TY  - JOUR
PY  - 2016//
TI  - Neurometabolic disorders: potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior
JO  - American journal of psychiatry
A1  - Pan, Lisa A.
A1  - Martin, Petra
A1  - Zimmer, Thomas
A1  - Segreti, Anna Maria
A1  - Kassiff, Sivan
A1  - McKain, Brian W.
A1  - Baca, Cynthia A.
A1  - Rengasamy, Manivel
A1  - Hyland, Keith
A1  - Walano, Nicolette
A1  - Steinfeld, Robert
A1  - Hughes, Marion
A1  - Dobrowolski, Steven K.
A1  - Pasquino, Michele
A1  - Diler, Rasim
A1  - Perel, James
A1  - Finegold, David N.
A1  - Peters, David G.
A1  - Naviaux, Robert K.
A1  - Brent, David A.
A1  - Vockley, Jerry
SP  - 42
EP  - 50
VL  - 174
IS  - 1
N2  - 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.<br><br>METHOD: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.<br><br>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.<br><br>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.<p />
LA  - en
SN  - 0002-953X
UR  - http://dx.doi.org/10.1176/appi.ajp.2016.15111500
ID  - ref1
ER  -