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Clinical features and serum cytokine and HPA axis function levels in patients with comorbid obsessive-compulsive disorder of unmedicated depression for the first episode

summary

Background: To explore the growing evidence that immune dysregulation plays an important role in the pathophysiology of affective disorders, but the exact mechanism of action and corresponding clinical manifestations are still unclear, we investigated the relationship between clinical features and immunoendocrine function in patients with comorbid obsessive-compulsive disorder of untreated depression for the first episode.

Methods: We enrolled 42 patients with obsessive-compulsive disorder (OCD), 44 patients with depression, 43 patients with comorbid OCD and 41 healthy controls with a DSM-5 diagnosis. The Hamilton Depression Rating Scale (HAMD), DSM-5 diagnostic criteria for obsessive-compulsive disorder, and the diagnostic criteria for mania/anxiety as exclusion criteria were used to control for confounding factors. Cytokines were measured by flow history cytometry, and plasma levels of plasma cortisol, CRP, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL12P70, IL-17, IL-1β, INF-a, INF-y and TNF-a were measured.

Results: The onset age of OCD comorbid depression was younger than that of the depression group, which increased the difficulty of early identification. The comorbid group had higher suicidal tendencies and higher levels of anxiety than the depression alone group. The level of cortisol in the obsessive-compulsive disorder group was lower, and the level of cortisol in the depression group alone was higher than that in the comorbid group, and there was no difference between the normal group. Immune cytokines: IL-6 and INF-y were changed in the OCD comorbid depression group, and there were no significant differences in IL-2, IL-1β and CRP.

Keywords: Inflammatory cytokines, comorbidities, biomarkers, interleukin, HPA axis

introduce

Obsessive-compulsive disorder (OCD) is a common mental disorder characterized by obsessive thoughts or compulsive behaviors, and patients often relapse and recur, causing significant harm to family, learning, and social functioning. Population-based epidemiological surveys have shown that the lifetime prevalence of OCD is between 2~3% [1].

Depression is a general term for the main manifestations of depressed mood, decreased interest, and anhedonia, with a lifetime prevalence of 8%~12% in most countries. Depression is the most common complication of OCD [3].

The diagnosis and treatment of clinical features of patients with comorbid depression with obsessive-compulsive disorder is of great significance, and the pathogenesis of immune dysregulation is unknown. Pro-inflammatory cytokines are small molecules secreted by the immune system in response to various stimuli, mainly including interleukins (IL), tumor bad factor (TNF), interferon (IFN), etc. IL-2, TNF-α, and IL-6, among others, their production is associated with the initiation of an inflammatory response. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18) are common inflammatory cytokines, which are usually produced by microglia in the peripheral and central nervous system, which not only play a key role in the inflammatory immune response, but also have an impact on the central nervous system. 16】。

Kluge M [5] et al. proposed that patients with OCD had increased HPA axis activity, and that nocturnal plasma concentrations of cortisol and ACTH were significantly higher than those in the control group compared to healthy controls. Rao NP [6] et al. found that the plasma levels of IL-2, IL-4, IL-6, IL-10, and TNF-a in patients with OCD were significantly higher than those in healthy controls. A study by Fan et al. [7] showed that IL-6 levels were positively correlated with HAMD-17 scores in patients with severe depression. Several studies have shown that the pathophysiology of comorbid obsessive-compulsive disorder of depression is associated with dysfunction of cortisol and immune system. By delving deeper into these interrelated characteristics, we can gain a more complete understanding of the complex nature of these diseases and potentially discover new avenues for therapeutic intervention.

This study uses a unified enrollment criterion to evaluate different cytokines, IL-2, IL-6, IL-17, IL-1β, tumor necrosis factor (TNF)-a, HPA axis, using flow cytometry. The plasma cytokines and clinical characteristics of patients with comorbid obsessive-compulsive disorder of depression were comprehensively analyzed, and compared with the obsessive-compulsive disorder group, depression group, and healthy control group. This study provides evidence that pro-inflammatory cytokines are associated with the patient's clinical characteristics, which can reflect the severity of some of the patient's symptoms to some extent.

Objects and Methods

1.1 Research Object:

According to the inclusion and exclusion criteria, psychiatric outpatients from Panyu Central Hospital Affiliated to Guangzhou Medical University were included from X year x to X year X month, and all patients were assessed by trained psychiatrists on a scale. Exclusion Criteria: 1. Illiterate, 2. Patients with generalized anxiety disorder excluded using the Hamilton Anxiety Scale, and patients with a lifetime diagnosis of bipolar disorder, schizophrenia, and substance dependence, as well as any current comorbid Axis 1 mental disorder. 3. Presence of serious medical illness; 4. Presence of cerebral organic psychiatric disorders; 5. Acute infection, or trauma, inflammation, fever and allergies in the past two weeks; 6. Females are pregnant or lactating. Obsessive-compulsive disorder is diagnosed using the DSM-5 and depression is diagnosed using the ICD-10. Enrollment criteria: 1. Male or female, aged between 12~45 years old; 2. Hamilton depression scale 17-item (HAMD-17) score ≥ 17; 3. OCD score ≥ 6. A total of 170 patients were selected according to the principle of randomization and equilibrium, including 42 patients with obsessive-compulsive disorder, 44 patients with depression, and 43 patients with comorbid depression with obsessive-compulsive disorder.

The healthy control group consisted of 41 local people in the same period, and the enrollment criteria were: 1. Male or female, aged between 12~45 years old; 2. No mental disorder in the past three months, no previous history of mental illness and family history; 3. There is no obvious immune disease in the physical examination, and there is no cardiovascular and cerebrovascular disease.

The procedures and contents of this study are in line with the ethical standards considered by the Ethics Committee of Panyu Central Hospital Affiliated to Guangzhou Medical University, and have been reviewed and approved by the Ethics Committee before being carried out. All study participants have been informed about the research project and have signed the informed consent form.

1.2 Methods

1.1 Sample collection

Prepare the required reagents: capture beads, experimental buffer, detection antibodies, prepared wash buffer, specimens stored in a -40°C freezer, and all reagents should be naturally restored to room temperature before use. The flow cytometer was determined by the laboratory of Panyu Central Hospital.

The status of cytokine-related blood samples was detected, and then 6 items/12 items of cytokines were simply sorted and centrifuged immediately (1000xg, 10min).

The convection tube number during centrifugation eliminates the need to separate plasma after centrifugation.

1.2 Cytokine assay test

Before the experiment, vortex the microspheres for 30s, add 2 5μL of capture microsphere antibody to the sample tube, and add 2 5μL of experimental buffer to the sample tubeAdd 25μL of plasma sample to the sample tube and 2 5μL of plasma sample to the sample tube, followed by vortexing for a few seconds at room temperature (25±1 °C) incubate for 2 h in the dark (shaking parameter is 400-500r/min), and add 2 5 to the sampleμLSA-PE (signal amplifier), then vortex for a few seconds, and incubate for 0.5 h at room temperature (25±1 °C) in the dark (shaking parameter is 400-500r/min), add 1 m1x wash buffer to the sample tube, vortex for a few seconds, centrifuge at 5 00g for 5 min, slowly pour out the liquid, and turn it upside down on absorbent paperAccording to the sample loading needs of the flow cytometer, 150 μL (currently 100) of wash buffer was added to each tube, and the beads were resuspended after vortexing for 10s, and the detection was carried out immediately.

1.2 Statistical Methods IBM SPSS Statistics 26.0 was used for statistical analysis, all data were expressed as mean ± standard deviations, and independent or paired samples t-test were used for comparison between groups, and the test level was α=0.05, two-sided test.

1.3 Results

Demographic and clinical characteristics of the sample: The age of onset of OCD comorbid depression patients was younger than that of the depression group, which increased the difficulty of early identification. More suicidal tendencies, more suicidal ideation, and higher scores of accompanying anxiety than in the depression alone group.

Cortisol levels were lower in the obsessive-compulsive disorder alone group; The level of cortisol in the depression group was higher than that in the comorbid group, and there was no difference between the normal group. There were no abnormalities in C-reactive protein.

Immune cytokines: interleukin 6 and interleukin 17 were changed in the comorbid depression group of obsessive-compulsive disorder. There was no significant difference between interleukin 2 and interleukin 1β. INF-γ levels were reduced in the comorbid group compared to the healthy control group.

4. IL-6: The level of IL-6 in the comorbid group was higher than that in the healthy control group. The depression alone group was higher than the comorbidity group. There was no statistically significant difference between the comorbid group and the obsessive-compulsive disorder group alone.

1.4 Discussion

We studied the clinical characteristics and changes in serum cytokine and HPA axis function levels in patients with comorbid obsessive-compulsive disorder of first-episode unmedicated depression, excluded patients with comorbid anxiety disorder, bipolar affective disorder, etc., and controlled for confounding factors in the included participants.

The age of onset of OCD comorbid depression was younger than that of the depression group, which increased the difficulty of early identification. There were more suicidal tendencies and more suicidal ideation than in the depression group alone, which supported the findings of Cassin SE et al. [4]. and anxiety scores were higher in the comorbid group. Peripherally produced pro-inflammatory cytokines can cross the blood-brain barrier and interact directly with central nervous system tissues [9], and peripheral cytokines can alter amygdala activity and increase anxiety-like behavior [10]. The correlation between anxiety levels and cytokines can be further investigated in the future.

Patients with OCD often have abnormal cortisol levels that are closely related to OCD symptoms. This abnormality is associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol levels were lower in the OCD alone group compared with the comorbid group, and there was no difference between the comorbid group and the depression alone group.

The results showed that the serum IL-6 and INF-y were altered in patients with comorbid depression with OCD, suggesting that they may play a role in the pathogenesis of OCD and depression, which showed contradictory results with previous cytokine studies on OCD patients. A meta-analysis of studies measuring plasma cytokine levels by Gray SM et al. [8] showed no significant difference in plasma levels of IL-6 and TNF-α in OCD subjects compared to controls. At present, the conclusions obtained are inconsistent, mainly due to small sample size, different clinical diagnostic criteria, patient age, medication, and disease heterogeneity.

Basic properties and biosynthesis of IL-6: The gene encoding human IL-6 consists of four introns and five exons and is mapped to chromosome 7p15-21 [13]. With a relative molecular weight of 21 000, IL-6 is a glycoprotein usually found in monomeric form that is made up of 184 amino acids forming 4 α helices with an isoelectric point of 5.0. IL-6 promotes T cell proliferation and activation, induces B cell differentiation, and regulates acute phase responses. IL-6 is produced by almost all stromal cells and immune system cells. IL-1β and TNF are the main activators of IL-6 expression, and other pathways such as Toll-like receptors, prostaglandins, adipkines, stress responses, and other cytokines also contribute to IL-6 synthesis.

The serum IL-6 level in the comorbid group was higher than that in the healthy control group. The depression alone group was higher than the comorbidity group. There was no statistically significant difference between the comorbid group and the obsessive-compulsive disorder group alone. Previous meta-analyses [14] have shown a significant reduction in IL-1β levels in OCD, with no significant differences in plasma IL-6 or TNF-α levels. Stratified subgroup analysis showed a moderating effect of comorbid depression on TNF-α levels. Elevated levels of TNF-α were reported in studies that included individuals with comorbid depression. At the same time, the study showed that pro-inflammatory cytokines, including tumor necrosis factor α and IL-6, were elevated in patients with depression compared with controls, and that levels of some inflammatory cytokines (such as IL-1β and possibly IL-6) were reduced in patients who were successfully treated with antidepressants.

This study also showed that there was no significant difference in the concentration levels of pro-inflammatory cytokines IL-2 and IL-1β. Suhee FI [11] et al.'s evaluation of the role of IL-2 in the pathophysiology of depression showed that serum IL-2 levels were elevated in patients with MDD. This may be due to the short duration of MDD analysed in this study and the limited representativeness of changes in cytokine levels. Rao NP [12] et al.'s study of plasma cytokines in drug-naïve patients with obsessive-comorbidity and without comorbidities showed that the plasma IL-2 levels in patients with OCD were significantly higher than those in healthy controls, suggesting a possible role of IL-2 in the pathogenesis of OCD. The presence of IL-2 as a potential biomarker has not been proven.

The cytokine interleukin-1β mediates alterations in dopaminergic neurotransmission [15], reducing DA synthesis levels by activating NO in relevant brain regions. However, YiGao Wu et al. [17] found that the serum IL-1β level of patients with first-episode OCD was significantly lower than that of the control group

Depression comorbidities and obsessive-compulsive disorder often lead to a decrease in the quality of life of patients [2], and the most serious consequence is suicide. The correlation between the severity of clinical symptoms of OCD and the level of inflammatory cytokines in serum needs to be further comprehensively and systematically studied.

Limitations: The geographical distribution of the study population is mostly in southern China, so the results of the study may not be widely applicable to all regions. The patient's somatization symptoms were not categorized, and other psychiatric disorders were not completely ruled out. In the future, the relationship between age at first presentation and age at onset can be further studied.

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