吃抗精神病药吃久了会不会伤害头脑 │ 文献导读
大约 50% 接受抗精神病药治疗的患者会出现代谢副作用（metabolic side effects）[1-2]。在年轻就发病的患者代谢副作用可能更多[3-4]。认知障碍和代谢异常具有重要的功能和身体后果。代谢疾病所致的心血管疾病可能导致患者寿命缩短约 20 年[5]，但是与此同时，精神疾病所致的认知功能损害可能导致个体出现严重的残疾[6]，而代谢失调也是一个严重的健康挑战，在非精神疾病的个体身上也能导致认知功能受损[7]。
在大多数精神分裂症患者中观察到认知缺陷，这些特定领域包括处理速度、注意力、工作记忆、语言学习和记忆、视觉学习和记忆、推理和解决问题以及社会认知[8]。这些缺陷在发病前就存在，并且往往会在整个疾病过程中持续存在[9]。然而，这些缺陷的过程并不完全清楚，但通常与阳性症状的关系较弱，而与阴性症状的严重程度有较强的相关性[10]。
抗精神病药与认知功能
抗精神病药物对认知的影响仍然存在争议[11]。一代抗精神病药被认为对认知功能无影响，甚至有害；二代抗精神病药被认为较一代抗精神病药相比能够改善认知功能。
氯氮平在注意力（attention）和语言流畅性（verbal fluency）方面显示出积极影响，在执行功能（executive functioning）[12]和延迟回忆（delayed recall）[13]方面有适度改善。
奥氮平在警觉性(vigilance)、选择性注意（selective attention）、延迟回忆（delayed recall）以及言语学习和记忆（verbal learning and memory）、言语流利度（verbal fluency）和执行功能方面也表现出显着改善。
利培酮通常表现出更温和的效果，在工作记忆、执行功能、注意力和延迟回忆 方面表现出适度的改善。
阿立哌唑已被证明可以通过改善对刺激的正确反应来改善反应时间以及言语认知功能[14-15]。
喹硫平已被证明可以在治疗的早期阶段改善整体认知功能和言语短期记忆[16]。
CATIE
干预有效性临床抗精神病药试验 (the Clinical Antipsychotic Trials of Intervention Effectiveness, CATIE) 研究的结果包括大量慢性精神分裂症患者的样本量和被认为反映一般精神分裂症人群的样本特征，表明 APs 在化学类别中的作用非常相似，而且这相似性延伸到 AP 对认知的影响。此外，发现改善认知的效果很小，临床意义值得怀疑。一项荟萃分析也强调了抗精神病药在认知功能方面存在争议的优势，该分析表明“老”药物实际上对认知有适度的有益作用。有几个混杂因素可能与这种关系有关，包括一般症状改善、疾病阶段和持续时间、AP 剂量、治疗依从性、药物相关镇静和抗胆碱能副作用。而且缺乏随访一年以上的研究[17]。
追求症状类型的改善能改善认知功能
考虑不同的症状领域如何相互作用（即阳性、阴性、认知），以及某些症状的改善是否与其他症状的改善相关。研究在这方面的研究结果有所不同。例如，多项研究表明，尽管使用抗精神病药可能会改善阳性（在某种程度上为阴性）症状，但这些变化不会影响认知功能。这也说明了认知缺陷的某些方面（即认知灵活性）可能是精神分裂症疾病所固有的，独立于阳性或阴性症状发生[18]，但是认知功能也会随着长期服用药物阴性症状改善后恢复[19]。
比较不同随访周期的研究能够发现，在不同的疾病干预阶段，特定症状领域的改善与随后的认知改善之间有关。抗精神病药开始治疗后，认知功能随着精神病性症状的改善获得小幅度的改善，此后的2年之中，认知功能就没有进一步改善了[20]。但是在3年和5年的随访中，可以发现患者的认知功能出现显著改善[21]。如果在精神病的早期阶段得到有效的治疗，那么认知能力的改善是显而易见的，而不会出现以后的下降。例外的是慢性精神分裂症，即患者如果在治疗的第一年之中，阳性和阴性症状没有明显的改善，那么认知功能将不会随着继续治疗而改善，患者可能进入慢性衰退[22]。
长期服用精神病药吃不同剂量对大脑不同的伤害
长期较大剂量的抗精神病药与较差的认知功能有关。但是这样的研究其实难以完全排除某些一直长期维持较大剂量的患者可能本身病情就较难控制住、反复发作，因此需要大量药物，或是不使用大剂量药物病情无法控制[23]。
抗精神病药维持在较低剂量时，认知在多个领域显着改善，包括记忆、视觉空间、语言、注意力和延迟记忆[24]。
长期服用较高剂量的抗精神病药，语言学习和回忆能力会随着时间的推移而显着下降，与发病年龄或疾病严重程度无关。
有趣的是，在 9 年的随访中，维持在低剂量的病例和非精神疾病对照组之间的认知能力下降没有显着差异[25]。
相反，在一项针对老年精神分裂症患者的荟萃分析中，在 1-6 年的随访中，根据氯丙嗪等效性的药物状态或剂量未能证明与认知有显着相关性[26]。
在考虑服药依从性的研究中，据报道，与不定期服药的人相比，坚持服药的人在认知方面表现出更大的改善[27]。然而，依从性差是否导致认知缺乏改善或与精神分裂症诊断相关的固有认知缺陷导致药物依从性差仍然是一个悬而未决的问题。
锥体外系不良反应和认知锥体外系症状 (EPS) 是抗精神病药物较为知名的副作用之一。虽然已发现这些副作用与认知能力受损有关，但即使在没有抗精神病药物治疗的情况下，认知障碍也可能与锥体外系症状相关[28]，意味明显的认知功能障碍可能在病前就有。有趣的是，随着二代抗精神病药的引入，EPS 的关注度降低了，研究通常不报告与认知的显着相关性[29]。话虽如此，在存在 EPS 的情况下，与抗胆碱能药物联合治疗对认知有负面影响，最常受损的认知方面包括记忆力和注意力。值得注意的是，当停止抗胆碱能治疗时，认知会得到改善[30]。
抗精神病药和代谢失调
不同抗精神病药存在不同的代谢失调倾向：[即，奥氮平 = 氯氮平 > 舍吲哚 > 利培酮 > = 喹硫平 > = 氨磺必利 > 齐拉西酮、鲁拉西酮、阿立哌唑]
Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al.. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. (2010) 123:225–33. 10.1016/j.schres.2010.07.012
然而，最近的研究表明，所有抗精神病药物都与早期显着的体重增加有关，尤其是在年轻的患者中[31]。一代抗精神病药对体重增加的影响也被认为是不影响代谢的。已发现氟哌啶醇导致首发患者体重显着增加，在治疗的前 3 个月内平均体重增加 3.8 kg。有趣的是，虽然缺乏检查 AP 引起的体重增加的长期前瞻性试验，但已经证明，当长期（> 2 年）对未接受药物治疗的首发患者进行随访时，抗精神病药物之间的差异消失了[32]。这可能表明治疗方法的差异更多地取决于体重增加的模式。
与体重增加的趋势相似，在抗精神病药治疗后 6 个月内，首发患者的糖代谢异常和二型糖尿病发病率显着升高。所有抗精神病药都会使精神分裂症患者患糖尿病的风险增加[33]。此外，虽然超重和肥胖是糖尿病的主要危险因素，但在动物和人类中的研究一致表明，即使在没有肥胖的情况下，抗精神病药也可以直接诱导胰岛素抵抗和葡萄糖代谢失调[34]。
精神分裂症的肥胖三高和认知损害
约 33.5% 的精神分裂症患者发生 Met代谢综合征 (90)。在无精神疾病的人群，代谢综合征【五项标准中的三项：腰围增加、甘油三酯升高、高密度脂蛋白 (HDL)、胆固醇、血压升高和空腹升高葡萄糖】与认知功能障碍有关，记忆力、视觉空间能力、执行力智力等均有关，既然精神疾病患者本身就容易胖、容易三高，那究竟是抗精神病药导致的认知功能损害，还是由于肥胖和三高导致的认知功能损害？
精神疾病患者的不良生活方式如吸烟、不良饮食习惯、久坐、懒散等行为均会导致肥胖与认知功能损害[35]。精神分裂症相关的基因与脂肪量、瘦素信号 、胰岛素信号、葡萄糖代谢和炎症的调节独立相关。此外，抗精神病药物已被证实会增加这个已经代谢脆弱的人群的代谢风险。已发现血清素受体基因 5HT2A 会影响血脂水平和葡萄糖耐受不良，以及注意力跨度和认知灵活性 。同样，亚甲基四氢叶酸还原酶 (MTHFR) 基因被认为会增加精神分裂症患者发生代谢综合征的易感性，并且还与较差的言语回忆和认知灵活性有关。因此，似乎与精神分裂症患者代谢不良结果有关的基因也可能与认知结果有关。[36]
对于精神疾病患者而言，代谢综合征的特定方面（即高血压）与较低的认知评分相关，而其他因素，如腰围增加和血脂异常则与精神分裂症患者认知障碍仍有争议。构成不良代谢特征的其他因素，例如高 BMI，也并未始终被发现可以预测多个认知领域的不良认知功能。[37]此外，在一项研究中，实际上发现高血糖可以预测更好的语言记忆能力[38]。
抗精神病药、肥胖和疾病哪个对认知功能影响大
抗精神病药可能（1）导致代谢失调（2）代谢失调影响认知（3）直接影响认知功能。这三者很难明确具体关系，因为本身病情严重的患者代谢综合征可能较明显；本身病情轻的患者代谢综合征也较轻；病程较长的患者代谢综合征可能较明显，而病程较长的患者认知功能也较差，这个趋势在服用二代抗精神病药的患者较明显[40]。
在服用抗精神病药的患者而言，代谢综合征的不同方面与认知功能的关系也不同，高血压已被证明与较低的语言认知分数相关，包括记忆力和流利度[41]。甘油三酯被证明与较差的认知评分相关[42]；然而，当胆固醇得到控制时，这种影响就不再存在[43]。至于腰围（腹部肥胖），关于它是否对认知，文献中存在分歧。
精神分裂症认知功能和代谢风险的潜在机制
一、直接受体作用：虽然所有抗精神病药物都与多巴胺、D2 受体结合，但它们中的大多数与多种其他受体结合，包括组胺、血清素、N和M受体。已知每个这些受体系统的拮抗作用会影响认知以及代谢结果，例如体重增加、胰岛素和葡萄糖失调以及血脂异常。因此，很可能抗精神病药对认知和代谢测量的影响实际上是同一枚硬币的两个方面：因为与给定受体的结合会导致对两个域的下游影响。例如，人类和啮齿动物的急性多巴胺耗竭会降低外周胰岛素敏感性 ，据称是通过纹状体中的中枢多巴胺效应。此外，胰岛素敏感性降低和肥胖与纹状体中多巴胺合成能力和内源性多巴胺水平降低有关。这些神经化学变化反过来可能与认知能力差有关[44]。
因此，精神分裂症中抗精神病药对中枢多巴胺受体的阻断可能会产生外周胰岛素抵抗和认知能力差，这似乎是合理的。有趣的是，有证据表明急性抗精神病药物暴露不会改变首发精神分裂症患者的纹状体多巴胺水平和多巴胺合成能力。虽然高度推测，但首发中这种高多巴胺水平可能有助于解释为什么代谢副作用与首发患者的认知缺陷无关。
二、肠道微生物：略。
三、中枢胰岛素抵抗(Central insulin resistance)：中枢胰岛素抵抗可能是代谢和认知结果相互作用的最终共同途径。中央胰岛素已被公认可以调节人类的认知。对中枢胰岛素作用的失调或抵抗可能导致认知受损，胰岛素抵抗已被证明与受损的海马突触可塑性和记忆力以及神经发生相关。这可能涉及棕榈酸途径（the palmitic acid pathway）[45]。
四、微血管病变（Microangiopathy）：抗精神病药、代谢异常和认知功能可能相互作用的另一种机制是微血管病或微血管异常。微血管病是众所周知的代谢异常的后果，包括糖尿病和代谢综合征，并且与胰岛素抵抗的发展密切相关。虽然经典的目标包括眼睛、肾脏和周围神经系统，但最近的工作表明这种影响更为广泛，并且还包括大脑和脂肪组织。大脑中的微血管病变与认知能力下降有关。微血管病的逐渐发展也可以部分解释为什么代谢异常和认知能力下降之间的关系会在病程的后期出现[46]。
结论：除了服用药物之外，认知功能是能够把握在自己手里的积极因素，而不是消极被动的，生活习惯能够明显改善代谢综合征（饮食、运动、不久坐）、康复锻炼、多动脑、社交对有显著良好的影响。
作者/编辑：Circle
本科复旦大学临床医学，辅修宗教学，精神病与精神卫生学博士,博士期间研究抗抑郁药治疗抑郁症，毕业之后则更着重于心理咨询与人格障碍作为各种精神症状的基础，如何在康复的视角看待精神疾病的跨学科治疗，non-binary，2012年开始学精神分析，打酱油的人类学爱好者。在学人本主义心理咨询。对一切抱有好奇，永远在研究的路上。
症状网络其它关于精神疾病药的的精彩科普：
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