Major depressive disorder (MDD) is a highly disabling mental disorder marked by core symptoms such as depressed mood, loss of interest, and anhedonia, imposing a heavy global burden of disease (1, 2). According to epidemiological estimates, the percentage of Chinese children and adolescents with depressive disorders is around 2.0% (3). Given that adolescence is a phase of crucial brain development and cognitive maturation, depression in this stage tends to be associated with more severe symptoms, a higher risk of recurrence, and a poorer long-term prognosis (4). Therefore, investigating the underlying mechanisms is of paramount importance for both clinical practice and public health.

Childhood trauma is widely recognized as a pivotal environmental risk factor in MDD. Research indicated that experiencing childhood trauma early in life may markedly increase the risk of developing depressive disorders in adolescents (5). Supporting this, a cohort study by Houtepen et al. (6) revealed that children and adolescents with a history of childhood trauma had 2.4 times the risk of developing depression in the future compared to their peers without such trauma. Furthermore, childhood trauma exerted a substantial impact on the psychopathological symptoms of adolescents with MDD, such as triggering more intense suicidal ideation and more pronounced alexithymia (7, 8). The studies by Kayan et al. and Lee et al.also indicated that childhood trauma is closely associated with suicidal ideation and behavior in depressed adolescents (9, 10). And substantial evidence supported that childhood trauma serves as a significant risk factor for difficulties in emotion recognition (i.e., alexithymia) in adolescents (11–13).

The long-term influence of childhood trauma is not confined to the psychological realm with growing evidence suggestingit may also lead to dysregulation of the inflammatory system (14–18). Specifically, a clinical study in Brazil observed that among adolescents with MDD, childhood trauma was closely associated with increased levels of inflammatory cytokines, including IL-6 and IL-10 (14). Similarly, a recent meta-analysis has demonstrated an overall association between childhood trauma and increased levels of inflammatory cytokines (e.g., IL-6 and TNF-α) in individuals with depression (16). However, the association remains debated, as some studies have reported no significant direct link between the two. For instance, Oliveira et al. (19) reported that while depressive patients had elevated levels of inflammatory cytokines (e.g., IL-1β, IL-6, IL-17A, and TNF-α) compared to healthy controls, they failed to find a significant link between childhood trauma history and these cytokine levels among the patients. The inconsistent results are likely attributable to methodological heterogeneity, including differences in participant characteristics and insufficient adjustment for crucial confounders, notably pharmacotherapy. It is noteworthy that inflammatory dysregulation itself may be linked to a spectrum of adverse outcomes, including the development of depression, increased suicide risk, and cognitive decline (20–22). Therefore, investigating the potential associations between childhood trauma and clinical features as well as inflammatory cytokines in adolescents with MDD is of significant importance.

Based on the above, this study aimed to systematically investigate (1) the detection rate of childhood trauma in adolescents with MDD; (2) the differences of childhood trauma, clinical features, and the levels of inflammatory cytokines between adolescents with MDD and healthy controls (HCs); and (3) whether the associations between childhood trauma and the aforementioned indicators exhibit disease-stage specificity, by distinguishing illness stages (first-episode vs. recurrent) and controlling for key confounding factors such as medication treatment.

This study found that, compared to HCs, adolescents with MDD in our sample showed significantly higher childhood trauma burden, both in terms of detection rate (80.59%) and CTQ scores (total and across all subscales), which is consistent with the existing literature (32, 33). Early childhood trauma may increase an individual’ s vulnerability to depression through multiple pathways, such as compromising psychological resilience, disrupting metabolic processes, and impairing cognitive function (34, 35). However, it is not clear whether the influence of childhood trauma changes with the stage of depressive illness, especially its associations with the inflammatory system. This study provides new evidence by comparing adolescents with first-episode MDD and recurrent MDD.

Regarding clinical features, this study found that childhood trauma was positively correlated with more severity of depression, suicidal ideation, and alexithymia in adolescents with MDD. These associations were consistently observed in both first-episode and recurrent patients, supporting the notion that childhood trauma exerts a long-term detrimental effect on mental health. Firstly, Evidence from prior research shows that a history of childhood trauma is associated with greater depression severity among patients with depressive disorders (36, 37). For example, a cross-sectional study by Chen et al. (36) reported that childhood trauma has a cumulative effect on depressive symptoms in college students. During the occurrence and development of depression, the negative cognitive patterns and perfectionist tendencies formed by childhood trauma experiences may play an important role in promoting and maintaining it (38, 39). Another study suggested that emotional abuse and neglect may impair anticipatory pleasure and cognitive reappraisal by altering the structure of the ventral striatum and cingulate cortex, which could be an important neural mechanism through which childhood trauma contributes to more severe depression symptoms (40).

Secondly, childhood trauma is strongly associated with an elevated risk of suicidal ideation, and this association which has been consistently demonstrated in the literature (41, 42). From a psychological perspective, individuals with childhood trauma frequently experience more intense feelings of pain and despair, along with heightened irritability and impulsivity, which substantially elevates their suicide risk (43, 44). The study by Wang et al. (45) revealed that, childhood emotional abuse may indirectly increase suicidal ideation by triggering rumination and experiential avoidance, thus identifying emotional dysregulation as a critical mediating mechanism. In terms of biological mechanisms, childhood trauma may result in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This dysregulation is often manifested as a blunted cortisol secretion response to stress, resulting in lower cortisol levels during stress and thereby increasing suicide risk (46, 47).

Finally, Early exposure to childhood trauma may foster an insecure environment, adversely affecting the development of emotional perception and processing in adolescents, contributing to the emergence of alexithymia, which features difficulty with emotional identification, description, and expression (8). For example, a network analysis study in China observed a significant link between exposure to childhood trauma and the occurrence of alexithymia in adolescents with MDD (48). Similarly, a previous cross-sectional study demonstrated that emotional abuse and neglect showed a strong connection to alexithymia in patients with MDD (49). Therefore, ongoing clinical attention to childhood trauma history should be given during the long-term treatment and follow-up of adolescents with MDD.

Notably, this study also found that adolescents with MDD had significantly higher plasma levels of several inflammatory cytokines (IL-1β, IL-6, IL-10, IL-17A, TNF-α) compared to HCs, a result supported by previous domestic and international research (50–52). For example, Becerril et al. (51) found that the peripheral IL-17A levels in adolescents with MDD were significantly higher than those in HCs. And this elevated inflammatory state showed a strong association with the patients’ childhood traumatic experiences. A case-control study reported that, compared to HCs, untreated adolescents with MDD not only had more severe childhood trauma and higher plasma IL-6 levels but also exhibited a significant positive correlation between these two factors (53). The close correlation between childhood trauma and high levels of inflammatory cytokines in patients with MDD may involve complex mechanisms. Firstly, childhood trauma has been shown to be significantly associated with elevated serum HMGB1 levels in adolescents with depression (54). HMGB1 is a key upstream mediator that activates the TLR4/NF-κB signaling pathway and drives transcription of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α (55). This mechanism is supported by clinical evidence of HMGB1 nuclear-to-cytoplasmic translocation observed in depressed patients (56). Secondly, childhood trauma may affect the DNA methylation status of the FKBP5 gene in peripheral blood, leading to the activation of the major immune regulatory factor NF-κB, which promotes a pro-inflammatory state and contributes to the development of depressive disorder (57, 58). Thirdly, evidence implicateed childhood trauma in processes such as heightened lipopolysaccharide sensitivity and microglial priming, potentially underlying a heightened vulnerability to comorbid mental and somatic illnesses (59, 60). Furthermore, employing the maternal separation model of early-life adversity, animal studies have shown a significant correlation between decreased prefrontal cortical parvalbumin levels and elevated plasma inflammatory cytokines (including IL-1β and IL-6) in adolescent rats (61).

Significantly, our study found a disease-stage specific association between childhood trauma and levels of inflammatory cytokines. While childhood trauma was correlated with and could independently predict levels of IL-1β, IL-6, IL-10, and IL-17A in first-episode patients, all inflammatory associations disappeared in recurrent patients. This first-episode specificity may reflect either a state-dependent inflammatory response during acute depression or a transient biological phenomenon specific to illness onset. These possibilities warrant longitudinal investigation. However, we cannot exclude that medication effects rather than illness chronicity explain the absent correlations in recurrent patients, as 67% were medicated versus 0% in the first-episode group. A prospective study found that plasma levels of IL-6 and IL-1β dropped significantly from baseline in adolescents with first-episode MDD following 6 to 8 weeks of fluoxetine treatment (62). A meta-analysis has demonstrated that antidepressant treatment may lead to a significant reduction in the levels of inflammatory cytokines (including IL-6, TNF-α, and IL-10) among depression patients (63). Thus, drug exposure may confound comparisons between first-episode and recurrent patients.

In addition, We also found that the plasma levels of IL-1 β and IL-8 in first-episode adolescents with MDD may be positively correlated with alexithymia. Our findings on IL-8 are similar to those of Uher et al. (64), who reported elevated cerebrospinal fluid IL-8 levels may be linked to alexithymia in non-inflammatory neurological disorders. In contrast, the positive correlation we observed between IL-1β and alexithymia diverges from previous reports. Mandarelli et al. (65) reported no significant difference in serum IL-1β levels between alexithymic and non-alexithymic subjects undergoing upper endoscopy, while Peters et al. (66) found that impaired facial recognition in adolescents was correlated with IL-1β levels. Due to the cross-sectional design, this study did not include any intervention. Future research with larger samples and prospective interventional designs is warranted to further validate the causal relationship between these variables.

There were some limitations to this study. First, although childhood trauma temporally precedes depression, our cross-sectional design limits causal inference. We could not dynamically observe the evolution of inflammatory and clinical symptoms post-trauma, nor fully rule out confounding by factors like genetic susceptibility or adverse environments. Hence, it remains unclear whether the observed first-episode specificity reflects a genuine temporal progression or is attributable to selection bias. Second, the modest sample size may have limited statistical power, particularly for subgroup analyses. The first-episode subgroup (n = 75) may be underpowered for multiple regression analyses, especially when examining cytokine associations with modest effect sizes, thereby increasing the risk of both Type I and Type II errors. Third, childhood trauma was assessed via retrospective self-report, a method susceptible to recall bias, mood-congruent memory effects in currently depressed adolescents, and social desirability bias, all of which may inflate its observed associations with current symptoms. Fourth, medication status was confounded with illness stage (0% vs. 67% medicated), precluding disentanglement of pharmacological effects from disease chronicity; other confounders (lifestyle, comorbidities, social support) were also unmeasured. Additionally, the regression models adjusted only for illness duration and BMI, without controlling for pubertal stage, recent life stressors, or socioeconomic status. Future studies should employ large-scale longitudinal designs to track patients from first onset to remission, clarifying the temporal dynamics among trauma, inflammation, and symptoms. Integrating neuroimaging and molecular techniques will be key to elucidating the mechanisms underlying the observed stage-specific associations.

In summary, this study found that childhood trauma is prevalent among adolescents with MDD and is closely associated with more severity of depression, suicidal ideation, and alexithymia. Notably, its association with inflammatory cytokines exhibits clear first-episode specificity. This first-episode specificity may reflect a state-dependent inflammatory response during acute depression, a transient biological phenomenon at illness onset, or confounding by antidepressant treatment. These possibilities require longitudinal studies to disentangle. Therefore, in clinical practice, childhood trauma should be routinely assessed in adolescents with MDD. For those with a history of trauma, active interventions should be implemented, aiming not only to alleviate clinical symptoms but also to mitigate inflammation, thereby potentially improving long-term prognosis.