Rahn K A, Cao Y-J, Hendrix C W, Kaplin A I
1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Transl Psychiatry. 2015 May 5;5(5):e563. doi: 10.1038/tp.2015.57.
Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed.
急性接触抗抑郁药会增加重度抑郁症（MDD）儿童和青少年的冲动行为频率和自杀念头。然而，长期抗抑郁治疗对儿童MDD有益，因此有必要探索新的治疗方法，以预防急性开始使用抗抑郁药可能产生的危险后果。在本研究中，在啮齿动物中测试了一种旨在逆转抗抑郁药急性负面行为影响的治疗策略。5-HT1A受体（5-HT1AR）拮抗剂WAY-100635与急性氟西汀（一种5-羟色胺再摄取抑制剂）联合使用可逆转其负面影响，但与去甲肾上腺素再摄取抑制剂瑞波西汀联合使用则无效，这支持了5-HT1AR参与介导急性选择性5-羟色胺再摄取抑制剂（SSRI）治疗的负面后果。目前尚无5-HT1AR拮抗剂被批准用于儿科人群，因此应探索替代策略。基于急性SSRI给药引起的5-HT1AR激活速率和随后对5-羟色胺能神经元活动的抑制与抗抑郁药的负荷速率成正比这一假设，提出了一种这样的策略。研究了现有的药理学数据，并观察到抗抑郁药的半衰期与自杀相关事件（SRE）发生率之间存在显著相关性。具体而言，半衰期较长的抗抑郁药SRE发生率较低。基于这些数据，为五种抗抑郁药制定了新的给药策略，以模拟半衰期最长的抗抑郁药氟西汀的药理学特征。在开发出更好的药物治疗方法之前，这些给药策略可用于降低儿童MDD中与急性抗抑郁治疗相关的SRE发生率。
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