Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and...

Area of Science:

• Neuroscience
• Metabolomics
• Psychiatry

Background:

• Treatment-refractory depression affects at least 15% of major depressive disorder cases, leading to significant disability.
• A previous case identified severe cerebrospinal fluid (CSF) tetrahydrobiopterin deficiency treatable with sapropterin, suggesting underrecognized metabolic contributions.

Purpose of the Study:

• To investigate the prevalence of metabolic abnormalities in adolescent and young adult patients with treatment-refractory depression.
• To determine if identified metabolic abnormalities are treatable and associated with symptom improvement.

Main Methods:

• A case-control study involving 33 patients with treatment-refractory depression and 16 healthy controls.
• Targeted metabolomic profiling of plasma, urine, and CSF using gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry.

Main Results:

• Metabolite abnormalities were found in 21 of 33 patients with treatment-refractory depression.
• Cerebral folate deficiency (low CSF 5-methyltetrahydrofolate with normal serum folate) was the most common abnormality (N=12).
• All patients with cerebral folate deficiency improved with folinic acid treatment; one also improved with sapropterin.

Conclusions:

• A significant proportion of patients with treatment-refractory depression have identifiable and potentially treatable metabolic abnormalities.
• Further research is needed to determine the underlying causes of these metabolic disorders.