In vivo investigation of the relationship between mGluR5 and suicidal ideation in two clinical populations.

Background: Posttraumatic stress (PTSD) and major depressive (MDD) disorders are independently associated with all forms of suicidal behavior (ideation, attempt, and death by suicide²), and risk increases markedly when they present together⁴. However, there is no pharmacological treatment developed specifically to reduce suicide and suicide-associated behaviors in these disorders. The current study was designed to evaluate a novel potential biomarker for suicide risk in this population. The metabotropic glutamate receptor 5 (mGluR5) is implicated in the pathophysiology of psychiatric disorders such as PTSD and MDD, as well as suicidal behavior. MGluR5 was also shown to play an important role in emotion regulation⁵, and heightened mGluR5 availability is associated with noted suicide risk factors, such as pain experience¹, and sleep disturbance³. In vivo, mGluR5 availability can be measured with radioligand [¹⁸F]-FPEB and positron emission tomography (PET) imaging. The purpose of the present study was to investigate the relationship between mGluR5 availability and suicidal ideation in a transdiagnostic sample. We hypothesized that mGluR5 availability would be higher in individuals with present suicidal ideation across diagnostic groups and regions of interest (e.g., OFC, dlPFC, amygdala, hippocampus).

Methods: Participants (n=29 PTSD, 12 with comorbid MDD; n=29 MDD) were recruited through the Yale Translational Brain Imaging Program and National Center for PTSD. All participants underwent physical and psychological screening (e.g. SCID-5, CAPS-5, MADRS, PCL-5). Responses on both the Beck Depression Inventory II (item 9), and on the clinician administered MADRS (item 10) were used to gauge scan-day SI. Individuals participated in one MRI scan and one [¹⁸F]-FPEB PET scan with the radiotracer administered as a bolus plus constant infusion. Volume of distribution (V_T), using venous sampling, was the outcome measure.

Results: PTSD and MDD groups did not differ significantly with respect to age, gender or smoking status. Mean depressive symptom ratings did not differ between groups at any timepoint, and were indicative of moderate to severe depressive symptom experience in both groups. Cross-diagnostically and within the MDD group, mGluR5 availability did not differ significantly in any brain regions as a function of scan-day SI. However, in the PTSD group, mGluR5 availability was significantly higher among those reporting scan-day SI (n = 14) across brain regions (p’s =.001-.007; 18-24% difference), with large effect sizes (d’s =1.11-1.55) suggesting clinically meaningful differences. Exploratory analyses revealed that mGluR5 availability was positively correlated with avoidance (vmPFC r=.57, p=.007), and measures of tension (vmPFC, r=.53, p=.007) and anxiety (vmPFC r=.47, p=.008) in individuals with PTSD. Interestingly, the opposite was observed among individuals with MDD; mGluR5 availability was inversely correlated with measures of tension (e.g., dlPFC= r=-.52, p=.01) and anxiety (e.g. OFC, r=-.38, p=.01).

Conclusions: Higher mGluR5 availability as a function of current SI was observed in the PTSD group only, implicating mGluR5 dysregulation as a possible state marker of SI specific to individuals with PTSD. Further, it appears individuals with PTSD may have higher mGluR5 availability as compared to the MDD group. These preliminary findings point to mGluR5 as a potential treatment target for PTSD, and to reduce SI in PTSD specifically.