Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

BACKGROUND: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. METHODS: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. RESULTS: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). CONCLUSIONS: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.

Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration.

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Cognitive function and treatment response trajectories in first-episode schizophrenia: evidence from a prospective cohort study.

OBJECTIVES: This prospective cohort study tested for associations between baseline cognitive performance in individuals early within their first episode and antipsychotic treatment of psychosis. We hypothesised that poorer cognitive functioning at the initial assessment would be associated with poorer antipsychotic response following the subsequent 6 weeks. DESIGN: Prospective cohort . SETTING: National Health Service users with a first-episode schizophrenia diagnosis, recently starting antipsychotic medication, recruited from two UK sites (King's College London, UK and University of Manchester, UK). Participants attended three study visits following screening. PARTICIPANTS: Eighty-nine participants were recruited, with 46 included in the main analysis. Participants required to be within the first 2 years of illness onset, had received minimal antipsychotic treatment, have the capacity to provide consent, and be able to read and write in English. Participants were excluded if they met remission criteria or showed mild to no symptoms. PRIMARY AND SECONDARY OUTCOME MEASURES: Antipsychotic response was determined at 6 weeks using the Positive and Negative Syndrome Scale (PANSS), with cognitive performance assessed at each visit using the Brief Assessment of Cognition in Schizophrenia (BACS). The groups identified (responders and non-responders) from trajectory analyses, as well as from >20% PANSS criteria, were compared on baseline BACS performance. RESULTS: Trajectory analyses identified 84.78% of the sample as treatment responsive, and the remaining 15.22% as treatment non-responsive. Unadjusted and adjusted logistic regressions observed no significant relationship between baseline BACS on subscale and total performance (BACS t-score: OR=0.98, p=0.620, Cohen's d=0.218) and antipsychotic response at 6 weeks. CONCLUSIONS: This investigation identified two clear trajectories of treatment response in the first 6 weeks of antipsychotic treatment. Responder and non-responder groups did not significantly differ on performance on the BACS, suggesting that larger samples may be required or that an association between cognitive performance and antipsychotic response is not observable in the first 2 years of illness onset. TRIAL REGISTRATION NUMBER: REC: 17/NI/0209.

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium.

INTRODUCTION: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. METHODS: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. RESULTS: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). IMPLICATIONS: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

Cross-sectional study comparing cognitive function in treatment responsive versus treatment non-responsive schizophrenia: evidence from the STRATA study.

BACKGROUND: 70%-84% of individuals with antipsychotic treatment resistance show non-response from the first episode. Emerging cross-sectional evidence comparing cognitive profiles in treatment resistant schizophrenia to treatment-responsive schizophrenia has indicated that verbal memory and language functions may be more impaired in treatment resistance. We sought to confirm this finding by comparing cognitive performance between antipsychotic non-responders (NR) and responders (R) using a brief cognitive battery for schizophrenia, with a primary focus on verbal tasks compared against other measures of cognition. DESIGN: Cross-sectional. SETTING: This cross-sectional study recruited antipsychotic treatment R and antipsychotic NR across four UK sites. Cognitive performance was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). PARTICIPANTS: One hundred and six participants aged 18-65 years with a diagnosis of schizophrenia or schizophreniform disorder were recruited according to their treatment response, with 52 NR and 54 R cases. OUTCOMES: Composite and subscale scores of cognitive performance on the BACS. Group (R vs NR) differences in cognitive scores were investigated using univariable and multivariable linear regressions adjusted for age, gender and illness duration. RESULTS: Univariable regression models observed no significant differences between R and NR groups on any measure of the BACS, including verbal memory (ß=-1.99, 95% CI -6.63 to 2.66, p=0.398) and verbal fluency (ß=1.23, 95% CI -2.46 to 4.91, p=0.510). This pattern of findings was consistent in multivariable models. CONCLUSIONS: The lack of group difference in cognition in our sample is likely due to a lack of clinical distinction between our groups. Future investigations should aim to use machine learning methods using longitudinal first episode samples to identify responder subtypes within schizophrenia, and how cognitive factors may interact within this. TRAIL REGISTRATION NUMBER: REC: 15/LO/0038.

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min-1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Mothers' reports of the difficulties that their children experience in taking methotrexate for Juvenile Idiopathic Arthritis and how these impact on quality of life.

BACKGROUND: Children who take methotrexate for juvenile idiopathic arthritis may experience side effects, including nausea and vomiting, leading to anticipatory nausea in some children, and fear of injections or blood tests. The aim of this study was to examine the prevalence and extent of these difficulties and their impact on quality of life. METHODS: Participants were mothers of children with JIA who were currently taking methotrexate (MTX). Mothers completed a questionnaire about MTX that was developed for the study, two questions from the treatment subscale of the Pediatric Quality of Life Inventory (PedsQL) Rheumatology scale to assess needle-related problems and the Child Health Questionnaire 50-item parent version (CHQ-PF50) to assess health-related quality of life (HRQoL). RESULTS: 171 mothers participated in the study. More than half of children were reported to have experienced one or more of: nausea or vomiting after taking MTX, anticipatory nausea, fear of blood tests or fear of injections. There was no significant difference in reported rates of sickness or needle-related problems between MTX responders (ACR70 or above), partial responders (ACR30 or ACR50) and non-responders. In multivariate analyses, variables that were significant independent predictors of one or more MTX-related difficulties included younger age, taking MTX subcutaneously and having a larger number of currently active joints. Feeling sick after taking MTX was a significant independent predictor of poorer scores on the physical summary scale of the CHQ-PF50. Anxiety about injections and feeling sick after taking MTX were significant independent predictors of poorer scores on the psychosocial summary scale. CONCLUSIONS: Difficulties in taking MTX are experienced by a significant proportion of children with JIA and these may have an adverse impact on HRQoL. Approaches to help minimize these difficulties are required.

A subgroup of juvenile idiopathic arthritis patients who respond well to methotrexate are identified by the serum biomarker MRP8/14 protein.

OBJECTIVES: In JIA there is an unmet need for biomarkers with which to identify patients who will respond well to MTX. The aim of this study was to define the prognostic value of baseline serum proteins and clinical variables in response to MTX to help inform the clinician at time of diagnosis whether the patient is likely to respond well to MTX. METHODS: JIA patients were recruited into the Childhood Arthritis Response to Medication Study (CHARMS). Clinical data and venous blood were collected before administration of MTX and at follow-up. MRP8/14 and inflammatory cytokines were measured by ELISA and multiplex immunoassay, respectively. CRP and ESR were measured as part of routine clinical assessment. To explore which baseline factors might predict successful treatment, binary logistic regression models were fitted for outcome. RESULTS: High disease activity (high serum MRP8/14, active joint count or physician's score) pre-MTX was observed in a subgroup of patients with a better response to therapy. In a multivariable analysis, after accounting for MRP8/14 at baseline, no other factors were independently significantly associated with outcome. Patients with baseline MRP8/14 >3000 ng/ml were more likely to respond to MTX at ACR50 or better: odds ratio 16.07 (95% CI 2.00, 129.3). CONCLUSION: We have demonstrated that high levels of baseline serum MRP8/14 have prognostic value in predicting a subgroup of patients whose arthritis will improve on MTX. Routine collection of serum prior to the start of medication would be a valuable step in collaborative validation of such biomarkers.

Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis.

OBJECTIVES: Methotrexate (MTX) is the mainstay treatment for juvenile idiopathic arthritis (JIA), however approximately 30% of children will fail to respond to the drug. Identification of genetic predictors of response to MTX would be invaluable in developing optimal treatment strategies for JIA. Using a candidate gene approach, single nucleotide polymorphisms (SNPs) within genes in the metabolic pathway of MTX, were investigated for association with response to treatment in JIA cases. METHODS: Tagging SNPs were selected across 13 MTX metabolic pathway genes and were genotyped using Sequenom genotyping technology in subjects recruited from the Sparks Childhood Arthritis Response to Medication Study. Response to MTX was defined using the American College of Rheumatology (ACR) paediatric response criteria and SNP genotype frequencies were compared between the worst and best responders (ACR-Ped70) to MTX. An independent cohort of US JIA cases was available for validation of initial findings. RESULTS: One SNP within the inosine triphosphate pyrophosphatase gene (ITPA) and two SNPs within 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) were significantly associated with a poor response to MTX. One of the ATIC SNPs showed a trend towards association with MTX response in an independent cohort of US JIA cases. Meta-analysis of the two studies strengthened this association (combined p value=0.002). CONCLUSIONS: This study presents association of a SNP in the ATIC gene with response to MTX in JIA. There is now growing evidence to support a role of the ATIC gene with response to MTX treatment. These results could contribute towards a better understanding of and ability to predict MTX response in JIA.

Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype.

OBJECTIVES: Little is known about the mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment. METHODS: Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after the treatment were selected for single nucleotide polymorphism (SNP) genotyping. Genotype frequencies were compared between nonresponders and responders (ACR-Ped70). An independent cohort was available for validation. RESULTS: Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, P<0.05) and 1065 when restricted to full responder cases only. Six highly differentially expressed genes were analyzed for genetic association in response to MTX. Three SNPs in the SLC16A7 gene showed significant association with MTX response. One SNP showed validated association in an independent cohort. CONCLUSION: This study is the first, to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyze genetic variation in differentially expressed genes. We have identified a gene, which may contribute to genetic variability in MTX response in JIA, and established as proof of principle that genes that are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis.

Do mothers and fathers hold similar views about their child's arthritis?

OBJECTIVE: Evaluations of the well-being of children with juvenile idiopathic arthritis (JIA) typically rely on parents as proxy respondents. An assumption of several studies appears to be that mothers' and fathers' ratings are interchangeable, as reports do not always specify which parent completed the assessments nor, in repeated measures, whether they were completed by the same parent. The aim of this study was to examine the level of agreement between mothers' and fathers' ratings of their child's quality of life (QOL) and to identify possible predictors of disagreement. METHODS: Mothers and fathers (n = 82) of children with JIA completed ratings of their child's symptoms, QOL, and measures of their mood and beliefs about their child's illness and treatment. The number of active and limited joints and the physician's global assessment were also recorded. RESULTS: Intraclass correlation coefficients between mothers' and fathers' ratings of physical and psychosocial QOL were high (0.824 and 0.755, respectively). However, calculation of difference scores revealed that 70.6% and 65.9%, respectively, were classified as discordant. Where parents differed, the direction of difference was not systematic. Discordance in parents' mood states and in their illness and treatment beliefs explained a small amount of the variance in discordance in QOL. CONCLUSION: It should not be assumed that proxy ratings of a child's well-being can be generalized from one parent to the other. Studies that take repeated assessments should ensure that the same parent completes assessments at all time points. Other factors that may explain discordance between parents' ratings need to be explored.