{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T18:35:25Z","timestamp":1781894125569,"version":"3.54.5"},"reference-count":28,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012621","name":"University College London Hospitals Biomedical Research Centre","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100012621","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Laboratory of Data Discovery for Health","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"CW Maplethorpe Fellowship","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Hong Kong Research Grant Council","award":["17112020"],"award-info":[{"award-number":["17112020"]}]},{"name":"Hong Kong Research Grant Council","award":["17114921"],"award-info":[{"award-number":["17114921"]}]},{"name":"Hong Kong Research Grant Council","award":["17126722"],"award-info":[{"award-number":["17126722"]}]},{"name":"Hong Kong Research Grant Council","award":["C7009-19GF"],"award-info":[{"award-number":["C7009-19GF"]}]},{"name":"Hong Kong Research Grant Council","award":["C7154-20G"],"award-info":[{"award-number":["C7154-20G"]}]},{"name":"Innovation and Technology Commission, Hong Kong","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"European Union Horizon 2020","award":["965381"],"award-info":[{"award-number":["965381"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["218497\/Z\/19\/Z"],"award-info":[{"award-number":["218497\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["NIHR201481"],"award-info":[{"award-number":["NIHR201481"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["NIHR206166"],"award-info":[{"award-number":["NIHR206166"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIHR North Thames Applied Research Collaboration","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100023699","name":"Health Data Research UK","doi-asserted-by":"publisher","award":["HDR-23012"],"award-info":[{"award-number":["HDR-23012"]}],"id":[{"id":"10.13039\/501100023699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["MR\/V023373\/1"],"award-info":[{"award-number":["MR\/V023373\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["MR\/W014386\/1"],"award-info":[{"award-number":["MR\/W014386\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Ment Health"],"accepted":{"date-parts":[[2025,11,16]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Evidence regarding the efficacy of adjunct statins to treat severe mental illness (SMI) is mixed. The varying pharmacokinetic properties of statins mean that specific statin-antipsychotic combinations might improve psychiatric symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To test whether some statin-antipsychotic\/mood stabiliser combinations result in psychiatric symptom improvement in patients with SMI, while others do not, using target trial emulation in observational data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We identified patients with SMI (schizophrenia, bipolar disorder, \u2018other\u2019 psychoses) prescribed antipsychotics\/mood stabilisers and statins from 2000 to 2019 in English linked primary care records (Clinical Practice Research Datalink). We defined hypothetical randomised trials and observational emulations: (1) blood-brain barrier (BBB)-penetrant (simvastatin) versus non-penetrant (atorvastatin\/pravastatin\/rosuvastatin) statins; (2A) P-glycoprotein inhibitors (simvastatin\/atorvastatin) versus non-inhibitors (pravastatin) in patients prescribed aripiprazole\/risperidone\/olanzapine (P-glycoprotein affinity); (2B) high (aripiprazole\/risperidone\/olanzapine) versus low (quetiapine) P-glycoprotein affinity antipsychotics in patients prescribed P-glycoprotein-inhibiting statins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>We found no reduction in our primary outcomes (12-month psychiatric admissions) in trial 1 (HR 1.07, 95% CI 0.88 to 1.31); trial 2A (HR 0.77, 95% CI 0.28 to 2.15); or trial 2B (HR 0.93, 95% CI 0.79 to 1.09). In trial 2B, we observed lower self-harm events (HR 0.60, 95% CI 0.38 to 0.97) in per-protocol analysis and lower psychiatric admissions in the \u2018other\u2019 psychoses subgroup (HR 0.53, 95% CI 0.34 to 0.85).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>BBB penetrance appears unlikely to be the mechanism by which statins improve SMI symptoms. Interaction with P-glycoprotein may have some effect. Further mechanistic and clinical research is needed to understand statin-antipsychotic interactions and the role of interaction with P-glycoprotein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical implications<\/jats:title>\n                    <jats:p>There is currently not enough evidence to guide the prescription of statins for psychiatric symptom improvement in patients with SMI. If there is an effect of statins, it may be through specific statin-antipsychotic combinations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjment-2025-302124","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T08:35:22Z","timestamp":1764664522000},"page":"1.2-8","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Do the pharmacokinetics of statins explain psychiatric symptom improvement from adjunctive statin prescribing in severe mental illness? Three target trial emulation studies"],"prefix":"10.1136","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-938X","authenticated-orcid":false,"given":"Naomi","family":"Launders","sequence":"first","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-9380","authenticated-orcid":false,"given":"Alvin","family":"Richards-Belle","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3044-3713","authenticated-orcid":false,"given":"Sarah","family":"Hardoon","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8645-1942","authenticated-orcid":false,"given":"Kenneth","family":"Man","sequence":"additional","affiliation":[{"name":"Research Department of Practice and Policy, UCL School of Pharmacy, London, UK"},{"name":"Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, University of Hong Kong Faculty of Medicine, Pokfulam, Hong Kong"},{"name":"Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, UK"},{"name":"Laboratory of Data Discovery for Health (D24H), New Territories, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-0014","authenticated-orcid":false,"given":"Ian C K","family":"Wong","sequence":"additional","affiliation":[{"name":"Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, University of Hong Kong Faculty of Medicine, Pokfulam, Hong Kong"},{"name":"Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, UK"},{"name":"Laboratory of Data Discovery for Health (D24H), New Territories, Hong Kong"},{"name":"Aston Pharmacy School, Aston University, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2519-1539","authenticated-orcid":false,"given":"David P J","family":"Osborn","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"},{"name":"Camden and Islington NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2286-3862","authenticated-orcid":false,"given":"Joseph F","family":"Hayes","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"},{"name":"Camden and Islington NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"2025120200351804000_28.1.1-c.1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3233\/JAD-2010-101179","article-title":"Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death","volume":"23","author":"Sierra","year":"2011","journal-title":"J Alzheimers Dis"},{"key":"2025120200351804000_28.1.1-c.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2018.02.018"},{"key":"2025120200351804000_28.1.1-c.3","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbab010"},{"key":"2025120200351804000_28.1.1-c.4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1515\/pteridines-2020-0028","article-title":"Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder","volume":"32","author":"Postolache","year":"2021","journal-title":"Pteridines"},{"key":"2025120200351804000_28.1.1-c.5","doi-asserted-by":"crossref","DOI":"10.3389\/fpsyt.2023.1203444","article-title":"Statin for mood and inflammation among adult patients with major depressive disorder: an updated meta-analysis","volume":"14","author":"Xiao","year":"2023","journal-title":"Front Psychiatry"},{"key":"2025120200351804000_28.1.1-c.6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/YIC.0000000000000159","article-title":"Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial","volume":"32","author":"Tajik-Esmaeeli","year":"2017","journal-title":"Int Clin Psychopharmacol"},{"key":"2025120200351804000_28.1.1-c.7","doi-asserted-by":"publisher","DOI":"10.1177\/2045125313511487"},{"key":"2025120200351804000_28.1.1-c.8","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbih.2022.100551","article-title":"Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial","volume":"26","author":"Aichholzer","year":"2022","journal-title":"Brain Behav Immun Health"},{"key":"2025120200351804000_28.1.1-c.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2014.08.021"},{"key":"2025120200351804000_28.1.1-c.10","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.psychres.2014.06.039","article-title":"Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial","volume":"219","author":"Ghanizadeh","year":"2014","journal-title":"Psychiatry Res"},{"key":"2025120200351804000_28.1.1-c.11","first-page":"1269","article-title":"Effects of Atorvastatin on Negative Sign in Chronic Schizophrenia: a Double Blind Clinical Trial","volume":"14","author":"Sayyah","year":"2015","journal-title":"Iran J Pharm Res"},{"key":"2025120200351804000_28.1.1-c.12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.euroneuro.2023.04.007","article-title":"A randomized controlled trial of add-on naproxen, simvastatin and their combination for the treatment of schizophrenia or schizoaffective disorder","volume":"73","author":"Weiser","year":"2023","journal-title":"Eur Neuropsychopharmacol"},{"key":"2025120200351804000_28.1.1-c.13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jad.2019.11.013","article-title":"The effect of atorvastatin on cognition and mood in bipolar disorder and unipolar depression patients: A secondary analysis of a randomized controlled trial","volume":"262","author":"Fotso Soh","year":"2020","journal-title":"J Affect Disord"},{"key":"2025120200351804000_28.1.1-c.14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.psychres.2017.11.033","article-title":"Statin add-on therapy in the antipsychotic treatment of schizophrenia: A meta-analysis","volume":"260","author":"Nomura","year":"2018","journal-title":"Psychiatry Res"},{"key":"2025120200351804000_28.1.1-c.15","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.genhosppsych.2024.05.001","article-title":"Statins as an adjuvant therapy for patients with schizophrenia: An up-to-date systematic review and meta-analysis","volume":"89","author":"Peng","year":"2024","journal-title":"Gen Hosp Psychiatry"},{"key":"2025120200351804000_28.1.1-c.16","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.2147\/NDT.S480921","article-title":"Lack of Efficacy of Simvastatin Adjunctive Therapy for Patients with Schizophrenia: A Meta-Analysis of Randomized Controlled Trials","volume":"20","author":"Chen","year":"2024","journal-title":"Neuropsychiatr Dis Treat"},{"key":"2025120200351804000_28.1.1-c.17","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1001\/jamapsychiatry.2018.3907","article-title":"Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness","volume":"76","author":"Hayes","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"2025120200351804000_28.1.1-c.18","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1192\/bjp.2024.85","article-title":"Lipid-modifying agents and risk of all-cause, natural and suicide mortality in schizophrenia: nationwide cohort study","volume":"225","author":"Chen","year":"2024","journal-title":"Br J Psychiatry"},{"key":"2025120200351804000_28.1.1-c.19","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.11.55"},{"key":"2025120200351804000_28.1.1-c.20","doi-asserted-by":"publisher","DOI":"10.1592\/phco.26.11.1601"},{"key":"2025120200351804000_28.1.1-c.21","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv098"},{"key":"2025120200351804000_28.1.1-c.22","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyz034"},{"key":"2025120200351804000_28.1.1-c.23","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1001885","article-title":"The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement","volume":"12","author":"Benchimol","year":"2015","journal-title":"PLoS Med"},{"key":"2025120200351804000_28.1.1-c.24","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1001\/jama.2025.13350","article-title":"Transparent Reporting of Observational Studies Emulating a Target Trial-The TARGET Statement","volume":"334","author":"Cashin","year":"2025","journal-title":"JAMA"},{"key":"2025120200351804000_28.1.1-c.25","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3618"},{"key":"2025120200351804000_28.1.1-c.26","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq439"},{"key":"2025120200351804000_28.1.1-c.27","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12059"},{"key":"2025120200351804000_28.1.1-c.28","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1004520","article-title":"Comparative cardiometabolic safety and effectiveness of aripiprazole in people with severe mental illness: A target trial emulation","volume":"22","author":"Richards-Belle","year":"2025","journal-title":"PLoS Med"}],"container-title":["BMJ Mental Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjment-2025-302124","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T08:35:25Z","timestamp":1764664525000},"score":1,"resource":{"primary":{"URL":"https:\/\/mentalhealth.bmj.com\/lookup\/doi\/10.1136\/bmjment-2025-302124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12,1]]},"published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1136\/bmjment-2025-302124"],"URL":"https:\/\/doi.org\/10.1136\/bmjment-2025-302124","relation":{},"ISSN":["2755-9734"],"issn-type":[{"value":"2755-9734","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]}}}