Neutrophil–lymphocyte ratio in patients with major depressive disorder undergoing no pharmacological therapy
Open accessAbstract
Studies attempting to clarify the relationship between major depressive disorder (MDD) and the immune system have been increasing in recent years. It was reported that increased production of the main proinflammatory cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, and that of acute phase reactants may play a role in the etiopathogenesis of depression. Stress and depression were reported to increase leukocyte and neutrophil counts and to decrease lymphocyte count. Biological determinants affecting the diagnosis, therapy, and prognosis of depression are quite limited. Therefore, new etiological models are needed to explain the pathophysiology of depression. In recent years, neutrophil-lymphocyte ratio (NLR) was determined to be a good indicator of inflammatory status. There is no study in the literature investigating NLR in MDD. This study aims to examine the role of inflammation in the etiology of depression based on the NLR in MDD patients who are undergoing no pharmacological therapy. A total of 41 patients diagnosed with MDD, who received no antidepressant therapy within the past 1 month, were included in the study, which took place between January and March 2015. The control group consisted of 47 healthy subjects with no psychiatric disorders. A sociodemographic information form and a Beck Depression Scale were administered, and the blood was taken for biochemical analysis. Significant differences were identified in the NLR, neutrophil count, lymphocyte percentage, and leukocyte values of the patient group when compared with the control group (P<0.05). Our study is the first in which NLR was investigated in MDD. The findings of the study reveal that NLR tends to be higher in patients with MDD, and a high NLR value supports the view that inflammation is a critical factor in the etiology of MDD.
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The sample size was comparable with several prior studies in the field.
“In addition, our sample size was comparable with several prior studies in the field [47,48,50,56].”
From Immune Cell Ratios Are Higher in Bipolar Affective than Unipolar Depressive Disorder and Modulated by Mood Episode: A Retrospective, Cross-Sectional Study (2023) · cites this paper as [47]
NLR, PLR, and MLR were all found to be elevated in patients with depression.
“NLR, PLR, and MLR were all found to be elevated in patients with depression (37–41).”
From Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Depression: An Updated Systematic Review and Meta-Analysis (2022) · cites this paper as [38]
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“Suicide attempt is a preventable cause of death that is common in patients with major depression, it affects the entire population, is seen higher in women, and is among the first causes of death [10,11,12].”
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“In addition, multiple studies have shown the same association between increased NLR and depression (Demir et al., 2015; Aydin et al., 2016; Ekinci and Ekinci, 2017).”
BackgroundNold, V., Sweatman, C., Karabatsiakis, A., Böck, C., Bretschneider, T., Lawless, N., Fundel‐Clemens, K., Kolassa, I., & Allers, K. A. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.04.006 · Cited by 27 · see citing works
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Associations Between Subclinical Inflammatory Markers and OCD: A Retrospective Study
Herdi, O., Akaslan, D. S., İlhan, R. S., Çolak, B., & Duman, B. (2020) · Psychiatry Research · doi:10.1016/j.psychres.2020.113065 · Cited by 24 · see citing works
Hussain, S., Ronaldson, A., de la Torre, J. A., Sima, R., Hatch, S. L., Hotopf, M. H., & Dregan, A. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.08.003 · Cited by 24 · see citing works
Bachiller, S., Hidalgo, I., García, M. G., Boza-Serrano, A., Paulus, A., Denis, Q., Haikal, C., Manouchehrian, O., Klementieva, O., Li, J.-Y., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02515-w · Cited by 25 · see citing works
“In addition, higher levels of neutrophils and leukocytes have been found in MDD [57], highlighting the importance of peripheral inflammation in mood disorders.”
BackgroundInfluentialWang, Q., Yu, C.-Y., Shi, S., Su, X., Zhang, J., Ding, Y., Sun, Y., Liu, M., Li, C., Zhao, X., et al. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.11.069 · Cited by 24 · see citing works
Simple peripheral markers for inflammation in adolescents with major depressive disorder
Uçar, H. N., Eray, Ş., & Murat, D. (2018) · Psychiatry and Clinical Psychopharmacology · doi:10.1080/24750573.2018.1423769 · Cited by 23 · see citing works
“On the other hand, studies which were conducted with the adult depression patients have stated a significant increase in inflammation markers in MDD [38,64].”
BackgroundMethodResultInfluentialCoulibaly, A. P. (2022) · Immunological Reviews · doi:10.1111/imr.13123 · Cited by 22 · see citing works
Kwatra, M., Ahmed, S., Gangipangi, V. K., Panda, S. R., Gupta, N., Shantanu, P. A., Gawali, B., & Naidu, V. G. M. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.10.021 · Cited by 22 · see citing works
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Lymphopenia as a Potential Predictor of Ipsilateral Breast Tumor Recurrence in Early Breast Cancer
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“…with previous studies, patients with very low (<4 · 10 9 /L) or high WBC (>12 · 10 9 /L) at baseline, suggestive for somatic illness, or obesity (BMI >30) were excluded (Velasco et al., 2020; Kayhan et al., 2017; Demircan et al., 2016; Cai et al., 2017; Demir et al., 2015; Hotamisligil, 2006).”
Post stroke depression: pathogenesis and molecular mechanisms of natural product-based interventions
Gao, H., Sai, Y., Shang, R., Zhong, X., Kong, L., Liu, J., & Wang, K. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1595160 · Cited by 19 · see citing works
Ghafori, S. S., Yousefi, Z., Bakhtiari, E., hasani, M. H. M. M., & Hassanzadeh, G. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100734 · Cited by 23 · see citing works
Capuzzi, E., Caldiroli, A., Capellazzi, M., Tagliabue, I., Auxilia, A. M., Ghilardi, G. I., Buoli, M., & Clerici, M. (2020) · CNS Spectrums · doi:10.1017/s1092852920002199 · Cited by 18 · see citing works
“One study reported statistically significant differences in NLR between men and women(52) and another article found that the NLR is normalized by the antidepressant treatment in subjects affected by MDD.(53) Finally, smoking seems to affect NLR values(54) and a recent study, conducted on patients undergoing coronary i…”
ResultLeśniak, A., Poznański, P., Religa, P., Nawrocka, A., Bujalska‐Zadrożny, M., & Sacharczuk, M. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.01.013 · Cited by 18 · see citing works
İlk atak psikoz hastalarında nötrofil lenfosit oranının değerlendirilmesi
Varsak, N., Aydın, M., & Eren, İ. (2016) · Family practice and palliative care · doi:10.22391/920.287411 · Cited by 18 · see citing works
Xia, J., Chen, M., Shao, H., Chen, H., Zhu, S., Zhao, M., Luo, W., Yang, J., & Wu, S. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2812356 · Cited by 17 · see citing works
The bidirectional relationship of depression and disturbances in B cell homeostasis: Double trouble
Wu, S., Yin, Y., & Du, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.110993 · Cited by 17 · see citing works
Serum levels of peptide cathelicidin LL-37 in elderly patients with depression
Kozłowska, E., Wysokiński, A., & Brzezińska‐Błaszczyk, E. (2017) · Psychiatry Research · doi:10.1016/j.psychres.2017.05.036 · Cited by 17 · see citing works
Masih, J., & Verbeke, W. J. M. I. (2018) · Journal of Depression & Anxiety · doi:10.4172/2167-1044.1000325 · Cited by 17 · see citing works
“First, in the case of people with acute depression, innate immune system cells – basophilic, eosinophil and neutrophil granulocytes – exhibit increased cell counts compared to non-depressed people [3,25].”
BackgroundMethodResultInfluentialThe lipid paradox in neuroprogressive disorders: Causes and consequences
Morris, G., Berk, M., Walder, K., O’Neil, A., Maes, M., & Puri, B. K. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.017 · Cited by 17 · see citing works
Moshfeghinia, R., Kavari, K., Mostafavi, S., Sanaei, E., Farjadian, S., & Javanbakht, A. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.05.031 · Cited by 16 · see citing works
Aziz, N. U. A., Chiroma, S. M., Moklas, M. A. M., Adenan, M. I., Ismail, A., Basir, R., Ali, R. M., & Baharuldin, M. T. H. (2021) · Journal of Traditional and Complementary Medicine · doi:10.1016/j.jtcme.2021.02.007 · Cited by 16 · see citing works
Wang, K., Ding, L., Yang, C., Hao, X., & Wang, C. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.608630 · Cited by 16 · see citing works
Li, X., Cai, Q., Jia, Z., Zhou, Y., Liu, L., Zhou, Y., Zhang, B., Ren, L., & Tang, Y. (2021) · Medicine · doi:10.1097/md.0000000000026520 · Cited by 16 · see citing works
“In that case, emotional disorders may worsen the COVID-19 patient’s state, aggravate the inflammatory response, and have a negative impact on the clinical prognosis.([38,45,46]) Therefore, special attention should be given to patients diagnosed with high SDS scores and/or SAS score accompanied by increased neutrophils…”
BackgroundMcFarland, D., Applebaum, A., Bengtsen, E., Alici, Y., Breitbart, W., Miller, A. H., & Nelson, C. (2021) · Psycho-Oncology · doi:10.1002/pon.5811 · Cited by 14 · see citing works
“Similarly, the neutrophil‐ lymphocyte ratio (NLR) obtained from the white blood cell differential on a complete blood count (CBC) measure has also been associated with both inflammation and depression in cancer and other clinical settings.(23,24) We previously studied biomarker changes in patients with metastatic lung…”
BackgroundShan, M., Lü, S., Cui, R., Yang, Y., Sun, Z., & Pan, Y. (2022) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2022.111041 · Cited by 15 · see citing works
Liu, Y., Li, C., Ren, H., Han, K., Wang, X., Zang, S., & Zhao, G. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.06.013 · Cited by 15 · see citing works
Szałach, Ł. P., Cubała, W. J., & Lisowska, K. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010479 · Cited by 14 · see citing works
“A few studies demonstrated that patients suffering from depression have a reduced percentage of blood lymphocytes [8,9] but a high concentration of serum IL-2, a cytokine essential for T-cell differentiation into effector cells [6,7,10].”
BackgroundSengupta, A., Das, U. B., Manna, K., Biswas, S., Datta, S., Khan, A., Bhattacharya, T., Saha, S., Mitra, T., Mukherjee, S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-49728-3 · Cited by 14 · see citing works
Child and Adolescent Psychiatry, U. O. H. S., Önen, Ö., Erkuran, H. Ö., Child and Adolescent Psychiatry, U. O. H. S., Bağ, Ö., Department of Social Pediatrics, U. O. H. S., Abacıgil, F., & Department of Public Health, A. A. M. U. F. O. M. (2021) · Psychiatry and Clinical Psychopharmacology · doi:10.5152/pcp.2021.21137 · Cited by 13 · see citing works
“Besides, it was stated that the white blood cell and neutrophil count increased and lymphocyte levels decreased, 17 and RDW levels were found to be significantly higher than the control group.”
BackgroundDoes Inflammation Play a Role in the Pathophysiology of Tinnitus?
Demir, M. E. (2021) · Nigerian Journal of Clinical Practice · doi:10.4103/njcp.njcp_381_19 · Cited by 13 · see citing works
Zhang, Y. P., Mei, H., Xiao, H., Zhang, Y., Gao, W., Qi, H., & Zhang, J. (2022) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2022.111101 · Cited by 13 · see citing works
Gorbunova, A. P., Rukavishnikov, G. V., Kasyanov, E. D., & Mazo, G. E. (2024) · V M BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY · doi:10.31363/2313-7053-2024-794 · Cited by 15 · see citing works
Department of Psychiatry, D. U. M. F., Uyar, B., Budak, E. A., & Department of Psychiatry, D. U. M. F. (2022) · PSYCHIATRIA DANUBINA · doi:10.24869/psyd.2022.687 · Cited by 12 · see citing works
Wang, J., Zhou, D., & Li, X. (2020) · BioMed Research International · doi:10.1155/2020/8297628 · Cited by 12 · see citing works
“reported that NLR was greater in 41 patients with depression than in a control group [28].”
BackgroundPDW and RDW are new parameters for bipolar episodes and unipolar depression
Gündoğmuş, İ., Algül, A., Karagöz, A., & Kıyançiçek, M. (2018) · Psychiatry and Clinical Psychopharmacology · doi:10.1080/24750573.2018.1468616 · Cited by 12 · see citing works
“trol groups were not statistically significant [5,8,20,22,23].”
Karatoprak, S., Uzun, N., Akıncı, M. A., & Dönmez, Y. E. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.4.669 · Cited by 12 · see citing works
“However, no potential predictive effects of the duration of SUD or the presence of the comorbid conditions CD, MDD, and ADHD on log-transformed NLR (p = 0.726, p = 0.513, p = 0.584, p = 0.394, respectively) or log-transformed PLR (p = 0.832, p = 0.210, p = 0.346, p = 0.359, respectively) were detected in the regressio…”
BackgroundInfluentialDifferential blood leukocyte populations based on individual variances and age
Kasten‐Jolly, J., & Lawrence, D. A. (2022) · Immunologic Research · doi:10.1007/s12026-021-09257-6 · Cited by 11 · see citing works
“Interestingly, patients with psychiatric disorders, such as depression, have also been found to have elevated NLRs [37, 38].”
BackgroundBlood cell ratios in mood and cognitive outcomes following electroconvulsive therapy
Ryan, K. M., Lynch, M., & McLoughlin, D. M. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.11.016 · Cited by 11 · see citing works
Xue, L., Lewis, E. T., Bocharova, M., Young, A. H., & Aarsland, D. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.01.029 · Cited by 12 · see citing works
Yoshida, Y., Iwasa, H., Kim, H., & Suzuki, T. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19158996 · Cited by 11 · see citing works
“Previous studies have shown that a high NLR is significantly associated with geriatric depression in women [28] and that it tends to be higher in patients with major depressive diseases [29].”
ResultKoureta, A., Asimakopoulos, L. O., Bozikas, V. P., & Agorastos, A. (2023) · Brain Sciences · doi:10.3390/brainsci13030448 · Cited by 12 · see citing works
“first investigated NLR in MDD and BD respectively, and both reported higher levels of NLR in MDD and BD patients compared to healthy controls [47,48].”
ResultInflammatory burden index is correlated with increased depression: a population-based study
Shao, X., Xie, Z., & Zhu, L. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-06730-6 · Cited by 10 · see citing works
“For instance, Demircan and Demir reported elevated NLR levels in patients with depression in two relatively small Turkish cohorts [28, 29].”
Efficacy of light therapy on non-seasonal depression and inflammatory markers
Demirkol, M. E., Namlı, Z., & Tamam, L. (2019) · The European Journal of Psychiatry · doi:10.1016/j.ejpsy.2019.03.002 · Cited by 10 · see citing works
Tang, M., Chang, X., Zheng, H., Zeng, F., Zhang, G., He, M., Fang, Q., & Yin, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1472616 · Cited by 9 · see citing works
Kahve, A. C., Kaya, H., Okuyucu, M., Göka, E., Barun, S., & Hacımusalar, Y. (2021) · Psychiatry Investigation · doi:10.30773/pi.2021.0029 · Cited by 9 · see citing works
Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited
Lang, U. E., & Walter, M. (2017) · Neurosignals · doi:10.1159/000482001 · Cited by 9 · see citing works
Chan, J. Z., Fernandes, M. F., Steckel, K. E., Bradley, R. M., Hashemi, A., Groh, M. R., Sciaini, G., Stark, K. D., & Duncan, R. E. (2022) · Scientific Reports · doi:10.1038/s41598-022-13463-z · Cited by 9 · see citing works
- Authors
- Atli, A., Demir, S., Bulut, M., Okan İbiloğlu, A., Güneş, M., Kaya, M., Demirpençe, Ö., & Sır, A.
- Affiliations
- Dicle University (TR)
- Sivas Cumhuriyet Üniversitesi (TR)
- Venue
- Neuropsychiatric Disease and Treatment
- Publisher
- Informa UK Limited
- Published
- 2015-08
- Volume
- 11
- Pages
- 2253
- ISSN
- 1176-6328 (ISSN-L)
- 1178-2021
- PMC
- PMC4556257
- OpenAlex
- W1904139310
- Cited by
- 156
- References
- 45
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 13 · 2023: 13 · 2022: 30 · 2021: 24 · 2020: 13 · 2019: 16 · 2018: 15 · 2017: 8 · 2016: 5 · 2015: 1
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neuropsychiatric Disease and Treatment (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, neutrophil-to-lymphocyte ratio, inflammation, inflammatory markers, white blood cell count, lymphocyte count, inflammatory cytokines, etiology of depression, non-pharmacological treatment
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