Cross A J, Widzowski D, Maciag C, Zacco A, Hudzik T, Liu J, Nyberg S, Wood M W
AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
AstraZeneca R&D, Shanghai, China.
Br J Pharmacol. 2016 Jan;173(1):155-66. doi: 10.1111/bph.13346. Epub 2015 Dec 1.
Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.
We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action.
Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635.
Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine.
喹硫平具有一系列不同于其他非典型抗精神病药物的临床活性，在双相抑郁、重度抑郁症和广泛性焦虑症的单药治疗中显示出疗效。这种临床特征背后的神经药理学机制尚未完全明确；然而，主要活性代谢物去甲喹硫平已被证明具有与广泛治疗范围相一致的独特体外药理学特征，可能对喹硫平的临床特征有所贡献。
我们使用已知与抗抑郁和抗焦虑药物作用相关靶点的体外结合和功能测定法对喹硫平和去甲喹硫平进行了评估，并将这些活性与一系列代表性的已确立的抗精神病药物和抗抑郁药物进行了比较。为了确定体外药理学特性如何转化为体内活性，我们使用了与已确立的抗抑郁样和抗焦虑样药物作用具有转化相关性的临床前动物模型。
去甲喹硫平在去甲肾上腺素转运体（NET）上与已确立的抗抑郁药物具有同等活性，而喹硫平无活性。去甲喹硫平在小鼠强迫游泳试验和大鼠习得性无助试验中具有活性。在体内受体占有率研究中，去甲喹硫平在行为相关剂量下对NET具有显著占有率。喹硫平和去甲喹硫平都是5-HT1A受体的激动剂，去甲喹硫平在大鼠惩罚性反应中的抗焦虑样活性被5-HT1A拮抗剂WAY100635阻断。
喹硫平和去甲喹硫平具有多种体外药理学作用，临床前研究结果表明，NET和5-HT1A受体的活性有助于喹硫平治疗患者的抗抑郁和抗焦虑作用。
