New Treatments For Refractory Affective Illness

在锂或卡马西平单药治疗的双盲、随机、1年试验中，只有四分之一的双相门诊患者显示出充分的临床预防反应。即使锂和卡马西平联合使用，也只有50%的门诊患者有反应。在额外使用丙戊酸盐的情况下，40%的患者仍然无反应。正是从这些难治性患者中，分支寻求更好地了解复发性单极和双相情感障碍的不同病理生理机制，并开发新的治疗方式。分支的主要新治疗举措是使用重复经颅磁刺激（rTMS）的大脑。前6名患者中有2名在左额叶皮层运动阈值80%的20 Hz刺激的初步研究中有反应（乔治等人，1995，NeuroReport）。一项双盲、随机、交叉试验表明，与假手术相比，活性rTMS持续两周具有显著的抗抑郁作用（乔治et al，1998，Am J Psychiatry）。下一项研究（现已完成）评估了在运动阈值的80%下，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。15名受试者的这些数据表明同一患者对这些不同频率的反应不同。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 et al，1998）。由于许多患者的临床应答率和幅度不足，因此启动了使用更高强度（100%运动阈值）的第四项研究（入组18例患者）（Speer et al，1998）。本研究重复了个体患者的差异反应性的发现，并揭示了20 Hz刺激增加0-15血流量，而1 Hz rTMS减少它。在正常志愿者中的进一步对照研究证实，1 Hz rTMS在额叶皮层上诱导PET上双侧额叶和纹状体代谢的相对减少。一项主要的住院患者药理学研究涉及一项双盲、随机试验，治疗6周，使用一种增强抑制性GABA能功能的药物（加巴喷丁[GPN]），与任何降低兴奋性GABA能功能的药物（拉莫三嗪[LTG]）相比，与安慰剂相比，患者交叉使用其他药物治疗，以确定不同的临床反应。这项研究涉及37例患者，已被普通精神病学文献积极评价，发现LTG（53%的应答率）优于GPN（27%）和安慰剂（22%）（Frye et al，1998）。初步证据表明，0-15 PET的基线灌注模式与对这两种药物的临床反应相互作用。应答者在基线时较低，并随着治疗而增加，而无应答者在正常范围内，并显示降低。一项双盲、随机试验，比较T3、TRH和安慰剂对文拉法辛的强化作用，正在研究TRH是否可以加速抗抑郁药起效的速度。在与预测因子的关系中，初步证据表明，PET显示具有整体高代谢的抑郁症患者，尤其是左丘脑，更可能对卡马西平有反应（N = 26），而那些具有更经典的额叶和左岛叶低代谢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。我们已经发现尼莫地平增加脑脊液（CSF）中的生长抑素，并且那些基线CSF生长抑素较低的人倾向于更可能对尼莫地平诱导的这些增加做出临床反应。因此，一些有前途的和机械新颖的治疗方法已率先在分支和额外的努力将旨在确定最佳参数的rTMS反应和阐明的临床和神经生物学标志物的这种反应。随着第一个由NIMH-Stanley基金会支持的双相情感障碍治疗结果网络的建立，在美国和欧洲建立了多个站点，这一工作以及为难治性双相情感障碍患者开发新治疗方法的相关工作也在更广泛的基础上进行。该临床试验网络讨论了NIMH 1989年和1994年关于双相情感障碍会议的大多数建议。

Only one-quarter of our bipolar outpatients show an adequate clinical prophylactic response in double-blind, randomized, one- year trials of lithium or carbamazepine monotherapy. Even with the combination of lithium and carbamazepine, only 50% of these outpatients respond. With the additional use of valproate, 40% of patients still remain unresponsive. It is from this pool of 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. The major new treatment initiative in the Branch is the use of repeated transcranial magnetic stimulation (rTMS) of the brain. 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, NeuroReport). A double-blind, randomized, crossover trial indicated significant antidepressant effects of active rTMS for two weeks compared with the sham (George et al, 1998, Am J Psychiatry). The next study, now completed, 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 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) has been initiated (18 patients enrolled) (Speer et al, 1998). This study replicated the findings of differential responsivity within individual patients and revealed that 20 Hz stimulation increases 0-15 blood flow while 1 Hz rTMS decreases it. 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. A major inpatient pharmacological study involves a double-blind, randomized trial of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin [GPN]), versus any 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 37 patients, has been favorably reviewed by the Archives of General Psychiatry and found significant benefit of LTG (53% response rate) over GPN (27%) and placebo (22%) (Frye et al, 1998). Preliminary evidence suggests that baseline patterns of perfusion on 0-15 PET interacted with clinical response to both of these agents. Responders were low at baseline and increased with treatment, while nonresponders were in the normal range and showed decreases. A double-blind, randomized trial of T3 versus TRH versus placebo augmentation of venlafaxine is examining whether TRH can accelerate the rapidity of antidepressant onset. In relationship to predictors, 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. We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and that those with lower CSF somatostatin at baseline tend to be more likely to respond clinically to these nimodipine-induced increases. Thus, a number of promising and mechanistically novel treatment approaches have been pioneered in the Branch and additional effort will be aimed at defining optimal parameters for rTMS response and the elucidation of clinical and neurobiological markers of such response. This and related work on the development of new treatment approaches for refractory bipolar patients is also being pursued on a wider basis with the establishment of the first NIMH-Stanley Foundation-supported Bipolar Treatment Outcome Network with multiple sites in the U.S. and one in Europe. This clinical trials Network addresses most of the recommendations of the NIMH 1989 and 1994 meetings on bipolar illness.