By Pauline Anderson
WebMD Health News
March 14, 2017
The proof-of-concept study provides evidence that central N-methyl-D-aspartate (NMDA) receptor signaling is enhanced in at least some patients with depression and is decreased in some patients with schizophrenia.
The study "picked up a strong signal" showing that in patients with schizophrenia, the NMDA receptor "is not functioning very well" and that in patients with depression, "it's hyperactive," lead author Handan Gunduz-Bruce, MD, Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.
"We hope that this will lead to a very useful biological marker in the clinic to help us distinguish between schizophrenia and depression in young people. We also hope in the near future to be able to select the right medicines for patients with these disorders."
The study was published online March 13 in Experimental Physiology.
No Blood Test
Research shows that only 35% of patients with early symptoms experience conversion to schizophrenia over 2.5 years. A similar percentage of patients develop mood disorders. Some patients may grow out of these early symptoms, which can be very vague and mild, said Dr Gunduz-Bruce.
Early in these disorders, symptoms may be similar, and currently there are no blood tests to distinguish schizophrenia from depression.
"Psychiatric evaluations and diagnoses depend entirely on verbal communication and observation of behavior," said Dr Gunduz-Bruce.
"If we can develop a physiological or biological or marker that will give us some indication as to which direction a particular young person is heading toward, that is going to be a lot of value."
It is critical to intervene early in patients showing signs of schizophrenia or depression, she said.
The NMDA receptor (NMDAR) is a major subtype of glutamate receptor that mediates fast synaptic transmission in the central nervous system.
Reduced NMDAR signaling has been implicated in the pathogenesis of schizophrenia and is thought to underlie the cognitive dysfunction and the symptom profile observed in patiens with this disorder.
Some patients with depression show a remarkable improvement following administration of an NMDA antagonist, raising the possibility of increased NMDA receptor signaling in depression, in contrast to schizophrenia.
Because both schizophrenia and depression are heterogeneous disorders, it is highly likely that the suspected abnormal NMDAR signaling represents subsets of patients. For example, the NMDAR antagonist ketamine affects some patients with schizophrenia more than others.
Release of the hormone arginine-vasopressin (AVP) is regulated by NMDAR in the central nervous system. AVP is synthesized in the cell bodies of magnocellular neurosecretary cells, which express functional NMDA receptors and release AVP in response to glutamatergic activation.
Physiologic studies have shown that plasma AVP (P[AVP]) response to plasma osmolality (POsm) is sensitive to the function of the NMDA receptor: when rats are infused with hypertonic saline, POsm increases linearly during the infusion.
The new study included 10 healthy control persons (mean age, 31 years), seven patients with schizophrenia (mean age, 39 years) and eight patients with unipolar depression (mean age, 42 years). Although there were more men with schizophrenia and more women with depression, the differences were not statistically significant.
The conditions of patients with depression and those with schizophrenia were stable on medication.
On the basis of findings from animal research, the researchers used a translational approach in their study. They stimulated the activity of the hypothalamic NMDA receptor by increasing POsm via intravenous hypertonic saline (HS) for 120 minutes. They obtained blood samples at regular intervals during the infusion to measure the concentration of AVP over time.
The investigators checked participants' heart rate and blood pressure. They also assessed thirst to ensure this would not confound results.
There is an "extraordinarily good relationship" between the perception of thirst and POsm during HS infusion and dehydration in young volunteers, the authors note.
The researchers determined the slopes in response to the hyperosmotic challenge. The lowest values were in the group with schizophrenia (fixed slope estimate, 0.07; 95% confidence interval [CI], 0.00 - 0.14).
The largest slope was found in patients with depression (slope = 0.22; 95% CI, 0.15 - 0.30). The slope for the control participants was between those of the patients with depression and those with schizophrenia (fixed slope estimate, 0.11; 95% CI, 0.05 - 0.17).
The slope for the group with depression was significantly larger than the slopes for the control participants (P = .02) and for the group with schizophrenia (P = .0025).
That the PAVP response to POsm in patients with depression was significantly higher than in the other groups is consistent with findings for the NMDA antagonist ketamine. Response to this agent in depression suggests overactive NMDAR signaling.
The spread of these slopes within the group with depressiosn suggests that patients at the upper range in this group have refractory depression, although this requires further testing, say the authors.
The slopes for control participants and for patients with schizophrenia were not significantly different. Dr Gunduz-Bruce noted that an outlier control participant had a slope that was outside the range of what is expected for healthy individuals.
Dr Gunduz-Bruce stressed that there was overlap in response between the groups.
"We are not saying that all schizophrenia is about an NMDA receptor, and we are not saying that all depression is about an NMDA receptor. But if you can identify a few subjects, that's going to give us a vulnerability marker in these disorders," said Dr Gunduz-Bruce.
"If you look at it from vulnerability marker point of view, you can argue that some healthy controls are vulnerable to depression; that doesn't mean that they will develop major depression."
Help in Treatment Decisions
A possible limitation of the study was that all of the patients with schizophrenia were being treated with antipsychotics, and all of those with depression were taking antidepressants.
Dr Gunduz-Bruce pointed out that there is no suggestion from animal studies that antipsychotics affect AVP response.
Although there is some evidence that antidepressants can cause hyponatremia through inappropriate antidiuretic hormone secretion, this is a rare event, especially in relatively young patients, said Dr Gunduz-Bruce.
Because animal studies show that long-term treatment with antidepressants might blunt the AVP response, the increased response found in the group with depression may even be an underestimation, said Dr Gunduz-Bruce.
Ideally, future studies would include patients who are not undergoing treatment with medications, she added.
There were no group differences in thirst or in heart rate measures. Systolic blood pressure was lower in patients with depression than in control participants and patients with schizophrenia, but group time interaction was not significant.
In addition to AVP, a handful of other hormones may be regulated by stimulation of the NMDA receptor, including gonadotropin-releasing hormone. However, measuring these molecules might be more challenging, said Dr Gunduz-Bruce.
Dr Gunduz-Bruce stressed that although the study results support the use of P[AVP] response to POsm to distinguish patients with depression from those with schizophrenia, this biomarker should be used together with psychiatric screening and when there is diagnostic uncertainty.
In addition to helping distinguish depression from schizophrenia early on, this biomarker could also help in treatment decisions, said Dr Gunduz-Bruce.
A number of pharmaceutical companies are developing NMDA blockers for depression and NMDA stimulants for schizophrenia, she said.
Dr Gunduz-Bruce has disclosed no relevant financial relationships.