title: Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior.
abstract: OBJECTIVE
  Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized.
  
  
  METHODS
  The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry.
  
  
  RESULTS
  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 (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality.
  
  
  CONCLUSIONS
  Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Lisa A
authors: LA
authors: Pan
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Petra
authors: P
authors: Martin
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Thomas
authors: T
authors: Zimmer
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Anna Maria
authors: AM
authors: Segreti
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Sivan
authors: S
authors: Kassiff
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Brian W
authors: BW
authors: McKain
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Cynthia A
authors: CA
authors: Baca
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Manivel
authors: M
authors: Rengasamy
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Keith
authors: K
authors: Hyland
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Nicolette
authors: N
authors: Walano
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Robert
authors: R
authors: Steinfeld
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Marion
authors: M
authors: Hughes
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Steven K
authors: SK
authors: Dobrowolski
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Michele
authors: M
authors: Pasquino
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Rasim
authors: R
authors: Diler
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: James
authors: J
authors: Perel
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: David N
authors: DN
authors: Finegold
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: David G
authors: DG
authors: Peters
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Robert K
authors: RK
authors: Naviaux
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: David A
authors: DA
authors: Brent
authors: From the Departments of Psychiatry, Pediatrics, Human Genetics, Pathology, and Obstetrics and Gynecology, University of Pittsburgh, School of Medicine, Pittsburgh; Medical Neurogenetics Laboratory, Atlanta; the Department of Pediatrics, University Medical Center Göttingen, Göttingen, Germany; and the Departments of Medicine, Pediatrics, and Pathology, School of Medicine, University of California, San Diego.
authors: Jerry
authors: J
authors: Vockley
mesh_terms: D000293:Adolescent; D061218:Depressive Disorder, Treatment-Resistant / Q000175:diagnosis* / Q000188:drug therapy* / Q000523:psychology; D004359:Drug Therapy, Combination; D005492:Folic Acid / Q000134:cerebrospinal fluid* / Q000627:therapeutic use*; D005494:Folic Acid Deficiency / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000188:drug therapy* / Q000523:psychology; D006801:Humans; D013406:Suicide, Attempted / Q000523:psychology*; D055815:Young Adult
chemical_list: D005492:Folic Acid