An analysis of the cerebral spinal fluid metabolome during intensive chemotherapy and its association with depressive symptoms in children with acute lymphoblastic leukemia

Abstract Improvements in pediatric acute lymphoblastic leukemia (ALL) treatment have led to five-year survival rates exceeding 90%. Despite this progress, up to 80% of patients suffer from psychiatric complications, with the most common being depression. To better understand the molecular mechanisms underlying these symptoms, this study evaluated cerebral spinal fluid (CSF) metabolites associated with depressive symptoms reported during ALL treatment. Eligible patients were age 7-18 years, diagnosed with ALL, and treated at Texas Children's Hospital between 2012 and 2018. Participants completed the Childhood Depression Inventory (CDI) during the start of delayed intensification therapy and standardized total scores were calculated. CSF samples collected within one week of completing the CDI underwent untargeted metabolomic profiling. Linear regression was used to evaluate associations between CSF metabolites and continuous depressive symptom scores, controlling for age, BMI z-score, sex, race, ethnicity, induction intensity, and metabolomic profiling batch. Statistical significance was defined at a Benjamini-Hochberg false discovery rate (BH-FDR) corrected p<0.05. A total of 92 eligible patients were included. The sample was 54% male, 64% Hispanic, with an average age of 12 years old. Depression scores ranged from 40-90, with a mean score of 50. Untargeted metabolomic profiling of CSF samples detected 260 metabolites. The relative abundance of three metabolites was significantly higher in individuals with elevated depressive symptoms, including mannose (Beta=4.2, BH-FDR = 0.004), pyruvate (Beta= 3.73, BH-FDR = 0.01), and mannitol/sorbitol (Beta=3.49, BH-FDR = 0.03). A quantitative enrichment analysis indicated that the most enriched pathway was fructose and mannose degradation (Holm p = 0.002), followed by galactose metabolism (Holm p= 0.004) and the glucose-alanine cycle (Holm p=0.006). As most newly-diagnosed patients with ALL achieve long-term survival, research efforts are increasingly focused on improving health-related quality of life among patients during and after treatment. This study identified three carbohydrates positively correlated with depressive symptoms during ALL treatment. Enrichment analyses implicated several pathways involving the identified carbohydrates and the energy metabolism. These findings align with previous research linking energy-related metabolites with depression symptoms. The implicated pathways may ultimately serve as biomarkers or novel therapeutic targets to mitigate depressive symptoms.