New Treatments For Refractory Affective Illness

难治性情感疾病的新疗法

基本信息

批准号：
6671609
负责人：
ROBERT M POST
金额：
--
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Only one-quarter of our bipolar outpatients show an adequate clinical prophylactic response in double-blind, randomized, one- year trials of either lithium or carbamazepine monotherapy. Even with the combination of lithium and carbamazepine, only 50% of these outpatients respond. With the additional use of valproate, 37% of the initial cohort of patients still remain unresponsive. It is from this large pool of highly treatment-refractory patients that the Branch seeks to better understand the differential pathophysiological mechanisms in recurrent unipolar and bipolar affective disorders and develop new therapeutic modalities. A recently completed study is a double-blind, randomized trail of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin, GPN), versus one that decreases excitatory glutamatergic function (lamotrigine, LTG), versus placebo, with patients crossing over to the other drug treatments in order to ascertain differential clinical response. This study, involving 45 patients, found significant benefit of LTG (53% response rate) over GPN (27%) and placebo (22%) (Frye et al, 2000). Correlates of lamotrigine response included male gender, bipolarity, fewer prior clinical trails, and hospitalizations for depression (Obrocea et al, 2002). Preliminary evidence suggests that a baseline pattern of hypo-perfusion on 0-15 PET was associated with clinical response. In relationship to the assessment of possible predictors of clinical response, preliminary evidence indicates that depressed patients with global hypermetabolism on PET, especially in the left insula, are more likely to be responsive to carbamazepine (N=26), while those with the more classic pattern of frontal and left insular hypometabolism are more likely to be responsive to the dihydropyridine L-type calcium channel blocker nimodipine (Ketter et al, 1999). We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and those with lower CSF somatostatin at baseline are more likely to respond clinically. The major treatment initiative in the Branch is now the use of repeated transcranial magnetic stimulation (rTMS) of the brain for the treatment of depression. Two of the first six patients responded in a pilot study of 20 Hz stimulation at 80% of motor threshold of left frontal cortex (George et al, 1995). A double-blind, randomized, crossover trial indicated significant antidepressant effects of active rTMS for two weeks compared with the sham (George et al, 1998). The next study assessed the differential responsivity to low-frequency (1 Hz) versus higher frequency (20 Hz) rTMS vs. sham stimulation over left frontal cortex at 80% of motor threshold. These data in 15 subjects suggest differential clinical and metabolic responses within the same patient to these different frequencies. Moreover, those with a pattern of baseline hypometabolism tend to respond to the 20 Hz stimulation, while those with baseline patterns of hypermetabolism are more likely to respond to the 1 Hz stimulation (Kimbrell et al, 1998). As the incidence and magnitude of clinical responsivity was not adequate for many patients, a fourth study using higher intensities (100% of motor threshold) was completed. This study replicated the findings of differential responsivity within individual patients and revealed that 20 Hz stimulation increased 0-15 blood flow while 1 Hz rTMS decreased it (Speer et al, 2000). A further controlled study in normal volunteers has confirmed that 1 Hz rTMS over frontal contex induces relative decrements in bilateral frontal and striatal metabolism on PET. The current rTMS study involves higher intensities of rTMS stimulation (110% MT) for a longer time (3 weeks) and continues to reveal moderate responsiveness compared to sham. Thus, a number of promising and mechanistically novel treatment approaches have been prioneered in the Branch and continued effort will be aimed at defining optimal parameters for rTMS response and the elucidation of clinical and neurobiological markers of differential clinical responsivity.

我们的躁郁症门诊患者中只有四分之一在双盲，随机的，一年的锂或卡马西平单一疗法中表现出足够的临床预防反应。即使结合锂和卡马西平的结合，这些门诊就只有50％做出反应。随着丙戊酸盐的额外使用，最初的患者中有37％仍然没有反应。该分支机构是从这大量高度治疗的难治性患者中，他们试图更好地了解复发性单极和双极情感障碍中的鉴别病理生理机制并发展出新的治疗方式。最近完成的研究是用一种用六周治疗的双盲，随机轨迹进行的，可增强抑制性Gabaergic功能（Gabapentin，GPN），而不是降低兴奋性谷氨酸能功能（Lamotrigine，LTG）的抑制性Gabaergic功能，对添加剂的兴奋性谷氨酸能功能（Lamotrigine，ltg，LTG），患者越过患者在其他药物治疗方面进行了不同的临床疾病，以确定确定的临床。这项涉及45例患者的研究发现，LTG（53％的应答率）比GPN（27％）和安慰剂（22％）（Frye等，2000）有显着好处。拉莫三嗪反应的相关性包括男性性别，双相情感，较少的临床跟踪和抑郁症住院治疗（Obrocea等，2002）。初步证据表明，0-15 PET的低渗透基线模式与临床反应有关。与评估临床反应预测因素的关系，初步证据表明，患有全球性超级代谢的抑郁症患者，尤其是在左岛岛上，更有可能对卡马西平（n = 26）有反应，而那些具有更经典的额叶和左二体性代谢的模式更可能对dihydihydropipers can can（dihydihydihydihydihydihy conimenter）响应（等，1999）。我们发现，尼莫地平增加了脑脊液（CSF）的生长抑素，而基线时CSF生长抑素较低的人则更有可能在临床上做出反应。该分支机构的主要治疗计划是使用大脑的重复经颅磁刺激（RTMS）用于治疗抑郁症。前六名患者中的两名在一项针对20 Hz刺激的试点研究中，在80％的左额叶皮层运动阈值的刺激下做出了反应（George等，1995）。一项双盲，随机，跨界试验表明，与假手术相比，活性RTM的显着抗抑郁作用（George等，1998）。下一项研究评估了对低频（1 Hz）的差异反应性与较高频率（20 Hz）的RTMS相比，在左侧额叶皮质上，在运动阈值的80％处对假手术刺激。 15个受试者中的这些数据表明，同一患者对这些不同频率的差异临床和代谢反应。此外，具有基线低代谢模式的人倾向于对20 Hz刺激做出反应，而那些具有超级代谢基线模式的人更有可能对1 Hz刺激做出反应（Kimbrell等，1998）。由于许多患者的临床反应性的发病率和幅度不足，因此完成了第四项使用较高强度（100％运动阈值）的研究。这项研究复制了个别患者中差异反应性的发现，并表明20 Hz刺激增加了0-15的血流，而1 Hz RTMS降低了它（Speer等，2000）。一项在正常志愿者中进行的进一步对照研究证实，额叶CONTEX上的1 Hz RTM会导致PET对双侧额叶和纹状体代谢的相对减少。当前的RTMS研究涉及更高的RTMS刺激强度（110％MT）长时间（3周），并且与假手术相比，RTMS刺激的强度较高（3周），并且继续揭示了适度的响应能力。因此，在分支机构中占有许多有希望的和机械新颖的治疗方法，持续的努力将旨在定义RTMS反应的最佳参数，并阐明具有差异临床反应性的临床和神经生物学标志物。