Witkin Jeffrey M, Wallace Tanya L, Martin William J
Witkin Consulting Group, Carmel, IN, USA.
BlackThorn Therapeutics, San Francisco, CA, USA.
Handb Exp Pharmacol. 2019;254:399-415. doi: 10.1007/164_2018_186.
Conventional antidepressants increase the efflux of biogenic amine neurotransmitters (the monoamine hypothesis of depression) in the central nervous system (CNS) and are the principle drugs used to treat major depressive disorder (MDD). However, the lack of efficacy in some patients, the slow onset of action, and the side effect profiles of existing antidepressants necessitate the exploration of additional treatment options. The discovery of the nociceptin/orphanin FQ peptide NOP receptor (N/OFQ-NOP receptor) system and its characterization in preclinical biological and pharmacological stress-related conditions supports the potential antidepressant and anti-stress properties of a NOP receptor antagonist for the treatment of neurobehavioral disorders. BTRX-246040 (formerly LY2940094) was designed to test this hypothesis in the clinic. A small clinical proof of concept study demonstrated efficacy of BTRX-246040 in MDD patients. In this study, BTRX-246040 (40 mg, p.o.) significantly reduced negative bias as assessed by the facial recognition test within 1 week of treatment and decreased depression symptoms after 8 weeks. BTRX-246040 also reduced depression symptoms in a second trial with heavy alcohol drinkers. Given the comorbidity of MDD and alcohol use disorder, a compound with such effects in patients could be a valuable addition to the medications available. A proof of concept study showed efficacy of BTRX-246040 in reducing heavy drinking and increasing the probability of abstinence in individuals diagnosed with alcohol dependence. In addition, plasma levels of gamma-glutamyl transferase were decreased by BTRX-246040 compared to placebo control implying improvement in liver function. Collectively, the clinical data reviewed within this chapter suggest that BTRX-264040 functions to normalize dysfunction in reward circuits. The overall efficacy and safety of this compound with a novel mechanism of action are encouraging of further clinical development. BTRX-246040 is currently under development for MDD by BlackThorn Therapeutics.
传统抗抑郁药可增加中枢神经系统（CNS）中生物胺神经递质的流出（抑郁症的单胺假说），是用于治疗重度抑郁症（MDD）的主要药物。然而，一些患者缺乏疗效、起效缓慢以及现有抗抑郁药的副作用，使得有必要探索其他治疗选择。伤害感受素/孤啡肽FQ肽NOP受体（N/OFQ-NOP受体）系统的发现及其在临床前生物学和药理学应激相关条件下的特征，支持了NOP受体拮抗剂治疗神经行为障碍的潜在抗抑郁和抗应激特性。BTRX-246040（原LY2940094）旨在在临床中验证这一假说。一项小型概念验证临床研究证明了BTRX-246040对MDD患者的疗效。在这项研究中，BTRX-246040（40毫克，口服）在治疗1周内通过面部识别测试评估可显著降低负性偏差，并在8周后减轻抑郁症状。在另一项针对重度饮酒者的试验中，BTRX-246040也减轻了抑郁症状。鉴于MDD与酒精使用障碍的共病情况，一种对患者有此类作用的化合物可能是现有药物的宝贵补充。一项概念验证研究表明，BTRX-246040在减少重度饮酒以及增加被诊断为酒精依赖个体的戒酒概率方面具有疗效。此外，与安慰剂对照相比，BTRX-246040可降低γ-谷氨酰转移酶的血浆水平，这意味着肝功能有所改善。总体而言，本章回顾的临床数据表明，BTRX-264040的作用是使奖赏回路中的功能障碍正常化。这种具有新作用机制的化合物的总体疗效和安全性令人鼓舞，值得进一步开展临床研究。BlackThorn Therapeutics公司目前正在对BTRX-246040进行MDD治疗的研发。
