Cognitive function in early-phase schizophrenia-spectrum disorder: IQ subtypes, brain volume and immune markers.

BACKGROUND: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. METHOD: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α. RESULTS: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. CONCLUSIONS: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Deconstructing depression and negative symptoms of schizophrenia; differential and longitudinal immune correlates, and response to minocycline treatment.

BACKGROUND: Immune dysfunction has been implicated in negative symptoms of schizophrenia and also in depression. These disorders are frequently co-morbid, with some symptoms such as anhedonia and apathy common to both. The anti-inflammatory agent minocycline may be ineffective in schizophrenia, but more positive effects have been seen in depression. Our aim was to investigate the role of immune dysfunction in depression and sub-domains of negative symptoms in schizophrenia by investigating their intercorrelation and the influence of treatment with minocycline. METHODS: We analysed longitudinal data from 207 patients within 5 years of onset of schizophrenia, from the randomised double-blind, placebo-controlled trial of minocycline (BeneMin). Symptom ratings and circulating IL-6, C-reactive protein (CRP) and TNF-α concentrations were collected at baseline and repeated over twelve months. The sample was not stratified by CRP prior to randomisation. Positive and Negative Syndrome Scale composite ratings of avolition-apathy and diminished expression, Calgary Depression Scale total scores, and immune markers were examined cross-sectionally using Spearman's rank, and longitudinally by linear mixed effect models that included body mass index and minocycline. Additionally, post hoc analysis of the sample stratified by elevated CRP (>1 mg/l and <10 mg/l at baseline) was carried out to assess whether minocycline had any effect on specific symptoms in an immune active sub-group of patients. RESULTS: Depression and avolition-apathy were significantly positively related, and depression correlated weakly with IL-6 at baseline. Diminished expression was associated with increased TNF-α both cross-sectionally and longitudinally. CRP was unrelated to any symptom domain. Minocycline did not affect any individual symptom or sub-domain in the full sample or in the immune active sub-group. DISCUSSION: IL-6 may have some specificity to depression in early schizophrenia. TNF-α may be an indicator of immune dysfunction relevant to negative symptoms, and our longitudinal findings add to this evidence. However, minocycline continues to show very little promise as a treatment for any symptom dimension of early schizophrenia.

Health beliefs and carer burden in first episode psychosis.

BACKGROUND: Carer burden is high during First Episode Psychosis (FEP) and evidence suggests that this is a predictor of poor long-term outcome. However our understanding of factors associated with higher burden is poor. We propose that carers' cultural backgrounds and health belief models will influence their perceived burden of care, over and above that explained by severity of illness. METHODS: Patients with FEP and their primary Carers were recruited from the Early Intervention Service. Patients and Carers completed a range of validated measures, self-report ethnicity and demographic information together with the Multidimensional Health Locus of Control and Caregiver Burden Inventory. RESULTS: Significant correlations were found between carer burden and health beliefs, which differed by ethnicity and gender. High physical burden was experienced by Black carers with an external locus of control; time restrictions and emotional burden correlated with an external locus of control in Asian carers. For White carers, external locus of control correlated with time dependence burden. In all ethnic groups female carers experienced more time dependency, physical and developmental burden. No significant correlations were found between patient measures of severity or duration of illness and carer burden. CONCLUSIONS: The type of burden experienced by carers differed between gender and ethnicity and was related to their health belief models. Thus the explanation and understanding of illness appears to be more salient than simply a patient's severity of illness when considering the development of carer burden. Interventions to tackle high carer burden, and thus expressed emotion to improve outcome in patients, may need increasing focus here.

An evaluation of the convergent validity of a face-to-face and virtual neuropsychological assessment counter balanced.

The COVID-19 pandemic has highlighted the need for further research evaluating the validity of conducting a battery of neuropsychological assessments virtually compared with face-to-face administration. Previous research has suggested that some neuropsychological assessments yield valid results when administered virtually, however, much of the previous research focused on older adults. To determine the validity of virtually administered neuropsychological tests, 28 healthy participants were assessed using a within-subjects, counter-balanced design. Participants completed a neuropsychological assessment battery covering tests of general intellectual functioning, memory and attention, executive functioning, language and information processing speed, as well as effort. There was no significant difference between face-to-face administration of the neuropsychological battery compared with virtual administration for the majority of the tests used. However, there were significant differences in the Colour Naming Task, with participants making fewer errors on the colour naming task and inhibition/switching task when administered virtually compared with face-to-face administration. There was also a significant age cohort effect in the inhibition/switching task. There was also a trending significant difference in mode of administration for the Verbal Fluency Task. Virtually administered neuropsychological assessments largely provide a valid alternative to face-to-face assessments; however, consideration must be given to test selection as well as the population of participants that are being assessed. Other important considerations must focus on preserving the security and integrity of test materials, as well as administration in a medico-legal setting. Future research should focus on validating assessments with specific patient populations and developing a neuropsychological assessment battery using information technology.

A meta-analytic review examining the validity of executive functioning tests to predict functional outcomes in individuals with a traumatic brain injury.

OBJECTIVES: Deficits in executive functioning are a common consequence of Traumatic Brain Injury (TBI) and the severity of TBI is known to predict functional outcomes. In this review, the authors examine the ability of three commonly used tests of executive functioning [The Trail Making Test (TMT-B), The Wisconsin Card Sorting Test (WCST), and Verbal Fluency (VF)] to predict domains of function. METHODS: Seven hundred and twenty articles were identified and twenty-four met inclusion criteria (original articles published in English examining an adult TBI population). Data were subject to a study quality analysis and then meta-analyzed to assess whether tests of executive functioning (TMT-B, WCST, and VF) can predict functional, employment, and driving outcomes following a TBI. RESULTS: The TMT-B (r = 0.29; 95% CI 0.17-0.41) and the WCST (r = 0.20; 95% CI 0.02-0.37) were significantly associated with functional outcomes. The TMT-B was also associated with a person's ability to return to driving (r = 0.3890; 95% CI 0.2678-0.5103). No test of executive functioning was associated with employment outcomes following a TBI. CONCLUSION: These findings are important to guide rehabilitation strategies and future planning. This review has also highlighted the scarcity of research on specific outcomes.

Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. FINDINGS: Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). INTERPRETATION: Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Self-harm and ethnicity: A systematic review.

AIMS: This review will focus on the rates, clinical characteristics, risk factors and methods of self-harm and suicide in different ethnic groups in the United Kingdom, providing an update synthesis of recent literature. METHODS: Studies that met the inclusion criteria between 2003 and 2013 were reviewed using the following databases: MEDLINE, PsycINFO, EMBASE and CINAHL. The methodological quality of each study was then assessed using a structured scoring system. RESULTS: A total of 2,362 articles were retrieved, 10 of which matched the inclusion criteria were reviewed. Significant differences were found in the rates of self-harm between ethnic groups with Asian males being least likely to self-harm and Black females being most likely to self-harm. Also, Black and South Asian people were less likely to repeat self-harm. Factors that may help protect or predispose individuals to self-harm or attempt suicide (such as religion, mental health and coping styles) also differ between ethnic groups. CONCLUSIONS: There are clear ethnic differences in self-harm and suicide, which may be affected by factors such as cultural pressures and prevalence of mental illness. An awareness of these differences is vital to help prevent further attempts of self-harm and suicide. Further research into differences between ethnic and cultural groups and self-harm continues to be important.