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Neurometabolic disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior
Pan LA, Martin P, Zimmer T, Segreti AM, Kassiff S, McKain BW, Baca CA, Rengasamy M, Hyland K,  Walano N, Steinfeld R, Hughes M, Dobrowolski SK, Pasquino M, Diler D, Perel J, Finegold DN, Peters DG, Naviaux RK, Brent DA and Vockley J.
American Journal of Psychiatry, 2017, 174(1):42-50

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. 

Dr. Lisa Pan and her colleagues 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 Dr. Pan to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is under-recognized. To test this theory, she 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.

In this study, Dr. Pan found that 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.

Findings from this study may offer new hope to individuals with difficult to treat depression and a history of suicidal behavior.  Examination of metabolic disorders in treatment refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. Further study of the etiology of these abnormalities are needed to determine the underlying causes of these metabolic findings.  Drs. Pan and Brent from the Department of Psychiatry, Dr. Vockley from the Department of Medical Genetics at Children's Hospital of Pittsburgh, Dr. David Peters from the Department of Obstetrics and Gynecology, and Dr. David Finegold from the Department of Human Genetics are leading these studies, supported by the CHP Foundation by an anonymous donation, The Fine Foundation, and the American Foundation for Suicide Prevention.

Contributors:
Lisa A. Pan, MD, Anna Maria Segreti, BS, Brian W. McKain, RN, MSN, Cynthia A. Baca, RN, MSN, Manivel Rengasamy, MD, Michele Pasquino, BS, Rasim Diler, MD, James Perel, PhD and David A. Brent, MD

Petra Martin, BS, Thomas Zimmer, BS, Sivan Kassiff, BS, (University of Pittsburgh School of Medicine)

David N. Finegold, MD, Nicolette Walano, MS (Department of Human Genetics, University of Pittsburgh Graduate School of Public Health)

David G. Peters, PhD (Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine)

Steven K. Dobrowolski, PhD (Department of Pathology, University of Pittsburgh School of Medicine)

Marion Hughes, MD (Department of Radiology, University of Pittsburgh School of Medicine)

Jerry Vockley, MD, PhD (Department of Pediatrics, University of Pittsburgh School of Medicine)

Robert Steinfeld, MD (Department of Genetics, University of Gottingen, Germany)

Robert K. Naviaux, MD, PhD (Department of Medicine, University of California/San Diego)

Keith Hyland, PhD (Medical Neurogenetics LLC, Atlanta, GA)

This story was published in the American Journal of Psychiatry.  To view the abstract, click here.