双相抑郁的治疗进展
Progress in Treatment of Bipolar Depression
DOI: 10.12677/acm.2024.1461790, PDF, HTML, XML, 下载: 35  浏览: 78 
作者: 贾 琳:济宁医学院精神卫生学院,山东 济宁;孟祥军*:青岛市精神卫生中心精神科,山东 青岛
关键词: 双相情感障碍抑郁躁狂治疗进展Bipolar Disorder Depression Mania Treatment Progress
摘要: 双相抑郁是一种复发性疾病,对患者及社会造成严重的负担。目前美国食品药品监督管理局共批准了五种治疗双相抑郁的方案。其中四种是应用第二代抗精神病药物,一种是应用第二代抗精神病药物联合抗抑郁药物。本文回顾了上述五种方案及临床常被使用的药物及非药物治疗方案选择,期望对进一步治疗双相抑郁提供参考。
Abstract: Bipolar depression is a recurrent disease that causes serious burden to patients and society. Currently, the US Food and Drug Administration has approved five treatment plans for bipolar depression. Four of them are using second-generation antipsychotic drugs, and one is using second-generation antipsychotic drugs in combination with antidepressants. This article reviews the above five regimens and the commonly used drug and non drug treatment options in clinical practice, with the hope of providing reference for further treatment of bipolar depression.
文章引用:贾琳, 孟祥军. 双相抑郁的治疗进展[J]. 临床医学进展, 2024, 14(6): 414-419. https://doi.org/10.12677/acm.2024.1461790

1. 引言

据统计,在双相I型和双相II型障碍中抑郁的天数是躁狂或轻躁狂的三倍[1],在双相情感障碍中,抑郁症状比躁狂/混合症状更普遍,因此造成更多的疾病负担。具体来说,与情绪高涨症状相比,双相抑郁会因工作效率下降和残疾率上升而导致更大的间接成本,且对患者整体功能的损害更大,并且与自杀未遂和自杀未遂的风险增加有关[1]。就工作效率损失和一般医疗问题而言,与情绪高涨症状相比,双相抑郁患者的照顾者也因抑郁而承受更大的负担。本文就对双相抑郁的治疗进展进行综述。

2. 非典型抗精神病药物

2.1. 奥氮平加氟西汀

奥氮平加氟西汀组合(OFC)是美国食品和药物管理局批准的第一种专门用于治疗双相情感障碍抑郁期的药物。OFC的主要优点是它将抗精神病药和抗抑郁药合并在一片中,可以增加患者的依从性[2]。在一项4项随机对照试验(RCT)的荟萃分析中显示,与安慰剂(优势比(OR):0.38,95%可信区间(CI):0.2至0.59)、奥氮平(OR:0.56,95%CI:0.36至0.86)和拉莫三嗪(OR:0.70,95%CI:0.49至0.99)相比,OFC治疗显著降低了抑郁症状的严重程度,与单独使用奥氮平治疗的患者相比,接受OFC治疗的患者复发率降低。但与拉莫三嗪相比效果并不显著。OFC在抑郁水平或自杀想法的平均变化方面没有显著差异。[2] OFC治疗的不良反应与奥氮平相似,但也更易出现恶心和腹泻的不良反应[3]

2.2. 喹硫平

在一项针对11项随机对照试验(包括3488名治疗1至12周的参与者)的荟萃分析报告中指出,相较于安慰剂,MADRS (Montgomery-Asberg抑郁评定量表)和CDRS-R (儿童抑郁评定量表)抑郁评分量表的变化有显著差异,喹硫平更有利(MD−4.66,95%CI−5.59至−3.73)。喹硫平300 mg/天和600 mg/天组的平均差异优于安慰剂组(MD为−4.72,95%CI为−6.02至−3.42,MD为−4.92,95%CI为−6.32至−3.51) [4],喹硫平对焦虑、睡眠质量和整体功能也有积极作用,同时常见的不良反应包括镇静、锥体外系症状(EPS)、嗜睡、头晕、疲劳、便秘、口干、食欲增加和体重增加[4]。因为喹硫平对组胺H1-和血清素2A型受体存在拮抗作用,其存在较强的镇静作用,被广泛应用于伴发失眠的治疗[5]

2.3. 鲁拉西酮

2013年7月,鲁拉西酮被批准用于双相抑郁症,既可以作为单一疗法,也可以作为锂或丙戊酸盐的辅助疗法[6]。鲁拉西酮是多巴胺(DA) D2和5-羟色胺2A (5-HT2A)受体的完全拮抗剂[7],同时也对5-HT1A受体有部分激动作用。Loebel等人的研究将患者随机分为三组,一组每天服用20~60 mg鲁拉西酮,另一组每天服用80~120 mg鲁拉西酮,最后一组服用安慰剂,双盲治疗6周[8]。主要评价标准是MADRS和用于双相情感障碍抑郁严重程度评分的CGI-BP量表的变化,在研究开始时和第6周再次测量。结果显示,与安慰剂组相比,鲁拉西酮治疗显著提高了20~60 mg/天组和80~120 mg/天组的MADRS评分。CGI-BP测量的抑郁严重程度评分的也显著降低。鲁拉西酮最常见的副作用是恶心、头痛、静坐障碍和嗜睡[9]

2.4. 卡利拉嗪

卡利拉嗪是一种新的治疗药物,作为部分D2,D3受体激动剂,优先作用于D3受体[10],一项纳入7项研究的荟萃分析显示,在急性抑郁的治疗上,经蒙哥马利亚斯伯格抑郁评定量表(MADRS)评估,卡利拉嗪在每日服用1.5 mg (SMD:−0.26,95%CI:−0.49至−0.02)和3 mg剂量(SMD:−0.21,95%CI:−0.41至−0.01)均可明显改善抑郁症状,但在0.75 mg时无效[11]。常见的不良事件包括恶心、腹泻、失眠和静坐症[10]

2.5. 氯美酮

氯美酮于2021年被批准作为单一疗法或辅助疗法与锂或丙戊酸治疗双相抑郁,包括双相I型抑郁及双相II型抑郁[12],在一项为期6周的随机双盲对照研究中,以42毫克/天的剂量接受氯美酮单药治疗与双相I型或双相II型患者重度抑郁发作症状的改善显著相关。在第1周(在第一次给药后评估时),使用氯美酮治疗与MADRS评分的快速和显著改善相关,并在整个6周的研究中持续改善[13]。在一项对377名患者的研究中,与安慰剂相比,氯美酮在第43天的MADRS应答率(51.1%比36.7%;OR = 2.98,p < 0.001)和缓解率(p = 0.02)显著高于安慰剂。氯美酮与既往药物的不同之处在于它可以同时调节5-羟色胺、多巴胺和谷氨酸[14]。其最常见副作用为镇静、恶心及头晕[12]

3. 心境稳定剂

3.1. 锂盐

锂作为情绪稳定剂被用于治疗双相情感障碍已经有半个多世纪的时间,大量研究报告,锂在躁狂的急性治疗和情绪的长期维持和预防方面是有效的[15],相比之下,它对抑郁症有效的证据并不多。首先,锂的抗抑郁作用具有相当大的时滞,通常为6~8周,因此锂可能被患者认为无效,从而导致临床试验的高放弃率,从而可能无法得到正确的结果[16]。其次,抑郁症的心理和社会原因复杂[17],因此研究样本不可避免地具有较强的异质性。除此之外,锂具有的独特的抗自杀特性,使其与其他药剂区别开来,尽管其抗自杀特性是作为长期益处而非快速或短期益处显现[18]

3.2. 拉莫三嗪

拉莫三嗪为苯基三嗪类抗癫痫药物,同时也可作为心境稳定剂用于双相情感障碍的治疗中[19],拉莫三嗪被FDA批准用于双相抑郁的维持期治疗,来自John R. Geddes等人的一项荟萃分析显示:拉莫三嗪的在急性双相抑郁的治疗中作用甚微[20],但在一项为期8周的安慰剂对照试验中,200 mg/天的拉莫三嗪辅助治疗的有效率高于安慰剂(51.6% vs. 31.7%)。表明拉莫三嗪对急性双相抑郁症可能有效[21]。临床应用拉莫三嗪最易发生的不良反应为皮疹,对一项拉莫三嗪单药治疗BD、癫痫或其他疾病的随机对照试验显示,在18,968例患者中,8.3%的患者出现了不良皮肤反应。SJS/TEN发生率为0.04%,皮疹的发生率,包括SJS/TEN,在疾病之间没有显着差异,表明没有遗传易感性[22]

4. 抗抑郁药物

尽管抗抑郁药物普遍用于双相抑郁,但通常缺乏多中心、随机对照试验来证明其疗效。在一项长达26周双盲的,应用安慰剂的对照研究中,179名接受情绪稳定剂加辅助抗抑郁治疗的受试者中有42名(23.5%)获得了持续缓解,187名接受情绪稳定剂加匹配安慰剂的受试者中有51名(27.3%)获得了持续缓解(p = 0.40)。个体实现可持续恢复或其他结果指标的可能性没有组间差异[23]。抗抑郁药物通常被视为二线治疗药物最主要的原因就是其可能导致的转躁风险,一项包括1088名患者数据的荟萃分析发现,三环类抗抑郁药的转换率为10%,而所有其他抗抑郁药的转换率为3.2%。4.7%的安慰剂治疗患者发生了转换,抗抑郁药和安慰剂之间的转换率总体上没有显著差异[24]。通常认为三环类药物的转换率最高,而选择性5-羟色胺再摄取抑制剂(SSRIs)和安非他酮的风险最低。血清素/去甲肾上腺素再摄取抑制剂(SNRIs)比SSRIs和安非他酮具有更高的风险[25]选择性5-羟色胺再摄取抑制剂(SSRIs)的常见副作用包括失眠、口干、恶心、腹泻、头痛、体重增加和性副作用[26]。安非他酮的副作用包括头痛、口干、恶心、失眠和极少数癫痫发作,但性功能障碍、体重增加和嗜睡的发生率较低[27]

5. 物理疗法

5.1. 电休克治疗

电休克疗法(ECT)临床上可快速起效,因此可用于紧急临床情况,例如出现自杀行为、严重精神病或紧张症。平均而言,BD-D患者在接受七次ECT治疗后受益明显。目前的研究表明,电休克疗法治疗双相抑郁症有很高的反应率。最强的预后因素是年龄较高、无共病强迫症或人格障碍以及既往药物治疗较少。来自K. Popiolek等人的一项队列研究显示80.2% (95%可信区间(CI)为77.8%~82.2%)的患者对ECT有反应[28]。副作用方面,记忆障碍最为常见,但记忆障碍通常在几周内可以恢复。

5.2. 经颅磁刺激

经颅磁刺激(TMS)被认为在BD-D中是安全和潜在有效的,目前关于经颅磁刺激治疗BD-D的研究仍然较为缺乏,在一项对14项研究(n = 274)的回顾中,重复TMS (rTMS)的缓解率(定义为与基线相比症状减轻50%)显著高于假治疗(OR = 2.72,95%CI:1.44至5.14) [29],TMS的不良反应较为罕见,包括听觉影响,少数患者在接受TMS后出现听阈暂时增加,另外可出现轻微头痛,但对身体无明显不良反应。

6. 小结

目前双相抑郁的治疗以应用药物治疗为主,包括抗精神病药物及心境稳定剂,通常可以达到理想治疗效果,并逐渐有新的药物被研发,但各种不良反应较多,抗抑郁药物临床应用有所争议,通常被视为二线治疗药物,电休克治疗、经颅磁刺激治疗等可作为辅助治疗改善患者预后,本文就目前已有治疗方案进行讨论,以期对临床治疗提供帮助。

NOTES

*通讯作者。

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