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

Weickert, Thomas W; Jacomb, Isabella; Lenroot, Rhoshel; Lappin, Julia; Weinberg, Danielle; Brooks, William S; Brown, David; Pellen, Daniel; Kindler, Jochen; Mohan, Adith; Wakefield, Denis; Lloyd, Andrew R; Stanton, Clive; O'Donnell, Maryanne; Liu, Dennis; Galletly, Cherrie; Shannon Weickert, Cynthia (2024). Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial. Brain, behavior, and immunity, 115, pp. 191-200. Elsevier 10.1016/j.bbi.2023.10.012

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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 samples. 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

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

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

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

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > University Psychiatric Services > University Hospital of Child and Adolescent Psychiatry and Psychotherapy

UniBE Contributor:

Kindler, Jochen

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0889-1591

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

18 Oct 2023 12:27

Last Modified:

13 Dec 2023 00:15

Publisher DOI:

10.1016/j.bbi.2023.10.012

PubMed ID:

37848096

Uncontrolled Keywords:

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

BORIS DOI:

10.48350/187270

URI:

https://boris.unibe.ch/id/eprint/187270

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