Institute of Mental Health Research, University of Ottawa, Ottawa, Canada.
Int J Psychiatry Clin Pract. 2007;11 Suppl 2:16-23. doi: 10.1080/13651500701388310.
The therapeutics of obsessive-compulsive disorder (OCD) involves the serotonergic system in the brain; the selective serotonin reuptake inhibitors (SSRIs) are the only class of drugs to be consistently effective for this disorder. Preclinical studies in the orbito-frontal cortex - a brain area known to be involved in mediation of OCD symptoms - show that sustained administration of SSRI for 2 months leads to enhanced 5-HT release. Initially, raised 5-HT levels, resulting from serotonin (5-HT) reuptake inhibition, over-activates the cell body 5-HT1A autoreceptor, which has an inhibitory effect on the neuronal firing rate. However, after long-term administration of SSRIs, these 5-HT1A autoreceptors become desensitized to the raised extracellular 5-HT levels, and increase 5-HT transmission. The recovery of neuronal firing rate is faster with escitalopram (the active S-enantiomer of citalopram) than with citalopram, which may be due to different mechanisms of action. The 5-HT system has reciprocal interactions with the noradrenaline (NA) system. Although not a major mediator in the treatment of OCD symptomatology, patients with anxiety disorders such as panic disorder have increased NA reactivity and/or tone. Long-term SSRI administration reduces the firing rate of NA neurones, unlike 5-HT neurones. Evidence indicates that accrued 5-HT levels have an inhibitory modulatory effect on NA transmission, thus indicating the clinical relevance of SSRI treatment for anxiety disorders. The different effectiveness of the SSRIs escitalopram and citalopram in enhancing synaptic 5-HT levels may be due to the inhibitory action of the R-enantiomer in racemic citalopram on S-enantiomer binding to the 5-HT transporter. This allows escitalopram to produce higher extracellular 5-HT levels than can be achieved by the equivalent S-enantiomer dose of citalopram. Escitalopram is therefore a viable front-line treatment option for people with anxiety disorders, and possibly for those who have failed to respond to conventional SSRI therapies.
强迫症（OCD）的治疗涉及大脑中的 5-羟色胺能系统；选择性 5-羟色胺再摄取抑制剂（SSRIs）是唯一一类对这种疾病始终有效的药物。在眶额皮层（已知参与调节 OCD 症状的大脑区域）的临床前研究中，显示 SSRIs 持续给药 2 个月可导致 5-HT 释放增加。最初，由于 5-羟色胺（5-HT）再摄取抑制，升高的 5-HT 水平过度激活细胞体 5-HT1A 自身受体，从而对神经元放电率产生抑制作用。然而，在长期服用 SSRIs 后，这些 5-HT1A 自身受体对升高的细胞外 5-HT 水平变得脱敏，并增加 5-HT 传递。与西酞普兰（西酞普兰的活性 S-对映体）相比，艾司西酞普兰（escitalopram）恢复神经元放电率更快，这可能是由于不同的作用机制。5-HT 系统与去甲肾上腺素（NA）系统相互作用。虽然 NA 系统不是 OCD 症状治疗的主要调节剂，但焦虑障碍（如恐慌症）患者的 NA 反应性和/或张力增加。与 5-HT 神经元不同，长期 SSRI 给药会降低 NA 神经元的放电率。有证据表明，积累的 5-HT 水平对 NA 传递具有抑制性调制作用，因此表明 SSRI 治疗对焦虑障碍的临床相关性。SSRIs 艾司西酞普兰和西酞普兰在增强突触 5-HT 水平方面的不同效果可能是由于消旋西酞普兰的 R-对映体对 S-对映体与 5-HT 转运体结合的抑制作用。这使得艾司西酞普兰能够产生比西酞普兰的等效 S-对映体剂量更高的细胞外 5-HT 水平。因此，艾司西酞普兰是焦虑障碍患者的可行一线治疗选择，对于那些对传统 SSRI 治疗反应不佳的患者也可能是一种选择。
