Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder with Modafinil

描述(由申请人提供)：尽管双相情感障碍的治疗取得了进展，但大多数患者并未实现完全的发作间歇期恢复，功能障碍是常见的。在相对缓解期，许多患者继续经历睡眠障碍、白天活动水平降低和神经认知功能障碍。这种疾病的这些持续特征代表了关键的治疗目标，因为它们不能通过标准的情绪稳定药物充分改善，而且它们与功能残疾和较差的生活质量密切相关。心理社会治疗的重点是稳定睡眠-觉醒周期和日常生活，如用餐时间和定期社交，从而显著减少情感复发。到目前为止，还没有研究试图通过药物干预来稳定双相情感障碍患者的昼夜节律。因此，这项拟议的为期8周的随机安慰剂对照试点研究将评估促进觉醒药物莫达非尼(Provigil(R))对48名优心型双相情感障碍患者的睡眠、白天活动和神经认知功能的安全性和初步疗效。莫达非尼被美国食品和药物管理局(FDA)批准用于治疗与几种睡眠障碍(发作性睡病、睡眠呼吸暂停和轮班工作障碍)相关的白天过度嗜睡。在非标签应用中，我们将以2：1的比例随机给予48名情感稳定的双相I型障碍患者服用2：1的活性莫达非尼(200 mg/天)或安慰剂，为期8周。我们将通过问卷调查和日常日记来测量患者对睡眠障碍和日间觉醒的主观体验。此外，我们将重点研究莫达非尼改善双相情感障碍患者的神经认知功能的潜力，包括注意力、记忆和更高阶认知过程，因为以前已经证明，它可以增强精神健康人、睡眠障碍患者和精神分裂症患者的认知能力。为了测量认知功能，我们将在使用莫达非尼之前和在为期8周的研究结束时再次进行几次纸笔和计算机测试。最后，虽然不是当前研究的主要重点，但我们也将调查莫达非尼对轻度抑郁症状的影响，这些症状与睡眠评分、社会节律的规律性和患者报告的生活质量无关。我们将密切监测患者的情绪症状中不可预见的变化，这些症状被认为会使他们处于躁狂或抑郁的风险中，并将在认为必要时停止试验。我们预计，这项研究的结果将确定一种新的方法来治疗那些目前的情绪稳定剂无法充分解决的双相情感障碍的持续性症状，有可能导致更完全的恢复和日常功能的改善。

DESCRIPTION (provided by applicant): Despite advances in the treatment of bipolar disorder, most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience sleep disturbances, reduced daytime activity levels, and neurocognitive dysfunction. These persistent features of the illness represent critical treatment targets, as they do not adequately improve with standard mood stabilizing medications and they are strongly associated with functional disability and poor quality of life. Psychosocial therapies have focused on the importance of stabilizing sleep-wake cycles and daily routines such as mealtimes and regular social interactions, resulting in significant reductions in affective relapse. No study, to date, has attempted to stabilize circadian rhythms using a pharmacologic intervention in bipolar patients. Thus, the proposed 8-week, randomized, placebo-controlled pilot study will evaluate the safety and preliminarily assess the efficacy of the wake-promoting drug, modafinil (Provigil(R)), on sleep, daytime activity, and neurocognitive functioning in 48 euthymic bipolar patients. Modafinil is approved by the US Food and Drug Administration (FDA) for excessive daytime sleepiness associated with several sleep disorders (narcolepsy, sleep apnea, and shift-work disorder). In an off-label application, we will administer randomize in a 2:1 ratio to active modafinil (200mg/day) or placebo to 48 affectively stable patients with bipolar I disorder for 8 weeks. We will measure patients' subjective experience of sleep disruption and daytime wakefulness by questionnaires and daily diaries. In addition, we will focus on modafinil's potential to improve neurocognitive functioning, including attention, memory and higher order cognitive processes in patients with bipolar disorder, as it has previously been shown to enhance cognition in psychiatrically healthy individuals, patients with sleep disorders, and patients with schizophrenia. To measure cognitive functioning, we will deploy several paper-pencil and computerized tests before modafinil is administered and again at the end of the 8-week study. Finally, although not a primary focus of the current study, we will also investigate the effects of modafinil on low-grade depressive symptoms independent of sleep ratings, regularity of social rhythms, and patient-reported quality of life. We will closely monitor patiets for unforeseen changes in mood symptoms that are deemed to place them at risk for developing mania or depression and will discontinue the trial as deemed necessary. We expect that findings from this study will identify a novel approach for treating those persistent symptoms of bipolar disorder not adequately addressed with current mood stabilizing agents, potentially resulting in a more complete recovery and improvement in day-to-day functioning.