{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:29:48Z","timestamp":1785428988730,"version":"3.56.0"},"reference-count":40,"publisher":"Royal College of Psychiatrists","issue":"1","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["BJPsych open"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec id=\"S2056472425109265_as1\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Negative neuropsychiatric symptoms, such as apathy, are a core feature of Alzheimer\u2019s disease. Previous studies have shown that levels of fasting plasma proline and differential activity of the catechol-O-methyltransferase (COMT) enzyme, which metabolises dopamine, influence negative symptoms in patients with severe psychiatric illness and those at risk for psychosis. For patients with the COMT high activity enzyme (as assessed via the COMT Val\n                      <jats:sup>158<\/jats:sup>\n                      Met polymorphism), high plasma proline was associated with less severe negative symptoms. Conversely, high proline was associated with more severe negative symptoms in patients with the low activity COMT enzyme.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S2056472425109265_as2\">\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      In this proof-of-concept cross-sectional study, we tested the hypothesis that proline and COMT Val\n                      <jats:sup>158<\/jats:sup>\n                      Met interact to modify negative symptom severity across neuropsychiatric disease, specifically now investigating patients with Alzheimer\u2019s disease dementia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S2056472425109265_as3\">\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      Least Absolute Shrinkage and Selection Operator regression was employed to model the interaction between proline and COMT on negative symptoms in\n                      <jats:italic>n<\/jats:italic>\n                      = 50 patients with probable Alzheimer\u2019s disease or mild cognitive impairment with underlying Alzheimer\u2019s disease biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S2056472425109265_as4\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The proline\n                      <jats:italic>\u00d7<\/jats:italic>\n                      COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale, interaction coefficient 0.025,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.031, with a trend toward significance when assessed via the Scale for Assessment of Negative Symptoms in Alzheimer\u2019s disease, interaction coefficient 0.075,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.055. Higher proline was beneficial for both Val\/Val and Val\/Met dementia patients, but detrimental to patients with the low activity Met\/Met COMT enzyme.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S2056472425109265_as5\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Higher proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia and further supports the development of therapeutics aimed at modulating this interaction pathway across neuropsychiatric disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1192\/bjo.2025.10926","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:19:31Z","timestamp":1765790371000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":0,"title":["A proof-of-concept study: investigating the impact of COMT genotype and proline on negative symptoms in Alzheimer\u2019s disease"],"prefix":"10.1192","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2597-1140","authenticated-orcid":false,"given":"James D.","family":"Clelland","sequence":"first","affiliation":[{"name":"The Nathan S. Kline Institute for Psychiatric Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector W.","family":"Cure","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Canizares","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia H.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bimala","family":"Rawal","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina A.","family":"Wong","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Kerner","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Huey","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"},{"name":"Alpert Medical School of Brown University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence S.","family":"Honig","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8597-1380","authenticated-orcid":false,"given":"Devangere P.","family":"Devanand","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia University Irving Medical Center"},{"name":"New York State Psychiatric Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9364-3974","authenticated-orcid":false,"given":"Catherine L.","family":"Clelland","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center"},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia University Irving Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"170","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"S2056472425109265_ref37","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-012-2162-4"},{"key":"S2056472425109265_ref12","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-03099-0"},{"key":"S2056472425109265_ref8","doi-asserted-by":"publisher","DOI":"10.1002\/gps.4002"},{"key":"S2056472425109265_ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2011.05.006"},{"key":"S2056472425109265_ref11","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.157"},{"key":"S2056472425109265_ref32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300542"},{"key":"S2056472425109265_ref9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.09.003"},{"key":"S2056472425109265_ref14","doi-asserted-by":"publisher","DOI":"10.1086\/425589"},{"key":"S2056472425109265_ref22","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2016.04.001"},{"key":"S2056472425109265_ref27","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2008.132"},{"key":"S2056472425109265_ref10","first-page":"1821","volume-title":"Metabolic and Molecular Basis of Inherited Disease","author":"Phang","year":"2001"},{"key":"S2056472425109265_ref21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063644"},{"key":"S2056472425109265_ref24","doi-asserted-by":"publisher","DOI":"10.2174\/1567205015666171212094229"},{"key":"S2056472425109265_ref33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.10.024"},{"key":"S2056472425109265_ref4","doi-asserted-by":"publisher","DOI":"10.1097\/00002093-200401000-00004"},{"key":"S2056472425109265_ref3","doi-asserted-by":"publisher","DOI":"10.1002\/gps.917"},{"key":"S2056472425109265_ref16","doi-asserted-by":"publisher","DOI":"10.1038\/nn1562"},{"key":"S2056472425109265_ref36","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.11.005"},{"key":"S2056472425109265_ref13","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199606000-00007"},{"key":"S2056472425109265_ref39","doi-asserted-by":"publisher","DOI":"10.1002\/gps.755"},{"key":"S2056472425109265_ref5","doi-asserted-by":"publisher","DOI":"10.1002\/gps.1895"},{"key":"S2056472425109265_ref23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.08.006"},{"key":"S2056472425109265_ref2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1176\/jnp.9.2.231","article-title":"Methylphenidate treatment of negative symptoms in patients with dementia","volume":"9","author":"Galynker","year":"1997","journal-title":"J Neuropsychiatry Clin Neurosci"},{"key":"S2056472425109265_ref19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1176\/ajp.149.2.251","article-title":"Glutamate and other CSF amino acids in Alzheimer\u2019s disease","volume":"149","author":"Pomara","year":"1992","journal-title":"Am J Psychiatry"},{"key":"S2056472425109265_ref25","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182574fa1"},{"key":"S2056472425109265_ref30","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12766"},{"key":"S2056472425109265_ref29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2013.07.004"},{"key":"S2056472425109265_ref35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0214146"},{"key":"S2056472425109265_ref40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajp.2024.103924"},{"key":"S2056472425109265_ref20","doi-asserted-by":"publisher","DOI":"10.1007\/s007020050057"},{"key":"S2056472425109265_ref31","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2011.08.017"},{"key":"S2056472425109265_ref6","doi-asserted-by":"publisher","DOI":"10.1176\/jnp.17.3.342"},{"key":"S2056472425109265_ref28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025882"},{"key":"S2056472425109265_ref34","doi-asserted-by":"publisher","DOI":"10.1017\/S003329171900062X"},{"key":"S2056472425109265_ref7","doi-asserted-by":"publisher","DOI":"10.1002\/gps.2125"},{"key":"S2056472425109265_ref15","doi-asserted-by":"publisher","DOI":"10.1038\/7777"},{"key":"S2056472425109265_ref18","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32869"},{"key":"S2056472425109265_ref26","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1988.01800330013001"},{"key":"S2056472425109265_ref1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1176\/ajp.153.3.424","article-title":"Negative symptoms in Alzheimers disease","volume":"153","author":"Reichman","year":"1996","journal-title":"Am J Psychiatry"},{"key":"S2056472425109265_ref38","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-804281-6.00020-3"}],"container-title":["BJPsych Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S2056472425109265","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:19:32Z","timestamp":1765790372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S2056472425109265\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["S2056472425109265"],"URL":"https:\/\/doi.org\/10.1192\/bjo.2025.10926","relation":{},"ISSN":["2056-4724"],"issn-type":[{"value":"2056-4724","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"assertion":[{"value":"\u00a9 The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists","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-NonCommercial-NoDerivatives licence (https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided that no alterations are made and the original article is properly cited. The written permission of Cambridge University Press or the rights holder(s) must be obtained prior to any commercial use and\/or adaptation of the article.","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"}],"article-number":"e15"}}