Background Randomized controlled trials (RCTs) of statins as adjunct therapy for severe mental illness (SMI) have produced mixed results. Specific statin-antipsychotic combinations might improve psychiatric symptoms through: 1) blood-brain barrier (BBB) penetrant statins being anti-inflammatory/neuroprotective, and/or 2) statins that inhibit p-glycoprotein enhancing the effects of antipsychotics with high p-glycoprotein affinity. Aim To investigate these mechanisms via three target trial emulation studies. Methods We identified patients with SMI (schizophrenia, bipolar disorder, "other" psychoses) prescribed antipsychotics/mood stabilisers and statins from 2000-2019 in English electronic health records. We defined three hypothetical RCTs and their observational analogues: 1) simvastatin (crosses BBB) vs. atorvastatin/pravastatin/rosuvastatin (non-penetrant); 2A) simvastatin/atorvastatin (p-glycoprotein inhibitors) vs. pravastatin in patients prescribed risperidone/olanzapine/aripiprazole (high p-glycoprotein affinity); 2B) risperidone/olanzapine/aripiprazole vs. quetiapine (low p-glycoprotein affinity) in patients prescribed simvastatin/atorvastatin. Primary outcome: 12-month psychiatric admissions. Secondary outcomes: self-harm, physical health, and accident/injury admissions. Results In 72,096 patients prescribed statins and antipsychotics/mood stabilisers, we found no reduction in psychiatric admissions at 12 months in patients prescribed: 1) BBB-penetrant vs. non-penetrant statins (HR:1.07; 95%CI:0.88-1.31); 2A) antipsychotics with p-glycoprotein affinity and p-glycoprotein inhibiting statins vs. statins without inhibition (HR:0.77; 95%CI:0.28-2.15); 2B) p-glycoprotein inhibiting statins with antipsychotics having p-glycoprotein affinity vs. antipsychotics without affinity (HR:0.93; 95%CI:0.79-1.09). In 2B we observed reduced self-harm (HR:0.60; 95%CI:0.38-0.97) in per-protocol analysis and reduced psychiatric admissions in the "other" psychoses subgroup (HR:0.53; 95%CI:0.34-0.85). Conclusions BBB permeability is unlikely to be the mechanism by which statins improve SMI symptoms. Further research is needed to understand statin-antipsychotic interactions, and whether interaction with p-glycoprotein is a plausible mechanism.

NL & ARB declare no conflicts of interest. JFH has received consultancy fees from juli Health and Wellcome. He is a co-founder and shareholder of juli Health. juli Health has a patent pending. ICKW reports research funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council of the Government of the Hong Kong SAR, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, and the National Health and Medical Research Council in Australia, consulting fees from IQVIA and World Health Organisation, payment for expert testimony for Appeal Court of Hong Kong and is a non-executive director of Jacobson Medical in Hong Kong, Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK) a former director of Therakind in England, outside of the submitted work. KKCM reports personal fees from IQVIA, unrelated to the current work.

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This work is supported by the UK Research and Innovation grant MR/V023373/1 (NL&JFH). It is additionally supported by UK Research and Innovation grant MR/W014386/1 (NL&DPJO), the University College London Hospitals NIHR Biomedical Research Centre (NL, JFH & DPJO), and the NIHR North Thames Applied Research Collaboration (NL, JFH & DPJO). These funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. NL is supported by an Health Data Research UK personal fellowship., This work is affiliated to Health Data Research UK (Big Data for Complex Disease- HDR-23012), which is funded by the Medical Research Council (UKRI), the National Institute for Health Research, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council (UKRI), the Engineering and Physical Sciences Research Council (UKRI), Health and Care Research Wales, Chief Scientist Office of the Scottish Government Health and Social Care Directorates, and Health and Social Care Research and Development Division (Public Health Agency, Northern Ireland). ICKW is partially supported by the Laboratory of Data Discovery for Health (D24H) funded by the by AIR@InnoHK administered by Innovation and Technology Commission, Hong Kong and received research funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council of the Government of the Hong Kong SAR, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, and the National Health and Medical Research Council in Australia, consulting fees from IQVIA and World Health Organisation, payment for expert testimony for Appeal Court of Hong Kong and is a non-executive director of Jacobson Medical in Hong Kong, Advance Data Analytics for Medical Science (ADAMS) Limited (HK), and OCUS Innovation Limited (HK, Ireland and UK) a former director of Therakind in England, outside of the submitted work. ARB is funded by the Wellcome Trust through a PhD Fellowship in Mental Health Science (218497/Z/19/Z). This research was funded in whole or in part by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission. KKCM reports grants from the CW Maplethorpe Fellowship, the European Union Horizon 2020, the UK National Institute of Health Research, the Hong Kong Research Grant Council, and the Hong Kong Innovation and Technology Commission.

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