[en] Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT${}_{1A}$) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT${}_{1A}$ binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [${}^{11}$C]DASB, a subset also received a PET scan using 5-HT1A tracer [11C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [11C]DASB and [${}^{11}$C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT${}_{1A}$ or the combination of both to predict post-treatment clinical scores. We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT${}_{1A}$ binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT${}_{1A}$ binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT${}_{1A}$ was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05). Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT${}_{1A}$ to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium.

[en] 

Purpose

To determine if one venous blood sample can substitute full arterial sampling in quantitative modeling for multiple positron emission tomography (PET) radiotracers using simultaneous estimation of the input function (SIME).

Procedures

Participants underwent PET imaging with [¹¹C]ABP688, [¹¹C]CUMI-101, and [¹¹C]DASB. Full arterial sampling and additional venous blood draws were performed for quantification with the arterial input function (AIF) and SIME using one arterial or venous (vSIME) sample.

Results

Venous and arterial metabolite-corrected plasma activities were within 6 % of each other at varying time points. vSIME- and AIF-derived outcome measures were in good agreement, with optimal sampling times of 12 min ([¹¹C]ABP688), 90 min ([¹¹C]CUMI-101), and 100 min ([¹¹C]DASB). Simulation-based power analyses revealed that SIME required fewer subjects than the AIF method to achieve statistical power, with significant reductions for [¹¹C]CUMI-101 and [¹¹C]DASB with vSIME. Replication of previous findings and test-retest analyses bolstered the simulation analyses.

Conclusions

We demonstrate the feasibility of AIF recovery using SIME with one venous sample for [¹¹C]ABP688, [¹¹C]CUMI-101, and [¹¹C]DASB. This method simplifies PET acquisition while allowing for fully quantitative modeling, although some variability and bias are present with respect to AIF-based quantification, which may depend on the accuracy of the single venous blood measurement.