Andrews Paul W, Bharwani Aadil, Lee Kyuwon R, Fox Molly, Thomson J Anderson
Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
Neurosci Biobehav Rev. 2015 Apr;51:164-88. doi: 10.1016/j.neubiorev.2015.01.018. Epub 2015 Jan 24.
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.
尽管经过数十年研究，血清素在抑郁症及抗抑郁治疗中的作用仍未得到解决。在本文中，我们提出三项主要观点。首先，血清素传递在多种抑郁表型中升高，包括忧郁症，这是一种与持续认知相关的亚型。对这一首要观点的主要挑战在于，大多数减轻症状药物的直接药理作用，如选择性血清素再摄取抑制剂（SSRI），是增加突触血清素。第二项观点对于解决这一矛盾至关重要，即血清素能系统进化而来是为了调节能量。通过增加细胞外血清素，SSRI会破坏能量稳态，并在急性治疗期间常常使症状恶化。我们的第三项观点是，症状减轻并非通过SSRI的直接药理特性实现，而是通过大脑试图恢复能量稳态的代偿反应实现。这些反应需要数周时间才能形成，这就解释了为什么SSRI存在治疗延迟。我们通过研究忧郁症动物模型以及急性和慢性SSRI治疗期间发生的情况来证明我们观点的实用性。
