Potential Biomarker for Suicidal Thoughts Identified in PTSD

Michael Vlessides

May 13, 2019

Metabotropic glutamatergic receptor 5 (mGluR5) is a potential biomarker for suicidal thoughts in patients with posttraumatic stress disorder (PTSD), new research suggests.

Investigators used positron emission tomography (PET) to quantify mGluR5 density in five brain regions in patients with PTSD or major depressive disorder (MDD) and in healthy controls.

The study showed that compared to healthy controls, mGluR5 availability was significantly higher in all five brain regions in patients with PTSD, as well as in three brain regions in those with MDD.

"Although both depression and PTSD are stress disorders that are prevalent in our society, it appears that some of the markers regulated by these disorders are different. As such, psychotherapy for these disorders could also be different," study investigator Irina Esterlis, MD, associate professor in psychiatry at Yale University School of Medicine, New Haven, Connecticut, told Medscape Medical News.

The findings were published online today in the Proceedings of the National Academy of Sciences.

Target of Interest

PTSD is an important risk factor for suicidal ideation and attempts as well as death by suicide, Esterlis noted. However, little is known about the biology underlying suicide in PTSD. Not surprisingly, limited pharmacologic options exist to treat PTSD patients at high risk for suicide.

In recent years, mGluR5 has emerged as a target of interest for PTSD and suicide research, as previous studies have implicated the receptor in mood and anxiety symptoms.

Furthermore, Esterlis and colleagues recently found that patients with PTSD had significantly higher mGluR5 availability than did matched control groups across many brain regions.

Other research has come to similar conclusions, including a 2014 postmortem study that showed upregulation of mGluR5 gene expression in the locus coeruleus was associated with suicide in tissue from depressed individuals.

Nevertheless, the relationship between mGluR5 and suicidal behavior has yet to be explored in vivo among patients with PTSD.

"A lot of the literature lumps depression and PTSD into one 'stress disorder' model, whereas we've been seeing — at least with respect to this marker — that depression and PTSD could be quite different. So we wanted to see if the mGluR5 marker is regulated differently with respect to suicidality in these two disorders," Esterlis said. 

The investigators hypothesized that dysregulation in mGluR5 may affect the development of suicidal behavior, both directly and through downstream effects.

The study included 29 people with PTSD (mean age, 35.5 years; 16 females), 29 individuals with MDD (mean age, 36.6 years; 14 females), and 29 individuals acting as the healthy controls group (mean age, 37.4 years; 14 females). The three groups were matched by age, race, sex, and smoking status. Interestingly, 16 of the 29 patients with PTSD also met criteria for MDD.

All 87 participants completed a battery of physical, psychiatric, and neurologic examinations at an initial screening visit, both to establish their diagnosis and to rule out any major medical or neurologic illnesses. The presence of suicidal ideation was established based on participants' scan-day report on the Montgomery-Asberg Depression Rating Scale (MADRS) and self-reported Beck Depression Inventory II.

The participants all underwent T1-weighted MRI scans, which were used to evaluate potential structural abnormalities as well as facilitate co-registration with PET data.

Regions of interest for PET scanning comprised three subdivisions of the prefrontal cortex — the ventromedial PFC, orbitofrontal cortex, and dorsolateral prefrontal cortex — as well as the hippocampus and amygdala.

Greater mGluR5 Availability

The investigators first performed multivariate analysis of variance (ANOVA) tests to evaluate group differences in mGluR5 availability, an exercise that revealed significant differences between the groups. In fact, mGluR5 availability was significantly higher in the PTSD group than in the healthy controls group in each of the five regions of interest.

Similarly, mGluR5 availability was also higher in patients with PTSD than in their counterparts with MDD in the orbitofrontal cortex (15%, P = .007), dorsolateral prefrontal cortex (17%, P = .007), and hippocampus (15%, P = .007). No differences were observed in mGluR5 availability between the MDD and control groups.

With respect to the relationship between mGluR5 availability and suicidal ideation, the study showed that the main effect of suicidal ideation was significant in the PTSD group (P = .01) but not in the MDD group (P = .96).

Post-hoc tests among individuals with PTSD and suicidal ideation showed significantly higher mGluR5 availability in each of the five regions of interest, with an average 24% difference.

In a series of secondary analyses, the researchers investigated the relationship between mGluR5 availability and a number of suicide-related endophenotypic variables. These analyses revealed a divergent pattern of associations between mGluR5 availability and Profile of Mood States (POMS) scores, which is a measure of mood disturbance.

Total POMS score was positively correlated with mGluR5 availability in the PTSD group (P < .001) and inversely correlated with mGluR5 availability in the MDD group (P = .003).

Further examinations revealed that the association between mGluR5 availability and total POMS score in the PTSD group was driven by the patients with PTSD and suicidal ideation (P = .005), as no such association was observed in those with PTSD but without suicidal ideation.

The findings have the potential for significant implications in both research and treatment, and support the idea that downregulating mGluR5 may reduce PTSD symptomology, Esterlis said.

"If you look at the animal literature, there's a lot of support for using this marker as treatment," she said. "But it's not clear when it's best to administer medications that target this marker — whether it's immediately after trauma to prevent consolidation of the memory or at some later point when the person actually exhibits symptoms of PTSD.

"Targeting this receptor can have both positive and negative benefit," Esterlis added. "So in order to not make the symptoms worse, this is something we need to figure out."

A First Biomarker

Commenting on the findings for Medscape Medical News, Gregor Hasler, MD, University of Fribourg, Switzerland, said effective treatments for suicide prevention in individuals with PTSD have been lacking.

"So one way to solve this problem is to have really good markers to indicate what kind of people are at high risk of suicide," said Hasler, who was not involved in the study. "And this is one of the first biomarkers that has a link to suicidal thoughts."

However, Hasler noted that immediate clinical benefits from the study may not be soon forthcoming, given the cost associated with PET scans. "But there are various drugs that specifically target mGluR5, so these findings may inspire pharmaceutical companies or academia to target these various drugs in PTSD," he said.

Hasler did see a potential link between the findings and the potential use of lithium. "We can't give lithium to everyone. But the mGluR5 receptor is linked to the effect of lithium. So if we have a marker, that would be really helpful," he said.

"Suicide is still rare in veterans, but if you could help identify these people, you might be able to give them lithium and perhaps prevent these suicides," Hasler added.

The study authors and Hasler have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online May 13, 2019. Abstract

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