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Exploring sex differences in endocannabinoid system biomarkers and their relationship with antidepressant treatment outcomes in major depressive disorder: a CAN-BIND 1 secondary analysis.

Maryam Sorkhou·Helena K Kim·Faranak Farzan·Jane A Foster·Benicio N Frey·Muhammad I Husain·Sidney H Kennedy·Raymond W Lam·Roumen Milev·Benoit H Mulsant·Daniel J Müller·Lena C Quilty·Claudio N Soares·Valerie H Taylor·Gustavo Turecki·Stefan Kloiber
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Abstract

BACKGROUND: Sex differences in major depressive disorder (MDD) are well documented, but it remains unclear whether sex-related variation in peripheral endocannabinoid system (ECS)-related biomarkers is detectable in MDD. OBJECTIVES: To examine baseline sex differences in ECS-related mRNA expression, DNA methylation, and single nucleotide polymorphisms (SNPs) in MDD, and associations between baseline ECS markers and antidepressant outcomes in sex-stratified analyses. METHODS: Among 178 participants with MDD from CAN-BIND-1, all received escitalopram for 8 weeks; non-responders then received adjunctive aripiprazole from Weeks 8-16.Response was defined as ≥ 50% reduction in MADRS score, and remission as MADRS ≤ 10. ANCOVAs examined baseline sex differences and sex-stratified biomarker associations with percent MADRS reduction at Weeks 8 and 16, as well as categorical response and remission outcomes. Covariates included site, baseline MADRS, age, and ethnicity. False discovery rate correction was applied. RESULTS: Baseline sex differences in methylation were observed for CACNA1H, GABRB2, MAGL, and GABRR2, though none survived correction. No baseline sex differences in mRNA expression or SNPs were detected after correction. Lower baseline DAGLA mRNA in males was associated with greater Week 8 symptom improvement (FDR corrected). This association was not observed in females. No associations with response or remission at Weeks 8 or 16 survived correction. IMPLICATIONS: Baseline sex differences in peripheral ECS-related markers were not detected in this sample. Larger studies are needed to verify whether ECS-related biomarkers, particularly DAGLA, contribute to antidepressant outcomes in a sex-specific manner.

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HumansMajor Depressive DisorderMaleFemaleEndocannabinoidsSex CharacteristicsPolymorphism, Single NucleotideTreatment Effect HeterogeneityAdultMiddle AgedAntidepressive AgentsDNA MethylationBiomarkersRNA, MessengerEscitalopramOutcome Assessment, Health CareEndocannabinoid systemMajor depressive disorderMethylation expressionSex differencesmRNA expressionJournal ArticleRandomized Controlled Trial

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Maryam Sorkhou, Helena K Kim, Faranak Farzan, Jane A Foster, Benicio N Frey, Muhammad I Husain, Sidney H Kennedy, Raymond W Lam, Roumen Milev, Benoit H Mulsant, Daniel J Müller, Lena C Quilty, Claudio N Soares, Valerie H Taylor, Gustavo Turecki, Stefan Kloiber. 2026-08-25. Exploring sex differences in endocannabinoid system biomarkers and their relationship with antidepressant treatment outcomes in major depressive disorder: a CAN-BIND 1 secondary analysis.. https://doi.org/10.1007/s00406-026-02362-3

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Journal Article; Randomized Controlled Trial resourceAdult subjectAntidepressive Agents subjectBiomarkers subjectDNA Methylation subjectFemale subjectHumans subjectJournal Article subjectMajor Depressive Disorder subjectMale subjectMiddle Aged subjectOutcome Assessment, Health Care subjectPolymorphism, Single Nucleotide subjectRandomized controlled trials study

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