Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial.

Anti-inflammatory drug Blood biomarker C-Reactive Protein Canakinumab Inflammation Interleukin-1β Positive Symptoms Randomized double-blind placebo-control trial Schizophrenia

Journal

Brain, behavior, and immunity
ISSN: 1090-2139
Titre abrégé: Brain Behav Immun
Pays: Netherlands
ID NLM: 8800478

Informations de publication

Date de publication:
Jan 2024
Historique:
received: 24 04 2023
revised: 11 10 2023
accepted: 14 10 2023
pubmed: 18 10 2023
medline: 18 10 2023
entrez: 17 10 2023
Statut: ppublish

Résumé

Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1β) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1β monoclonal antibody, interferes with the bioactivity of IL-1β and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1β, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Sections du résumé

BACKGROUND BACKGROUND
Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1β) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1β monoclonal antibody, interferes with the bioactivity of IL-1β and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown.
TRIAL DESIGN METHODS
We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation.
METHODS METHODS
Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1β, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection.
RESULTS RESULTS
Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued.
CONCLUSIONS CONCLUSIONS
Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Identifiants

DOI: 10.1016/j.bbi.2023.10.012 PMID: 37848096
pubmed: 37848096
pii: S0889-1591(23)00312-4
doi: 10.1016/j.bbi.2023.10.012
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

191-200

Informations de copyright

Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Thomas W Weickert (TW)

Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: weickert@upstate.edu.

Isabella Jacomb (I)

Neuroscience Research Australia, Sydney, New South Wales, Australia.

Rhoshel Lenroot (R)

Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.

Julia Lappin (J)

School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.

Danielle Weinberg (D)

Neuroscience Research Australia, Sydney, New South Wales, Australia.

William S Brooks (WS)

Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.

David Brown (D)

NSW Health Pathology-ICPMR, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

Daniel Pellen (D)

Neuroscience Research Australia, Sydney, New South Wales, Australia.

Jochen Kindler (J)

Neuroscience Research Australia, Sydney, New South Wales, Australia; University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.

Adith Mohan (A)

School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.

Denis Wakefield (D)

School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Andrew R Lloyd (AR)

Viral Immunology Systems Program, Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

Clive Stanton (C)

Neuroscience Research Australia, Sydney, New South Wales, Australia; Prince of Wales Hospital, Sydney, New South Wales, Australia.

Maryanne O'Donnell (M)

Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; Prince of Wales Hospital, Sydney, New South Wales, Australia.

Dennis Liu (D)

Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Northern Adelaide Locah Health Network, Adelaide, South Australia, Australia.

Cherrie Galletly (C)

Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Northern Adelaide Locah Health Network, Adelaide, South Australia, Australia.

Cynthia Shannon Weickert (C)

Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.

Classifications MeSH