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The pathoetiology of TD is not well understood but a possible mechanism involves dopaminergic overactivity in the nigrostriatal pathway. If this theory is correct, then levels of neuromelanin (a long-term marker of dopaminergic activity) should be higher in people with TD than those without TD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The aim of the study was to test the hypothesis that neuromelanin levels are higher in patients with TD relative to those without TD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Data from 27 participants (TD:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200913; non-TD\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200914) with a diagnosis of schizophrenia, all taking antipsychotic drugs, were used. Neuromelanin was measured in the midbrain via Magnetic Resonance Imaging (MRI) and compared between the groups. Movement symptoms were measured using the Abnormal Involuntary Movement Scale (AIMS), and antipsychotic dose recorded.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MRI-measured neuromelanin levels were significantly higher in patients with TD, as compared to those without (mean\u2009=\u20090.223; t(17.27)\u2009=\u20093.817,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001; g\u2009=\u20091.386, 95% CI=[0.559, 2.213]). This remained significant after controlling for age, sex, substantia nigra\/ventral tegmental area volume and antipsychotic dose (ANCOVA: F(1,20)\u2009=\u200912.08,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0024; adjusted \u03b2\u2009=\u20090.0301, 95% CI [0.0120, 0.0481]). The most pronounced difference was seen in the ventral substantia nigra.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The finding of higher midbrain neuromelanin in patients with TD aligns with the dopamine overactivity hypothesis of TD aetiology. It also supports a neurobiological basis for treatment of TD with drugs that target presynaptic dopamine activity, such as VMAT2 inhibitors. Additionally, it identifies the ventral substantia nigra as a key locus. Future longitudinal studies are needed to delineate if dopamine overactivity develops in response to antipsychotic treatment or is a trait vulnerability marker for risk of TD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-026-07173-x","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:31:54Z","timestamp":1790663514000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The mechanism underlying tardive dyskinesia: an exploratory test of the dopamine overactivity hypothesis using MRI imaging of midbrain neuromelanin"],"prefix":"10.1007","author":[{"given":"Bernard R.","family":"Bukala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke J.","family":"Vano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Cummings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McCutcheon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Statton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaine","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Sedlacik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Terry-Lorenzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietrich","family":"Haubenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver D.","family":"Howes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"6","key":"7173_CR1","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1001\/jamapsychiatry.2025.0432","volume":"82","author":"J Ahrens","year":"2025","unstructured":"Ahrens J, Ford SD, Schaefer B, Reese D, Khan AR, Tibbo P, Rabin R, Cassidy CM, Palaniyappan L (2025) Convergence of Cannabis and Psychosis on the Dopamine System. 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The studies were approved by the UK National Health Service (NHS) research ethics committees: London Dulwich Research Ethics Committe (REC) ref. 21\/LO\/0312, London Central Research Ethics Committee REC ref. 21\/LO\/0188, East of Scotland REC ref. 20-ES-0107.","order":1,"name":"Ethics","label":"Research involving human participants","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed written consent was provided by all individual participants in the studies.","order":2,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was partially funded by Neurocrine Biosciences. BR Bukala has served as a consultant for Candesic and Relation Therapeutics. RAM has received speaker\/consultancy fees from Angelini Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Karuna, Lundbeck, Newron, Otsuka, and Viatris, and co-directs a company that designs digital resources to support treatment of mental ill health. RTL, DA, and DH are full-time employees of Neurocrine Biosciences, Inc. and hold equity in the company. DH received royalties from publishing with Oxford University Press. OD Howes has received investigator-initiated research funding from and\/or participated in advisory or speaker meetings organized by AbbVie, Alkermes, Angelini, Autifony, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb (Karuna), Clinical Ink, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck, Merck, Neumora, Neurocrine, Ono, Ontrack\/Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, Rovi, and Viatris\/Mylan; he was previously a part-time employee of Lundbeck.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}