Skip to main content
Download PDF

Systemic inflammatory biomarkers in Schizophrenia are changed by ECT administration and related to the treatment efficacy

BMC Psychiatry volume 24, Article number: 53 (2024) Cite this article

Abstract

Immune inflammation has long been implicated in the pathogenesis of schizophrenia. Despite as a rapid and effective physical therapy, the role of immune inflammation in electroconvulsive therapy (ECT) for schizophrenia remains elusive. The neutrophils to lymphocytes (NLR), platelets to monocytes (PLR) and monocytes to lymphocytes (MLR) are inexpensive and accessible biomarkers of systemic inflammation. In this study, 70 schizophrenia patients and 70 age- and sex-matched healthy controls were recruited. The systemic inflammatory biomarkers were measured before and after ECT. Our results indicated schizophrenia had significantly higher peripheral NLR, PLR and MLR compared to health controls at baseline, while lymphocytes did not differ. After 6 ECT, the psychiatric symptoms were significantly improved, as demonstrated by the Positive and Negative Syndrome Scale (PANSS). However, there was a decline in cognitive function scores, as indicated by the Mini-Mental State Examination (MMSE). Notably, the neutrophils and NLR were significantly reduced following ECT. Although lymphocytes remained unchanged following ECT, responders had significantly higher lymphocytes compared to non-responders. Moreover, the linear regression analyses revealed that higher lymphocytes served as a predictor of larger improvement in positive symptom following ECT. Overall, our findings further highlighted the presence of systemic inflammation in schizophrenia patients, and that ECT may exert a therapeutic effect in part by attenuating systemic inflammation. Further research may therefore lead to new treatment strategies for schizophrenia targeting the immune system.

Peer Review reports

Introduction

Schizophrenia is a devastating psychiatric disorder that has a detrimental impact on a considerable population worldwide, severely limiting psychosocial functioning and imposing a significant burden on society [1]. Epidemiological studies have frequently linked maternal infections to the development of schizophrenia in offspring [2]. Moreover, environmental factors such as autoimmune diseases, and acute stress could increase maternal immune responses, leading to an elevated risk of schizophrenia [3]. Notably, growing evidence suggests that dysregulation in innate and adaptive branches of the immune system plays a role in schizophrenia [4].

Neutrophils are the first line of defense against infection and can induce inflammation and oxidative stress. A recent study reported that neutrophils were positively correlated with the severity of psychiatric symptoms and the reduced brain grey matter volume in first-episode schizophrenia [5]. However, lymphocytes play an important role in adaptive immunity, with both regulatory and protective functions and low levels reflecting poor health conditions [6]. Since the blood-brain barrier (BBB) may be impaired under certain pathological conditions, especially in schizophrenia [7, 8], allowing for the entry of peripheral cells into the brain [9]. Actually, evidence has suggested neutrophils may exert a destructive effect on the cerebral tissue after infiltrating the brain [10, 11]. Notably, the infiltration of monocytes into the brain may lead to neuronal damage in mice [12]. Conversely, most studies showed that lymphocytes appear to have a protective effect on the brain [10], and the lack of lymphocytes led to an aggravation of symptoms in animal models of Alzheimer’s disease [13]. The neutrophil-to-lymphocyte ratio (NLR) is the ratio of neutrophils active in the innate immune response to lymphocytes active in the adaptive immune response [14, 15], which is a well-established marker of immune system homeostasis. NLR was originally developed to reflect systemic inflammation in critically ill patients, and was reported to have prognostic value in a range of diseases, including diabetes [16], cancer [17], etc. The platelet-to-lymphocyte ratio (PLR) is an indicator derived from platelet aggregation and systemic inflammation [18], while the monocyte-to-lymphocyte ratio (MLR) serves as a potential peripheral marker of microglia activation in the brain, as monocytes could be recruited to the brain under inflammatory conditions where they interact with or differentiate into microglia [19]. Collectively, the three ratios are important biomarkers of systemic inflammation that can be calculated directly from a complete blood count test, which has been demonstrated to play a role in various neuropsychiatric disorders, including depression, autism and other diseases [20,21,22,23]. Most importantly, recent research indicated schizophrenia patients had significantly higher NLR, PLR and MLR compared to healthy controls [24,25,26,27].

Electroconvulsive therapy (ECT) is a fast-acting physical therapy for schizophrenia [28]. Evidence has suggested ECT combined with clozapine was more effective than antipsychotics [29]. Moreover, a recent study indicated schizophrenia patients treated with ECT showed lower readmissions [30]. Although studies suggested that ECT may cause cognitive impairment, recent research showed that the effects of ECT on cognitive function are mildly tolerable, transient and reversible [31, 32]. Notably, some studies even showed improved results [31, 32]. Despite being a fast and effective form of physical therapy for schizophrenia [33], the mechanisms of ECT are rarely explored. Given the possible immunomodulatory effects of ECT [34], observing the cost-effective and readily available systemic inflammatory biomarkers following ECT can help explore the role of inflammation in ECT for schizophrenia. In the present study, we compared the systemic inflammatory biomarkers between schizophrenia patients and healthy controls, and aimed to investigate changes in systemic inflammatory biomarkers following ECT and its relationship with clinical efficacy.

Materials and methods

Participants

Schizophrenia patients were recruited from Xuzhou Oriental People’s Hospital. Inclusion criteria were as follows: (1) age between18-65 years; (2) diagnosis of schizophrenia according to ICD-10 diagnostic criteria; (3) Indication for ECT under the assessment of experienced clinicians and anesthesiologists, including schizophrenia of intense psychomotor agitation or retardation, suicide attempts, pronounced aggressive behavior, intolerance to pharmacotherapy, and lack of response to previous antipsychotic treatment at adequate doses and durations. The exclusion criteria were (1) history of ECT within 6 months; (2) brain disease such as Alzheimer’s Disease, Parkinson’s Disease, stroke et al.; immune disease such as SLE (systemic Lupus Erythematosus), asthma, systemic Sclerosis et al.; (3) recent (three months) infection, fever, or using anti-inflammatory drugs; (4) lactating and premenopausal women; and (5) use of alcohol, narcotics and other psychoactive substances. The healthy controls were recruited from the physical examination center of Xuzhou Medical University Affiliated Hospital. They were matched with patients for age and sex and had no history of psychiatric disorders or inflammatory events recently (three months). All participants signed a written informed consent form, and the ethical approval was obtained Ethics Committee of Xuzhou Oriental People’s Hospital. During ECT, 5 patients dropped out from the study (3 patients were excluded due to fever and 2 patients were excluded due to controversial diagnosis). Therefore, a total of 140 participants (70 patients and 70 matched healthy controls) were included in the follow-up analyses.

ECT procedure

Patients received bilateral temporal ECT combined with antipsychotic medication (all patients had been on antipsychotic medication for a fortnight prior to ECT). ECT (Thymatron System IV Integrated ECT Instrument) was administered twice or three times a week. Methohexital (0.75 mg/kg-1.0 mg/kg) and succinylcholine (0.5 mg/kg–1.0 mg/kg) were used for anesthesia and muscle relaxation, respectively. During ECT, the type and dose of antipsychotic drugs kept constant and have been converted to chlorpromazine equivalents. The study focused on observing patients at two time points: pre-ECT, and after six ECT sessions (post-ECT). However, the study did not affect the treatment plan. Patients who did not meet the criteria for recovery after six ECT sessions continued to receive ECT and medication based on their individual conditions. During ECT, seven patients were treated with antidepressants for mild depressed mood (sertraline n = 3, 50 mg/day; paroxetine, n = 4, 20 mg/day); two patients with lithium carbonate (0. 3 g/day) for unstable mood; five patients with propranolol (10 mg/day) for rapid heart rate; three patients with benzodiazepines for anxiety (lorazepam n = 1, 1.5 mg/day; clonazepam n = 1, 2 mg/day; alprazolam n = 1, 0.2 mg/day), and 14 patients used non-benzodiazepine aids for sleep problems (zopiclone n = 14, 7.5 mg/day).

Clinical assessments

The PANSS was used to assess the severity of psychiatric symptoms during ECT. The reduction rate in the PANSS scores was calculated by the formula: (pre-PANSS– post-PANSS) / (pre-PANSS − 30) × 100%, where pre-PANSS is the score at baseline and post-PANSS is the score at follow-up. Patients were defined as responders when the reduction rate of the PANSS total score was more than 50% [35]. Moreover, the Mini-Mental State Examination (MMSE) was used to assess cognitive function during ECT.

Blood cell analysis

Fasting blood samples were collected 06:00–07:00 before the first ECT and 1 day following 6 ECT, and fasting control blood samples were taken 07:30–09:30 on assessment days. The samples were collected in an EDTA anticoagulation tube, and performed using the Sysmex XN-1000 fully automated hematology analyzer developed by Sysmex Japan. The test results included PLT (10^9/L), neutrophils (10^9/L), lymphocytes (10^9/L), monocytes (10^9/L), and three important ratios PLR, NLR and MLR.

Statistical analysis

Demographic and clinical data were managed and analyzed using IBM SPSS Statistics v.25 and GraphPad prism 9.0.0. Data was presented as mean (standard deviation, SD) or number (%) per group where appropriate. Chi-square tests were used to calculate group differences regarding smoking status and gender. Data were tested for normality using the Shapiro-Wilk or Kolmogorov-Smirnov test and Q-Q plots, which has shown most data were not normally distributed. Thus, logarithmic transformation was used to transform the blood test values (including PLT, neutrophils, lymphocytes, monocytes, and three important ratios PLR, NLR and MLR) to achieve normal distribution. Independent Samples t-test was used to compare differences in systemic inflammatory biomarkers between healthy controls and schizophrenia, and Paired Samples t-test was used to identify changes in systemic inflammatory biomarkers following ECT. Linear correlation analysis was employed to explore the associations between systemic inflammatory biomarkers and psychiatric symptoms, with age, gender, BMI, education, duration of illness, and chlorpromazine equivalent doses included as covariates. Response to ECT in terms of psychiatric symptom, positive symptom, negative symptom and cognitive function was measured as the variation of PANSS, P-PANSS, N-PANSS and MMSE from pre-ECT to post-ECT that we indicated as Δ PANSS, Δ P-PANSS, Δ N-PANSS and Δ MMSE. All statistical tests were two-tailed, with P < 0.05 being significant.

Results

Schizophrenia patients showed elevated systemic inflammatory biomarkers compared to health controls

Demographic and clinical characteristics were listed in Table 1. A total of 140 participants (70 schizophrenia patients and 70 health controls) were included in the study. The results showed significant differences in BMI and education (t=-2.01, P = 0.044; t=-3.16, P = 0.002, respectively), while no differences in age, gender distribution and smoking between the two group (all P > 0.05) (Table 1).

Table 1 Demographic and clinical characteristics between schizophrenia patients and healthy controls
Full size table

At baseline, schizophrenia showed significantly higher PLT (t=-2.781, P = 0.006), neutrophils (t=-6.639, P < 0.0001), monocytes (t=-7.613, P < 0.0001), NLR (t=-6.028, P < 0.0001), PLR (t=-2.434, P = 0.016) and MLR (t=-7.264, P < 0.0001) compared to health controls, while lymphocytes (t = 0.131, P = 0.896) did not differ (Fig. 1).

Fig. 1
figure 1

Differences in systemic inflammatory biomarkers in schizophrenia and controls and changes following ECT. Data was expressed as mean ± standard deviation (SD). a PLT was significantly elevated in schizophrenia compared to healthy controls (HCs) but remained stable following ECT. b Neutrophils was significantly elevated in schizophrenia and reduced following ECT. c Lymphocytes showed no differences between schizophrenia and HCs and kept stable following ECT. d Monocytes were significantly elevated in schizophrenia and decreased following ECT. e the neutrophil-to-lymphocyte ratio (NLR) was significantly higher in schizophrenia and reduced following ECT. f the PLT-to-lymphocyte ratio (PLR) was elevated in schizophrenia, while demonstrated no differences following ECT. g the monocytes- to-lymphocyte ratio (MLR) was higher in schizophrenia and significantly downregulated following ECT. *p < 0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001

Full size image

The elevated systemic inflammatory biomarkers were reduced following ECT in Schizophrenia patients

After ECT, the PANSS scores and its subscales (P-PANSS and N-PANSS) were significantly decreased, with a 61.76% reduction in total PANSS scores. In addition, the MMSE scores were significantly reduced following ECT.

Considering the systemic inflammatory biomarkers, the results indicated the neutrophils (t=-2.684, P = 0.009), monocytes (t=-2.102, P = 0.039), NLR (t=-2.57, P = 0.012) and MLR (t=-2.725, P = 0.008) were significantly reduced following 6 ECT sessions. However, PLT (t=-0.768, P = 0.445), lymphocytes (t = 1.066, P = 0.29) and PLR (t=-1.353, P = 0.181) remained unchanged following ECT (Supplementary Tables 1 and Fig. 1).

Higher lymphocytes levels were associated with better improvement in psychiatric symptoms following ECT

We subsequently used the reduction rate of PANSS to assess treatment responses to ECT, and patients with a PANSS reduction rate of ≥ 50% was defined as responders [35]. Overall, 52 of 70 schizophrenia patients were responders, while 18 patients were non-responders. Moreover, there were no differences in age, BMI, education, duration of illness and chlorpromazine equivalent doses between responders and non- responders (all P > 0.05).

Regarding systemic inflammation biomarkers, the results showed responders had significantly higher baseline lymphocytes (t=-2.808, P = 0.006) compared to non-responders, while other showed no differences between the two groups (Supplementary Table 2).

Since responders exhibited higher lymphocytes compared to non-responders. Subsequently, we applied linear regression to explore the association of lymphocytes and the improvement of psychiatric symptoms. The results indicated a significant association between lymphocytes and ΔP-PANSS (F = 2.797, p = 0.014), while lymphocytes showed no correlation with other scales (all p > 0.05). Notably, higher baseline lymphocytes levels were identified as a significant predictor of the decrease inΔP-PANSS following ECT (β = 23.032, p = 0.007). In addition, the results showed that chlorpromazine equivalent doses were negatively associated with ΔP-PANSS (β = -0.007, p = 0.030) (Table 2).

Table 2 Higher baseline lymphocytes were associated with larger improvement in ΔP-PANSS following ECT
Full size table

Discussions

To our knowledge, this is the first and most comprehensive report to date on the effects of ECT on systemic inflammatory biomarkers in schizophrenia. Schizophrenia patients showed significantly higher PLT, neutrophils, monocytes, and the three important ratios NLR, PLR and MLR compared to healthy controls. Notably, neutrophils, NLR were significantly reduced following ECT. Moreover, responders exhibited higher lymphocytes compared to non-responders, and the linear regression analyses reveled that higher lymphocyte levels were a predictor of better improvement of positive psychiatric symptom following ECT.

At baseline, schizophrenia patients showed significantly higher PLT, neutrophils, monocytes, NLR, PLR and MLR compared to healthy controls, replicating previously findings [36, 37]. The relationship between systemic inflammatory biomarkers and psychiatric symptoms remains elusive. While some studies reported a positive correlation between NLR and total PANSS scores, others reported NLR did not correlate with clinical symptoms [38, 39]. After 6 ECT, the neutrophils, monocytes, NLR and MLR were significantly reduced in patients with schizophrenia. Together with a significant reduction in pro-inflammatory factor TNF-α after 10 sessions of ECT suggests that ECT may work in part by reducing inflammation in the treatment of schizophrenia [40]. Few studies have examined the relationship between systemic inflammatory biomarkers and response to ECT in schizophrenia. Previous study found anti-inflammatory factor IL-4 was elevated after 9 ECT, and IL-4 was negatively correlated with BPRS, while NF-κB, a major pathway involved in the immune inflammation response, did not change following ECT [41]. However, previous studies suggested BBB may be disrupted in schizophrenia, thus allowing more circulating cytokines as well as leukocytes to infiltrate the brain [42]. In this case, the elevated peripheral inflammatory signals may be transmitted to the brain, these signals can activate microglia, the brain’s resident macrophages, ultimately leading to alterations in neuroplasticity and neurotransmitters [43], which is consistent with the elevated microglia activity observed in schizophrenia [44]. Notably, previous animal studies using ECS to mimic the function of ECT found that ECS had the ability to reduce the activity of microglia in both normal animal models [45, 46] and schizophrenia animal models [47]. The findings thus suggest ECT may treat schizophrenia in part by reducing inflammation.

Although previous studies suggested lymphocytes were significantly lower in schizophrenia patients [48, 49], lymphocytes did not differ in our study, which may be due to the fact that our patients had received at least 2 weeks of antipsychotic medication prior to inclusion in the study [37]. Furthermore, although lymphocytes did not change after ECT in our study, the results indicated responders had significantly higher lymphocytes compared to non-responders. Moreover, although not schizophrenia animal models, a recent study showed the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), was the only microglial transcript significantly reduced by electroconvulsive stimulation (ECS) [50]. Notably, previous study suggested a negative correlation between lymphocytes and PANSS [48], our findings indicated lymphocytes served as a predictor for greater improvement in positive symptom following ECT, which provided further evidence suggesting lymphocytes may be a protective factor for schizophrenia. Actually, a study showed active enhancer enrichment in CD19 and CD20 lymphocytes in 108 significant loci in schizophrenia [51]. The subsets of lymphocytes such as regulatory T cells (Tregs) and B cells (Bregs) could prevent chronic inflammation by suppressing immune responses, down-regulating production of leukocytes and pro-inflammatory cytokines, which may influence the development of schizophrenia though affecting brain development, immunity, etc [52]. Furthermore, previous studies showed schizophrenia had disrupted lymphocyte subsets [53], and a meta-analysis demonstrated first-episode schizophrenia had elevated CD4/CD8 and significantly lower CD3% [54]. Additionally, CD3 levels were significantly elevated following antipsychotic treatment, and the reduction in CD3 was consistent with reduced levels of the anti-inflammatory factor IL-2. In contrast, CD19 B lymphocytes were elevated in schizophrenia and reduced after treatment [55], suggesting different lymphocyte subsets may have different roles in schizophrenia, highlighting the importance to explore different lymphocyte subsets following ECT in schizophrenia patients.

The increased peripheral blood cytokines were associated with cognitive deficits and reduced brain volume in schizophrenia [56]. In this study, the MMSE scores were reduced after ECT. Actually, the activation of monocytes has been consistently reported in schizophrenia, and first-episode schizophrenia had higher MCP-1 (Monocyte chemoattractant protein-1) both in the cerebrospinal fluid and blood [57]. Moreover, a recent study demonstrated atypical monocyte genes were negative correlated with cortical thickness and cognitive function in healthy controls, however, the correlation was attenuated in schizophrenia [58], highlighting the importance to explore monocyte subsets in the deterioration of cognitive function after ECT. Moreover, since peripheral systemic inflammation can lead to microglia activation in the brain, in vivo assessment of microglia activity before and after ECT by 18-kDa translocator protein (TSPO) PET can help to further clarify whether ECT treats schizophrenia by reducing neuroinflammation [59, 60].

Several limitations of this current study should be mentioned here. Firstly, although the chlorpromazine equivalent has a minimal impact on the improvement of psychiatric symptom following ECT in our study (β=-0.007, p = 0.030), and the type and doses of antipsychotics kept stable during ECT, antipsychotics may affect systemic inflammatory biomarkers [25]. Thus, including a group of schizophrenia patients who only take antipsychotics could help determine whether the reduction in inflammation is due to ECT or simply a result of other treatment and environmental factors surrounding ECT. Secondly, a follow-up study is needed to further determine whether changes in systemic inflammatory biomarkers were due to disease status or the effects of ECT. Thirdly, we used MMSE to assess the cognitive function of schizophrenia, which is not as comprehensive as MCCB (MATRICS Consensus Cognitive Battery). Ultimately, future research considering the drug interference, combining clinical and animal studies, and utilizing more appropriate cognitive assessment tools, may provide a more adequate understanding of the role of inflammation in ECT for schizophrenia.

Conclusions

In conclusion, our findings further highlighted the role of inflammation in the pathogenesis of schizophrenia, as demonstrated by the elevated NLR in schizophrenia patients. Notably, NLR was significantly reduced following ECT, indicating that ECT may treat schizophrenia by reducing inflammation. Furthermore, lymphocytes may play a protective role, as they were significantly higher in responders, and served as a significant predictor for greater positive symptom improvement following ECT.

Data availability

All data generated or analyzed during this study were included in this published article.

References

  1. Weye N, Santomauro DF, Agerbo E, Christensen MK, Iburg KM, Momen NC, Mortensen PB, Pedersen CB, Whiteford HA, McGrath JJ, et al. Register-based metrics of years lived with disability associated with mental and substance use disorders: a register-based cohort study in Denmark. The Lancet Psychiatry. 2021;8(4):310–9.

    Article  PubMed  Google Scholar 

  2. Estes ML, McAllister AK. Maternal immune activation: implications for Neuropsychiatric Disorders. Science. 2016;353(6301):772–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Park GH, Noh H, Shao Z, Ni P, Qin Y, Liu D, Beaudreault CP, Park JS, Abani CP, Park JM, et al. Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia. Nat Neurosci. 2020;23(11):1352–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Szabo A, O’Connell KS, Ueland T, Sheikh MA, Agartz I, Andreou D, Aukrust P, Boye B, Boen E, Drange OK, et al. Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation. Brain Behav Immun. 2022;99:299–306.

    Article  CAS  PubMed  Google Scholar 

  5. Nunez C, Stephan-Otto C, Usall J, Bioque M, Lobo A, Gonzalez-Pinto A, Pina-Camacho L, Vieta E, Castro-Fornieles J, Rodriguez-Jimenez R, et al. Neutrophil Count is Associated with reduced Gray Matter and Enlarged ventricles in First-Episode Psychosis. Schizophr Bull. 2019;45(4):846–58.

    Article  PubMed  Google Scholar 

  6. Bhikram T, Sandor P. Neutrophil-lymphocyte ratios as inflammatory biomarkers in psychiatric patients. Brain Behav Immun. 2022;105:237–46.

    Article  CAS  PubMed  Google Scholar 

  7. Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull. 2013;39(6):1174–9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Jeppesen R, Orlovska-Waast S, Sorensen NV, Christensen RHB, Benros ME. Cerebrospinal fluid and blood biomarkers of Neuroinflammation and blood-brain barrier in psychotic disorders and individually matched healthy controls. Schizophr Bull 2022.

  9. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and Disease. Nat Neurosci. 2017;20(2):136–44.

    Article  CAS  PubMed  Google Scholar 

  10. Gadani SP, Walsh JT, Lukens JR, Kipnis J. Dealing with Danger in the CNS: the response of the Immune System to Injury. Neuron. 2015;87(1):47–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kenne E, Erlandsson A, Lindbom L, Hillered L, Clausen F. Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. J Neuroinflammation. 2012;9:17.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, Dingledine R. Infiltrating monocytes promote Brain Inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci USA. 2016;113(38):E5665–5674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, Fote GM, Lau L, Weinger JG, Lane TE, et al. The adaptive immune system restrains Alzheimer’s Disease pathogenesis by modulating microglial function. Proc Natl Acad Sci USA. 2016;113(9):E1316–1325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic Diseases in Asian population. Int Arch Med. 2012;5(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Buonacera A, Stancanelli B, Colaci M, Malatino L. Neutrophil to lymphocyte ratio: an emerging marker of the relationships between the Immune System and Diseases. Int J Mol Sci 2022, 23(7).

  16. Fang L, Wang Y, Zhang H, Jiang L, Jin X, Gu Y, Wu M, Pei S, Cao Y. The neutrophil-to-lymphocyte ratio is an important indicator correlated to early neurological deterioration in single subcortical infarct patients with Diabetes. Front Neurol. 2022;13:940691.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sato MT, Ida A, Kanda Y, Takano K, Ohbayashi M, Kohyama N, Morita J, Fuji K, Sasaki H, Ogawa Y, et al. Prognostic model for overall survival that includes the combination of platelet count and neutrophil-lymphocyte ratio within the first six weeks of sunitinib treatment for metastatic renal cell carcinoma. BMC Cancer. 2022;22(1):1214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Luo S, Yang WS, Shen YQ, Chen P, Zhang SQ, Jia Z, Li Q, Zhao JT, Xie P. The clinical value of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and D-dimer-to-fibrinogen ratio for predicting Pneumonia and poor outcomes in patients with acute intracerebral Hemorrhage. Front Immunol. 2022;13:1037255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sargeant TJ, Fourrier C. Human monocyte-derived microglia-like cell models: a review of the benefits, limitations and recommendations. Brain Behav Immun. 2022;107:98–109.

    Article  PubMed  Google Scholar 

  20. Zinellu A, Zinellu E, Mangoni AA, Pau MC, Carru C, Pirina P, Fois AG. Clinical significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in acute exacerbations of COPD: present and future. Eur Respir Rev 2022, 31(166).

  21. Shan M, Lu S, Cui R, Yang Y, Sun Z, Pan Y. Association between neutrophil to lymphocyte ratio and depression among US adults: from a large population-based cross-sectional study. J Psychosom Res. 2022;162:111041.

    Article  PubMed  Google Scholar 

  22. Esnafoglu E, Subasi B. Association of low 25-OH-vitamin D levels and peripheral inflammatory markers in patients with autism spectrum disorder: vitamin D and inflammation in Autism. Psychiatry Res. 2022;316:114735.

    Article  CAS  PubMed  Google Scholar 

  23. Singh D, Guest PC, Dobrowolny H, Vasilevska V, Meyer-Lotz G, Bernstein HG, Borucki K, Neyazi A, Bogerts B, Jacobs R, et al. Changes in leukocytes and CRP in different stages of major depression. J Neuroinflammation. 2022;19(1):74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2019;206:4–12.

    Article  PubMed  Google Scholar 

  25. Bioque M, Catarina Matias-Martins A, Llorca-Bofi V, Mezquida G, Cuesta MJ, Vieta E, Amoretti S, Lobo A, Gonzalez-Pinto A, Moreno C et al. Neutrophil to lymphocyte ratio in patients with a first episode of psychosis: a two-year longitudinal follow-up study. Schizophr Bull 2022.

  26. Ozdin S, Boke O. Neutrophil/lymphocyte, platelet/lymphocyte and monocyte/lymphocyte ratios in different stages of schizophrenia. Psychiatry Res. 2019;271:131–5.

    Article  PubMed  Google Scholar 

  27. Mazza MG, Lucchi S, Rossetti A, Clerici M. Neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in non-affective psychosis: a meta-analysis and systematic review. World J Biol Psychiatry. 2020;21(5):326–38.

    Article  PubMed  Google Scholar 

  28. Gazdag G, Ungvari GS. Electroconvulsive therapy: 80 years old and still going strong. World J Psychiatry. 2019;9(1):1–6.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sanghani SN, Petrides G, Kellner CH. Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature. Curr Opin Psychiatry. 2018;31(3):213–22.

    Article  PubMed  Google Scholar 

  30. Ying YB, Jia LN, Wang ZY, Jiang W, Zhang J, Wang H, Yang NQ, Wang RW, Ren YP, Gao F, et al. Electroconvulsive therapy is associated with lower readmission rates in patients with schizophrenia. Brain Stimul. 2021;14(4):913–21.

    Article  PubMed  Google Scholar 

  31. Seow LSE, Subramaniam M, Chan YWC, Martin DM, Abdin E, Chong SA, Liu J, Peh CX, Tor PC. A retrospective study of cognitive improvement following electroconvulsive therapy in Schizophrenia inpatients. J ECT. 2019;35(3):170–7.

    Article  PubMed  Google Scholar 

  32. Danenberg R, Ruimi L, Shelef A, Paleacu Kertesz D. A pilot study of cognitive impairment in Longstanding Electroconvulsive Therapy-treated Schizophrenia patients Versus Controls. J ECT. 2021;37(1):24–9.

    Article  CAS  PubMed  Google Scholar 

  33. Davarinejad O, Hendesi K, Shahi H, Brand S, Khazaie H. A pilot study on Daily Intensive ECT over 8 days improved positive and negative symptoms and general psychopathology of patients with treatment-resistant Schizophrenia up to 4 weeks after treatment. Neuropsychobiology. 2019;77(2):83–91.

    Article  PubMed  Google Scholar 

  34. Cano M, Camprodon JA. Understanding the mechanisms of Action of Electroconvulsive Therapy: revisiting Neuroinflammatory and Neuroplasticity hypotheses. JAMA Psychiatry. 2023;80(6):643–4.

    Article  PubMed  Google Scholar 

  35. Yu H, Yan H, Wang L, Li J, Tan L, Deng W, Chen Q, Yang G, Zhang F, Lu T, et al. Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study. The Lancet Psychiatry. 2018;5(4):327–38.

    Article  PubMed  Google Scholar 

  36. Labonte C, Zhand N, Park A, Harvey PD. Complete blood count inflammatory markers in treatment-resistant schizophrenia: evidence of association between treatment responsiveness and levels of inflammation. Psychiatry Res. 2022;308:114382.

    Article  CAS  PubMed  Google Scholar 

  37. Zhou X, Wang X, Li R, Yan J, Xiao Y, Li W, Shen H. Neutrophil-to-lymphocyte ratio is independently Associated with severe psychopathology in Schizophrenia and is changed by Antipsychotic Administration: a large-scale cross-sectional retrospective study. Front Psychiatry. 2020;11:581061.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yuksel RN, Ertek IE, Dikmen AU, Goka E. High neutrophil-lymphocyte ratio in schizophrenia Independent of infectious and metabolic parameters. Nord J Psychiatry. 2018;72(5):336–40.

    Article  PubMed  Google Scholar 

  39. Moody G, Miller BJ. Total and differential white blood cell counts and hemodynamic parameters in first-episode psychosis. Psychiatry Res. 2018;260:307–12.

    Article  PubMed  Google Scholar 

  40. Valiuliene G, Valiulis V, Dapsys K, Vitkeviciene A, Gerulskis G, Navakauskiene R, Germanavicius A. Brain stimulation effects on serum BDNF, VEGF, and TNFα in treatment-resistant psychiatric disorders. Eur J Neurosci. 2021;53(11):3791–802.

    Article  CAS  PubMed  Google Scholar 

  41. Kartalci S, Karabulut AB, Erbay LG, Acar C. Effects of Electroconvulsive Therapy on some inflammatory factors in patients with treatment-resistant Schizophrenia. J ECT. 2016;32(3):174–9.

    Article  CAS  PubMed  Google Scholar 

  42. Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12.

    Article  CAS  PubMed  Google Scholar 

  43. Lehmann ML, Weigel TK, Poffenberger CN, Herkenham M. The behavioral sequelae of Social Defeat require Microglia and are driven by oxidative stress in mice. J Neurosci. 2019;39(28):5594–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Parellada E, Gasso P. Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia. Transl Psychiatry. 2021;11(1):271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang SZ, Wang QQ, Yang QQ, Gu HY, Yin YQ, Li YD, Hou JC, Chen R, Sun QQ, Sun YF, et al. NG2 glia regulate brain innate immunity via TGF-beta2/TGFBR2 axis. BMC Med. 2019;17(1):204.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Jinno S, Kosaka T. Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol. 2008;212(2):440–7.

    Article  CAS  PubMed  Google Scholar 

  47. Limoa E, Hashioka S, Miyaoka T, Tsuchie K, Arauchi R, Azis IA, Wake R, Hayashida M, Araki T, Furuya M, et al. Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat. J Neuroinflammation. 2016;13(1):230.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kulaksizoglu B, Kulaksizoglu S. Relationship between neutrophil/lymphocyte ratio with oxidative stress and psychopathology in patients with schizophrenia. Neuropsychiatr Dis Treat. 2016;12:1999–2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ozdin S, Sarisoy G, Boke O. A comparison of the neutrophil-lymphocyte, platelet-lymphocyte and monocyte-lymphocyte ratios in schizophrenia and bipolar disorder patients - a retrospective file review. Nord J Psychiatry. 2017;71(7):509–12.

    Article  PubMed  Google Scholar 

  50. Rimmerman N, Verdiger H, Goldenberg H, Naggan L, Robinson E, Kozela E, Gelb S, Reshef R, Ryan KM, Ayoun L, et al. Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation. Mol Psychiatry. 2022;27(2):1120–35.

    Article  CAS  PubMed  Google Scholar 

  51. Network, Pathway Analysis Subgroup of Psychiatric Genomics C. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015;18(2):199–209.

    Article  Google Scholar 

  52. van Mierlo HC, Broen JCA, Kahn RS, de Witte LD. B-cells and schizophrenia: a promising link or a finding lost in translation? Brain Behav Immun. 2019;81:52–62.

    Article  PubMed  Google Scholar 

  53. Miller BJ, Goldsmith DR. Towards an immunophenotype of Schizophrenia: Progress, potential mechanisms, and future directions. Neuropsychopharmacology. 2017;42(1):299–317.

    Article  CAS  PubMed  Google Scholar 

  54. Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73(10):993–9.

    Article  CAS  PubMed  Google Scholar 

  55. Maino K, Gruber R, Riedel M, Seitz N, Schwarz M, Muller N. T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment. Psychiatry Res. 2007;152(2–3):173–80.

    Article  CAS  PubMed  Google Scholar 

  56. Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS, Weickert CS. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry. 2016;21(8):1090–8.

    Article  CAS  PubMed  Google Scholar 

  57. Orhan F, Schwieler L, Fatouros-Bergman H, Malmqvist A, Cervenka S, Collste K, Flyckt L, Farde L, Sellgren CM, Piehl F, et al. Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis. Acta Psychiatr Scand. 2018;138(5):432–40.

    Article  CAS  PubMed  Google Scholar 

  58. Chen S, Fan F, Xuan FL, Yan L, Xiu M, Fan H, Cui Y, Zhang P, Yu T, Yang F, et al. Monocytic subsets impact cerebral cortex and cognition: differences between healthy subjects and patients with First-Episode Schizophrenia. Front Immunol. 2022;13:900284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, Sommer IEC, Howes OD. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2019;49(13):2186–96.

    Article  PubMed  Google Scholar 

  60. De Picker LJ, Haarman BCM. Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker. Eur J Nucl Med Mol Imaging. 2021;49(1):164–73.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the National Natural Science Foundation of China (82371510, 81971255 and 82101572), Social Development Foundation of Jiangsu Province, China (No. BE2023668, BE2019610), the Key Project supported by Medical Science and Technology Development Foundation, Nanjing Department of Health (YKK20090), the Science and Technology Development Program of Nanjing Medical University (NMUB2019107), Nanjing Major Science and Technology Project (Life and Health, No 202305035) and Medical Science and Technology Innovation Project of Xu’zhou Health Commission for Young Scholars (No.XWKYHT20200064).

Author information

Author notes

  1. Yu Wang, Guangfa Wang and Muxin Gong contributed to this work equally. They should be regarded as Joint First Author.

Authors and Affiliations

  1. Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, 210029, Nanjing, Jiangsu, China

    Yu Wang, Yuru Ling, Xinyu Fang, Tingting Zhu, Zixu Wang & Xiangrong Zhang

  2. The Affiliated Xuzhou Oriental Hospital of Xuzhou Medical University, 221004, Xuzhou, Jiangsu, China

    Guangfa Wang, Muxin Gong, Yujing Yang, Xiangrong Zhang & Caiyi Zhang

Authors
  1. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guangfa Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muxin Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yujing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuru Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinyu Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tingting Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zixu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiangrong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Caiyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the preparation of the manuscript. YW conceptualized and designed the study. YW, GW, MG, YL, YY, ZW and TZ recruited the participants and completed the screening assessments. YW, XF, and CZ analyzed the data and performed the statistical analysis. YW wrote the first draft of the manuscript. XZ acquired funding. All authors approved the final manuscript.

Corresponding authors

Correspondence to Xiangrong Zhang or Caiyi Zhang.

Ethics declarations

Ethical approval and consent to participate

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Xuzhou Oriental People’s Hospital. Written informed consent was obtained from individual or guardian participants.

Consent for publication

Not applicable.

Competing interests

No potential conflict of interests to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Wang, G., Gong, M. et al. Systemic inflammatory biomarkers in Schizophrenia are changed by ECT administration and related to the treatment efficacy. BMC Psychiatry 24, 53 (2024). https://doi.org/10.1186/s12888-023-05469-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12888-023-05469-2

Keywords

BMC Psychiatry

ISSN: 1471-244X

Contact us