Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography

Abstract

Context: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant.

Objectives: To assess in vivo brain serotonin transporter binding potential (BP(1), proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype.

Design: Case-control study.

Setting: University hospital.

Participants: A sample of 18 medication-free patients with bipolar depression and 41 controls.

Main outcome measures: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([(11)C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms.

Results: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP(1) in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP(1).

Conclusions: Lower serotonin transporter BP(1) in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions.

Figure 1

Lower radiolabeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)-phenyl]pyrrolo-[2,1-a]-isoquinoline ([¹¹C](+)-McNeil 5652) binding potential (BP₁) to the serotonin transporter (5-HTT) in nonmedicated patients with bipolar disorder in 6 regions of interest compared with controls (F_1,58=5.41; P=.02). ACC indicates anterior cingulate cortex; AMY, amygdala; HIP, hippocampus; MID, midbrain; PUT, putamen; and THA, thalamus. Vertical bars represent the mean likelihood approach to the graphical method modeled BP₁ (V_T[region]–V_T[cerebellum]) for each region; error bars, ±1 SD.

Figure 2

The radiolabeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)-phenyl]pyrrolo-[2,1-a]-isoquinoline ([¹¹C](+)-McNeil 5652) binding to serotonin transporter (5-HTT) in the amygdala. Each circle represents a single measurement of likelihood approach to the graphical method modeled binding potential. Horizontal bars indicate mean.

Figure 3

Magnetic resonance images from a control (A) were used to coregister the maps of serotonin transporter binding potential (BP₁) from a control (B) and a patient with bipolar disorder (C) whose midbrain BP₁ was closest to the respective group mean. Each voxel intensity is a single BP₁ measurement. The color bar represents milliliters per gram. Serotonin transporter BP₁ was significantly lower in the midbrain (columns 1 and 2), amygdala (column 3), thalamus (columns 1 and 3), anterior cingulate cortex (column 1), hippocampus (column 2), and putamen (data not shown).

Figure 4

Mean serotonin transporter binding potential according to 5-HTTLPR triallelic polymorphism genotype in patients with bipolar disorder. There are no statistically significant differences among genotypes. Error bars represent SD. LL indicates mean BP₁ in patients homozygous for L_G; LS, mean BP₁ in heterozygous patients (L_GS’); and SS, mean BP₁ in patients homozygous for S’ (L_A or S).