NIMODIPINE IN LITHIUM-REFRACTORY BIPOLAR PATIENTS

钙通道阻滞剂尼莫地平在情感性精神障碍中的应用 减债战略基于若干经验和理论依据。l型 据报道，钙通道阻滞剂维拉帕米在 治疗急性躁狂症，但不是抑郁症;尼莫地平有不同的 与维拉帕米相比的效果。尼莫地平是：更脂质 可溶性;阻断可卡因诱导的活动过度、致敏和多巴， 地雷溢出;阻断腺苷转运蛋白和A1受体， 具有较好的抗惊厥作用。尼莫地平治疗房颤的阳性反应 在10/30（33.3%）的可评价患者中观察到感染性疾病 难治性抑郁症患者，包括快速和 超昼夜循环障碍在四个案例中， 关-开-关-开（B-A-B-A）设计。在联合治疗中， 反应是实现了盲加卡马西平（CBZ）， 2/14例患者。由于我们小组最近发现CBZ抑制 通过NMDA受体的钙内流，这些数据提高了 对钙（或其他）有不同作用的药物 机制）可以在难治性患者中组合使用。几 尼莫地平的反应者在盲交叉中未能保持良好， 苯烷基胺维拉帕米，但确实显示出持续的反应， 伊拉地平，表明二羟基吡啶L-型钙通道 阻滞剂可能比其他类别的药物更有效， 在L型通道上具有不同结合位点的阻断剂。一 复发性短暂抑郁症（RBD）的小系列患者重新 对尼莫地平的盲人机构反应良好。尼莫地平高度 在21例患者中，CSF生长抑素显著增加，而在21例患者中， 减少TRH;即，与CBZ的效果相反。患者 额叶代谢减退更可能对尼莫地平有反应， 多动症患者对卡马西平有反应。治疗患者 尼莫地平显示其外周型显著增加 苯二氮卓受体，而那些与外周型治疗 benzodiazeine antagonist没有。这些数据表明， 尼莫地平治疗难治性心绞痛的临床研究 情感障碍和检查钙代谢改变的作用 生长抑素的增加与尼莫地平反应有关。的 增加的细胞内钙在血液元素的积累， 在文献中已经报道了情感疾病患者，现在 我们的团队 在基础水平和5-HT诱导水平， 细胞内钙，与锂结合， 正常化 我们还发现了初步证据， 可能发生在PKC调节水平。 我们希望进一步 探索这一发现的机械含义，看看它是否 将有助于预测哪些患者对钙活性 治疗策略，如尼莫地平。

Utilization of the calcium channel blocker nimodipine in affective disor- ders is based on several empirical and theoretical rationales. The L-type calcium channel blocker verapamil has been reported effective in the treatment of acute mania but not depression; nimodipine has a different profile of effects compared with verapamil. Nimodipine is: more lipid soluble; blocks cocaine-induced hyperactivity, sensitization, and dopa- mine overflow; blocks adenosine transporters and A1 receptors, and also has better anticonvulsant effects. Positive response to nimodipine in af- fective illness has been observed in 10/30 (33.3%) of the evaluable patients with refractory depression, including those with rapid and ultradian cycling disorder. In four instances this was confirmed in an off-on-off-on (B-A-B-A) design. In combination therapy a more complete response was achieved with the blind addition of carbamazepine (CBZ) in 2/14 patients. Since CBZ has recently been found by our group to inhibit calcium influx through the NMDA receptor, these data raise the possibility that drugs with differential effects on calcium (or other mechanisms) may be useful in combination in refractory patients. Several responders to nimodipine failed to remain well in a blind crossover to the phenylalkylamine verapamil, but did show a sustained response to isradipine, suggesting that the dihydroxypyridine L-type calcium channel blockers may be differentially more effective than other classes of blockers that have a different binding site on the L-type channel. A small series of patients with recurrent brief depression (RBD) have re- sponded well to the blind institution of nimodipine. Nimodipine highly significantly increased CSF somatostatin in 21 patients, while it tended to decrease TRH; i.e., effects opposite those of CBZ. Patients with frontal hypometabolism are more likely to respond to nimodipine, while those with hyperactivity respond to carbamazepine. Patients treated with nimodipine show significant increases in their peripheral type benzodiazepine receptors while those treated with the peripheral type benzodiazeine antagonist do not. These data suggest the importance of further exploring the clinical profile of nimodipine in refractory affective disorders and examining the role of altered calcium metabolism and increases in somatostatin in relationship to nimodipine response. The increased accumula-tion of intracellular calcium in the blood element of affectively ill patients has been reported in the literature and now by our group. It is evident in both basal and 5-HT-induced levels of intracellular calcium, an effect which, in combination with lithium, normalizes. We have also found preliminary evidence that this alteration may be occurring at the level of PKC regulation. We wish to further explore this finding for its mechanistic implications and to see if it would help predict which patients would be responsive to calcium-active therapeutic strategies such as nimodipine.