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Daniel C. Javitt, MD | Columbia University Department of Psychiatry



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The Nathan S. Kline Institute for Psychiatric Research
Daniel Javitt, M.D., Ph.D.
Department Director
Schizophrenia Research
845-398-6534
[e-mail]
Dr. Daniel C. Javitt, a world-renowned researcher in the study of schizophrenia and cognition, directs the Schizophrenia Research program at NKI. In addition, Dr. Javitt is Professor and Director, Division of Experimental Therapeutics, Departments of Psychiatry and Neuroscience, Columbia University College of Physicians and Surgeons

https://www.nki.rfmh.org/faculty/daniel-javitt-md-phd

The Nathan S. Kline Institute for Psychiatric Research
About Us
As one of the nation’s most respected research centers focused on mental health, investigators at the Nathan S. Kline Institute for Psychiatric Research (NKI) study the causes, treatment, prevention, and rehabilitation of severe and persistent mental illnesses. As a facility of the New York State Office of Mental Health, founded in 1952, NKI has earned a reputation for its landmark contributions in psychiatric research, especially in the areas of psychopharmacological treatments for schizophrenia and major mood disorders, dementia research, clinical trials methodology, neuroimaging, therapeutic drug monitoring, and the application of computer technology to mental health services.

A broad range of studies is conducted at NKI, from basic laboratory science to clinical trials and translational research. Our basic research focuses on the genetic, molecular, and neurological underpinnings of mental disease. Our patient-oriented research programs emphasize screening, assessment, diagnosis, treatment, prevention, and care of severe and chronic mental disorders. In addition, NKI conducts research on the cost, quality, disparities and effectiveness of mental health services in New York State and beyond.

https://www.nki.rfmh.org/about-nki/about-us

Isr J Psychiatry Relat Sci. 2010;47(1):4-16.
Glutamatergic theories of schizophrenia.
Javitt DC1.
Author information
Abstract
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 20 years, however, limitations of the dopamine model have become increasingly apparent, necessitating development of alternative models. Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate NMDA receptor-mediated neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Encouraging results have been observed as well with agents such as metabotropic 2/3 agonists that decrease resting glutamate levels, reversing potential disruption in firing patterns within prefrontal cortex and possibly other brain regions. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.

https://www.ncbi.nlm.nih.gov/pubmed/20686195

Neuropsychopharmacology. 2012 Jan; 37(1): 4–15.
Published online 2011 Sep 28. doi: 10.1038/npp.2011.181

From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment
Bita Moghaddam1,* and Daniel Javitt2


Abstract
Glutamate is the primary excitatory neurotransmitter in mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimer's disease, and autism-spectrum disorders. Glutamatergic theories of schizophrenia are based on the ability of N-methyl--aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex. Based on this mechanism, normalizing excess glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to potential identification of the first non-monoaminergic target with comparable efficacy as conventional antipsychotic drugs for treating positive and negative symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that are active targets for drug development, several of which show promise in preclinical/early clinical trials targeting both symptoms and cognition. To date, most studies have been done with orthosteric agonists and/or antagonists at specific sites. However, allosteric modulators, both positive and negative, may offer superior efficacy with less danger of downregulation.

.......

THE REVOLUTION
The dopamine hypothesis of schizophrenia, which remains the most prominent theory in the field, can be seen as originating from the fortuitous discovery of the antipsychotic effects of chlorpromazine in the mid-1950s. So too, glutamatergic theories can be dated to a precise observation, in this case the synthesis in the late 1950s of the dissociative anesthestics phencyclidine (PCP) and ketamine (Chen and Weston, 1960), followed shortly thereafter by the demonstration of their psychotogenic potential in humans (Luby et al, 1962), the discovery of the PCP receptor (Zukin and Zukin, 1979), and finally the discovery that these compounds function by blocking the N-methyl--aspartate receptor (NMDAR) channel (Javitt and Zukin, 1991). PCP and ketamine induced negative symptoms and cognitive dysfunction similar to that of schizophrenia, suggesting that this model may be particularly relevant to persistent, poor-outcome forms of schizophrenia.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238069/

ABSTRACT
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 20 years, however, limitations of the dopamine model have become increasingly apparent, necessitating development of alternative models. Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate NMDA receptor-mediated neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Encouraging results have been observed as well with agents such as metabotropic 2/3 agonists that decrease resting glutamate levels, reversing potential disruption in firing patterns within prefrontal cortex and possibly other brain regions. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.

http://www.rfmh.org/pubattach/%5Cnkipubsversion12%5C3805%5Cjavitt2010.pdf

Temporal dynamics of neurophysiological patterns as treatment targets in Sz
Javitt, Daniel C.
Columbia University (N.Y.), New York, NY, United States

Abstract
This project responds to PAR 14-153, Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders. As described in the RFA, a rich body of evidence suggests that cognitive processes are associated with particular patterns of neural activity. These data indicate that oscillatory rhythms, their co-modulation across frequency bands, spike-phase correlations, spike population dynamics, and other patterns might be useful drivers of therapeutic development for cognitive improvement in neuropsychiatric disorders. This project uses parallel human and non-human primate (NHP) investigations to evaluate effects of transcranial direct current stimulation (tDCS)/transcranial alternating current stimulation (tACS) on neural oscillatory patterns underlying auditory cognitive impairments in schizophrenia (Sz), with particular emphasis on impairments in theta and delta phase reset mechanisms and delta/gamma phase amplitude coupling. In addition it evaluates the role of N- methyl-D-aspartate receptors (NMDAR) in the etiology of oscillatory dysfunction in Sz, as well as the ability of tDCS/tACS to reverse NMDAR antagonist-induced impairments in NHP as a model for future therapeutic development. The project addresses Topic 1 of the RFA by mapping neuro-oscillatory patterns underlying impaired auditory information processing in Sz using parallel human and NHP studies; Topic 2 by investigating mechanisms underlying NMDAR antagonist-induced effects; Topic 3 by evaluating tDCS/tACS effects on neuro-oscillatory function in both NHP and Sz; and Topic 4 by evaluating relative effects of high definition (HD-tDCS) and conventional tDCS using neurocomputational mapping approaches. The project includes active manipulations in both humans and NHP, and tests specific hypotheses regarding low frequency (delta, theta) oscillation and cross-frequency (e.g. delta/gamma) phase-amplitude coupling impairments as a basic mechanism of neurocognitive impairment in Sz. The recording methods detect neural activity directly using multichannel surface/intracranial electrodes in humans and NHP, respectively, and employ spectral analyses of EEG data along with quantitative behavioral measures as the primary outcome variables. Auditory dysfunction, as reflected both behaviorally and by impaired generation of mismatch negativity (MMN) and other auditory potentials is a prominent and severe feature of Sz and contributes directly to global functional outcome via direct impact on processes such as auditory hallucinations, phonological processing impairments and social cognition. Deficits in MMN generation, moreover, predict conversion to psychosis among at risk individuals. The proposed stimulation approaches including HD- tDCS and delta frequency tACS are highly novel and will have direct, real-world impact not only on neurocognitive dysfunction in Sz, but also on related forms of neurocognitive impairments across relevant associated neuropsychiatric disorders.

Public Health Relevance
Schizophrenia is a severe neuropsychiatric disorder associated with prominent impairments in the pattern of brain rhythmic activity (?neurooscillations?). Transcranial direct current stimulation (tDCS) is a novel approach for modulation for modulating neurooscillatory activity. This project evaluates the ability of tDCS and related methods to reverse neurooscillatory impairments both in schizophrenia and in animal models.

http://grantome.com/grant/NIH/R01-MH109289-02