European Journal of Cardiovascular Medicine

Psychotic disorders, particularly schizophrenia, often manifest during late adolescence or early adulthood and are characterized by a range of symptoms including delusions, hallucinations, and cognitive impairments. The first episode of psychosis (FEP) is considered a critical period for understanding the underlying neurobiological mechanisms and initiating effective therapeutic interventions (1). Increasing evidence suggests that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and heightened inflammatory responses may play a significant role in the pathophysiology of psychosis (2,3).

Cortisol, a glucocorticoid hormone released in response to stress, is a key component of the HPA axis. Altered cortisol levels have been associated with the onset and severity of psychotic symptoms, suggesting an overactive stress response system in FEP patients (4). Simultaneously, inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been found elevated in individuals with psychotic disorders, indicating an activated immune state (5,6). These alterations may not only contribute to symptom severity but also influence treatment outcomes and prognosis (7).

The concept of a neuroimmune interface, where stress and inflammation converge to influence brain function, has gained traction in recent years. Elevated IL-6 and CRP levels have been linked to cognitive deficits, negative symptoms, and increased risk of relapse in psychosis (8,9). Moreover, studies suggest that these biomarkers could serve as early indicators of psychosis and may offer novel therapeutic targets (10).

Despite these findings, research on cortisol and inflammatory markers in FEP remains limited and inconsistent.

This study aims to assess serum cortisol, IL-6, and CRP levels in patients with FEP and compare them with healthy controls, thereby contributing to the growing body of evidence regarding the neuroendocrine and immunological underpinnings of psychosis.

Study Design and Participants: The study population included two groups: 30 patients diagnosed with first-episode psychosis (FEP) and 30 healthy controls matched for age and sex. Patients were recruited from the outpatient and inpatient departments of psychiatry, while controls were selected from hospital staff and volunteers with no personal or family history of psychiatric illness. Inclusion criteria for the FEP group included individuals aged 18–35 years, experiencing their first psychotic episode, and not having received antipsychotic medication for more than two weeks. Exclusion criteria for both groups included the presence of chronic medical illness, substance abuse, or recent infection or inflammatory condition.

Clinical Assessment:
Psychiatric evaluation of FEP participants was performed using the Structured Clinical Interview for DSM-5 (SCID-5) criteria. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS). A trained psychiatrist administered the PANSS to ensure consistency in scoring.

Biological Sample Collection:
Venous blood samples were drawn from all participants between 8:00 and 9:00 AM to minimize diurnal variation in cortisol levels. Participants were instructed to fast overnight and avoid strenuous activity before sampling. Blood was collected into plain vacutainers and allowed to clot at room temperature. Serum was separated by centrifugation at 3000 rpm for 10 minutes and stored at −80°C until further analysis.

Biochemical Analysis:
Serum cortisol levels were quantified using a chemiluminescent immunoassay technique. Concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturers' instructions. All assays were performed in duplicate to ensure reliability of results.

Statistical Analysis:
Data were analyzed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were computed for demographic and clinical variables. Independent sample t-tests were used to compare mean biomarker levels between groups. Pearson correlation analysis was performed to examine the relationship between biomarker levels and PANSS scores. A p-value < 0.05 was considered statistically significant.

A total of 60 participants were included in the study, comprising 30 individuals with first-episode psychosis (FEP) and 30 age- and sex-matched healthy controls. The mean age of FEP patients was 24.3 ± 3.8 years, while the control group had a mean age of 25.1 ± 4.2 years. There were no statistically significant differences in age or gender distribution between the two groups (p > 0.05).

Biochemical analysis revealed that mean serum cortisol levels were significantly higher in the FEP group (21.8 ± 6.2 µg/dL) compared to controls (14.5 ± 4.3 µg/dL, p < 0.001). Similarly, IL-6 levels were elevated in FEP patients (5.6 ± 1.8 pg/mL) versus the control group (2.9 ± 1.2 pg/mL, p = 0.002). CRP concentrations were also significantly higher in FEP individuals (4.1 ± 1.5 mg/L) than in controls (1.7 ± 0.9 mg/L, p = 0.003) (Table 1).

Additionally, a positive correlation was observed between serum cortisol levels and total PANSS scores among FEP patients (r = 0.42, p = 0.01). IL-6 levels were significantly correlated with CRP values (r = 0.53, p < 0.001), suggesting an interplay between neuroendocrine stress response and systemic inflammation (Table 2).

Table 1. Comparison of Mean Biomarker Levels Between First-Episode Psychosis Patients and Controls

Table 2. Correlation of Biomarkers With Clinical Variables in FEP Group

The findings suggest a statistically significant elevation of both stress-related and inflammatory biomarkers in individuals experiencing their first psychotic episode (Table 1), with measurable associations between biological stress response and symptom severity (Table 2).

The present study provides evidence of significant neuroendocrine and inflammatory alterations in individuals experiencing first-episode psychosis (FEP), as reflected by elevated levels of serum cortisol, interleukin-6 (IL-6), and C-reactive protein (CRP). These findings align with emerging literature that implicates dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and immune system in the early stages of psychotic disorders (1,2).

Elevated cortisol levels observed in our study support the hypothesis of an overactive HPA axis in FEP patients, which may be a physiological response to psychological stress or an intrinsic component of the pathophysiology of psychosis (3). Previous studies have reported hypercortisolemia in drug-naïve patients with schizophrenia, linking it to hippocampal volume reduction and cognitive impairments (4,5). Sustained cortisol elevation is thought to contribute to neural toxicity and may exacerbate psychotic symptoms by impairing synaptic plasticity and modulating dopamine activity (6,7).

In parallel with cortisol findings, significantly raised IL-6 and CRP levels in FEP patients reinforce the role of systemic inflammation in psychotic disorders. Elevated IL-6 has been consistently associated with the acute phase of psychosis and is believed to modulate neurotransmission and brain connectivity, particularly in prefrontal and limbic circuits (8,9). CRP, a nonspecific inflammatory marker, has similarly been found to correlate with negative symptoms and cognitive dysfunction in schizophrenia (10,11).

The positive correlation between cortisol and PANSS total scores observed in our study suggests that HPA axis dysfunction may be associated with overall symptom severity, supporting prior evidence of a link between neuroendocrine markers and clinical presentation (12). Moreover, the significant relationship between IL-6 and CRP levels indicates a coordinated inflammatory response, as also reported in longitudinal studies tracking immune activation in early psychosis (13).

Several mechanisms may underlie these findings. Pro-inflammatory cytokines such as IL-6 can influence the HPA axis, creating a feedback loop that perpetuates both stress hormone release and immune activation (14). This bidirectional communication between the neuroendocrine and immune systems may contribute to the progression and chronicity of psychotic disorders.

Despite consistent trends, it is important to consider certain limitations. The cross-sectional design precludes causal interpretations, and the sample size may limit generalizability. Future longitudinal studies with larger cohorts are warranted to establish predictive value and potential for biomarker-guided interventions. Nevertheless, the current study highlights the clinical relevance of monitoring cortisol and inflammatory markers as potential adjuncts in early psychosis management (15).

This study highlights the significant dysregulation of cortisol and inflammatory biomarkers (IL-6 and CRP) in individuals experiencing first-episode psychosis, supporting the role of HPA axis hyperactivity and immune activation in the early stages of psychotic disorders. The observed associations with symptom severity suggest that these biomarkers may serve as useful indicators for early diagnosis, clinical monitoring, and targeted intervention strategies in psychosis management. Further longitudinal studies are needed to validate their prognostic value.

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