Ananth Mala, Bartlett Elizabeth A, DeLorenzo Christine, Lin Xuejing, Kunkel Laura, Vadhan Nehal P, Perlman Greg, Godstrey Michala, Holzmacher Daniel, Ogden R Todd, Parsey Ramin V, Huang Chuan
Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, 11794, USA.
Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2417-2428. doi: 10.1007/s00259-020-04681-6. Epub 2020 Feb 13.
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) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT 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 [C]DASB, a subset also received a PET scan using 5-HT tracer [C]-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 [C]DASB and [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-HT1A 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 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 binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT 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 to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium.
PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957.
锂盐是双相抑郁（BPD）少数有效的治疗方法之一，据推测其作用机制是增强血清素能传递。尽管有临床前证据，但锂盐是否通过血清素能系统发挥作用尚不清楚。在此，我们研究了血清素转运体（5-HTT）或血清素1A受体（5-HT）预处理结合情况预测锂盐治疗反应和缓解情况的潜力。我们假设预处理时较低的5-HTT结合和较高的5-HT结合可预测更好的临床反应。额外分析研究了BPD患者与健康对照之间的组间差异以及治疗前后结合变化与临床反应之间的关系。27例目前处于抑郁发作期的未服药BPD患者接受了使用5-HTT示踪剂[C]DASB的正电子发射断层扫描（PET），其中一部分患者在锂盐单一疗法8周前后还接受了使用5-HT示踪剂[C]-CUMI-101的PET扫描。代谢物校正动脉输入函数用于估计与受体可用性成比例的结合潜力。14例同时进行了[C]DASB和[C]-CUMI-101预处理扫描且有8周治疗后临床评分的BPD患者被纳入预测分析，以研究预处理时5-HTT或5-HT1A或两者结合预测治疗后临床评分的潜力。
我们发现预处理时较低的5-HTT结合（p = 0.003）和较低水平的5-HT结合（p = 0.035）均与临床反应改善显著相关。预处理时的5-HTT以71%的准确率预测缓解情况（特异性77%，敏感性60%），而5-HT结合能够以85%的准确率预测缓解情况（敏感性87%，特异性80%）。使用5-HTT和5-HT两者的联合预测分析能够以84.6%的准确率预测缓解情况（特异性87.5%，敏感性60%）。对BPD患者与对照组治疗前或治疗后的额外分析以及结合变化不显著且与治疗反应无关（p > 0.05）。
我们的研究结果表明，虽然锂盐可能并非直接通过5-HTT或5-HT来改善抑郁症状，但预处理结合情况可能是锂盐成功治疗BPD的潜在生物标志物。
双相情感障碍的PET和MRI脑成像标识符：NCT01880957；网址：https://clinicaltrials.gov/ct2/show/NCT01880957 。
