Pinheiro D
Service de psychiatrie adulte, centre hospitalier Sainte-Marie, route de Montredon, B.P. 21, 43001 Le-Puy-en-Velay cedex, France.
Encephale. 2008 Sep;34(4):409-15. doi: 10.1016/j.encep.2007.10.006. Epub 2008 Jan 14.
Dementia, besides the dominant cognitive disorders that define it, is associated with behavioral disturbances, the consequences of which are, on various levels, a determining factor for the handling of these patients. The treatment of behavioral and psychological symptoms is essential and although, to date, no therapeutic solution is satisfactory, it is necessary to look for an alternative to the neuroleptics usually employed, which raise real problems of tolerance in this geriatric population.
For several years, anticonvulsants, among which some have shown mood stabilizing activity, have been the object of research in this indication. The purpose of this review of the literature is to assess the interest and the limits of anticonvulsant mood stabilizers (carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate, oxcarbazepine) in the treatment of the so-called "noncognitive" symptoms of dementia. Their mechanism of action in mood disorders is not well known, but it would appear to be via the modulation of glutamate-mediated excitatory synaptic transmission and gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission that anticonvulsants might reduce behavioral symptoms in demented patients.
The method employed in this work was a systematic bibliographic review, in which only the double-blind placebo-controlled studies or the clinically detailed enough open-labelled studies using validated scales were retained.
Among these medications, only carbamazepine demonstrated its efficacy in behavioral and psychological symptoms of dementia (BPSD) in controlled studies, notably that of Tariot et al. [J Am Geriatr Soc 42 (1994) 1160-1166 and Am J Psychiatry 155 (1998) 54-61] and Olin et al. [Am J Geriatr Psychiatry 9 (2001) 400-405], but with significant adverse events (sedation, hyponatremia, cardiac toxicity), particularly in the elderly and, being a strong enzymatic inducer, with a high likelihood of drug-drug interactions. Valproic acid showed some interesting results in BPSD within a large number of open studies and case reports. However, among the five controlled studies that have been published [Curr Ther Res 62 (2001) 51-67; Am J Geriatr Psychiatry 9 (2001) 58-66; Int J Geriatr Psychiatry 17 (2002) 579-585; Curr Alzheimer Res 2 (2005) 553-558 and Am J Geraitr Psychiatry 13 (2005) 942-945], none confirmed its efficacy on these symptoms. Regarding its tolerability in the geriatric population, no notable major side effect was reported (haematologic and hepatic effects are not more frequent than in the general population), except possible excessive sedation. Moreover, it appears that valproic acid could have neuroprotective effects, even if the contrary has been observed in a recent study. More studies need to be (and are being) conducted, notably on the interest of valproic acid in prophylaxis of BPSD. Gabapentin seems to be worthwhile and well tolerated in this indication, but no controlled study has been conducted to prove its efficacy, even if a quite important number of case reports and open studies have shown encouraging results. Concerning lamotrigine, which may potentially induce severe cutaneous side effects when administered with valproic acid, this drug has shown its efficacy in bipolar disorders and two recent case reports seem to indicate some interest in BPSD. Furthermore, lamotrigine appears to have neuroprotective effects. Although topiramate has shown interesting results in one open study in BPSD, its use in demented patients cannot be recommended because of its deleterious effect on cognitive functions. Oxcarbazepine, theoretically, could be an alternative to carbamazepine, which is, as aforesaid, the only anticonvulsant that proved its interest in BPSD. However, no clinical study has yet been published to support this hypothesis. This drug is better tolerated than carbamazepine, but induces severe and more frequent hyponatremia.
Finally, although we all know that antipsychotics should no longer be prescribed in the elderly, the treatment of behavioral and psychological symptoms of dementia remains a difficult problem, considering the lack of a real alternative to these medications. Anticonvulsant mood stabilizers are an interesting solution but none of them, other than carbamazepine, which did, but which is not better tolerated than the usual drugs in this population - was able to prove its efficacy in this indication. Among these medications, valproic acid, gabapentin and lamotrigine should be studied further, and the neuroprotective effect of some of them is an interesting route for research.
痴呆症除了具有定义它的主要认知障碍外，还伴有行为障碍，其后果在各个层面上都是处理这些患者的决定性因素。行为和心理症状的治疗至关重要，尽管迄今为止，尚无令人满意的治疗方案，但有必要寻找一种替代通常使用的抗精神病药物的方法，因为这些药物在老年人群中会引发实际的耐受性问题。
几年来，抗惊厥药物，其中一些已显示出情绪稳定活性，一直是该适应症研究的对象。这篇文献综述的目的是评估抗惊厥情绪稳定剂（卡马西平、丙戊酸、加巴喷丁、拉莫三嗪、托吡酯、奥卡西平）在治疗痴呆症所谓的“非认知”症状方面的价值和局限性。它们在情绪障碍中的作用机制尚不清楚，但抗惊厥药物似乎可能通过调节谷氨酸介导的兴奋性突触传递和γ-氨基丁酸（GABA）介导的抑制性突触传递来减轻痴呆患者的行为症状。
本研究采用的方法是系统的文献综述，仅纳入双盲安慰剂对照研究或使用经过验证的量表且临床细节足够的开放标签研究。
在这些药物中，只有卡马西平在对照研究中证明了其对痴呆症行为和心理症状（BPSD）的疗效，特别是塔里奥特等人的研究[《美国老年医学会杂志》42（1994）1160 - 1166和《美国精神病学杂志》155（1998）54 - 61]以及奥林等人的研究[《美国老年精神病学杂志》9（2001）400 - 405]，但存在显著的不良事件（镇静、低钠血症、心脏毒性），尤其是在老年人中，并且作为一种强效酶诱导剂，药物相互作用的可能性很高。丙戊酸在大量开放研究和病例报告中显示出一些有趣的结果。然而，在已发表的五项对照研究中[《当代治疗研究》62（2001）51 - 67；《美国老年精神病学杂志》9（2001）58 - 66；《国际老年精神病学杂志》17（2002）579 - 585；《当代阿尔茨海默病研究》2（2005）553 - 558和《美国老年精神病学杂志》13（2005）942 - 945]，没有一项证实其对这些症状的疗效。关于其在老年人群中的耐受性，除了可能的过度镇静外，未报告明显的主要副作用（血液学和肝脏影响并不比一般人群更频繁）。此外，丙戊酸似乎可能具有神经保护作用，即使最近一项研究得出了相反的结果。需要（并且正在）进行更多的研究，特别是关于丙戊酸在预防BPSD方面的价值。加巴喷丁在该适应症中似乎值得一试且耐受性良好，但尚未进行对照研究来证明其疗效，尽管相当数量的病例报告和开放研究显示出令人鼓舞的结果。关于拉莫三嗪，与丙戊酸合用时可能会引发严重的皮肤副作用，该药物在双相情感障碍中已显示出疗效，最近的两项病例报告似乎表明它对BPSD也有一定价值。此外，拉莫三嗪似乎具有神经保护作用。尽管托吡酯在一项关于BPSD的开放研究中显示出有趣的结果，但由于其对认知功能的有害影响，不建议在痴呆患者中使用。理论上，奥卡西平可以替代卡马西平，如前所述，卡马西平是唯一证明对BPSD有价值的抗惊厥药物。然而，尚未发表临床研究来支持这一假设。该药物的耐受性比卡马西平好，但会引发严重且更频繁的低钠血症。
最后，尽管我们都知道老年人不应再使用抗精神病药物，但考虑到缺乏这些药物的真正替代品，痴呆症行为和心理症状的治疗仍然是一个难题。抗惊厥情绪稳定剂是一个有趣的解决方案，但除了卡马西平（它确实有效，但在该人群中的耐受性并不比常用药物好）外，没有一种药物能够证明其在该适应症中的疗效。在这些药物中，丙戊酸、加巴喷丁和拉莫三嗪应进一步研究，并且它们中的一些药物的神经保护作用是一个有趣的研究方向。
