Jane Lees

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.

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.

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

RationaleThe 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.ObjectivesWe 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.MethodsIn 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)).ResultsAS 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.ConclusionsWe 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.

The effects of ketamine and risperidone on eye movement control in healthy volunteers

The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml−1 ketamine, 2 mg oral risperidone, 100 ng ml−1 ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P<0.01) but had no significant effects on PS or AS (all P⩾0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P⩽0.04). No ketamine by risperidone interactions were found (all P⩾0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.

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.

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.

Differential effect of amisulpride on cognition in schizotypy: validation of models for the early identification of cognitive enhancing agents

Abstract Background The cognitive impairment associated with schizophrenia is a major target for drug development but none of the drugs designed to address this problem has shown consistent efficacy. The most common causes for failure in the registration trials could be preempted by testing novel agents in milder forms of the disorder, such as schizotypy and assessing the effect with validated biomarkers. In this study we aimed to test this approach by comparing the effects of risperidone, amisulpride, and nicotine in a double-blind placebo-controlled three-centre study on the cognitive performance in schizotypy. Methods We recruited healthy volunteers who scored high and average on the Schizotypal Personality Questionnaire (122 in each group). 244 participants were randomised to an acute dose of risperidone (n=62, capsule plus placebo patch), amisulpride (n=62, capsule plus placebo patch), nicotine (n=61, placebo capsule plus nicotine patch), or placebo (n=59, placebo capsule plus placebo patch) and proceeded to complete cognitive tests (n-back, verbal fluency, and spatial working memory tasks). Primary outcome measures were percentage correct, errors of commission, and response latencies (n-back), number of correct words and category transitions (verbal fluency), and between-search and within-search errors (spatial working memory tasks). This trial has not been registered. Findings We found evidence for worse performance in the high schizotypy group on the n-back and verbal fluency tasks (p 2 =0·059 and p 2 =0·064, respectively). Amisulpride had a differential effect on the two groups in respect to these two tasks (p=0·02 and p=0·04, respectively): it improved performance in the high schizotypy group but impaired the controls. By contrast, risperidone impaired both groups while nicotine had a beneficial effect for the low baseline performers. There was a statistically significant increase in the reaction time latency in the n-back task in the risperidone arm compared with all other arms. Interpretation We attribute the effects of amisulpride to its presynaptic dopamine enhancing action at low doses. The deterioration of performance with risperidone on the other hand was probably due to sedation while nicotine showed signs of general vigilance improvement. Our findings confirm that cognitive abnormalities in schizotypy are replicable in multisite studies and responsive to drug challenges. Importantly, these results underline the importance of dopamine agonism in the pathophysiology of the cognitive deficits in the schizophrenia spectrum disorders. Funding P1vital Ltd.

The Effects of a Combined Intervention for Cognition in Schizophrenia On Cogstate Schizophrenia Battery

Background Cognitive impairment in schizophrenia is a strong predictor of the functional outcome and no effective treatments are available. MATRICS Consensus Cognitive Battery (MCCB) is approved by the FDA as outcome measure for trials of cognitive-enhancing drugs in schizophrenia. CogState Schizophrenia Battery (CSB) provides a briefer cognition assessment with minimal practice effects and a strong correlation between the CSB and MCCB composite scores. We tested the sensitivity of CSB as a cognitive outcome measure in a clinical trial in schizophrenia, where a cognitive-enhancing drug and cognitive training were combined. Methods 49 participants with schizophrenia were enrolled in a double-blind, placebo-controlled study. Participants were randomised to modafinil (200mg/day) or placebo and underwent a cognitive training program for 10 weekdays. CSB was administered twice at baseline to minimise practice effects, at the last day of the intervention and two weeks after the completion of the intervention. Results There was a significant time effect at the end of the intervention on the CSB composite score (p=0.042). There was no significant treatment effect on CSB composite score at the end of the intervention (p=0.686) or at follow up (p=0.120). Conclusions Multiple administrations of CSB were well tolerated by participants. The significant time effects on the composite score may suggest the operation of practice effects. Several factors could have contributed to the lack of treatment effects on CSB, such as the burden of multiple neuropsychological testing in a relatively brief study, the duration of modafinil treatment and also the intensive nature of cognitive training.