Refractory depression metabolomics study involving RK Naviaux

h3ro

Active Member
Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior

Lisa A. Pan, M.D., Petra Martin, B.S., Thomas Zimmer, B.S., Anna Maria Segreti, B.S., Sivan Kassiff, B.S., Brian W. McKain, R.N., M.S.N., Cynthia A. Baca, R.N., M.S.N., Manivel Rengasamy, M.D., Keith Hyland, Ph.D., Nicolette Walano, M.S., Robert Steinfeld, M.D., Marion Hughes, M.D., Steven K. Dobrowolski, Ph.D., Michele Pasquino, B.S., Rasim Diler, M.D., James Perel, Ph.D., David N. Finegold, M.D., David G. Peters, Ph.D., Robert K. Naviaux, M.D., Ph.D., David A. Brent, M.D., Jerry Vockley, M.D., Ph.D.

Received: November 29, 2015
Accepted: May 20, 2016

Published online: August 13, 2016 | http://dx.doi.org/10.1176/appi.ajp.2016.15111500

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.

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.

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.

http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2016.15111500
 

ShyestofFlies

Well-Known Member
Wow super relevent to me. I have MDD with long episodes (in partial remission, last episode was about 7 years long) and have been on 6+ treatments or combos, nothing really makes a substantial difference and the one time it did there were significant side effects and I could not continue.

I am wondering what the recomendations from this and studies that will hopefully follow will be.
 

Issie

Well-Known Member
https://ghr.nlm.nih.gov/condition/tetrahydrobiopterin-deficiency

BH4 is something connected to the methylation cycle and genetics. There are supplements you can use to up BH4. Some of us with POTS have mutations in this gene and also MTHFR. Interesting the newer studies coming out addressing methylation mutations. But just because you have a mutation doesn't mean it positively will activate. You can make lifestyle changes and use supplements to keep things level.

Issie
 

ShyestofFlies

Well-Known Member
https://ghr.nlm.nih.gov/condition/tetrahydrobiopterin-deficiency

BH4 is something connected to the methylation cycle and genetics. There are supplements you can use to up BH4. Some of us with POTS have mutations in this gene and also MTHFR. Interesting the newer studies coming out addressing methylation mutations. But just because you have a mutation doesn't mean it positively will activate. You can make lifestyle changes and use supplements to keep things level.

Issie
Thanks for the resource! I've been reading about MTHFR lately, should probably do more. :)
 

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