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Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior.

  • Pan, Lisa A1, 2, 3, 4
  • Segreti, Anna Maria1
  • Wrobleski, Joseph1
  • Shaw, Annie1
  • Hyland, Keith5
  • Hughes, Marion1
  • Finegold, David N2, 3, 4
  • Naviaux, Robert K6
  • Brent, David A1
  • Vockley, Jerry1
  • Peters, David G1, 4, 7
  • 1 University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
  • 2 New Hope Molecular, Pittsburgh, PA 15228, USA.
  • 3 University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA 15261, USA.
  • 4 Panomics Mental Health Initiative, Pittsburgh, PA 15228, USA.
  • 5 Medical Neurogenetics Laboratory, Atlanta, Georgia 30342, USA. , (Georgia)
  • 6 University of California at San Diego, School of Medicine, San Diego, California 92103, USA.
  • 7 Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Published Article
Psychological Medicine
Cambridge University Press
Publication Date
Oct 01, 2023
DOI: 10.1017/S0033291722003233
PMID: 36330595


Refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. Approximately 15% of patients with major depressive disorder are refractory to currently available treatments. We hypothesized metabolic abnormalities contributing to treatment refractory depression are associated with distinct findings identifiable in the cerebrospinal fluid (CSF). Our hypothesis was confirmed by a previous small case-controlled study. Here we present a second, larger replication study. We conducted a case-controlled, targeted, metabolomic evaluation of 141 adolescent and adult patients with well-characterized history of depression refractory to three maximum-dose, adequate-duration medication treatments, and 36 healthy controls. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry, and high-performance liquid chromatography, electrospray ionization, tandem mass spectrometry. Abnormalities were identified in 67 of 141 treatment refractory depression participants. The CSF abnormalities included: low cerebral folate (n = 20), low tetrahydrobiopterin intermediates (n = 11), and borderline low-tetrahydrobiopterin intermediates (n = 20). Serum abnormalities included abnormal acylcarnitine profile (n = 12) and abnormal serum amino acids (n = 20). Eighteen patients presented with two or more abnormal metabolic findings. Sixteen patients with cerebral folate deficiency and seven with low tetrahydrobiopterin intermediates in CSF showed improvement in depression symptom inventories after treatment with folinic acid and sapropterin, respectively. No healthy controls had a metabolite abnormality. Examination of metabolic disorders in treatment refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities and their potential roles in pathogenesis remain to be determined.

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