Jacobsen Jacob P R, Krystal Andrew D, Krishnan K Ranga R, Caron Marc G
Department of Cell Biology, Duke University, Durham, NC 27710, USA.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USA.
Trends Pharmacol Sci. 2016 Nov;37(11):933-944. doi: 10.1016/j.tips.2016.09.001. Epub 2016 Sep 28.
Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HT). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HT beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HT beyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.
血清素转运体(SERT)抑制剂通过提高大脑细胞外5-羟色胺(5-HT)来治疗抑郁症。然而,只有三分之一的患者有充分反应。难治性抑郁症(TRD)是一个尚未得到满足的主要需求。有趣的是,将5-HT提高到超过SERT抑制剂所能达到的水平似乎可以治疗TRD。在人体中,辅助使用5-羟色氨酸(5-HTP)可安全地将5-HT提高到超过SERT抑制剂的作用水平;然而,由于其药代动力学较差,5-HTP不能成为一种临床上可行的药物。预计缓释(SR)给药模式将克服5-HTP的药代动力学限制,大幅增强其药理作用,并将5-HTP转变为一种临床上可行的药物。动物研究证实了这一预测。因此,辅助使用5-HTP SR可能是治疗TRD的一种重要新疗法。在此,我们综述了这种疗法的临床和临床前证据。