A large proportion of patients with severe, refractory depression have metabolic disorders that, once treated, appear to alleviate depressive symptoms over the long term.
"Our findings, if replicated, suggest that neurometabolic disorders may contribute to treatment-refractory psychiatric disorders even without other systemic illness," the authors, led by Lisa A. Pan, MD, University of Pittsburgh School of Medicine in Pennsylvania, write.
"An important question is whether early identification and treatment of an underlying metabolic abnormality early in the course of psychiatric illness could prevent long-term emotional and cognitive complications," they add.
The study was published in the January issue of the American Journal of Psychiatry.
Dramatic, Durable Remission
The impetus for the current study was a previous case reported by the same investigators and published in the BMJ. It involved a 19-year-old man with treatment-refractory depression who had attempted suicide multiple times. The researchers found that the man had a severe deficiency of cerebrospinal fluid (CSF) tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis.
Upon undergoing replacement therapy with the tetrahydrobiopterin analogue sapropterin, the patient experienced dramatic and long-lasting remission of his depression.
To investigate further, the researchers conducted a case-control study that included 33 adolescent and young adult patients with refractory depression and 16 healthy control persons. Refractory depression was defined as depression for which at least three courses of medication administered at a maximum dose for an adequate duration failed.
The patients with treatment-refractory depression were aged 14 to 40 years. For these patients, the depression was of relatively early onset (mean age of onset, 12.4 years). Half the patients reported at least one suicide attempt. Severity of depression at the time of study screening was moderate to severe.
A metabolomic analysis that included testing of central nervous system–specific metabolites showed CSF metabolite abnormalities among 21 of 33 of the patients with treatment-refractory depression, compared to none of the healthy control patients.
The most common abnormality, present in 12 (36%) participants, was cerebral folate deficiency (CFD), in which serum folate levels were normal but levels of CSF 5-MTHF were low (<40 nmol/L). CFD can be caused by mutations in the cerebral folate receptor gene (FOLR1), although genetic testing of eight patients with CFD indicated that none had the mutation.
Importantly, none of the patients had primary neurologic symptoms or other overt clinical disease, suggesting previously reported causes of the abnormalities were unlikely, the authors note.