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The proline dehydrogenase (<jats:italic>PRODH<\/jats:italic>) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the <jats:italic>Prodh<\/jats:italic>-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-<jats:italic>O<\/jats:italic>-methyltransferase (<jats:italic>COMT<\/jats:italic>), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and <jats:italic>COMT<\/jats:italic> Val<jats:sup>158<\/jats:sup>Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and <jats:italic>COMT<\/jats:italic> on negative symptoms in schizophrenia (<jats:italic>P<\/jats:italic>&lt;0.0001, <jats:italic>n<\/jats:italic>=95). In <jats:italic>COMT<\/jats:italic> Val\/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (<jats:italic>P<\/jats:italic>=0.007, <jats:italic>n<\/jats:italic>=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and <jats:italic>COMT<\/jats:italic> genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by <jats:italic>COMT<\/jats:italic> genotype, may have implications for therapeutic decisions.<\/jats:p>","DOI":"10.1038\/tp.2016.157","type":"journal-article","created":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T13:48:05Z","timestamp":1473774485000},"page":"e891-e891","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder"],"prefix":"10.1038","volume":"6","author":[{"given":"C L","family":"Clelland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Drouet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K C","family":"Rilett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J A","family":"Smeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R H","family":"Nadrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Rajparia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L L","family":"Read","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J D","family":"Clelland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,13]]},"reference":[{"key":"BFtp2016157_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.schres.2011.01.011","volume":"127","author":"MS Keshavan","year":"2011","unstructured":"Keshavan MS, Nasrallah HA, Tandon R . 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In addition, this research was supported in part by New York University CTSA grant (UL1 TR000038) and Columbia University Medical Center CTSA grant (KL2 RR024157: KL2 awardee CC), from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. CLC and JDC are inventors on two patent applications that are based in part upon this study data. If awarded, the patents will be owned by their respective institutions, and CLC and JDC may benefit financially in the future if these patents are licensed. CLC and JDC declare no other financial relationships that are directly or indirectly related to this work. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}