Major depressive disorder (MDD) is a common mental illness in adolescents. The prevalence of MDD in adolescents has been rapidly increasing in recent years (Daly, 2022). In a recent epidemiologic survey, the prevalence of MDD in Chinese children and adolescents was 2.0 % (Li et al., 2022). Depression in adolescents is characterized by high rates of suicide and self-harm, high rates of relapse, high illness burden, and depressive symptoms that may persist into adulthood, which severely affecting their mental health and social functioning (Daly, 2022; Miller and Campo, 2021). Currently, MDD is considered to be a complex disorder associated with the interaction of various environmental and physiological factors, whose exact pathophysiological mechanisms remain unclear.

A growing body of evidence has suggested that alterations in cytokines levels caused by inflammatory response mechanisms may significantly contribute to the onset of MDD (Das et al., 2021; Oliveira et al., 2023; Tang et al., 2021; Xu et al., 2023). Currently, the more widely studied inflammatory cytokines in patients with MDD mainly include pro-inflammatory cytokines [e.g., interleukin (IL)-1β, IL-6, IL-17 A, tumor necrosis factor-α (TNF-α), etc.] and anti-inflammatory cytokines (e.g., IL-8, IL-10, etc.), which perform crucial functions in controlling and regulating inflammation (Harsanyi et al., 2022). First, a series of previous case-control studies and meta-analyses have shown that patients with MDD have higher levels of peripheral circulating cytokines compared to healthy controls (HCs) (Oliveira et al., 2023; Osimo et al., 2020; Xu et al., 2023). Moreover, higher levels of inflammatory cytokines usually mean a more severe disease (D'Acunto et al., 2019; Xu et al., 2023). After treatment with antidepressant medications, patients' levels of IL-1β, IL-6, IL-10, and TNF-α are significantly reduced (Çakici et al., 2021; García-García et al., 2022; Goldsmith et al., 2016). In addition, a meta-analysis of 20 clinical studies also showed a positive effect of anti-inflammatory drugs on improving depressive symptoms (Kappelmann et al., 2018), which further confirmed the strong association between inflammatory factors and depression. Despite the large number of evidence mentioned above suggesting that MDD relates to increased pro-inflammatory activity, there were still some studies that have gotten inconsistent results. For example, some studies found no changes in inflammatory cytokines levels in patients with MDD compared to HCs (Einvik et al., 2012) and there was no correlation with disease severity (Haapakoski et al., 2015). Hence, some researchers have speculated that increased levels of inflammatory cytokines may be more associated with certain clinical features of MDD, such as suicidal ideation and sleep disorders (Chu et al., 2019; Ganança et al., 2021; Strumberger et al., 2023).

Insomnia is to be one of the most common comorbid symptoms of MDD which is usually considered to be associated with a poor prognosis (Kennard et al., 2018). One study found that approximately 64.6 % of Chinese patients with MDD reported suffering from insomnia symptoms (Zhao et al., 2018). Given the importance of insomnia to the development of depression, it is important to understand the biological mechanisms. Recently, there is evidence to support a close link between sleep disturbance and alterations in the levels of inflammatory cytokines (Irwin and Piber, 2018), which has been tentatively demonstrated in normal populations and in patients with psychiatric disorders. For instance, D'Antono et al. reported a strong association between sleep quality and inflammation in healthy population (D'Antono and Bouchard, 2019). A case-control study also found that in patients with schizophrenia, the worse the sleep quality, the higher the levels of C-reactive protein (CRP) and IL-6 (Lee et al., 2019). Similarly, one study found that CRP was significantly correlated with insomnia symptoms, and not with depression severity in children and adolescents with MDD (Strumberger et al., 2023). However, there are also studies that have reached inconsistent conclusions. For example, Walker et al. found no associations between insomnia and IL-1β, IL-6, and TNF-α (Walker et al., 2021). These inconsistent findings may be explained by the heterogeneity of study samples (e.g., different periods of the disease).

Over 50 % of patients experience at least one additional depressive episode after the initial one (Burcusa and Iacono, 2007), and elevated levels of pro-inflammatory cytokines increase the likelihood of MDD recurrence (Liu et al., 2019). Additionally, the associations between inflammatory cytokines and psychopathology may also be inconsistent in patients with first-episode and recurrent MDD. For instance, Jeenger et al. found that depression severity was associated with elevated serum CRP levels in adults with first-episode MDD, but not in those with recurrent MDD (Jeenger et al., 2017). Insomnia and inflammatory abnormalities have been broadly studied in patients with MDD. However, we could not find a study comparing differences in the associations between insomnia symptoms and inflammatory cytokines in patients with first-episode and recurrent MDD, especially in the adolescent population.

Therefore, this study aimed (1) to compare differences in inflammatory cytokines levels and prevalence of insomnia symptoms in adolescents with MDD and HCs; and (2) to investigate the associations between insomnia and inflammatory cytokines levels in adolescents with first-episode and recurrent MDD.