Combined oral contraceptive use and serotonin 2A and 2C receptor brain architecture in healthy women

ObjectivesCombined oral contraceptive (COC) use is linked to increased depression risk, potentially via serotonergic pathways. This study examined whether serotonin 2A/2C receptor (5-HT2AR/5-HT2CR) brain binding differs between healthy women using COCs and non-users. Methods71 healthy women had been scanned with either [18F]Altanserin (17 COC users, 22 non-users) or [11C]Cimbi-36 Positron Emission Tomography (17 COC users, 15 non-users). Multiple linear regression and latent variable models were used to assess associations between COC use and neocortical 5-HT2AR and subcortical-HT2AR/5-HT2CR binding, respectively.. Analyses were performed on data pooled across both radiotracers and on each tracer, separately. ResultsIn pooled analyses across both tracers, COC use was not significantly associated with 5-HT2AR binding in the neocortex (-7.7%, 95% CI [-18.9;5.2], p=0.22), nor with 5-HT2AR/5-HT2CR in subcortical regions (-7.8, 95% CI [-21.7;7.7], p=0.31). In [11C]Cimbi-36-only analyses, COC use was associated with -12.6% (95% CI [-22.1;-1.9], p=0.02) lower 5-HT2AR binding in neocortex and -23.5% lower 5-HT2AR/5-HT2CR binding in subcortical regions (95% CI [-35.6;-9.1], p=0.002). No significant differences were observed in the [18F]Altanserin-only analyses. ConclusionThe [11C]Cimbi-36 data indicated lower cortical 5-HT2AR and subcortical 5-HT2AR/5-HT2CR binding in COC users compared to non-users, but this was not observed in the [18F]Altanserin data. This may reflect better signal-to-noise properties of [11C]Cimbi-36 and the fact that it binds more selectively to the high-affinity, biologically active receptor state. These results offer potential mechanistic insights into the depression risk associated with COC use and may have implications for treatments targeting 5-HT2AR/5-HT2CR, underscoring the need for replication and further investigation. Highlights1) COC use was associated with lower 5-HT2AR/CR brain binding in Cimbi-36 PET data 2) COC use was not associated with 5-HT2AR brain binding in [18F]Altanserin PET data 3) We speculate if lower 5-HT2AR/CR levels may affect treatments targeting 5-HT2AR/CR