Clinical Efficacy and Target Engagement of Glutamatergic Drugs: Placebo-Controlled RCTs of Pomaglumetad and TS-134 for Reversal of Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers

Kantrowitz, Joshua T.; Grinband, Jack; Goff, Donald C.; Lahti, Adrienne C.; Marder, Stephen R.; Kegeles, Lawrence S.; Girgis, Ragy R.; Sobeih, Tarek; Wall, Melanie M.; Choo, Tse‐Hwei; Green, Michael F.; Yang, Yvonne S.; Lee, Jung‐Hee; Horga, Guillermo; Krystal, John H.; Potter, William Z.; Javitt, Daniel C.; Lieberman, Jeffrey A.

doi:10.1101/2020.03.09.20029827

Cited by 3 publications

(1 citation statement)

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“…Taken together, our findings from ketamine challenge studies lend empirical support to the putative link between NMDA receptor hypofunction, disruption in brain function and glutamate excess and provide a theoretical framework for the interpretation of abnormal brain signatures in schizophrenia in the context of NMDA receptor hypofunction. It is important to note that this type of framework can also be leveraged to test target engagement for putative novel pharmacological agents as recently demonstrated a multi-center proof of mechanism study of pomaglumetad (102), which will ideally translate into accelerated development of novel drugs.…”

Section: Can Pharmacological Challenge Studies Provide a Framework Fomentioning

confidence: 99%

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Kraguljac

Lahti

2021

Front. Psychiatry

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Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.

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Section: Can Pharmacological Challenge Studies Provide a Framework Fomentioning

confidence: 99%