Imaging the serotonin 1A receptor using [11C]WAY100635 in healthy controls and major depression

Abstract

As a neurotransmitter, serotonin (5-HT) is widely used throughout the brain and known to play a role in many processes including emotion and brain development. Of the 15 subtypes of 5-HT receptors, the 1A receptor (5-HT(1A)) has been implicated in depression and suicide. Using the [carbonyl-(11)C]WAY100635 ([(11)C]WAY) ligand and positron emission tomography, we have studied the 5-HT(1A) receptor, first in a group of healthy controls, then in two separate groups of subjects with major depressive disorder (MDD) (antidepressant exposed and not recently medicated), and, lastly, in a group of subjects remitted from MDD. All MDD subjects were medication-free at the time of scan. We found higher 5-HT(1A) binding potential (BP(F)) in MDD subjects not recently exposed to an antidepressant compared with controls and recently medicated MDD subjects; and higher BP(F) in subjects with the C(-1019)G promoter polymorphism. We replicated these findings in a novel cohort and reconciled our discrepant findings with other groups using alternate quantification techniques. We also reported higher BP(F) in subjects remitted from a major depressive episode than in controls. From this work, we proposed a temporal model in which 5-HT(1A) BP(F) may be a trait abnormality of MDD. To further explore the genetic components of MDD and utility of 5-HT(1A) imaging as a potential tool for biomarker or treatment response prediction, these findings should be replicated in a larger cohort using the [(11)C]CUMI-101 agonist tracer.

Figure 1.

Temporal model of serotonin 1A receptor binding potential over the lifetime of subjects with major depression compared with controls. Subjects may be born with a preexisting vulnerability towards major depression (position A) or not (position B).

Figure 2.

Mean voxel BP_F maps of 5-HT_1A [carbonyl-¹¹C]WAY100635 binding. Not recently medicated (NRM) subjects show visibly higher binding throughout the brain than do controls.

Figure 3.

The C(-1019)G 5-HT_1A promoter polymorphism in controls and NRM subjects. Binding potential (BP_F) shows a stepwise increase in the raphe nuclei with G allele frequency: CC < CG < GG (d.f. = 1,78; F = 7.13; p = 0.009). The height of the bars indicates the weighted mean BP_F, while the error bars represent the corresponding equivalent of the standard deviation of each weighted mean. Dark grey bar represents CC (n = 22), black bar represents CG (n = 47) and light grey bar represents GG (n = 11).