Efficacy of the Melatonin Agonist in the Treatment of Depression

描述(申请人提供)：P2D公司正在开发一种合成的褪黑素激动剂PD6735，用于治疗抑郁症。初步研究表明，PD6735在啮齿类动物中具有抗抑郁作用。其他临床前研究表明，PD6735是安全的，是MT1和MT2受体的高亲和力激动剂。这项第一阶段SBIR建议的目标是确定PD6735在两种广泛使用的抑郁症啮齿动物模型中的疗效。初步研究表明，PD6735和抗抑郁药丙咪嗪在开放领域的临床前抑郁症模型中产生类似于抗抑郁药的效果。我们建议扩展我们的初步研究，并确定PD6735在两个广泛使用的抑郁症模型中的有效性：1)强迫游泳试验(Porsolt试验)，2)抑郁症的慢性轻度应激模型。在这两个模型中，我们还将使用三环类抗抑郁药丙咪嗪和选择性5-羟色胺摄取抑制剂(SSRI)氟西汀作为阳性对照。此外，还将确定褪黑素的抗抑郁作用。我们的具体目标是：特定目标1：在强迫游泳实验(Porsolt实验)中测定褪黑素激动剂PD6735急性和慢性给药的抗抑郁活性。具体目的2：测定褪黑素激动剂PD6735对慢性轻度应激抑郁模型大鼠的抗抑郁活性。PHS 398/2590(版本09/04)页面延续格式页面本申请旨在确定我们的专利褪黑素激动剂PD6735是否在抑郁症的临床前模型中显示出抗抑郁效果。根据美国国家心理健康研究所的数据，大约10%的美国男性和高达25%的女性在一生中会经历抑郁症。在美国，抑郁症导致了高达70%的精神科住院和约40%的自杀。据NIMH估计，美国抑郁症的成本为830亿美元，其中包括260亿美元的治疗成本和570亿美元的损失，如旷工、工作效率下降以及自杀相关死亡导致的终身收入价值。

DESCRIPTION (provided by applicant): P2D Inc. is developing a synthetic melatonin agonist, PD6735, for the treatment of depression. Preliminary Studies indicate that PD6735 produces an antidepressant-like effect in rodents. Additional preclinical studies indicate that PD6735 is safe and is a high-affinity agonist at MT1 and MT2 receptors. The goal of this Phase 1 SBIR proposal is to determine PD6735 efficacy in two widely employed rodent models of depression. Preliminary Studies indicate that the PD6735 and the antidepressant imipramine produce similar antidepressant-like effects in a preclinical model of depression, open filed. We propose to extend our Preliminary Studies and determine PD6735 efficacy in two widely employed models of depression: 1) the forced swim test (Porsolt test), and 2) the chronic mild stress model of depression. In both models we will also employ the tricyclic antidepressant imipramine and the selective serotonin uptake inhibitor (SSRI) fluoxetine as positive comparators. Additionally, the antidepressant effect of melatonin will be determined. Our Specific Aims are: Specific Aim 1: Determine the antidepressant activity of acute and chronic administration of the melatonin agonist PD6735 in the forced swim test preclinical model of depression (Porsolt test) in rats. Specific Aim 2: Determine the antidepressant activity of acute and chronic administration of the melatonin agonist PD6735 in the chronic mild stress model of depression in rats. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page This application proposed to determine if our proprietary melatonin agonist, PD6735, demonstrates antidepressant efficacy in preclinical models of depression. About 10% of all men in America and up to 25% of all women will experience depression in their lifetime according to the National Institute of Mental Health. In the United States, depression is responsible for up to 70% of all psychiatric hospitalizations and about 40% of suicides. The cost of depression in the United States was estimated by NIMH to be $83 billion including both $26 billion in costs of treatment and $57 billion in losses such as absenteeism, reduced productivity at work and the value of lifetime earnings due to suicide-related deaths.