C-Reactive Protein: Higher During Acute Psychotic Episodes and Related to Cortical Thickness in Schizophrenia and Healthy Controls

Copyright © 2018 Jacomb, Stanton, Vasudevan, Powell, O'Donnell, Lenroot, Bruggemann, Balzan, Galletly, Liu, Weickert and Weickert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.There is increasing evidence for the role of inflammation in schizophrenia, yet the stability of increased peripheral inflammation in acute psychosis and the degree to which peripheral inflammation relates to cortical thickness, a measure of the degree of neuropathology, are unknown. In independent samples, we assessed the peripheral inflammation marker C-reactive protein (CRP) to determine the extent to which: (1) CRP was elevated and stable across admissions for acute psychosis, (2) cognition, daily function and symptom severity are characteristic of chronically ill patients with schizophrenia displaying elevated CRP, and (3) CRP levels predict cortical thickness. Study 1 assessed peripheral CRP (primary outcome) and other blood measures in 174/280 people with acute psychosis while Study 2 assessed peripheral CRP, cognition and cortical thickness (primary outcomes), symptoms, and daily function in 85/97 chronically ill patients with schizophrenia and 71/87 healthy controls. In acute psychosis, CRP and neutrophil-to-lymphocyte ratio were significantly elevated relative to a normal cutoff (with 59.8% of patients having elevated CRP) which remained elevated across admissions. CRP was significantly elevated in 43% of chronically ill patients with schizophrenia compared to 20% in controls. Elevated CRP patients displayed significantly worse working memory and CRP was inversely correlated with cortical thickness in frontal, insula, and temporal brain regions. This work supports the role of inflammation in psychotic illnesses and suggests that use of peripheral markers (e.g., CRP) in conjunction with diagnosis could be used to identify patients with more cortical neuropathology and cognitive deficits

C-Reactive Protein: Higher During Acute Psychotic Episodes and Related to Cortical Thickness in Schizophrenia and Healthy Controls

There is increasing evidence for the role of inflammation in schizophrenia, yet the stability of increased peripheral inflammation in acute psychosis and the degree to which peripheral inflammation relates to cortical thickness, a measure of the degree of neuropathology, are unknown. In independent samples, we assessed the peripheral inflammation marker C-reactive protein (CRP) to determine the extent to which: (1) CRP was elevated and stable across admissions for acute psychosis, (2) cognition, daily function and symptom severity are characteristic of chronically ill patients with schizophrenia displaying elevated CRP, and (3) CRP levels predict cortical thickness. Study 1 assessed peripheral CRP (primary outcome) and other blood measures in 174/280 people with acute psychosis while Study 2 assessed peripheral CRP, cognition and cortical thickness (primary outcomes), symptoms, and daily function in 85/97 chronically ill patients with schizophrenia and 71/87 healthy controls. In acute psychosis, CRP and neutrophil-to-lymphocyte ratio were significantly elevated relative to a normal cutoff (with 59.8% of patients having elevated CRP) which remained elevated across admissions. CRP was significantly elevated in 43% of chronically ill patients with schizophrenia compared to 20% in controls. Elevated CRP patients displayed significantly worse working memory and CRP was inversely correlated with cortical thickness in frontal, insula, and temporal brain regions. This work supports the role of inflammation in psychotic illnesses and suggests that use of peripheral markers (e.g., CRP) in conjunction with diagnosis could be used to identify patients with more cortical neuropathology and cognitive deficits

Physical context regulates the renewal of fear in indirect pathways : an examination of fear reduction processes using verbal information provision and modelling

Among adults, classically conditioned fears that have been extinguished can recover through a change of physical context. Recovery of fear via a change of physical context is typically termed ‘renewal’. In this study, we investigated whether adults also exhibit renewal via the verbal threat information pathway. Fifty adult participants (M = 20 years-old; range: 18 to 45 years of age) acquired fear beliefs about a novel and fictitious animal through the provision of threatening information about the animal. Fears were reduced via the verbal provision of positive information and modelling. Participants were randomised to receive fear reduction in either the same context (Context A) or in a different context (Context B) to the context used for fear acquisition (Context A). All participants were then tested back in the context of acquisition. Results showed fears recovered when the context of fear reduction and the context of test were different, indicating physical context regulates the renewal of verbally acquired and reduced fear. The findings are discussed in terms of current theoretical and developmental models for fear extinction and the implications for relapse models of adult anxiety disorders.15 page(s

A stepped wedge cluster randomised trial of a cognitive remediation intervention in alcohol and other drug (AOD) residential treatment services

Background: Executive functioning impairment is common in substance use disorder and is a major risk factor for poor treatment outcomes, including treatment drop-out and relapse. Cognitive remediation interventions seek to improve executive functioning and offer a promising approach to increase the efficacy of alcohol and other drug (AOD) treatments and improve long-term therapeutic outcomes. This protocol describes a study funded by the NSW Agency for Clinical Innovation that assesses the effectiveness of delivering a six-week group-based intervention of cognitive remediation in an ecologically valid sample of people attending residential AOD treatment services. We primarily aim to investigate whether cognitive remediation will be effective in improving executive functioning and treatment retention rates. We will also evaluate if cognitive remediation may reduce long-term AOD use and rates of health service utilisation, as well as improve personal goal attainment, quality of life, and client satisfaction with treatment. In addition, the study will involve an economic analysis of the cost of delivering cognitive remediation. Methods/design: The study uses a stepped wedge cluster randomised design, where randomisation will occur at the cluster level. Participants will be recruited from ten residential AOD treatment services provided by the non-government sector. The intervention will be delivered in 12 one-hour group-based sessions over a period of six weeks. All participants who are expected to receive treatment for the duration of the six-week intervention will be asked to participate in the study. The clusters of participants who are randomly assigned to the treatment condition will complete cognitive remediation in addition to treatment as usual (TAU). Primary and secondary outcome assessments will be conducted at pre-cognitive remediation/TAU phase, post-cognitive remediation/TAU phase, two-month follow-up, four-month follow-up, six-month follow-up, and eight-month follow-up intervals. Discussion: This study will provide comprehensive data on the effect of delivering a cognitive remediation intervention within residential AOD treatment services. If shown to be effective, cognitive remediation may be incorporated as an adjunctive intervention in current treatment programs. Trial registration: Australian and New Zealand Clinical Trials Register (ANZCTR): ACTRN12618001190291. Prospectively registered 17th July 2018

A stepped wedge cluster randomised trial of a cognitive remediation intervention in alcohol and other drug (AOD) residential treatment services

Abstract Background Executive functioning impairment is common in substance use disorder and is a major risk factor for poor treatment outcomes, including treatment drop-out and relapse. Cognitive remediation interventions seek to improve executive functioning and offer a promising approach to increase the efficacy of alcohol and other drug (AOD) treatments and improve long-term therapeutic outcomes. This protocol describes a study funded by the NSW Agency for Clinical Innovation that assesses the effectiveness of delivering a six-week group-based intervention of cognitive remediation in an ecologically valid sample of people attending residential AOD treatment services. We primarily aim to investigate whether cognitive remediation will be effective in improving executive functioning and treatment retention rates. We will also evaluate if cognitive remediation may reduce long-term AOD use and rates of health service utilisation, as well as improve personal goal attainment, quality of life, and client satisfaction with treatment. In addition, the study will involve an economic analysis of the cost of delivering cognitive remediation. Methods/design The study uses a stepped wedge cluster randomised design, where randomisation will occur at the cluster level. Participants will be recruited from ten residential AOD treatment services provided by the non-government sector. The intervention will be delivered in 12 one-hour group-based sessions over a period of six weeks. All participants who are expected to receive treatment for the duration of the six-week intervention will be asked to participate in the study. The clusters of participants who are randomly assigned to the treatment condition will complete cognitive remediation in addition to treatment as usual (TAU). Primary and secondary outcome assessments will be conducted at pre-cognitive remediation/TAU phase, post-cognitive remediation/TAU phase, two-month follow-up, four-month follow-up, six-month follow-up, and eight-month follow-up intervals. Discussion This study will provide comprehensive data on the effect of delivering a cognitive remediation intervention within residential AOD treatment services. If shown to be effective, cognitive remediation may be incorporated as an adjunctive intervention in current treatment programs. Trial registration Australian and New Zealand Clinical Trials Register (ANZCTR): ACTRN12618001190291. Prospectively registered 17th July 2018

The impact of premorbid and current intellect in schizophrenia:Cognitive, symptom, and functional outcomes

BACKGROUND: Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group. METHODS: A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups. RESULTS: A total of 157 patients (29%) classified as 'preserved' performed within one s.d. of control means in all cognitive domains. Patients classified as 'deteriorated' (n = 239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as 'compromised,' performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures. CONCLUSIONS: In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group

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

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

Additional file 2: Table S2. of Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder

Significant correlations between serum and plasma cytokines. (DOCX 14 kb