Amphetamine alters an EEG marker of reward processing in humans and mice.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine.

EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants.

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week.

Electrophysiological biomarkers of behavioral dimensions from cross-species paradigms.

There has been a fundamental failure to translate preclinically supported research into clinically efficacious treatments for psychiatric disorders. One of the greatest impediments toward improving this species gap has been the difficulty of identifying translatable neurophysiological signals that are related to specific behavioral constructs. Here, we present evidence from three paradigms that were completed by humans and mice using analogous procedures, with each task eliciting candidate a priori defined electrophysiological signals underlying effortful motivation, reinforcement learning, and cognitive control.

Auditory discrimination and frequency modulation learning in schizophrenia patients: amphetamine within-subject dose response and time course.

Background: Auditory frequency modulation learning ('auditory learning') is a key component of targeted cognitive training (TCT) for schizophrenia. TCT can be effective in enhancing neurocognition and function in schizophrenia, but such gains require significant time and effort and elude many patients.

Methods: As a strategy to increase and/or accelerate TCT-induced clinical gains, we tested the dose- and time-course effects of the pro-attentional drug, amphetamine (AMPH; placebo, 2.

Memantine effects on auditory discrimination and training in schizophrenia patients.

The uncompetitive low-affinity NMDA receptor antagonist, memantine, acutely increases electrophysiological measures of auditory information processing in both healthy subjects (HS) and patients with schizophrenia. Memantine effects on functional measures of auditory discrimination performance and learning are not known; conceivably, beneficial effects on these measures might suggest a role for memantine in augmenting the cognitive and functional impact of auditory targeted cognitive training (TCT). Here, carefully characterized HS (n = 20) and schizophrenia patients (n = 22) were tested in measures of auditory discrimination performance (words-in-noise (WIN), quick speech-in-noise (QuickSIN), gaps-in-noise) and auditory frequency modulation learning (a component of TCT) on 2 days about a week apart, after ingesting either placebo or 20 mg memantine po, in a double-blind, within-subject cross-over random order design.

Memantine Effects on Electroencephalographic Measures of Putative Excitatory/Inhibitory Balance in Schizophrenia.

Background: Abnormalities in cortical excitation and inhibition (E/I) balance are thought to underlie sensory and information processing deficits in schizophrenia. Deficits in early auditory information processing mediate both neurocognitive and functional impairment and appear to be normalized by acute pharmacologic challenge with the NMDA antagonist memantine (MEM).

Methods: Thirty-six subjects with a diagnosis of schizophrenia and 31 healthy control subjects underwent electroencephalographic recordings.

Lessons learned by giving amphetamine to antipsychotic-medicated schizophrenia patients.

Experimental Medicine studies in psychiatric populations test specific, mechanistic hypotheses related to the biology of mental illness, by combining well-characterized neurobiological probes and laboratory-based measures of behavioral performance and neurobiology. However, scientific inquiry through the acute administration of psychoactive drugs to patients with serious mental illness raises important ethical issues. These issues arise in studies in which the psychostimulant, amphetamine, is used as an Experimental Medicine probe in patients with schizophrenia.

Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge.

Many patients with chronic psychotic disorders including schizophrenia (SZ) maintain meaningful levels of plasticity (i.e., capacity for change) within neurocognition-relevant brain mechanisms, as evidenced by gains in neurocognition and function after interventions such as targeted cognitive training.

Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients.

Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects.

Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors.

Background: Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects.

Methods: Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design.

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species.

Background: Neurodevelopmental disorders including Tourette's syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are characterized by significant impairment in attention and cognitive control. These cognitive deficits persist throughout development, contribute significantly to socio-occupational impairment, and are relatively impervious to available treatment. A critical challenge in pro-cognitive drug discovery is translatability of findings across species, underscoring the need for developing valid and reliable cross-species cognitive tasks.

Sensorimotor gating in healthy adults tested over a 15 year period.

Background: Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to study normal and pathological brain function. From 2001 to 2016, we screened healthy subjects (HS) to establish their suitability for tests of drug effects on PPI. Because of the size and systematic characterization of this sample across variables of relevance to PPI, we now report these screening results.

Amphetamine Enhances Gains in Auditory Discrimination Training in Adult Schizophrenia Patients.

Targeted cognitive training (TCT) of auditory processing enhances higher-order cognition in schizophrenia patients. TCT performance gains can be detected after 1 training session. As a prelude to a potential clinical trial, we assessed a pharmacological augmentation of cognitive therapy (PACT) strategy by testing if the psychostimulant, amphetamine, augments TCT gains in auditory processing speed (APS) in schizophrenia patients and healthy subjects (HS).

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy.

Rationale: Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug's pro-cognitive effects.

Objective: This study aims to use an experimental medicine model to test the hypothesis that "target engagement" predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs.

Methods: MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs.

The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: summaries of oral sessions.

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries.

The COMT Met158 allele and violence in schizophrenia: a meta-analysis.

Background: The Met158 allele of catechol-O-methyl transferase (COMT) gene is associated with increased levels of catecholamines in the prefrontal cortex and may increase the likelihood of aggressiveness. We conducted a meta-analysis to test the hypothesis that the Met158 allele of the COMT gene is associated with aggressive and violent behavior in schizophrenia.

Methods: MEDLINE search (12/31/11) yielded 14 studies examining the association of the COMT gene polymorphism (rs4680) and aggression in schizophrenia (total n=2219).

Familial vulnerability to an unusual cognitive adverse effect of topiramate: Discussion of mechanisms.

Background: Some patients experience cognitive disturbances with topiramate.

Case Histories: A 19-year-old bipolar woman and her 46-year-old mother with paranoid personality disorder both used topiramate (25-50 mg/day) off-label for weight loss. Both women suffer from learning disorders, and both are excessively sensitive to the sedative adverse effects of psychotropic medications.

Systematic enhancement of functioning as a therapeutic technique in conversion disorder.

To explicitly outline a therapeutic technique for symptom removal in conversion disorder. We describe one patient with conversion dumbness and another with conversion paraplegia. The first patient was successfully treated in a single session, and the second was successfully treated across two weeks, both using systematic enhancement of functioning as a technique for symptom removal.

Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study.

Background: Low nighttime levels of melatonin have been demonstrated in patients with insomnia, and melatonin has been shown to have hypnotic properties in some groups of such subjects. Low melatonin levels have also been observed in patients with schizophrenia; however, there is little literature on the efficacy of exogenous melatonin in treating insomnia associated with schizophrenia.

Method: Stable DSM-IV schizophrenic outpatients (N = 40) with initial insomnia of at least 2 weeks' duration were randomly assigned to augment their current medications with either flexibly dosed melatonin (3-12 mg/night; N = 20) or placebo (N = 20).

Controversy revisited: Selective serotonin reuptake inhibitors in paediatric depression.

Background: Selective serotonin reuptake inhibitors (SSRIs) are currently controversial treatments for paediatric depression. There have been several publications on the subject during recent years. This article summarizes their findings and provides some original thoughts, suggestions, and perspectives.