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However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite \u2013 i.e., <jats:italic>reductions<\/jats:italic> in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [<jats:sup>18<\/jats:sup>F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an <jats:italic>inverse<\/jats:italic> association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D<jats:sub>2\/3<\/jats:sub> dopamine receptor availability in an overlapping cohort using [<jats:sup>18<\/jats:sup>F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.<\/jats:p>","DOI":"10.1038\/s41380-024-02873-2","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T20:17:31Z","timestamp":1735330651000},"page":"2645-2652","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D2\/3 receptor availability in healthy individuals"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4306-9342","authenticated-orcid":false,"given":"Daniel Paul","family":"Eisenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael Keir","family":"Blackman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Tietcheu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Kohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin S.","family":"Bettina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Kolachana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-2978","authenticated-orcid":false,"given":"Karen F.","family":"Berman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"2873_CR1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1192\/bjp.2021.61","volume":"220","author":"D Siskind","year":"2022","unstructured":"Siskind D, Orr S, Sinha S, Yu O, Brijball B, Warren N, et al. 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Procedures were conducted under study protocols that were approved by the NIH Institutional Review Board and the NIH Radiation Safety Committee (NCT00024622, NCT00942981, NCT00001486). Informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}