Imaging mGluR5 and Synaptic Density in Psychiatric Disorders

With the recent advancements in the positron emission tomography (PET) and radioligand development, the investigators are now able to image and quantify the metabotropic glutamatergic system (mGluR5) in vivo in human subjects. The investigators propose a novel investigation using \[18F\]FPEB in depression and bipolar disorder to obtain critical data to advance the understanding of the etiology of depression and bipolar disorder and its associated symptoms of cognitive dysfunction. The findings with mGluR5 by themselves are limited. Changes in mGluR5 availability could be due to changes in synaptic density. Recently, the Yale PET center synthesized a new radioligand \[11C\]UCB-J (referred to as \[11C\]APP311 at the Yale University PET Center) that binds to synaptic vesicle glycoproteins (SV2A), which represent the number of synapses in the brain. Thus, the investigators will also measure synaptic density in the brain and relate to mGluR5 availability. Aim 1: To determine mGluR5 availability with mood disorders compared to healthy controls as measured with PET brain imaging using \[18F\]FPEB. Hypothesis 1: decrease in mGluR5 availability in individuals with mood disorders in regions responsible for emotional and cognitive processes, including the amygdala, hippocampus, thalamus, anterior cingulate, and frontal cortices. Aim 2: To determine if glutamate cycling in individuals with mood disorders is altered as compared to healthy controls as measured with \[1H\]MRS and \[13C\]MRS. Hypothesis 2: increase in glutamate number in individuals with mood disorders as compared to controls. Aim 3: To determine if the PET alterations in the glutamatergic system of depressed individuals are associated with cognitive deficits observed in depression, including concentration, attention, and memory (cognitive testing performance), and distractibility and startle. Hypothesis 3: positive relationship between mGluR5 availability and cognitive functioning, such that individuals with higher receptor availability will perform better on tests of concentration, attention, memory, distractibility, and startle than individuals with lower receptor availability. Aim 4: To examine whether changes in mGluR5 availability are dependent on state, or whether the lower availability is due to trait. Hypothesis: normalization (or increase) in mGluR5 availability in euthymia as compared to depressed state. Aim 5: To examine synaptic density changes associated with mood disorders using \[11C\]APP311 Hypothesis 5: lower synaptic density in individuals with MDD and bipolar disorder (BD), and associations between synaptic density changes and mood severity. Investigators also hypothesize there might be a relationship between synaptic density and mGluR5 availability.