Gloor Pascal, Haeberling Isabelle, Spanaus Katharina, Kullak-Ublick Gerd A, Berger Gregor, Visentin Michele
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
J Nutr. 2025 Jul;155(7):2267-2274. doi: 10.1016/j.tjnut.2025.05.012. Epub 2025 May 14.
Low concentrations of systemic folates have been associated with a higher risk of major depressive disorder (MDD) and more severe symptoms. Moreover, folate supplementation has been shown to increase the response to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Folates reach the brain through the choroid plexus via transcytosis mediated by the folate receptor alpha (FRα). FRα also represents the main mechanism of folate retrieval from the nascent urine. Autoantibodies against the FRα autoantibodies(FRAAs) have been found in the serum of individuals with cerebral folate deficiency.
This study aimed to assess the role of serum FRAA titer on serum folate concentration, disease severity, and response to the SSRI/SNRI treatment in adolescents with MDD.
Serum samples at baseline obtained from the participants of a large multicenter intervention trial in moderately to severely depressed youth were analyzed. Quantification of FRAA was performed by enzyme-linked immunosorbent assay. Serum folate concentration was determined by radioligand binding assay.
FRAA titer in the patients with folate deficiency (≤3.0 ng/mL) was significantly higher than that in the patients with a normal folate concentration, and a low FRAA titer was associated with a reduced risk of folate deficiency. No correlation was found between the Children's Depression Rating Scale-Revised score and the serum folate concentration or the FRAA titer. In regression analysis, the effect size of the serum folate concentration on the response to SSRI/SNRI was larger than that of the FRAA titer. The response rate to the treatment in the high-folate group was ∼4 times that in the low-folate group (28.5% compared with 6.7%).
In conclusion, patients with high-FRAA titers carry a higher risk of folate deficiency. Moreover, the response to SSRI/SNRI treatment is less likely in patients with folate deficiency.
