Daniel C. Javitt

The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (Nu2009>u20091000), deeply phenotyped, community-ascertained, lifespan sample (ages 6–85u2009years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

The Spectrotemporal Filter Mechanism of Auditory Selective Attention

Although we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli.

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.

Decreased Interhemispheric Coordination in Schizophrenia: A Resting State fMRI Study

Schizophrenia has been increasingly conceptualized as a disorder of brain connectivity, in large part due to findings emerging from white matter and functional connectivity (FC) studies. This work has focused primarily on within-hemispheric connectivity, however some evidence has suggested abnormalities in callosal structure and interhemispheric interaction. Here we examined functional connectivity between homotopic points in the brain using a technique called voxel-mirrored homotopic connectivity (VMHC). We performed VMHC analyses on resting state fMRI data from 23 healthy controls and 25 patients with schizophrenia or schizoaffective disorder. We found highly significant reductions in VMHC in patients for a number of regions, particularly the occipital lobe, the thalamus, and the cerebellum. No regions of increased VMHC were detected in patients. VMHC in the postcentral gyrus extending into the precentral gyrus was correlated with PANSS Total scores. These results show substantial impairment of interhemispheric coordination in schizophrenia.

Glutamatergic Abnormalities In Schizophrenia: a review of proton MRS findings

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 ((1)H-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. (1)H-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 (1)H-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.

Twenty-five Years of Glutamate in Schizophrenia: Are We There Yet?

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression

Antagonism of N-methyl-D-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. D-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ≥ 50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.

Predictive Suppression of Cortical Excitability and Its Deficit in Schizophrenia

Recent neuroscience advances suggest that when interacting with our environment, along with previous experience, we use contextual cues and regularities to form predictions that guide our perceptions and actions. The goal of such active “predictive sensing” is to selectively enhance the processing and representation of behaviorally relevant information in an efficient manner. Since a hallmark of schizophrenia is impaired information selection, we tested whether this deficiency stems from dysfunctional predictive sensing by measuring the degree to which neuronal activity predicts relevant events. In healthy subjects, we established that these mechanisms are engaged in an effort-dependent manner and that, based on a correspondence between human scalp and intracranial nonhuman primate recordings, their main role is a predictive suppression of excitability in task-irrelevant regions. In contrast, schizophrenia patients displayed a reduced alignment of neuronal activity to attended stimuli, which correlated with their behavioral performance deficits and clinical symptoms. These results support the relevance of predictive sensing for normal and aberrant brain function, and highlight the importance of neuronal mechanisms that mold internal ongoing neuronal activity to model key features of the external environment.

Glycine Transport Inhibitors in the Treatment of Schizophrenia

Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported.

D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial

BACKGROUNDnAntagonists 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.nnnMETHODSnWe 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.nnnFINDINGSnWe 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).nnnINTERPRETATIONnThis 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.nnnFUNDINGnNational Institutes of Health.