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A Translational Approach for NMDA Receptor Profiling as a Vulnerability Biomarker for Depression and Schizophrenia—Commentary

05/08/17 William Coryell, MD, University of Iowa Carver College of Medicine;

The Journal of Experimental Physiology has published a study on a potential biomarker for depression (Gunduz-Bruce et al. 2017). The study used arginine vasopressin (AVP) responses to an infusion of hypertonic saline to compare patients with schizophrenia, patients with major depressive disorder (MDD), and a group of unmatched healthy controls. The investigators designed the protocol to test their hypothesis that, in comparisons to normal controls, N-methyl-D-aspartate (NMDA) receptor sensitivity is lower in individuals with schizophrenia and higher in those with MDD. They predicted that, because of these differences in NMDA sensitivity, the three patient groups would release different amounts of AVP after infusion of hypertonic saline, a response mediated by NMDA. Specifically, the greater NMDA receptor signaling in depressed patients would cause more AVP release following a given stimulus. To compare AVP release, the investigators looked at the values of the slope of the relationship between changes in osmolality and changes in AVP concentrations. The hypothesis was that the slope would be lower for patients with schizophrenia and higher for those with MDD.

In partial support of their predictions the AVP/osmolality slope value for depressed patients was significantly greater than that for well controls and for individuals with schizophrenia. However, the mean slope value for patients with schizophrenia did not differ significantly from that of controls.

Pending adequate confirmation of these findings by future studies, the authors suggest two potential applications; first, that AVP response to osmolality challenge could provide a diagnostic tool for clinical distinctions between MDD and schizophrenia and, second, that test results might aid in treatment selection. Perhaps drugs targeting glutamatergic pathways would be more effective in the subgroup of patients with abnormal AVP responses to osmolality challenge.

Of these two possibilities, the first is by far the more remote. Many biological measures have shown promise as diagnostic tools in psychiatry, most notably the dexamethasone suppression test for melancholia in the early 80s (Carroll et al. 1981). Although many of these measures accumulated substantially more evidence in support of their potential as a diagnostic tool, none have been accepted for clinical use (Perlis 2011). Moreover, the effects of variables such as age, sex, race, illness acuity (Goldman et al. 2009), and medication  use on test results are unknown and the groups in the study differed substantially on most of these measures. Even if these, or other unmeasured group differences, were not at play, the results of the current study showed modest specificity and little sensitivity in separating MDD and schizophrenia groups; only three (43%) of the patients with depression had values that did not overlap with those of the patients with schizophrenia.

The search for biological tests, or even specific symptom measures, of use for treatment selection has been equally discouraging. Here, though, tests of AVP response to osmolality changes may hold more promise in as much as the test measures NMDA receptor sensitivity and several promising newer treatments for treatment-resistant depression target glutamatergic systems. Even if subsequent studies show AVP/osmolality challenge test results to be predictors of, for instance, an antidepressant response to ketamine, the test’s complexity (a 2-hr IV infusion followed by serial blood sampling for 2 hrs) would comprise a major hurdle to its clinical application. 


Gunduz-Bruce H, Kenney J, Changlani S, et al: A translational approach for NMDA receptor profiling as a vulnerability marker for depression and schizophrenia. Exp Physiol 102:587–597, 2017. doi: 10.1113/EP086212

Carroll B, Feinberg M, Greden J, et al: A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 38:15–22, 1981. 

Goldman MB: The mechanism of life-threatening water imbalance in schizophrenia and its relationship to the underlying psychiatric illness. Brain Res Rev 61:210–220, 2009.

Perlis RH: Translating biomarkers to clinical practice. Mol Psychiatry 16:1076–1087, 2011. doi:10.1038/mp.2011.63