Research study · Translational Psychiatry · 2025
Major depressive disorder in children and adolescents is associated with reduced hair cortisol and anandamide (AEA): cross-sectional and longitudinal evidence from a large randomized clinical trial
Verified on PubMed Oxford CEBM Level 1B: Randomized Controlled Trial
A 2025 randomized controlled trial in Translational Psychiatry tested hydrocortisone in major depressive disorder. The results were mixed, with some clear differences and some that did not hold up. This study shows that depressed young people in this group had lower levels of a stress hormone and a body chemical in their hair than healthy.
In plain language
Study overview
This study looked at young people aged 8 to 17 who had depression, and compared them with young people without depression. Researchers measured two chemicals that are stored in hair over several months: a stress hormone called cortisol and a body chemical called anandamide. They also tracked the young people with depression over about nine months, while some of them took fish-oil capsules or a dummy pill.
Findings
The results were mixed, with some clear differences and some that did not hold up. Young people with depression had lower levels of both chemicals in their hair than young people without depression, and the stress hormone level tended to be lower when their depression was more severe.
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The deeper readScientific analysis
Pediatric major depressive disorder (MDD) represents a leading cause of disability worldwide in children and adolescents, while its underlying pathophysiology remains largely elusive. The endocannabinoid system (ECS) and the hypothalamus-pituitary-adrenal (HPA) axis are considered intertwined regulatory systems crucially implicated in the pathophysiology of depressive disorders. This study explores the cross-sectional and longitudinal association between the ECS, specifically anandamide (AEA), and the HPA axis with its main effector cortisol and MDD status and severity in children and adolescents. Utilizing data from the omega-3-pMDD trial, a phase III Randomized Clinical Trial assessing the efficacy and safety of omega-3 fatty acid supplementation in pediatric MDD, we examined hair AEA and cortisol concentrations in 110 children and adolescents aged 8-17 years, with MDD. Associations between MDD, symptom severity and hair AEA and cortisol concentrations were explored across four measurement time points (baseline, week 6, 24 and 36). Additionally, 127 healthy children and adolescents were examined once to enable cross-sectional comparisons between MDD cases and healthy controls. Baseline comparisons for the 237 children and adolescents showed lower cortisol and AEA levels in hair of children and adolescents with MDD compared to healthy controls. Longitudinal multi-level analysis over all time-points further corroborated negative longitudinal associations between hair cortisol and depressive symptoms in children and adolescents with MDD. Taken together, reduced baseline AEA and cortisol levels emerge as robust biomarker in depressed youth, while the negative longitudinal association between hair cortisol and depression symptoms might provide useful for therapy monitoring purposes. These results hold implications for early detection, diagnosis, and therapeutic response prediction in pediatric MDD.
The paper
Citation
Walther A, Eggenberger L, Debelak R, Kirschbaum C, Häberling I, Osuna E, et al. Major depressive disorder in children and adolescents is associated with reduced hair cortisol and anandamide (AEA): cross-sectional and longitudinal evidence from a large randomized clinical trial. Translational Psychiatry (2025). PubMed 40413177 · DOI
Limitations the authors noted
Comorbid conditions (ADHD, anxiety, behavioral disorders) were not excluded and may confound results. Prior psychotherapy or medication use before enrollment was not controlled. Hormonal contraceptive use was not recorded, relevant for female participants. Race/ethnicity and socioeconomic status were not systematically collected. Narrow age range (mean 15.7, SD 1.6) limits generalizability to younger or adult populations. Cross-sectional design cannot establish causality; the pediatric cohort is majority female among cases and the authors could not model covariates in the RQ2 models due to convergence problems. Hair samples represent only two 6-week segments for cases; the healthy control sample was not followed longitudinally. The paper discusses both hypo- and hyper-activity explanations for low cortisol without resolving which applies, and the proposal for synthetic glucocorticoid tre
In practice
Why this matters
This study shows that depressed young people in this group had lower levels of a stress hormone and a body chemical in their hair than healthy peers, and that the stress hormone moved in step with depression severity over time. It does not show that these chemicals cause depression, that they predict who will respond to treatment, or that they are ready to be used as a test in clinics. The findings leave open whether they hold in younger children, in other groups of young people, and with other forms of treatment, and the follow-up was relatively short.
Frequently asked questions
Clinical Questions & Answers
What were the primary clinical findings regarding Endocannabinoids and Major depressive disorder?
The results were mixed, with some clear differences and some that did not hold up. Young people with depression had lower levels of both chemicals in their hair than young people without depression, and the stress hormone level tended to be lower when their depression was more severe.
What study limitations or clinical safeguards should patients keep in mind?
Comorbid conditions (ADHD, anxiety, behavioral disorders) were not excluded and may confound results. Prior psychotherapy or medication use before enrollment was not controlled. Hormonal contraceptive use was not recorded, relevant for female participants.
Browse related research
Condition: Major depressive disorder Topic: Endocannabinoids Topic: Hydrocortisone Topic: Polyunsaturated alkamides
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Reviewed by Dr. Caplan on October 29, 2026.
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