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.

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.

Uptake of internet-delivered UK adult hearing assessment.

OBJECTIVE: To evaluate uptake of the internet-based hearing test, with respect to the 11% of UK adults that have hearing loss but do not use hearing aids. DESIGN: Feasibility study in a primary care practice in the North of England. STUDY SAMPLE: Adults aged 50-74 years were sent postal invitations to complete an internet hearing test (N = 600). Those who completed the test, those who failed (>35 dB HL in the better ear) and demographic correlates (age, gender, ethnicity and socioeconomic level) were recorded. RESULTS: 11.2% of invited adults completed the hearing test and 7.7% failed it. Those who took the test tended to have a higher socioeconomic background than those who did not. There were no differences in age, ethnicity or gender between those who took the test and those who did not. CONCLUSIONS: An estimated 70% (7.7%/11.0%) of adults with hearing loss but who do not use hearing aids took the test. Uptake was equitable across most demographic categories. Uptake was high among a study sample that was substantially more deprived than the general UK population. Internet-based hearing testing offers an efficient paradigm for identifying hearing loss.

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.

A longitudinal comparison of two neurocognitive test batteries in patients with schizophrenia and healthy volunteers: Time effects on neuropsychological performance and their relation to functional outcome.

Cognitive impairment is a major unmet need in the treatment of schizophrenia. Over the last decade, the MATRICS Consensus Cognitive Battery (MCCB) has been used to assess the effects of novel treatments for cognitive impairment in schizophrenia. However, other cognitive-neuroscience-based cognitive batteries, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) have been suggested as an alternative to the MCCB. Although both batteries purport to assess cognitive function in psychosis, no previous study has attempted to examine their validity longitudinally and the potential overlap between the two batteries over time. The aim of the current study was to assess the relationship between the MCCB and the CANTAB in the longitudinal assessment of cognitive impairment in schizophrenia. A sample of 39 stable schizophrenia outpatients and 18 controls completed the MCCB and the CANTAB battery at baseline, and at 2, 4 and 8-weeks follow-up. Correlation analyses and a mixed-model repeated measures approach were used. We found no significant effect of time in the MCCB. In contrast, for the CANTAB a significant effect of time consistent with practice effects for the attention domain in the control group and for the visual learning, reasoning and problem-solving, and social cognition domains in patients, with subjects performing better at follow-up. In particular, a significant time ∗ battery interaction was found for those cognitive domains. These findings suggest there are specific differences across cognitive tests to assess cognitive impairments in schizophrenia and that measures derived from the CANTAB appear to be more prone to practice effects in these patients.

Calibration and cross-validation of MCCB and CogState in schizophrenia.

RATIONALE: Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison. OBJECTIVES: The objective of this study was to assess the reliability and validity of these two assessment batteries. METHODS: One hundred forty-three participants with DSM-IV schizophrenia and schizoaffective disorder were recruited into three similar studies. Each study administered MCCB and SB tests on consecutive days (baseline 1 and 2) and follow-up 3-4 weeks later. RESULTS: Batteries' test-retest reliability was similar: SB composites correlated r = 0.66-0.78 between baselines, MCCB domains r = 0.69-0.90. Baseline 2 and follow-up SB composites correlated r = 0.65-0.80 and MCCB domains r = 0.62-0.87. MCCB tasks' practice effects (Glass' ∆ = 0.02-0.46) exceeded SB's (Glass' ∆ = 0.02-0.34). While the batteries' total scores correlated strongly (r = 0.79-0.82), apparently equivalent cognitive domains on each battery (e.g. psychomotor-attention) correlated r = 0.22-0.60, indicating substantial differences between some supposed counterparts. CONCLUSIONS: Clinical trials using either battery would benefit from initial practice sessions to ameliorate practice effects but the SB may be more suitable to measure change in the absence of repeated baselines. The MCCB domains' better correlations with social skills performance suggest that it may have an advantage for measuring cognition in relation to functional outcome.

Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

Effects of risperidone, amisulpride and nicotine on eye movement control and their modulation by schizotypy.

RATIONALE: The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers. OBJECTIVES: We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia. METHODS: In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555-564, 1991)). RESULTS: AS error rate showed a main effect of Drug (p < 0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p = 0.04), indicating higher error rates in medium schizotypes (p = 0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p = 0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p ≤ 0.01) indicating impaired performance with risperidone. CONCLUSIONS: We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.

A validation of cognitive biomarkers for the early identification of cognitive enhancing agents in schizotypy: a three-center double-blind placebo-controlled study.

A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.

Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study.

CONTEXT: Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. OBJECTIVES: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. DESIGN: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. SETTING: Wellcome Trust Clinical Research Facility, Manchester, England. PARTICIPANTS: Thirty-three healthy, right-handed men were recruited by advertisements. INTERVENTIONS: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. MAIN OUTCOME MEASURES: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. RESULTS: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. CONCLUSIONS: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

Gender differences and the effects of ketamine in healthy volunteers.

We present a critical perspective of the impact of gender differences on a widely accepted model of ketamine psychosis in healthy volunteers. Male and female patients with schizophrenia present with different symptomatology, disease course and response to pharmacological intervention. Accordingly, it is expected that ketamine psychosis in healthy volunteers fulfils this face validity. Pre-clinical studies in rats indicate a gender difference in response to ketamine administration. However, a review of the literature to date indicates that studies carried out in healthy volunteers have used all male or mixed samples, indicating the need for further studies comparing the psychopathological effects of ketamine in males and females.