Oxytocin Dysfunction in Severe Mental Illnesses following Adverse Childhood Experiences: a systematic review

Adverse childhood experiences (ACEs) are recognized as a transdiagnostic risk factor for developing severe mental illnesses (SMIs), including schizophrenia (SCZ), major depressive disorder (MDD), or bipolar disorder (BPD). However, the specific associations and underlying mechanisms linking ACEs and SMIs remain unclear. In recent years, oxytocin (OT), a neuropeptide known for its role in social bonding and stress regulation, has emerged as a crucial pathway linking SMIs and ACEs. This study aimed to investigate the relationship between SMIs among individuals with a history of childhood adversity and oxytocin dysregulation both at biochemical and genetic levels. We aimed to identify the mechanisms through which OT dysfunction may contribute to the onset, progression, and symptomatology of SMIs. A comprehensive search of PsycINFO, MEDLINE, Web of Science, and PubMed was undertaken to identify studies reporting the impact of ACEs with or without SMIs and measurements of OT or single nucleotide polymorphisms (SNPs) in the gene encoding oxytocin receptor ( OXTR ). Comparisons were made between SMI groups and healthy controls (HCs). We excluded non-English studies, animal research, and extreme trauma contexts. Data were extracted and appraised independently by two reviewers using the Mixed Methods Appraisal Tool (MMAT). Primary outcomes included group differences in ACE scores, a measure that reflects the type, quantity, and severity of childhood trauma. We also compared group differences in OT levels, genotype frequencies of OXTR SNPs, and pathways linking ACEs, OT dysregulation, and SMIs. This systematic review protocol was registered in PROSPERO: CRD42024555819. Of 513 reports identified by the search, 14 studies with 5,624 participants met the inclusion criteria. Most studies (n = 13; 92.86%) reported individuals with SMIs exhibited significantly higher ACE scores than HCs. Among the fourteen studies that measured OT levels, 66% (n = 6) reported lower OT levels in SMIs irrespective of the subgroups, including in SCZ and borderline personality disorder (BoPD). Several polymorphisms in OXTR were found to have a modulatory effect on SMI outcomes. A subset of SNPs conferred susceptibility, whereas others served as protective factors. This review highlights a strong association between ACEs, OT system dysregulation, and SMI susceptibility, particularly in SCZ and BoPD. However, methodological inconsistencies, gender biases, and reliance on peripheral OT measurements require further investigation. Future longitudinal studies are needed to clarify pathways and inform clinical interventions aimed at mitigating the impact of ACEs on mental health.