The findings, if replicated, suggest that early identification and treatment of an underlying metabolic abnormality early in the course of psychiatric illness could prevent long-term emotional and cognitive complications, say Lisa Pan, M.D., of the University of Pittsburgh Medical Center and colleagues at several other institutions.
In the study, participants aged 14 to 40 with depression who had not responded to at least three maximum-dose medication trials of at least six weeks each were recruited by advertisement through the Clinical and Translational Science Institute’s Research Participant Registry at the University of Pittsburgh or by clinical referral.
CSF metabolic testing was compared in 33 adolescent and young adult patients with histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments) and 16 healthy comparison subjects. Testing for CNS-specific metabolic abnormalities included 5-methyltetrahydrofolate, tetrahydrobiopterin, neopterin, pyridoxal-5-phosphate, 5-hydroxyindoleacetic acid, homovanillic acid, and amino-adipic semialdehyde.
CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (n=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate levels. All patients with cerebral folate deficiency showed improvement in depression symptom inventories after treatment with folinic acid. None of the healthy comparison subjects had a metabolite abnormality.
The study was prompted by the case of a young adult with treatment-refractory depression and multiple suicide attempts who was found to have a severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. After treatment with sapropterin, a tetrahydrobiopterin analogue, the patient experienced a dramatic and long-lasting remission of depression.
“If these findings are replicated, they suggest that the identification of new inborn errors of metabolism or secondary disorders of metabolism contributing to psychiatric illness may allow repurposing of currently approved orphan drugs,” the researchers stated.
For related information, see the Psychiatric News article "Metabolites Offer New Clues About Medication Response."