New Treatments For Refractory Affective Illness

在双相情感障碍中，治疗抵抗的发生率非常高。学术中心约三分之二的患者尽管进行了积极的药物治疗，但仍有高度症状。抑郁的天数是狂躁天数的三倍。这一大型难治性患者库一直是分支研究的重点，旨在更好地了解复发性单极和双相情感障碍的病理生理机制，并开发新的治疗方式。 随着目前一系列治疗方案的可用性，找到患者对给定治疗反应最好的临床和生物学标记物是该领域的关键需求。例如，一项双盲、随机试验，用一种增强抑制性GABA能功能的药物（加巴喷丁，GPN）与一种降低兴奋性GABA能功能的药物（拉莫三嗪，LTG）与安慰剂治疗6周，发现LTG（20/39或51%应答率）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、双极性、既往临床试验较少和既往因抑郁症住院较少（Obrocea et al）。初步证据表明，0-15 PET扫描的低灌注基线模式与临床反应相关。 与临床反应的可能预测因素评估相关，PET显示全身代谢亢进的抑郁患者，尤其是左额叶代谢亢进的患者，更可能对卡马西平有反应（N=26），而具有更典型的额叶和左额叶代谢减退模式的患者更可能对二氢吡啶L型钙通道阻滞剂尼莫地平有反应（Ketter et al）。我们发现尼莫地平增加了脑脊液（CSF）中的生长抑素，基线时CSF生长抑素水平较低的患者更可能对尼莫地平有临床反应（Frye et al）。分支现在正在分析一系列研究，这些研究是关于使用重复经颅磁刺激（rTMS）治疗抑郁症的，我们已经帮助开创了这一领域。一些患者在左额叶皮层运动阈值的80%的第一次高频（20 Hz）刺激的初步研究中有反应。然后，一项双盲、随机、交叉试验表明，与假手术组相比，持续两周的20 Hz活性rTMS具有显著的抗抑郁作用（乔治et al）。下一项研究评估了在运动阈值（MT）的80%时，左额叶皮层对低频（1 Hz）与高频（20 Hz）rTMS与假刺激的差异反应性。这项研究发现，同一患者对这些不同频率的临床和代谢反应不同。此外，具有基线低代谢模式的患者倾向于对20 Hz刺激做出反应，而具有基线高代谢模式的患者更可能对1 Hz刺激做出反应（Kimbrell等人）。 由于临床反应的发生率和幅度对许多患者来说不够，因此进行了第四项使用更高强度（100% MT）的rTMS研究。该研究重复了个体患者内不同反应性的发现，并且惊人地揭示了20 Hz刺激以持久的方式增加0-15血流量，而1 Hz rTMS降低了血流量（Speer等人）。在正常志愿者中进行的进一步对照研究证实，额叶皮层上的1 Hz rTMS在PET上诱导双侧额叶和纹状体代谢的相对减少。在正常志愿者中进行的另外两项研究显示，与前额叶皮层相比，在运动上传递的1Hz rTMS在PET上的激活模式不同（Speer等人）。这些对患者和志愿者的研究共同验证了高频率与低频率rTMS和刺激的大脑区域的不同生理效应。 最近的rTMS研究使用更高强度的rTMS刺激（110% MT），持续更长时间（3周），试图提高应答率。本研究将患者随机分为20 Hz、1 Hz和假刺激组，目前正在分析结果和反应的局部脑活动相关性。因此，一些有前途的和机制上的新的治疗方法已优先在分支和目前的努力是为了定义更好的最佳参数rTMS反应和定义临床和神经生物学标记的个人反应。

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.