Faculty Bibliography

PURPOSE/BACKGROUND: Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist d-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia. METHODS/PROCEDURES: Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. FINDINGS/RESULTS: No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessments. IMPLICATIONS/CONCLUSIONS: These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). Mismatch negativity showed high test-retest reliability, supporting its use as a target engagement measure.

There has been recent interest in understanding the role that sleep disturbance plays in patients at Clinical High Risk for psychosis (CHR). We assessed sleep disturbance in 194 CHR patients and 66 healthy control subjects and their relationship to symptoms (positive, negative and general functioning). Patients experienced significantly more sleep disturbance than healthy control subjects and their sleep disturbance was related to greater positive and negative symptoms and worse overall functioning. Targeting sleep disturbance in CHR individuals may provide alternative means of treating the CHR syndrome.

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal ("prosodic") features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and rsfMRI was assessed in the subset who performed all assessments (14 patients, 21 controls). As predicted, patients showed robust reductions in MMN across FM stimulus type (p = 0.005), particularly to modulations in F0M, along with impairments in AER and FM tone discrimination. MMN source analysis indicated dipoles in both auditory cortex and anterior insula, whereas rsfMRI analyses showed reduced auditory-insula connectivity. MMN to FM tones and functional connectivity together accounted for approximately 50% of the variance in AER performance across individuals. These findings demonstrate that impaired preattentive processing of tonal information and reduced auditory-insula connectivity are critical determinants of social cognitive dysfunction in schizophrenia, and thus represent key targets for future research and clinical intervention. SIGNIFICANCE STATEMENT: Schizophrenia patients show deficits in the ability to infer emotion based upon tone of voice [auditory emotion recognition (AER)] that drive impairments in social cognition and global functional outcome. This study evaluated neural substrates of impaired AER in schizophrenia using a combined event-related potential/resting-state fMRI approach. Patients showed impaired mismatch negativity response to emotionally relevant frequency modulated tones along with impaired functional connectivity between auditory and medial temporal (anterior insula) cortex. These deficits contributed in parallel to impaired AER and accounted for approximately 50% of variance in AER performance. Overall, these findings demonstrate the importance of both auditory-level dysfunction and impaired auditory/insula connectivity in the pathophysiology of social cognitive dysfunction in schizophrenia.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H3 receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7weeks (4weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

BACKGROUND: Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. METHODS: We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620. FINDINGS: We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35.7% (SD 17.8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7.6 [SEM 1.4] for D-serine group vs 11.3 [1.2] for placebo group; d=0.68, p=0.03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). INTERPRETATION: This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. FUNDING: National Institutes of Health.

Schizophrenia patients exhibit impairments in auditory-based social cognition, indicated by deficits in detection of prosody, such as affective prosody and basic pitch perception. However, little is known about the psychometric properties of behavioral tests used to assess these functions. The goal of this paper is to characterize the properties of prosody and pitch perception tasks and to investigate whether they can be shortened. The pitch perception test evaluated is a tone-matching task developed by Javitt and colleagues (J-TMT). The prosody test evaluated is the auditory emotion recognition task developed by Juslin and Laukka (JL-AER). The sample includes 124 schizophrenia patients (SZ) and 131 healthy controls (HC). Properties, including facility and discrimination, of each item were assessed. Effects of item characteristics (e.g., emotion) were also evaluated. Shortened versions of the tests are proposed based on facility, discrimination, and/or ability of item characteristics to discriminate between patients and controls. Test-retest reliability is high for patients and controls for both the original and short forms of the J-TMT and JL-AER. Thus, the original as well as short forms of the J-TMT and JL-AER are suggested for inclusion in clinical trials of social cognitive and perceptual treatments. The development of short forms further increases the utility of these auditory tasks in clinical trials and clinical practice. The large SZ vs. HC differences reported here also highlight the profound nature of auditory deficits and a need for remediation.

The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy (1H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. 1H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of 1H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.

BACKGROUND:Intact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia. METHOD/METHODS:Auditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory performance. RESULTS:Patients showed large effect-size deficits across auditory measures. Sarcasm deficits correlated significantly with general functioning and impaired pitch processing both across groups and within the patient group alone. Patients also showed reduced sensitivity to alterations in mean pitch and variability. For patients, sarcasm discrimination correlated exclusively with the level of rsFC within primary auditory regions whereas for controls, correlations were observed exclusively within core-mentalizing regions (the right posterior superior temporal gyrus, anterior superior temporal sulcus and insula, and left posterior medial temporal gyrus). CONCLUSIONS:These findings confirm the contribution of auditory deficits to theory of mind (ToM) impairments in schizophrenia, and demonstrate that FC within auditory, but not core-mentalizing, regions is rate limiting with respect to sarcasm detection in schizophrenia.

Introduction: Schizophrenia patients show decreased ability to identify emotion based upon tone of voice (voice emotion recognition), along with deficits in basic auditory processing. Interrelationship among these measures is poorly understood. Methods: Forty-one patients with schizophrenia/schizoaffective disorder and 41 controls were asked to identify the emotional valence (happy, sad, angry, fear, or neutral) of 38 synthesized frequency-modulated (FM) tones designed to mimic key acoustic features of human vocal expressions. The mean (F0M) and variability (F0SD) of fundamental frequency (pitch) and absence or presence of high frequency energy (HF500) of the tones were independently manipulated to assess contributions on emotion identification. Forty patients and 39 controls also completed tone-matching and voice emotion recognition tasks. Results: Both groups showed a nonrandom response pattern (P < .0001). Stimuli with highest and lowest F0M/F0SD were preferentially identified as happy and sad, respectively. Stimuli with low F0M and midrange F0SD values were identified as angry. Addition of HF500 increased rates of angry and decreased rates of sad identifications. Patients showed less differentiation of response across frequency changes, leading to a highly significant between-group difference in response pattern to maximally identifiable stimuli (d = 1.4). The differential identification pattern for FM tones correlated with deficits in basic tone-matching ability (P = .01), voice emotion recognition (P < .001), and negative symptoms (P < .001). Conclusions: Specific FM tones conveyed reliable emotional percepts in both patients and controls and correlated highly with deficits in ability to recognize information based upon tone of voice, suggesting significant bottom-up contributions to social cognition and negative symptom impairments in schizophrenia

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. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.