{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:35:20Z","timestamp":1787319320962,"version":"build-2736575974"},"reference-count":45,"publisher":"Cambridge University Press (CUP)","issue":"13","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Anonymous Donors through Children's Hospital of Pittsburgh"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Psychol. Med."],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"S0033291722003233_sec_a1\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0033291722003233_sec_a2\" sec-type=\"methods\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0033291722003233_sec_a3\" sec-type=\"results\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Abnormalities were identified in 67 of 141 treatment refractory depression participants. The CSF abnormalities included: low cerebral folate (\n                      <jats:italic>n<\/jats:italic>\n                      = 20), low tetrahydrobiopterin intermediates (\n                      <jats:italic>n<\/jats:italic>\n                      = 11), and borderline low-tetrahydrobiopterin intermediates (\n                      <jats:italic>n<\/jats:italic>\n                      = 20). Serum abnormalities included abnormal acylcarnitine profile (\n                      <jats:italic>n<\/jats:italic>\n                      = 12) and abnormal serum amino acids (\n                      <jats:italic>n<\/jats:italic>\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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0033291722003233_sec_a4\" sec-type=\"conclusions\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1017\/s0033291722003233","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T03:01:15Z","timestamp":1667530875000},"page":"6046-6054","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":14,"title":["Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior"],"prefix":"10.1017","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0875-876X","authenticated-orcid":false,"given":"Lisa A.","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8572-2111","authenticated-orcid":false,"given":"Anna Maria","family":"Segreti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Wrobleski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Hyland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Finegold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Naviaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Vockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"S0033291722003233_ref30","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2012.11071114"},{"key":"S0033291722003233_ref32","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.2007.164.7.1035"},{"key":"S0033291722003233_ref26","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2016.15111500"},{"key":"S0033291722003233_ref16","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.8157su1c.03"},{"key":"S0033291722003233_ref15","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(03)00231-2"},{"key":"S0033291722003233_ref21","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.02.005"},{"key":"S0033291722003233_ref37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.10.002"},{"key":"S0033291722003233_ref40","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.07.008"},{"key":"S0033291722003233_ref42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.08.025"},{"key":"S0033291722003233_ref27","doi-asserted-by":"publisher","DOI":"10.1136\/bcr.03.2011.3927.corr1"},{"key":"S0033291722003233_ref38","volume-title":"Suicidal ideation questionnaire: Professional manual","author":"Reynolds","year":"1987"},{"key":"S0033291722003233_ref39","volume-title":"Cerebral folate deficiency. Presentation at behavioural and psychiatric aspects of inborn errors of metabolism","author":"Sedel","year":"2013"},{"key":"S0033291722003233_ref20","first-page":"103","article-title":"Treatment with mefolinate (5-methyltetrahydrofolate), but not folic acid or folinic acid, leads to measurable 5\u2013methyltetrahydrofolate in cerebrospinal fluid in methylenetetrahydrofolate reductase deficiency","volume":"29","author":"Knowles","year":"2016","journal-title":"Journal of Inherited Metabolic Disease"},{"key":"S0033291722003233_ref4","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.11r07237"},{"key":"S0033291722003233_ref3","year":"2014"},{"key":"S0033291722003233_ref9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160542"},{"key":"S0033291722003233_ref17","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000309223.98616.e4"},{"key":"S0033291722003233_ref10","first-page":"45","volume-title":"The prediction of suicide","author":"Beck","year":"1974"},{"key":"S0033291722003233_ref36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2004.tb00451.x"},{"key":"S0033291722003233_ref24","first-page":"68","article-title":"The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders","volume":"13","author":"Morris","year":"2015","journal-title":"BioMed Central Medicine"},{"key":"S0033291722003233_ref18","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9159-6"},{"key":"S0033291722003233_ref22","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-021-02363-7"},{"key":"S0033291722003233_ref41","first-page":"16","article-title":"Treatment resistant depression","volume":"67","author":"Souery","year":"2006","journal-title":"Journal of Clinical Psychiatry"},{"key":"S0033291722003233_ref45","doi-asserted-by":"publisher","DOI":"10.2174\/1389200024605073"},{"key":"S0033291722003233_ref34","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0217-2"},{"key":"S0033291722003233_ref12","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291700038447"},{"key":"S0033291722003233_ref35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0264404"},{"key":"S0033291722003233_ref33","volume-title":"Children's depression rating scale revised (CDRS-R)","author":"Poznanski","year":"1996"},{"key":"S0033291722003233_ref8","first-page":"199","article-title":"Biogenic amines and their impact in psychiatry","volume":"4","author":"Axelrod","year":"1972","journal-title":"Seminars in Psychiatry"},{"key":"S0033291722003233_ref31","doi-asserted-by":"publisher","DOI":"10.1080\/15257770.2022.2028827"},{"key":"S0033291722003233_ref29","first-page":"1","article-title":"Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: Results from a randomized clinical trial","author":"Papakostas","year":"2014","journal-title":"The Journal of Clinical Psychiatry"},{"key":"S0033291722003233_ref6","doi-asserted-by":"publisher","DOI":"10.1080\/09540260074148"},{"key":"S0033291722003233_ref23","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2015.1055322"},{"key":"S0033291722003233_ref5","doi-asserted-by":"publisher","DOI":"10.1038\/515163a"},{"key":"S0033291722003233_ref19","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.12020wc3"},{"key":"S0033291722003233_ref43","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3066"},{"key":"S0033291722003233_ref2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2019.11.122"},{"key":"S0033291722003233_ref13","unstructured":"Centers for Disease Control and Prevention. (2022). Center for Disease Control and Prevention Data and Statistical Fatal Injury Report."},{"key":"S0033291722003233_ref44","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-013-9618-y"},{"key":"S0033291722003233_ref28","doi-asserted-by":"publisher","DOI":"10.1007\/s40142-012-0004-0"},{"key":"S0033291722003233_ref1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2018.05.005"},{"key":"S0033291722003233_ref7","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1976.01770100055005"},{"key":"S0033291722003233_ref11","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1961.01710120031004"},{"key":"S0033291722003233_ref25","unstructured":"NIMH (1992). NIMH Genetics Initiative. Family Interview for Genetic Studies (FIGS). Rockville, MD: National Institute of Mental Health."},{"key":"S0033291722003233_ref14","first-page":"1997","volume-title":"GeneReviews","author":"Cohen","year":"2010"}],"container-title":["Psychological Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S0033291722003233","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T04:22:47Z","timestamp":1695615767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S0033291722003233\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":45,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["S0033291722003233"],"URL":"https:\/\/doi.org\/10.1017\/s0033291722003233","relation":{},"ISSN":["0033-2917","1469-8978"],"issn-type":[{"value":"0033-2917","type":"print"},{"value":"1469-8978","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,4]]},"assertion":[{"value":"Copyright \u00a9 The Author(s), 2022. Published by Cambridge University Press","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http:\/\/creativecommons.org\/licenses\/by\/4.0\/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}]}}