Quantification of the Serotonin 1A Receptor Using PET: Identification of a Potential Biomarker of Major Depression in Males

Abstract

Multiple lines of research have implicated the serotonin 1A (5-HT1A) receptor in major depressive disorder (MDD). Despite this, quantification of 5-HT1A is yet to yield a clinically relevant MDD biomarker. One reason may be that reported sex differences in the serotonergic system confound the comparison between diagnostic groups. Therefore, this study sought to determine whether differences in 5-HT1A binding between depressed and control subjects are affected by sex. Using positron emission tomography (PET), serotonin 1A binding was quantified in 50 patients with MDD (34 female, 16 male) and 57 healthy controls (32 female, 25 male). The subjects' 5-HT1A density (BPF, equal to the product of the density of available receptors and tracer affinity), was determined by using the PET tracer [carbonyl-C-11]-WAY-100635, a selective 5-HT1A antagonist. Results indicated that male MDD subjects had a 67.0% higher BPF across 13 brain regions compared with male controls (df=103, p<0.0001). The greatest difference between MDD subjects and controls was in the raphe (132%, p=0.000). Furthermore, by using a threshold, male controls can be distinguished from depressed males with high sensitivity and specificity (both >80%). In females, the separation between diagnostic groups yields much lower sensitivity and specificity. This data therefore suggests a specific biosignature for MDD in males. Identification of such a biosignature could provide a deeper understanding of depression pathology, help identify those at highest risk, and aid in the development of new therapies. Further, these findings suggest that combining male and female cohorts may not be optimal for some MDD studies.

The 5-HT1A receptor in Major Depressive Disorder

“…Weighed means, which incorporate potential BP F errors, are more accurate since less reliable points are deweighted. In this analysis, no significant genotype effect was observed in the raphe or hippocampus for: controls (raphe: p =0.19, hippocampus: p =0.45), MDD subjects who had either never received antidepressant treatment or had not received antidepressant treatment within the previous 4 years (defined as Not Recently Medicated ‘NRM’) (raphe: p =0.62, hippocampus: p =0.60) and when all subjects are combined (raphe: p =0.22, hippocampus: p =0.39) (Figure 7) (Kaufman et al, 2015). Similarly, no genotype effect was seen in the raphe or hippocampus when genotype was coded for the presence of at least 1 G allele i.e.…”

“…Whether these differences in symptomatology are related to differences in psychopathology is still under investigation. However, whether due to genetic, environmental, or physiological differences, characterization of the etiology of sex differences in a psychopathology as prevalent as MDD is of utmost import for the field of psychiatry (Kaufman et al, 2015). …”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…These findings suggest that increased 5-HT1A presynaptic and decreased postsynaptic activity may co-occur in MDD. Several studies using PET imaging demonstrated elevated 5-HT1A binding in the brain of MDD subjects, especially in the raphe (Parsey et al 2010;Kaufman et al 2015). 5-HT1A density distinguished male controls from depressed males with high sensitivity and specificity (both >80%) (Kaufman et al 2015).…”

“…Several studies using PET imaging demonstrated elevated 5-HT1A binding in the brain of MDD subjects, especially in the raphe (Parsey et al 2010;Kaufman et al 2015). 5-HT1A density distinguished male controls from depressed males with high sensitivity and specificity (both >80%) (Kaufman et al 2015). A reduction in raphe 5-HT1A autoreceptor binding was demonstrated during SSRI treatment and was associated with symptom improvement (Gray et al 2013).…”

A positron emission tomography study of the serotonergic system in relation to anxiety in depression

“…A linear regression model incorporating measurement error in predictors was used to study the relationship between [ 11 C]WAY-100635 BP F and [ 11 C]DASB V T / f P , after adjusting for sex and medication status as they have been shown to affect [ 11 C]WAY-100635 binding (Kaufman et al, 2015; Parsey et al, 2006a; Parsey et al, 2002). Both BP F and V T / f P were log-transformed in order to ensure model assumptions were met.…”