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Antipsychotics are effective in normalizing positive symptoms of psychosis in the short term (delusions, hallucinations and disordered thought). Their long-term use is, however, associated with side effects, including several types of movement (extrapyramidal syndrome, dyskinesia, akathisia), metabolic and cardiac disorders. Furthermore, higher lifetime antipsychotic dose-years may be associated with poorer cognitive performance and blunted affect, although the mechanisms driving the latter associations are not well understood. In this article, we propose a novel model of the long-term effects of antipsychotic administration focusing on the changes in brain metabolic homeostasis induced by the medication. We propose here that the brain metabolic normalization, that occurs in parallel to the normalization of psychotic symptoms following antipsychotic treatment, may not ultimately be sustainable by the cerebral tissue of some patients; these patients may be characterized by already reduced oxidative metabolic capacity and this may push the brain into an unsustainable metabolic envelope resulting in tissue remodeling. To support this perspective, we will review the existing data on the brain metabolic trajectories of patients with a diagnosis of schizophrenia as indexed using available neuroimaging tools before and after use of medication. We will also consider data from pre-clinical studies to provide mechanistic support for our model.<\/jats:p>","DOI":"10.1093\/schbul\/sbz119","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T21:24:46Z","timestamp":1572557086000},"page":"484-495","source":"Crossref","is-referenced-by-count":24,"title":["Normalizing the Abnormal: Do Antipsychotic Drugs Push the Cortex Into an Unsustainable Metabolic Envelope?"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3766-3815","authenticated-orcid":false,"given":"Federico E","family":"Turkheimer","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"},{"name":"MRC Centre for Neurodevelopmental Disorders, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-0700","authenticated-orcid":false,"given":"Pierluigi","family":"Selvaggi","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitul A","family":"Mehta","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Veronese","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Zelaya","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Dazzan","sequence":"first","affiliation":[{"name":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C","family":"Vernon","sequence":"first","affiliation":[{"name":"MRC Centre for Neurodevelopmental Disorders, King\u2019s College London, London, UK"},{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,11,22]]},"reference":[{"issue":"9","key":"2020041011554036600_CIT0001","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1001\/jamapsychiatry.2013.19","article-title":"Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction\/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial","volume":"70","author":"Wunderink","year":"2013","journal-title":"JAMA Psychiatry."},{"issue":"3","key":"2020041011554036600_CIT0002","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/schbul\/sbi026","article-title":"Do patients with schizophrenia ever show periods of recovery? 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