Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis
Introduction Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted t...
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BMJ Publishing Group
2023-03-01
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| Series: | BMJ Open |
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| author | Stephen Burgess Peter Jones Rachel Upthegrove Carmine Pariante Graham K Murray Anthony David Martin Wilson Nicholas Barnes Paola Dazzan John Suckling Valeria Mondelli Muzaffer Kaser Neil Harrison Georgios Gkoutos Golam M Khandaker Deepak Jadon James MacCabe Gary Donohoe Alice Egerton Bill Deakin Jack Rogers Éimear M Foley Sian Lowri Griffiths Alexander Murray Fabiana Corsi-Zuelli Hannah Hickinbotham Ella Warwick Nicholas M Barnes Golam Khandaker David Cotter Ed Bullmore Eva Meisenzahl Joanna Neill Nikos Koutsouleris Stephen Wood |
| author_facet | Stephen Burgess Peter Jones Rachel Upthegrove Carmine Pariante Graham K Murray Anthony David Martin Wilson Nicholas Barnes Paola Dazzan John Suckling Valeria Mondelli Muzaffer Kaser Neil Harrison Georgios Gkoutos Golam M Khandaker Deepak Jadon James MacCabe Gary Donohoe Alice Egerton Bill Deakin Jack Rogers Éimear M Foley Sian Lowri Griffiths Alexander Murray Fabiana Corsi-Zuelli Hannah Hickinbotham Ella Warwick Nicholas M Barnes Golam Khandaker David Cotter Ed Bullmore Eva Meisenzahl Joanna Neill Nikos Koutsouleris Stephen Wood |
| collection | DOAJ |
| description | Introduction Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.Methods and analysis A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.Ethics and dissemination The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.Trial registration number ISRCTN23256704. |
| first_indexed | 2024-03-12T15:09:14Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-12T15:09:14Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-68df20bff4534eeebe80122791e230572023-08-11T21:20:08ZengBMJ Publishing GroupBMJ Open2044-60552023-03-0113310.1136/bmjopen-2022-067944Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis Stephen BurgessPeter JonesRachel Upthegrove0Carmine ParianteGraham K Murray1Anthony DavidMartin Wilson2Nicholas BarnesPaola DazzanJohn Suckling3Valeria MondelliMuzaffer Kaser4Neil HarrisonGeorgios GkoutosGolam M Khandaker5Deepak Jadon6James MacCabeGary DonohoeAlice EgertonBill Deakin7Jack Rogers8Éimear M Foley9Sian Lowri Griffiths10Alexander Murray11Fabiana Corsi-Zuelli12Hannah Hickinbotham13Ella Warwick14Nicholas M Barnes15Golam KhandakerDavid CotterEd BullmoreEva MeisenzahlJoanna NeillNikos KoutsoulerisStephen WoodInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKDepartment of Psychiatry, University of Cambridge, Cambridge, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKDepartment of Psychiatry, University of Cambridge, Cambridge, UKDepartment of Psychiatry, University of Cambridge, Cambridge, UKAvon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UKDepartment of Medicine, University of Cambridge, Cambridge, UKFaculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKMRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKDepartment of Psychiatry, University of Cambridge, Cambridge, UKInstitute for Mental Health and Centre for Human Brain Health, University of Birmingham, Birmingham, UKInstitute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKIntroduction Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.Methods and analysis A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.Ethics and dissemination The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.Trial registration number ISRCTN23256704.https://bmjopen.bmj.com/content/13/3/e067944.full |
| spellingShingle | Stephen Burgess Peter Jones Rachel Upthegrove Carmine Pariante Graham K Murray Anthony David Martin Wilson Nicholas Barnes Paola Dazzan John Suckling Valeria Mondelli Muzaffer Kaser Neil Harrison Georgios Gkoutos Golam M Khandaker Deepak Jadon James MacCabe Gary Donohoe Alice Egerton Bill Deakin Jack Rogers Éimear M Foley Sian Lowri Griffiths Alexander Murray Fabiana Corsi-Zuelli Hannah Hickinbotham Ella Warwick Nicholas M Barnes Golam Khandaker David Cotter Ed Bullmore Eva Meisenzahl Joanna Neill Nikos Koutsouleris Stephen Wood Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis BMJ Open |
| title | Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis |
| title_full | Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis |
| title_fullStr | Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis |
| title_full_unstemmed | Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis |
| title_short | Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis |
| title_sort | protocol for the psychosis immune mechanism stratified medicine pims trial a randomised double blind placebo controlled trial of single dose tocilizumab in patients with psychosis |
| url | https://bmjopen.bmj.com/content/13/3/e067944.full |
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