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Exp Physiol. 2017 May 1;102(5):587-597. doi: 10.1113/EP086212. Epub 2017 Apr 12.

A translational approach for NMDA receptor profiling as a vulnerability biomarker for depression and schizophrenia.

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Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
VA Medical Center, Psychiatry Service 116A, 950 Campbell Avenue, West Haven, CT, USA.
Current affiliation: Sage Therapeutics, Cambridge, MA, USA.
Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
The John B. Pierce Laboratory, New Haven, CT, USA.
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.


What is the central question of this study? Can the change in plasma arginine vasopressin concentration (P[AVP] ) in response to osmotic stimulation (POsm ) serve as a biomarker for NMDA receptor signalling in schizophrenia and depression and thereby distinguish between these mental illnesses? What is the main finding and its importance? In response to hyperosmotic challenge, depressed subjects showed increased P[AVP] response compared with healthy control and schizophrenic subjects. However, schizophrenic subjects were not different from healthy control subjects in this small sample. The 'P[AVP] response to POsm ' is a suitable biomarker to distinguish depressed versus schizophrenic patients when used with psychiatric screening. This is the first objective physiological measure for schizophrenia or depression. Altered NMDA receptor activity and glutamate signalling might underlie the pathogenesis of both schizophrenia and depression in subgroups of patients. In schizophrenia, pharmacological modelling, post-mortem and imaging data suggest reduced NMDA signalling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signalling. We conducted a proof-of-concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function. For this purpose, we used a translational approach, based on findings from animal studies that NMDA receptor is a key mediator of arginine vasopressin (AVP) release into the bloodstream. Using hypertonic saline to increase plasma osmolality (POsm ) and thereby induce AVP release, as done in animal studies, we found that in depressed patients the NMDA receptor-mediated AVP release induced by hypertonic saline infusion was significantly increased [0.24 (0.15) pg ml-1  mosmol-1 , P < 0.05] compared with schizophrenia patients [0.07 (0.07) pg ml-1  mosmol-1 ]. Slopes for healthy control subjects were 0.11 (0.09) pg ml-1  mosmol-1 which was less than the depressed group. These findings are consistent with implicated NMDA receptor-related abnormalities in depression and schizophrenia in subgroups of patients and provide the first in vivo evidence of this dichotomy.


NMDA receptor; arginine vasopressin; osmolality

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