Are CSF Metabolic Abnormalities Linked to Refractory Depression?

Metabolic abnormalities in cerebrospinal fluid (CSF) may be an unrecognized contributor to treatment-refractory depression, according to a study in AJP in Advance.

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 test results were compared in 33 adolescent and young adult patients with histories of treatment-refractory depression and 16 healthy comparison subjects. Testing for CNS-specific metabolic abnormalities included 5-methyltetrahydrofolate (5-MTHF), 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 (CFD), a metabolic abnormality in which the serum folate level is normal but the CSF 5-MTHF level is low (less than 40 nmol/L), was the most common metabolic abnormality identified, present in 12 participants (36 percent). One participant with CFD also had low CSF levels of tetrahydrobiopterin metabolites. Abnormalities were identified in nine additional participants: five with an acylcarnitine profile abnormality, one with a low guanidinoacetate level and a creatine/creatinine ratio consistent with a creatine synthesis deficit, one with Fabry’s disease, and two with microdeletions of chromosomes relevant to metabolic status.

Of the 12 patients with CFD, all were treated with folinic acid for at least six weeks while continuing their pre-evaluation treatment regimen. Ten of the 12 patients showed reductions in symptom inventory scores at follow-up. (One patient was lost to follow-up, and one was nonadherent with the folinic acid treatment.)

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.

Pan and colleagues said that the findings indicate a need for further evaluation of the role of neurometabolic abnormalities in treatment-refractory depression.

“The remarkably high incidence of actionable abnormalities and some evidence of symptom improvement with treatment strongly support the need for larger studies,” they wrote. “Historically, a diagnosis of a metabolic disorder has been considered in the context of a family history of a known disorder or symptoms that are exacerbated by significant physiologic stresses, especially with multisystem involvement, neither of which was present in our patient population. Our findings, if replicated, suggest that neurometabolic disorders may contribute to treatment-refractory psychiatric disorders even without other systemic illness. 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.

“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. ■

“Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior” can be accessed here.