European Journal of Cardiovascular Medicine

Major Depressive Disorder (MDD) is a highly prevalent psychiatric illness with a global lifetime prevalence estimated at 15–20% and a one-year prevalence ranging from 4% to 8% across various populations [1]. Traditionally conceptualized as a neurochemical imbalance, MDD is now increasingly understood as a systemic disorder, involving immune activation, metabolic dysregulation, and neuroendocrine imbalance [2].

This broader view is supported by converging evidence of immune-inflammatory involvement, where markers such as C-reactive protein (CRP) have been consistently found to be elevated in patients with active depression [3]. Elevated CRP has been associated with symptom severity, cognitive decline, and resistance to pharmacological treatments in MDD [4]. Systematic reviews and meta-analyses have underscored the reproducibility of this link, positioning CRP as a potential peripheral biomarker for clinical monitoring [5].

Alongside inflammatory markers, metabolic and energy-related parameters have gained attention in the pathophysiology of depression. Lactate dehydrogenase (LDH), a key enzyme in anaerobic metabolism and mitochondrial function, has shown intriguing associations with psychiatric symptomatology. Recent evidence suggests lower serum LDH levels in depressed individuals, particularly in those with suicide attempts, indicating a link to neuroenergetic dysfunction [6]. Additional studies support LDH's diagnostic utility, with variations observed across mood disorders such as bipolar disorder and post-stroke depression [7,8].

A recent comparative study of adolescents with mood disorders further suggests that CRP and LDH may serve as differential biomarkers in distinguishing between depressive subtypes and bipolar depression [9]. In a similar vein, Tan et al. found significant differences in biochemical indices between stable-phase MDD and bipolar disorder, reinforcing the relevance of systemic biomarkers in mood disorder profiling [10].

Despite these developments, no consensus exists on the combined use of CRP and LDH as routine clinical markers in MDD. This retrospective, hospital-based study aims to evaluate the relevance and correlation of serum CRP and LDH with clinical severity in patients diagnosed with Major Depressive Disorder. By examining routinely available biochemical data, we seek to contribute to the development of a more biologically-informed approach to depression diagnosis and management.

Study Design and Setting

This hospital-based case–control study was conducted at Vilasrao Deshmukh Government Medical College, Latur, following approval from the Institutional Ethics Committee. The study period spanned from March 2022 to March 2023. All procedures were carried out in accordance with the Declaration of Helsinki and institutional ethical standards.

Participants
A total of 145 individuals were enrolled, comprising cases diagnosed with Major Depressive Disorder (MDD) (n = 72) and age- and sex-matched healthy controls (n = 73). The diagnosis of MDD was established according to DSM-5 criteria following psychiatric evaluation by a qualified clinician.

Inclusion and Exclusion Criteria

Patients aged 18–65 years diagnosed with MDD were included. Individuals with comorbid psychiatric illnesses, chronic inflammatory or infectious diseases, malignancies, liver or renal dysfunction, or those receiving immunomodulatory or antioxidant therapy were excluded. Controls were recruited from healthy hospital staff and volunteers with no personal or family history of psychiatric disorders.

Sample Collection and Biochemical Analysis

Following informed consent, 3 mL of venous blood was collected from each participant using sterile vacutainers. Samples were centrifuged and serum was separated for analysis.

- C-Reactive Protein (CRP) levels were estimated using the quantitative turbidimetric immunoassay method.
- Lactate Dehydrogenase (LDH) levels were determined by the NADH oxidation method.

Both assays were performed on a fully automated clinical chemistry analyzer (EM 360, Transasia Biomedical Ltd.). All quality control procedures were adhered to according to the manufacturer’s protocol.

Data Collection and Depression Severity Assessment

Clinical data including demographics, psychiatric history, and depression severity (based on Hamilton Depression Rating Scale – HDRS) were recorded. Suicidal ideations were noted where applicable and stratified according to standard clinical thresholds.

Statistical Analysis

Data were analyzed using IBM SPSS Statistics, version 27.0 (IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) or median (IQR), and categorical variables as counts and percentages. Between-group comparisons were performed using the student’s t-test or Mann–Whitney U test, as appropriate. Correlations between serum biomarker levels and depression severity scores were analyzed using Pearson’s or Spearman’s correlation coefficients. A p-value of < 0.05 was considered statistically significant.

A total of 145 participants were included in the analysis, comprising 72 patients with Major Depressive Disorder (MDD) and 73 age- and sex-matched healthy controls. The baseline demographic and clinical characteristics are summarized in Table 1. The mean age of participants in the MDD group was 37.0 ± 9.1 years, slightly higher than that of controls (35.7 ± 10.6 years). The sex distribution was comparable between the two groups. A higher proportion of MDD patients reported a positive family history of depression and presence of comorbid conditions. The mean BMI was modestly higher in controls (24.5 ± 2.7) than in MDD cases (23.1 ± 3.2). The average Hamilton Depression Rating Scale (HDRS) score among MDD patients was 22.2 ± 4.4.

Table 1. Baseline Characteristics of Study Participants

Serum CRP and LDH Levels

The serum concentrations of C-reactive protein (CRP) and lactate dehydrogenase (LDH) were significantly different between patients with Major Depressive Disorder (MDD) and healthy controls. The mean CRP level was markedly elevated in the MDD group (5.82 ± 1.42 mg/L) compared to controls (2.61 ± 1.03 mg/L), whereas the mean LDH level was substantially lower in MDD cases (158.0 ± 18.0 U/L) than in the control group (182.1 ± 15.0 U/L). Independent samples t-tests revealed that both differences were statistically significant (CRP: t = 13.79, df = 118.4, p < 0.00001; LDH: t = –8.48, df = 140.1, p < 0.00001), with very large effect sizes (Cohen’s d = 2.30 for CRP, –1.41 for LDH), indicating strong discrimination of these biomarkers between diagnostic groups. (Table1, figures 1A and 1B)

Table 2. Mean Serum Levels of CRP and LDH in MDD Cases and Controls

Figure 1. Distribution of Serum CRP and LDH Levels in MDD Cases and Controls.

Boxplots show the comparative distribution of serum C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels between patients diagnosed with Major Depressive Disorder (MDD) and healthy control subjects. CRP levels were significantly elevated, while LDH levels were significantly reduced in the MDD group (p < 0.00001 for both comparisons), suggesting strong biochemical differentiation between groups.

Correlation with Depression Severity (HDRS Score)

To investigate the relationship between serum biomarkers and the severity of depression, correlation analyses were performed between HDRS scores and CRP/LDH levels in patients with Major Depressive Disorder (MDD). As shown in Table 3, no statistically significant correlations were found. The Pearson correlation between CRP and HDRS score was r = 0.08 (p = 0.51060), and for LDH, r = 0.06 (p = 0.61463). Similarly, Spearman’s rho values were 0.15 (p = 0.19724) for CRP and 0.09 (p = 0.47169) for LDH. These findings suggest that while CRP and LDH levels differ significantly between cases and controls, their absolute levels may not correlate linearly with depression severity (Figure 2).

Table 3. Correlation of Serum CRP and LDH with HDRS Score

Figure 2. Scatter plots illustrating the relationship between HDRS score and serum CRP (left) and LDH (right) in MDD patients. No significant correlation was observed between either biomarker and depression severity.

Association with Suicidal Ideation in MDD Patients

To assess whether serum CRP and LDH levels differ between MDD patients with and without suicidal ideation, both parametric and non-parametric tests were applied. As summarized in Table 4, the mean levels of CRP and LDH were not significantly different between the two groups. Additionally, Chi-square analysis using binary (above/below median) categorization also showed no significant associations (Table 5). These findings suggest that CRP and LDH may not serve as state markers for suicidal ideation.

Table 4. Mean Serum CRP and LDH Levels by Suicidal Ideation

Table 5. Statistical Analysis for Biomarkers vs. Suicidal Ideation

Figure 3: Mean CRP/LDH vs. suicidal status

Figure 3. Bar plots of mean serum CRP (left) and LDH (right) levels in MDD patients with and without suicidal ideation. Error bars represent standard deviations. No significant differences were observed.

Figure 4. Receiver Operating Characteristic (ROC) Curves for CRP and LDH

ROC curves illustrating the discriminatory performance of serum CRP and LDH levels in predicting suicidal ideation among patients with Major Depressive Disorder (MDD). The area under the curve (AUC) was 0.57 for CRP and 0.56 for LDH, indicating poor sensitivity and specificity. These results suggest that while CRP and LDH may be useful in distinguishing MDD from controls, they do not serve as effective biomarkers for suicide risk within this population.

Overview of Key Findings

This study found that serum C-reactive protein (CRP) levels were significantly higher in MDD patients (5.82 ± 1.42 mg/L) compared to healthy controls (2.61 ± 1.03 mg/L), while lactate dehydrogenase (LDH) levels were significantly lower in MDD patients (158.0 ± 18.0 U/L) than in controls (182.1 ± 15.0 U/L). These differences were statistically significant (CRP: t = 13.79, p < 0.00001, Cohen’s d = 2.30; LDH: t = –8.48, p < 0.00001, Cohen’s d = –1.41), indicating large effect sizes.

However, within the MDD group, neither biomarker showed a significant correlation with Hamilton Depression Rating Scale (HDRS) scores (CRP: Pearson’s r = 0.08, p = 0.5106; LDH: r = 0.06, p = 0.6146), nor were they predictive of suicidal ideation (AUC: CRP = 0.57; LDH = 0.56). These findings suggest that although CRP and LDH can distinguish MDD from controls, their utility in tracking symptom severity or suicide risk is limited.

The current findings add to a growing body of evidence suggesting a complex, non-linear relationship between peripheral biochemical markers and psychiatric symptoms in Major Depressive Disorder (MDD). Despite the significant group-level differences in serum CRP and LDH between MDD cases and healthy controls, neither marker demonstrated robust predictive value for suicidal ideation, as reflected by modest AUC values (<0.60). This aligns with prior studies, which have shown mixed associations between peripheral inflammation and suicide risk [9, 11, 12].

Trait vs. State Biomarker Interpretation

An important distinction emerged between the between-group and within-group analyses in this study. While serum CRP and LDH levels demonstrated statistically significant differences between MDD patients and healthy controls—supporting their potential diagnostic utility—no significant correlation was observed between these biomarkers and HDRS scores within the MDD cohort. This suggests that although CRP and LDH may effectively discriminate MDD from non-MDD status at the group level, their levels do not vary consistently with the severity of depressive symptoms. Such a pattern highlights the possibility that these biomarkers are more reflective of underlying pathophysiological alterations associated with MDD diagnosis, rather than state-dependent markers of symptom burden. These findings align with prior biomarker literature that distinguishes between trait markers (diagnostic) and state markers (severity-linked), and emphasize the need for multi-dimensional biomarker models in affective disorder profiling [11,14].

Limited Predictive Utility for Suicidal Ideation

Despite the robust between-group differences observed for CRP and LDH, their utility in predicting suicidal ideation within the MDD cohort was limited. Mean CRP levels were not significantly different between patients with suicidal ideation (6.15 ± 1.76 mg/L) and those without (5.75 ± 1.70 mg/L), and LDH levels showed a similar pattern (160.37 ± 14.78 U/L vs. 155.16 ± 17.28 U/L). Independent t-tests revealed no statistically significant differences (CRP: p = 0.34379; LDH: p = 0.17557). Additionally, ROC curve analysis demonstrated poor discriminatory ability (AUC for CRP = 0.57; for LDH = 0.56). These findings suggest that CRP and LDH, while potentially useful as diagnostic biomarkers, are unlikely to serve as reliable predictors of suicidal risk in MDD patients.

This aligns with recent literature suggesting that peripheral inflammatory markers, including hs-CRP, are more indicative of general systemic dysregulation than suicide-specific neurobiology [15,16]. Furthermore, studies in mood disorder subtypes—including mixed features in MDD and bipolar spectrum presentations—have shown that biochemical profiles may differ across affective subpopulations, limiting the generalizability of CRP and LDH as standalone predictors [15,17]. Collectively, these results emphasize the need for multidimensional biomarker panels and reinforce the importance of comprehensive clinical assessment when evaluating suicide risk.

  Biomarker Literature

CRP and LDH have repeatedly shown promise as systemic markers of inflammation and metabolic dysregulation in affective disorders. Tan et al. (2023) noted biochemical differences between bipolar and MDD patients even in stable periods, emphasizing diagnostic rather than dynamic use. Surface et al. (2023) [18] proposed composite indices—combining CRP, LDH, immune markers, and albumin—as superior predictors of severity. Zou et al. (2020) additionally highlighted how life stress interacts with inflammatory markers to influence suicide risk, implying a need for multi-dimensional predictive models [19].

Clinical and Research Implications

CRP and LDH may serve as accessible diagnostic aids to distinguish MDD patients from non-depressed individuals, but their standalone application for predicting suicide risk or symptom severity is not supported. Integration with broader immune, neuroendocrine, and metabolomic panels appears necessary, a view supported by studies from Tuna and Bai et al. (2020) [20,21]. Future research should prioritize longitudinal and mechanistic studies, integrating dynamic biomarker changes with psychometric trajectories to refine clinical application.

Limitations

This study's retrospective design limits causal interpretation and is susceptible to data incompleteness. Key confounders such as comorbid conditions, medication status, and inflammatory comorbidities were not controlled. Suicidal ideation was identified from clinical notes rather than standardized assessments, and biomarker evaluation was limited to CRP and LDH without inclusion of broader inflammatory panels. Finally, the single-centre setting may restrict generalizability.

Serum CRP and LDH levels significantly differed between MDD patients and healthy controls, supporting their potential utility as diagnostic adjuncts. However, these biomarkers did not correlate meaningfully with depression severity or suicidal ideation, limiting their value as state-dependent or prognostic indicators. While CRP and LDH reflect underlying systemic alterations associated with depressive illness, their isolated use in risk stratification—particularly for suicidality—appears inadequate. Future research should adopt longitudinal, multimodal biomarker approaches integrating clinical, biochemical, and psychometric data to refine their applicability in personalized psychiatry.

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