Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?

Abstract

BACKGROUND: Mood disorders and suicidality have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) binding potential. However, it is unclear whether these alterations reflect heritable risk or resilience markers, compensatory mechanisms, or illness-related changes as 5-HT1A binding has never been reported in unaffected high risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset. METHODS: PET imaging quantified brain 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV) and three groups with one or more relatives with early-onset mood disorder and suicide attempt: 1. HR individuals; 2. HR individuals with a lifetime mood disorder (HR-MOOD); and 3. HR-MOOD individuals with lifetime history of suicide attempt (HR-MOOD/SA). Two additional studies included HV, individuals with low familial risk and current mood disorder (MOOD) and MOOD with lifetime suicide attempt (MOOD/SA) to identify differences persisting across independent cohorts (total N=185: 59 HV, 23 HR, 64 HR-MOOD or MOOD, and 39 HR-MOOD/SA or MOOD/SA). Univariate analysis tested for regional differences and multivoxel pattern analysis (MVPA) tested whether 5-HT1A BPND could distinguish HV, HR, HR-MOOD and HR-MOOD/SA. RESULTS: Low ventral prefrontal 5-HT1A BPND in lifetime MOOD/SA vs. HV and HR was consistently observed across study populations. MVPA distinguished HV from HR-MOOD/SA with informative regions in ventral prefrontal and temporal cortex (peak out-of-sample area under the ROC curve=0.74, p<0.001 corrected). MOOD alone groups did not consistently differ from HV groups. CONCLUSIONS: Low ventral prefrontal 5-HT1A BPND may reflect suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND may confer resilience for developing suicidal behavior in the context of mood disorders. If so, it could be a potential suicide prevention target.

In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity

“…While studies using [ 11 C]-WAY100635 have consistently found depressed vs. HV differences in raphe nuclei 5-HT 1A R [34,36,87], the [ 11 C]CUMI-101-measured difference in 5-HT 1A R binding here seems to be limited to the hippocampus. Two recent analyses with [ 11 C]-CUMI-101 found differences in 5-HT 1A R binding potential between BD and HV groups in the raphe nuclei and across a large set of ROIs that included the hippocampus [37] and between a mixed-mood disorder sample at high-risk for mood disorder comprising https://doi.org/10.1192/j.eurpsy.2023.4 Published online by Cambridge University Press participants with MDD, BD, dysthymia and depressive disorder not otherwise specified and HVs in the ventromedial prefrontal cortex and the medial orbitofrontal cortex [88]. However, in Ananth et al 2020, there were no differences between BD and HV groups in the raphe nuclei or in a large set of ROIs [44].…”