Dexamethasone is a synthetic long-acting glucocorticoid that inhibits the production of CRH by the hypothalamus and ACTH by the pituitary gland. Although there is some controversy about the specificity of dexamethasone suppression tests (DSTs) in children and adolescents (Guerry and Hastings, 2011), in healthy adults, dexamethasone can inhibit the release of CORT. Dexamethasone non-suppression or early escape from dexamethasone suppression is thought to be partly the result of glucocorticoid receptor downregulation at hippocampal, hypothalamic, or pituitary levels and contributes to HPA axis hyperactivity in depressed adults (Zalsman et al., 2006; Guerry and Hastings, 2011; Wyller et al., 2016). In a test of dexamethasone suppression in children and adolescents, Lopez-Duran et al. found that children and adolescents with depression exhibited higher CORT production (or less suppression) after a DST compared to controls without depression and that, on average, approximately 45% of children and adolescents with depression and only 18% of control participants without depression had positive DST results in the mean of all studies (Lopez-Duran et al., 2009). These findings suggest that, unlike adults, the HPA axis in young adults with depression becomes active due to insensitivity to the hormonal “braking” system or early escape.

Emerging studies found that the serotonergic system are associated with suicide, impulsive violence, and anxiety (Tyano et al., 2006). The HPT axis has a regulatory role in the 5-hydroxytryptamine system of the brain. Zalsman et al. measured plasma serotonin (p5-HT) to assess the relationship between p5-HT levels and psychometric measures. In the adolescent population, p5-HT levels were negatively correlated with suicide and violence in a subgroup of participants who were suicidal; however, p5-HT was higher in the entire clinical group compared with normal controls (Tyano et al., 2006). Therefore, the underlying mechanism needs to be further investigated.

Drugs that stimulate the serotonergic system result in the release of prolactin and CORT. In adult studies, the most commonly used drug was fenfluramine, which showed a weakened prolactin response in patients with depression compared to controls (Zhang et al., 2012). L-5-hydroxytryptamine (L-5-HTP) is a precursor of serotonin and increases serotonin turnover in the central nervous system. In a study of children with depression using L-5-HTP, Ryan et al. found reduced CORT levels but a higher prolactin response than normal controls and limited to girls with depression (Ryan et al., 1992). In comparing abused children with depression, unabused children with depression, and unabused normal controls, it was found that the abused and depressed group had increased prolactin release after L-5-HTP stimulation compared to the other two groups (Kaufman et al., 1998). These results suggest that aggressive and suicidal behavior in adolescents differs from that in adults. It is associated with more sensitive responsiveness of adolescent 5-hydroxytryptaminergic with 5-HT1A or 5-HT2 receptors, affecting their prolactin release. In addition, people with depression often suffer from disrupted sleep. However, no abnormal sleep was found in children and adolescents with depression. Emslie et al. (1990) found that hospitalized children with depression had shorter rapid eye movement (REM) latencies, longer sleep latencies, and more REM sleep time compared to normal controls, but no differences in stage 4 sleep, possibly related to less 5-HT neurotransmission or more central cholinergic activity (Zalsman et al., 2006).

Growth hormone (GH) is secreted by the anterior pituitary gland. Its secretion is stimulated by GH-releasing hormone and inhibited by somatostatin. Notably, Children with GH deficiency (GHD) exhibit psychological immaturity, which is manifested by a lack of social confidence and symptoms of depression (Akaltun et al., 2018). Akaltun studied 122 children and adolescents aged 7–17 years with GHD (of which 87 were treated for GHD, and 35 were untreated) and 122 healthy volunteers and found that children with GHD had significantly more severe generalized anxiety disorder and social anxiety disorder compared to healthy controls (Akaltun et al., 2018).

GH insensitivity may be a characteristic marker of depression. A distinctive feature of post-traumatic stress disorder (PTSD) is the hyperactivation of the sympathetic and noradrenergic systems. GH response to the α2 agonist clonidine can be assayed for noradrenergic receptor function. A study by Morris et al. (2004) to examine whether young subjects with combat-related PTSD (with or without comorbid depression) had an attenuated GH response to clonidine found that participants with depression and PTSD had slow GH responses to clonidine. This finding suggests that postsynaptic α2 receptors are sub-sensitive (Morris et al., 2004). A study by Fu et al. (2001) in which positron emission tomography scans were performed during clonidine stimulation found diminished noradrenergic function in the prefrontal cortex in depression, suggesting that GH sensitivity in depression is related to HPA function. Dahl et al. (1992) found no difference in GH levels between adolescents with MDD and the control. However, the MDD group with suicidal behavior (defined as having detailed plans or attempts) had reduced sleep GH secretion compared to the group without suicidal behavior. Abnormalities in the GH axis may be limited to preadolescent children with depression (Zalsman et al., 2006), but the role of GH in adolescent suicide is unclear and requires further study.

Pubertal maturation is a critical process in the development of the HPA axis, which can be influenced by sex hormone activation and their tissue effects. For example, the production and secretion of adrenal steroids in the HPA axis increase during early puberty, which stimulates the release of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, thus promoting the production of gonadal steroids. The dramatic and rapid rise in gonadal hormones promotes reproductive maturation, physical growth, and the development of secondary sexual characteristics in adolescents. Elevated gonadal hormone levels also contribute to the organization and activation effects of the developing adolescent brain, which affects the HPA axis and may lead to the emergence of gender differences in HPA axis function. There is a great need to study the role of sex steroids and their potential mechanisms in developing the HPA axis.

di Luigi et al. (2006) examined the relationship between age 13.3 ± 2.1-year-old male adolescents before and after acute exercise to investigate the correlation between pubertal characteristics and salivary CORT (C), dehydroepiandrosterone sulfate (DHEAS), and DHEAS/C ratio. They found that after exercise-related stress, the mean pre-stress C and DHEAS concentrations significantly increased, while the DHEAS/C ratio significantly decreased. Pre-stress C was positively correlated with age, and changes in post-stress C concentration were negatively correlated with puberty, mean testicular volume, and pre-stress salivary DHEAS. In addition, salivary DHEAS concentrations and DHEAS/C ratios before and after exercise stress were positively associated with age, puberty, pre-stress salivary testosterone (T), testicular volume, and body mass index (di Luigi et al., 2006), suggesting that stress-related risk may be increased in males during early adolescence. It follows that differences in age at pubertal onset may also lead to different developmental trajectories of the HPA axis and ultimately contribute to gender differences in the HPA stress response.

In addition, there are other factors, such as endogenous cannabinoids (Hill et al., 2008; Zajkowska et al., 2014) and telomere length (Zajkowska et al., 2021), that are associated with mental disorders, all of which are somewhat controversial and lack clear clinical data support.

Numerous meta-analyses have shown that regular physical activity can improve various physiological and psychological factors in patients with depression (Kvam et al., 2016; Schuch et al., 2018). Exercise therapy has been shown to be effective in the treatment of depression in adults, and Kvam et al. included 23 randomized controlled trials and 977 participants in a meta-analysis, demonstrating that physical exercise is an effective intervention for the treatment of depression and may also be a viable adjunctive therapy in combination with anti-depressants (Kvam et al., 2016). In a meta-analysis of 49 prospective cohort studies (comprising 1,837,794 persons), Schuch et al. found that physical activity prevented the onset of depression regardless of age and geographic region (Schuch et al., 2018). However, fewer studies have been conducted on adolescent inpatients with depression. Philippot et al. assessed depression and anxiety symptoms using the Hospital Anxiety Depression Scale in 52 adolescent inpatients who were physically active three to four times a week for 6 weeks (a total of 20 h), concluding that planned physical exercise can be used as a complementary measure to adolescent psychiatric inpatient treatment to reduce their depressive symptoms (Philippot et al., 2022) and demonstrating the effectiveness of physical exercise in adolescent depression inpatient treatment. Another meta-analysis of 115,540 children and adolescents from 12 countries found a good correlation between meeting all three exercise recommendations in the 24-h guidelines and better mental health indicators in children and adolescents (Sampasa-Kanyinga et al., 2020). Several meta-analyses of exercise interventions for adolescents with depression have similarly concluded that physical activity is a promising primary intervention for adolescents with a diagnosis or threshold of symptoms of depression (Carter et al., 2016; Bailey et al., 2018).

However, the results from different studies varied. In a meta-analysis that included 16 studies with a total of 1,191 participants aged 11–19 years, Larun et al. showed that exercise had a small effect in reducing depression and anxiety scores compared to the general population of children and adolescents, regardless of whether the intensity of exercise was high or low (Larun et al., 2006). Also, in another meta-analysis that included 13,307 references with participants aged 12–18 years and predominantly female, it was found that although exercise interventions may be associated with a reduction in the severity of depression in adolescents, data were scarce. One of the trials found no significant decrease in the severity of depression at a six-month follow-up (Axelsdóttir et al., 2021). The limited number of studies and the clinical diversity of participants, interventions, and measurement methods may limit the drawing of conclusions. Therefore, the effect of exercise on treating anxiety and depression in children and adolescents remains unclear due to the lack of evidence. Because of the limited assessment of the effects of exercise therapy, the actual impact can vary greatly. Therefore, large-scale, high-quality trials of physical activity interventions for adolescent mental disorders, including follow-up periods, are required.

Paolucci et al. (2018) studied 61 college students who underwent 6 weeks of high-intensity interval training (HIT), moderate continuous training (MCT), or no exercise (CON) during the semester. They found increased depression in the CON group and decreased depression in both the MCT and HIT groups. However, MCT reduced the levels of the pro-inflammatory cytokine TNF-α, while HIT increased perceived stress, TNF-α, and IL-6 (Paolucci et al., 2018). These changes may be due to higher levels of physical stress caused by a strenuous physical exercise. Imboden et al. conducted an experiment where patients with depression between 18 and 60 years of age were assigned aerobic exercise (AE) and basic stretching activities (control group) three times a week for 6 weeks. The severity of depression was assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory, and the results showed that AE significantly reduced depression and had additional benefits on memory function compared to stretching exercises. Another meta-analysis that included eight randomized controlled trials also demonstrated that moderate-to-high intensity aerobic exercise is effective in reducing symptoms such as attention deficiency, hyperactivity, impulsivity, anxiety, executive function, and social barriers in children with attention-deficit/hyperactivity disorder (Cerrillo-Urbina et al., 2015).

Regular physical activity has been repeatedly shown to promote cognitive, emotional, and motor benefits while reducing pain and adverse effects. It is preventive in anxiety and depressive states and supports mental health in adolescents and adults. Exercise improves several biomarkers associated with depressive states: HPA axis homeostasis, anti-neurodegenerative effects, monoamine metabolic regulation, and neuroimmune function. Physical activity can serve as a “scaffold” to support the anti-inflammatory defense and nerve repair processes of BDNF (Archer et al., 2014).

Physical activity has different effects on the various levels of the HPA axis. It was found that wheel running can reduce the binding and expression of the mineralocorticoid receptors in mice’s hippocampus and increase the glucocorticoid receptors’ levels in rats. Running exercise can reduce CRF mRNA in the PVN, thereby limiting the increase of proopiomelanocortin mRNA in the anterior pituitary, activating tyrosine hydroxylase mRNA in the adrenal glands, and increasing corticosterone levels (Stranahan et al., 2008). Eight weeks of moderate-intensity group jogging significantly reduces 24-h urinary CORT and adrenaline secretion in young women with moderate depression (Nabkasorn et al., 2006). Aerobic running training for 120 consecutive days maintained the stability of BDNF, insulin-like growth factor 1, vascular endothelial growth factor, and C, preventing physical and psychological deterioration (Abeln et al., 2022).

The amygdala and hippocampus are critical centers in the limbic system. Both structures are connected to the HPA axis and can regulate the HPA stress response. The amygdala is primarily excitatory for HPA axis function, while the hippocampus is predominantly inhibitory (Radley and Sawchenko, 2011; Herman, 2013). Furukawa et al. (2021) found that exercise promotes increased adult hippocampal neurogenesis by releasing the systemic antioxidant selenium transporter protein selenoprotein P, which activates the quiescent hippocampal neural precursor cells. This finding suggests that physical exercise may promote increased hippocampal neurogenesis in the brain and play a specific role as an “exercise pill” in fighting depression. The medial prefrontal cortex (mPFC) responds to traumatic events by modulating the amygdala’s response, and different mPFC regions are associated with different roles in regulating the HPA axis (Murphy et al., 2022). Yan et al. (2022) found that exercise mediated the restoration of m6A in the mPFC and promoted mPFC activity to achieve anti-anxiety effects in mice.

The levels of other anti-depressant hormones related to physical activities, including salivary and plasma steroid hormones (CORT, T, and DHEA) and GH, correlate with the type, duration, and intensity of exercise. A systematic review found preliminary evidence that one-off acute exercise may exert its anti-depressant effects by increasing cardiac natriuretic peptide, brain natriuretic peptide, copeptin, and GH in patients with severe depression (Schuch et al., 2016). In contrast, long-term exercise may exert its anti-depressant effects by promoting long-term adaptation of copeptin, thiobarbituric acid reactive species, and total mean frequency. A recent acute exercise study (Kallies et al., 2019) and long-term randomized controlled trial (Kerling et al., 2017) suggest that aerobic exercise may exert its effects by increasing BDNF. However, a preliminary meta-analysis on only six randomized controlled trials and 176 participants (Dinoff et al., 2018) found no significant long-term change in BDNF.

Paolucci et al. (2018) studied the relief of depression through exercises from an inflammatory factor perspective in 61 college students who underwent 6 weeks of HIT, MCT, or no exercise (CON) during the semester. They found increased depression in the CON group but decreased depression in both the MCT and HIT groups and decreased levels of the pro-inflammatory cytokine TNF-α in the MCT group. However, physical activity also increased perceived stress, TNF-α, and IL-6 relative to MCT (Paolucci et al., 2018). These changes may be due to higher levels of physical stress caused by a more strenuous exercise regimen.