New Treatments For Refractory Affective Illness

在双相情感障碍中，耐药的发生率非常高。尽管进行了积极的药物治疗，但学术中心约三分之二的患者仍有高度症状。抑郁的天数比躁狂的天数多三倍。这一庞大的治疗难治性患者池一直是分部研究的重点，目的是更好地了解复发性单相和双相情感障碍的病理生理机制，并开发新的治疗方法。 随着目前一系列治疗方案的可用，寻找患者对给定治疗反应最好的临床和生物标记物是该领域的迫切需要。例如，一项双盲随机试验发现，与安慰剂相比，使用增强抑制性GABA能功能的药物(加巴喷丁，GPN)和降低兴奋性谷氨酸能功能(拉莫三嗪，LTG)的药物治疗6周，LTG(20/39或51%的有效率)明显优于GPN(11/40或28%)和安慰剂(8/28或21%)。拉莫三嗪反应的相关因素包括男性、两极、先前较少的临床试验和较少的抑郁症住院(Obrocea等人)。初步证据表明，0-15次正电子发射计算机断层扫描的低灌注基线模式与临床反应有关。 与临床反应的可能预测因素的评估有关，PET表现为整体高代谢的抑郁症患者，特别是左侧脑岛，更有可能对卡马西平有反应(N=26)，而那些额叶和左侧脑岛代谢较典型的患者更有可能对二氢吡啶L型钙通道阻滞剂尼莫地平有反应(Ketter等人)。我们发现尼莫地平可增加脑脊液(CSF)中的生长抑素水平，那些脑脊液中生长抑素水平在基线水平较低的患者更有可能对尼莫地平有临床反应(Frye等人)。该分部目前正在分析一系列研究，这些研究使用重复的经颅磁刺激(RTMS)大脑来治疗抑郁症，这是我们帮助开创的。在一项初步研究中，几名患者在左侧额叶皮质运动阈值的80%处进行了第一次高频(20赫兹)刺激。然后，一项双盲、随机、交叉试验表明，与假手术组相比，活跃的20赫兹rTMS治疗两周有显著的抗抑郁作用(George等人)。下一项研究评估了在运动阈值(MT)的80%时，左侧额叶皮质对低频(1赫兹)与高频(20赫兹)rTMS刺激与假刺激的不同反应性。这项研究发现同一患者对这些不同的频率有不同的临床和代谢反应。此外，那些具有基线低代谢模式的人倾向于对20赫兹的刺激做出反应，而那些具有基线高代谢模式的人更有可能对1赫兹的刺激做出反应(Kimbrell等人)。 由于临床反应性的发生率和大小对许多患者来说并不合适，因此进行了第四次使用较高强度(MT的100%)的rTMS研究。这项研究重复了个体患者不同响应性的发现，令人惊讶的是，20赫兹刺激以一种持久的方式增加了0-15的血流量，而1赫兹rTMS则减少了血流量(Speer等人)。一项对正常志愿者的进一步对照研究证实，额叶皮质上1赫兹的rTMS可导致PET上双侧额叶和纹状体代谢的相对减慢。另外两项在正常志愿者身上的研究表明，与前额叶皮质相比，1赫兹rTMS通过运动传递对PET的激活模式不同(Speer等人)。这些研究在患者和志愿者身上共同验证了高频rTMS和低频rTMS以及大脑刺激区域的不同生理效应。 最近的rTMS研究使用较高强度的rTMS刺激(110%MT)较长时间(3周)，试图提高应答率。这项研究将患者随机分为20赫兹、1赫兹和假刺激，结果和局部脑活动与反应的相关性目前正在分析中。因此，一些有希望的和机械上新颖的治疗方法已经在分部率先采用，目前的努力旨在为rTMS反应确定更好的最佳参数，并确定个体反应的临床和神经生物学标记物。

There is a very high incidence of treatment resistance in bipolar illness. Some two thirds of patients in academic centers remain highly symptomatic despite aggressive pharmacotherapy. Days depressed exceed days manic by a factor of three. This large pool of treatment-refractory patients has been the focus of study of the Branch both to better understand the pathophysiological mechanisms in recurrent unipolar and bipolar disorders and develop new therapeutic modalities. With the current availability of a series of treatment options, finding clinical and biological markers of which patients respond best to a given treatment, is a critical need for the field. For example, a double-blind, randomized trial 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, found significant benefit of LTG (20/39 or 51% response rate) over GPN (11/40 or 28%) and placebo (8/28 or 21%). Correlates of lamotrigine response included male gender, bipolarity, fewer prior clinical trials, and fewer prior hospitalizations for depression (Obrocea et al). Preliminary evidence suggests that a baseline pattern of hypo-perfusion on 0-15 PET scans was associated with clinical response. In relationship to the assessment of possible predictors of clinical response, 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 insula hypometabolism are more likely to be responsive to the dihydropyridine L-type calcium channel blocker nimodipine (Ketter et al). We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and those with lower CSF somatostatin levels at baseline are more likely to respond clinically to nimodipine (Frye et al). The Branch is now analyzing a series of studies of the use of repeated transcranial magnetic stimulation (rTMS) of the brain for the treatment of depression that we have helped pioneer. Several patients responded in a pilot study of the first high frequency (20Hz) stimulation at 80% of motor threshold of left frontal cortex. A double-blind, randomized, crossover trial then indicated significant antidepressant effects of active 20 Hz rTMS for two weeks compared with the sham (George et al). The next study assessed the differential responsivity to low-frequency (1 Hz) vs. higher frequency (20 Hz) rTMS vs. sham stimulation over left frontal cortex at 80% of motor threshold (MT). This study found 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). Because the incidence and magnitude of clinical responsivity was not adequate for many patients, a fourth rTMS study using higher intensities (100% of MT) was conducted. This study replicated the findings of differential responsivity within individual patients, and strikingly, revealed that 20Hz stimulation increased 0-15 blood flow in a long lasting fashion, while 1 Hz rTMS decreased it (Speer et al). A further controlled study in normal volunteers has confirmed that 1 Hz rTMS over frontal cortex induces relative decrements in bilateral frontal and striatal metabolism on PET. Two other studies in normal volunteers showed the different patterns of activation on PET of 1Hz rTMS delivered over motor compared with prefrontal cortex (Speer et al). Together these studies in patients and volunteers validate the different physiological effects of high vs. low frequency rTMS and area of brain stimulated. The most recent rTMS study used higher intensities of rTMS stimulation (110% MT) for a longer time (3 weeks) in an attempt to increase the response rate. This study randomized patients to 20 Hz vs. 1Hz vs. sham stimulation, and results and regional brain activity correlates of response are currently being analyed. Thus, a number of promising and mechanistically novel treatment approaches have been prioneered in the Branch and the current effort is aimed at defining better optimal parameters for rTMS response and defining clinical and neurobiological markers of individual responsiveness.