to carry out an observational and cross-sectional method, that’s why we could not intervene patients’ current pharmacological treatment or try experimental pharmacological approach on them. Furthermore, our hypothesis was the presence of low-grade chronic inflammation in PTSD patients not evaluating the effect of anti-inflammatory treatment in these PTSD group. In order to verify if there is a positive effect of anti-inflammatory treatment, studies concerning anti-inflammatory drug intervention and its effect on patients’ long-term survey are needed.

Conclusion

When all findings are evaluated, NLR, PLR and SII; by revealing systemic inflammation for PTSD, they may be effective and inexpensive blood biomarkers to identify patients who may benefit from anti-inflammatory pharmacological treatment. As a result, since our study is single-center and the relatively small number of patients may affect the generalizability of the results, more definitive results can be achieved with prospective and multi-center planned studies in this field.

Abbreviations

CRP

C-reactive protein

DSM-5

Diagnostic and Statistical manual of Mental Diseases, Fifth Edition

HPA

Hypothalamic-pituitary-adrenal axis

IL-1B

Interleukin-1 beta

IL-6

Interleukin-6

NLR

Neutrophil-lymphocyte ratio

PLR

Platelet-lymphocyte ratio

PTSD

Post-traumatic stress disorder

SCID-1

Structured clinical study form for DSM-V Axis 1 disorders

SII

Systemic immune inflammation index

TNF-alpha

Tumor Necrosis Factor alpha

Author contributions

GY wrote main text, patient enrollment, data conceptualization, statistical analysis. EAM revised article text, English translation, prepared tables.

Funding

None.

Data availability

“The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.”

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the principles of the Declaration of Helsinki. All participants were expected to give signed informed consent. The local ethics committee approved the study protocol (Samsun Üniversitesi Klinik Araştırmalar Etik Kurulu, protocol code: SÜKAEK-2023 2/1).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.