Department of Psychiatry The University of British Columbia, Vancouver, British Columbia, Canada.
TRIUMF Positron Emission Tomography Program , The University of British Columbia, Vancouver, British Columbia, Canada.
Int J Neuropsychopharmacol. 2018 Feb 1;21(2):108-113. doi: 10.1093/ijnp/pyx066.
Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy.
In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7.
Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L.
These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.
喹硫平在治疗重性抑郁障碍和双相障碍的抑郁症状方面有效，但该药的抗抑郁作用机制尚不清楚。喹硫平的代谢产物去甲喹硫平对去甲肾上腺素转运体具有高亲和力，这可能与其治疗效果有关。
在这项研究中，我们使用 [(S,S)-11C]O-甲基去甲文拉法辛正电子发射断层扫描来估计去甲肾上腺素转运体密度，并评估喹硫平 XR 对去甲肾上腺素转运体的占有率与重性抑郁障碍（n=5）和双相障碍（n=5）患者抑郁改善之间的关系。在正电子发射断层扫描基线扫描后，患者接受喹硫平 XR 治疗，重性抑郁障碍的目标剂量为 150mg，双相障碍的目标剂量为 300mg。患者在第 2 周末进行第二次正电子发射断层扫描，在第 7 周末进行最后一次扫描。
与健康受试者相比，患者蓝斑中的去甲肾上腺素转运体密度显著降低。此外，在第 2 周末，喹硫平 XR 剂量与蓝斑中的去甲肾上腺素转运体占有率之间存在显著正相关。第 2 周末下丘脑的去甲肾上腺素转运体占有率而非其他区域的占有率与从基线到第 7 周末 MADRS 评分降低所反映的抑郁改善相关。第 2 周末达到 50%去甲肾上腺素转运体占有率时所需的喹硫平 XR 估计剂量为 256mg，达到 50%去甲肾上腺素转运体占有率时所需的去甲喹硫平估计血浆水平为 36.8μg/L。
这些数据初步支持了去甲喹硫平对去甲肾上腺素转运体的占有率可能是喹硫平抗抑郁作用的一个贡献因素的假说。
