Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET

Abstract

Background: 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-HT1A) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT1A 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 [11C]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 [11C]-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-HT1A or the combination of both to predict post-treatment clinical scores.

Results: We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT1A 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-HT1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT1A 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).

Conclusions: Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium.

Clinical trial registration: PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://ichgcp.net/clinical-trials-registry/NCT01880957.

Keywords: Bipolar depression; Lithium; PET; Prediction; Serotonin transporter; Serotonin-1A.

Conflict of interest statement

Competing interests

The authors report no competing interests

Figures

Figure1A:

Regression plots of model adjusted VT/fP (X-axis) by HDRS-24 post-treatment score (Y-axis) in the brain regions selected as significant predictors of treatment response with penalized logistic regression (elasticnet). Model β estimate shown in solid orange lines, with the model 95% confidence intervals in dashed orange lines (n=14). 1B: VT /fP [11C]DASB voxel maps from single subjects representing range of clinical response. 1C: Regression plots showing model adjusted BPF [11C]CUMI-101 binding potential (X-axis) by HDRS-24 post-treatment score (Y-axis) in the regions selected as significant predictors of treatment response with penalized logistic regression (elastic-net). Model β estimate shown in solid orange lines, with the model 95% confidence intervals in dashed orange lines (n=14). 1D: Single subject voxel-wise BPF [11C]CUMI-101 voxel maps representing range of clinical response.

Figure 2A:

Regression plots of model adjusted pre-treatment VT/fP (X-axis) by HDRS-24 post-treatment score (Y-axis) for the brain regions selected as significant predictors of treatment response with penalized logistic regression. 2B. Regression plots of model adjusted BPF (X-axis) by HDRS-24 post-treatment score (Y-axis) for the brain regions selected as significant predictors of treatment response with penalized logistic regression (elasticnet).

Figure 3A:

Group-wise averaged VT /fP voxel maps displaying lithium effect on [11C]DASB 5-HTT binding, where pre-treatment is in top pane and post-treatment is in bottom pane. 3B: Group-wise averaged BPF voxel maps displaying lithium effect on [11C]-CUMI-101 5-HT1A binding, where pre-treatment is in left pane and post-treatment is in right pane.

Figure 4A:

Regression plots of model adjusted VT/fP (X-axis) by the change in HDRS-24 score (Y-Axis) in a representative a priori region (n=19). 4B: Regression plots showing model adjusted BPF (X-axis) and the change in HDRS-24 score (Y-Axis) in representative a priori regions: Raphe Nucleus (somatodendritic), Hippocampus (post-synaptic) (n=13).