Impaired central methylation capacity in drug-naïve first-episode psychosis: Evidence from cerebrospinal fluid one-carbon metabolism.

BACKGROUND

One-carbon metabolism is implicated in psychotic disorders, yet most evidence relies on peripheral markers that are susceptible to confounding by antipsychotic exposure and illness chronicity. Direct cerebrospinal fluid (CSF)-based assessment at the onset of psychosis provides insight into central metabolic alterations largely independent of peripheral confounding; however, such evidence remains limited. We examined CSF markers of methylation capacity in patients with drug-naïve first-episode psychosis (FEP).

METHODS

In this cross-sectional comparative study, CSF concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), the SAM/SAH ratio, and 5-methyltetrahydrofolate (5-MTHF) were measured in 17 drug-naïve male patients with FEP and 17 controls. A broad CSF amino acid panel was quantified to assess global amino acid availability and coordination with methylation-related metabolites.

RESULTS

Patients with FEP showed markedly lower CSF SAM and a substantially reduced SAM/SAH ratio compared with controls (both p < 0.001), indicating constrained central methylation capacity at first clinical presentation. CSF 5-MTHF was also lower in patients (p = 0.014), consistent with reduced folate-dependent remethylation support. CSF SAH and absolute CSF amino acid concentrations were largely comparable between groups. Secondary analyses suggested altered associations between methylation-related metabolites and select amino acids in FEP.

CONCLUSIONS

CSF evidence indicates that impaired central methylation capacity and reduced folate-dependent remethylation support are already present at the onset of psychosis, independent of antipsychotic treatment. These findings suggest that alterations in central one-carbon metabolism may already be present at the onset of psychosis rather than representing solely downstream consequences of chronic illness or long-term treatment exposure.