潘 惠，杜向東

(1.常熟市第三人民醫(yī)院，江蘇 常熟 215500；2.蘇州大學(xué)附屬廣濟(jì)醫(yī)院，江蘇 蘇州 215000*通信作者：杜向東，E-mail:xiangdong-du@163.com)

精神分裂癥陰性癥狀的藥物治療進(jìn)展

潘 惠1,2，杜向東2*

(1.常熟市第三人民醫(yī)院，江蘇 常熟 215500；2.蘇州大學(xué)附屬廣濟(jì)醫(yī)院，江蘇 蘇州 215000
*通信作者：杜向東，E-mail:xiangdong-du@163.com)

陰性癥狀作為精神分裂癥核心癥狀之一，目前仍缺乏有效的靶向性治療，是影響預(yù)后的主要不利因素。根據(jù)不同的生物學(xué)機(jī)制，當(dāng)前臨床研究主要關(guān)注抗精神病藥單用或其聯(lián)合抗抑郁藥、抗焦慮藥、谷氨酸化合物及抗炎藥等對陰性癥狀的療效，本文通過對精神分裂癥陰性癥狀常用的藥物療法進(jìn)行歸納總結(jié)，分析不同療法的效果，以期為臨床治療陰性癥狀提供參考。

精神分裂癥；陰性癥狀；藥物治療

精神分裂癥是一種由遺傳、發(fā)育和環(huán)境等多因素促發(fā)的復(fù)雜性精神疾病，核心特征包括陽性癥狀、陰性癥狀及認(rèn)知功能損害。陰性癥狀是指正常精神功能的減退或缺失，臨床上主要表現(xiàn)為情感淡漠、思維貧乏和社交退縮等。一般認(rèn)為，原發(fā)陰性癥狀的病因與精神分裂癥的核心精神病理學(xué)改變相關(guān)，即當(dāng)中腦-皮質(zhì)多巴胺(Dopamine，DA)通路功能低下時(shí)出現(xiàn)；繼發(fā)陰性癥狀則是其他相關(guān)因素的衍生物，可由陽性癥狀、情感癥狀、神經(jīng)系統(tǒng)的藥物副反應(yīng)及環(huán)境因素等引起。盡管多巴胺模型能較好地解釋精神分裂癥陽性癥狀，但陰性癥狀生物學(xué)機(jī)制較復(fù)雜，很難用單一的生物學(xué)假說或遺傳因素解釋，是目前精神分裂癥治療的主要難點(diǎn)之一[1]。根據(jù)不同的生物學(xué)機(jī)制，當(dāng)前臨床研究主要關(guān)注單用抗精神病藥物或聯(lián)合抗抑郁藥、抗焦慮藥、谷氨酸化合物及抗炎藥等對陰性癥狀的療效，本文對陰性癥狀常用的藥物療法進(jìn)行歸納總結(jié)，分析不同療法的效果，以期為陰性癥狀的臨床治療提供參考。

1 單用抗精神病藥

藥物治療是精神分裂癥治療的首選，抗精神病藥是治療精神分裂癥的基石[2]。典型抗精神病藥主要通過阻斷中樞多巴胺2型受體(Dopamine receptor D2，DRD2)降低DA神經(jīng)系統(tǒng)的功能，對陽性癥狀有效；非典型抗精神病藥的藥理學(xué)特點(diǎn)呈現(xiàn)多樣性，但均具備了“非典型性”的關(guān)鍵特點(diǎn)，即阻斷5-羥色胺(Serotonin，5-HT)受體，理論上不僅對陽性癥狀有效，還能通過改善情感癥狀及降低錐體外系副反應(yīng)的發(fā)生風(fēng)險(xiǎn)，進(jìn)而改善繼發(fā)陰性癥狀，但對原發(fā)陰性癥狀的療效尚不確定[3]。2009年Lancet雜志發(fā)表了一篇包括150個(gè)隨機(jī)雙盲對照研究(含21 533例精神分裂癥患者)的薈萃分析[4]，比較了典型和非典型抗精神病藥治療精神分裂癥的效果，其中95個(gè)研究以高效能抗精神病藥氟哌啶醇為對照，28個(gè)研究以低效能抗精神病藥氯丙嗪為對照，其余研究以其他典型抗精神病藥為對照，結(jié)果顯示，非典型抗精神病藥中僅氯氮平、奧氮平、氨磺必利和利培酮對陰性癥狀的療效優(yōu)于典型抗精神病藥，齊拉西酮、阿立哌唑、喹硫平、佐替平和舍吲哚對陰性癥狀的療效均與典型抗精神病藥相當(dāng)。2012年更新的《精神分裂癥生物治療指南》也認(rèn)為，即使是非典型抗精神病藥，對陰性癥狀的療效也是有限的[5]。

2 抗精神病藥聯(lián)合抗抑郁藥和抗焦慮藥

陰性癥狀與抑郁癥狀不論在表現(xiàn)形式還是神經(jīng)生物學(xué)背景方面均存在重疊，有時(shí)很難嚴(yán)格區(qū)分[6]。盡管證據(jù)有限，但聯(lián)合抗抑郁藥仍是目前針對陰性癥狀使用最廣泛的治療策略[7]。同時(shí)，聯(lián)合具有5-HT1A受體激動(dòng)作用的新型抗焦慮藥也越來越受到關(guān)注。

2.1 抗精神病藥聯(lián)合選擇性5-羥色胺再攝取抑制劑(Selective Serotonin Reuptake Inhibitors，SSRIs)

Chertkow等[8]研究顯示，以下機(jī)制可能參與了SSRIs與抗精神病藥對陰性癥狀的協(xié)同作用：通過特殊的5-HT受體和酪氨酸羥化酶促進(jìn)DA釋放；通過谷氨酸脫羧酶、蛋白激酶C影響γ-氨基丁酸(Gamma-Aminobutryic Acid，GABA)系統(tǒng)；通過磷酸化環(huán)磷酸腺苷反應(yīng)元件結(jié)合蛋白、成纖維母細(xì)胞生長因子2等調(diào)節(jié)神經(jīng)元生長發(fā)育，促進(jìn)細(xì)胞損傷后修復(fù)；通過鈣信號、白細(xì)胞介素8和趨化因子受體等降低中樞神經(jīng)系統(tǒng)的免疫應(yīng)答。Singh等[9]的一項(xiàng)關(guān)于抗抑郁藥輔助治療精神分裂癥陰性癥狀的薈萃分析(含23個(gè)隨機(jī)雙盲對照研究，共819例病程>2年的精神分裂癥患者)結(jié)果顯示，在原有抗精神病藥的基礎(chǔ)上聯(lián)合SSRIs等抗抑郁藥對精神分裂癥患者的陰性癥狀療效更好。

2.2 抗精神病藥聯(lián)合雙重神經(jīng)遞質(zhì)作用藥物

M?ller等[7]研究結(jié)果顯示，突觸前α2腎上腺素受體拮抗劑可促使前額葉皮層DA釋放，從而改善精神分裂癥的陰性癥狀。Hecht等[10]發(fā)表的一項(xiàng)薈萃分析(包括8個(gè)隨機(jī)對照研究，每個(gè)研究含18～41例慢性精神分裂癥患者)結(jié)果顯示，抗精神病藥聯(lián)合米氮平或米安色林等具有α2腎上腺素受體拮抗作用的雙通道抗抑郁藥治療4～8周能有效改善陰性癥狀，同時(shí)結(jié)合漢密爾頓抑郁量表(Hamilton Depression Scale，HAMD)分析發(fā)現(xiàn)，陰性癥狀的改善獨(dú)立于抑郁癥狀的變化。Kishi等[11]發(fā)表的一項(xiàng)含12個(gè)隨機(jī)雙盲對照研究(其中7個(gè)以米氮平為研究組，5個(gè)以米安色林為研究組，各含221例和141例慢性精神分裂癥患者)的薈萃分析結(jié)果也顯示，抗精神病藥聯(lián)合米氮平或米安色林均能有效改善陰性癥狀。

2.3 抗精神病藥聯(lián)合丁螺環(huán)酮

3 抗精神病藥聯(lián)合谷氨酸化合物

谷氨酸-多巴胺在紋狀體和前額葉間神經(jīng)環(huán)路中釋放的平衡對陰性癥狀有重要影響[17]。目前研究主要聚焦于如何通過突觸后神經(jīng)元的N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受體和突觸前神經(jīng)元的代謝型谷氨酸受體(Metabotropic glutamate receptor，mGluR)對谷氨酸介導(dǎo)的神經(jīng)傳遞進(jìn)行調(diào)節(jié)[18]。

3.1 抗精神病藥聯(lián)合NMDA受體激動(dòng)劑

NMDA受體功能低下導(dǎo)致前額葉、腹側(cè)紋狀體和丘腦皮質(zhì)投射功能的改變，這些改變可能引起陰性癥狀[19]。初步研究表明，甘氨酸結(jié)合位點(diǎn)激活劑(如甘氨酸、D-絲氨酸、D-環(huán)絲氨酸、D-丙氨酸)能增強(qiáng)NMDA受體活性，從而改善陰性癥狀[20-21]，而非選擇性甘氨酸再攝取抑制劑肌氨酸也能改善陰性癥狀[22-23]。目前分別有薈萃分析報(bào)道了D-絲氨酸、肌氨酸和甘氨酸治療陰性癥狀的優(yōu)勢[24-25]，但迄今為止，樣本量最大的甘氨酸和D-絲氨酸輔助治療精神分裂癥的隨機(jī)雙盲對照研究并未發(fā)現(xiàn)其對陰性癥狀有確切療效[26]。此外，也有臨床研究表明，聯(lián)用D-氨基酸氧化酶抑制劑苯甲酸鈉可改善慢性精神分裂癥患者的陰性癥狀[27]，這可能與苯甲酸鈉降低D-絲氨酸的分解代謝、提高突觸間隙D-絲氨酸水平而增強(qiáng)了NMDA受體活性有關(guān)[28]。

3.2 抗精神病藥聯(lián)合mGluR激動(dòng)劑

通過靶向修飾的mGluR，尤其是突觸前膜mGluR2激活后可減少病理過程中谷氨酸的過度釋放并阻斷后續(xù)的細(xì)胞興奮毒性損害。盡管初期研究發(fā)現(xiàn)mGluR2/3的完全激動(dòng)劑LY2140023可能對精神分裂癥有效，但最終結(jié)果卻顯示該藥不宜作為陰性癥狀治療的輔助用藥[29]。

4 抗精神病藥聯(lián)合抗炎藥

近期發(fā)表于The American Journal of Psychiatry的研究顯示，精神分裂癥超高危及確診的個(gè)體大腦中小膠質(zhì)細(xì)胞更為活躍[30]。大腦促炎性因子的增多可促進(jìn)谷氨酸能和DA能神經(jīng)遞質(zhì)相互作用，導(dǎo)致小膠質(zhì)細(xì)胞及其他支撐性中樞神經(jīng)細(xì)胞的保護(hù)功能下降，從而引起或加重精神分裂癥陽性癥狀、陰性癥狀及認(rèn)知功能損害[31]。親脂性抗炎藥可減少細(xì)胞因子的激活，并降低中樞神經(jīng)系統(tǒng)的免疫應(yīng)答，對精神分裂癥可產(chǎn)生有益的治療作用。

米諾環(huán)素是一種廣譜、半合成的第二代四環(huán)素，臨床研究顯示其具有治療陰性癥狀的潛能，具體機(jī)制為：①對大腦灰質(zhì)缺失的神經(jīng)保護(hù)作用，大腦灰質(zhì)缺失通常發(fā)生在精神分裂癥早期[32]，米諾環(huán)素可能通過阻滯灰質(zhì)缺失來抑制陰性癥狀。②抗炎作用，米諾環(huán)素的抗炎作用可預(yù)防精神分裂癥患者的神經(jīng)變化，這與小膠質(zhì)細(xì)胞和細(xì)胞因子的作用有關(guān)[33]。③穩(wěn)定NMDA受體，氯胺酮通過阻斷NMDA受體，造成谷氨酸功能失調(diào)，使健康個(gè)體出現(xiàn)類似精神分裂癥的癥狀[34]；米諾環(huán)素可抑制氯胺酮活性，這可能會穩(wěn)定NMDA受體的釋放[35]。同時(shí)，米諾環(huán)素可直接作用于谷氨酸的釋放或預(yù)防谷氨酸對神經(jīng)分支和膠質(zhì)細(xì)胞的神經(jīng)毒性[36]。米諾環(huán)素的上述機(jī)制可能單獨(dú)存在或共同作用，但只有在神經(jīng)退行性改變被激活的早期，上述三種機(jī)制才能發(fā)揮作用。因此，米諾環(huán)素可能在精神分裂癥早期階段發(fā)揮作用。Lisiecka等[37]在226例早期精神分裂癥患者接受標(biāo)準(zhǔn)治療基礎(chǔ)上，隨機(jī)給予米諾環(huán)素(100 mg/d)或安慰劑治療12個(gè)月，結(jié)果顯示米諾環(huán)素具有改善陰性癥狀的潛力。

5 抗精神病藥聯(lián)合其他藥物

5.1 抗精神病藥聯(lián)合膽堿酯酶抑制劑

精神分裂癥患者部分腦區(qū)的煙堿型乙酰膽堿受體(Nicotinic acetylcholine receptor, nAChR)濃度低于正常人[38-39]。同時(shí)，遺傳學(xué)研究顯示nAChRα7亞型基因多態(tài)性與精神分裂癥易感性相關(guān)[40]。這些結(jié)果均提示nAChR功能的失調(diào)可能影響精神分裂癥的疾病進(jìn)程。Choi等[41]的一項(xiàng)關(guān)于輔助治療精神分裂癥的薈萃分析(包括26個(gè)隨機(jī)雙盲對照研究，每個(gè)研究含11～104例精神分裂癥患者)結(jié)果顯示，抗精神病藥聯(lián)合膽堿酯酶抑制劑(多奈哌齊、加蘭他敏)在改善認(rèn)知障礙的同時(shí)還能部分緩解陰性癥狀[41]。

5.2 抗精神病藥聯(lián)合單胺氧化酶抑制劑

雷沙吉蘭屬于第二代單胺氧化酶抑制劑，通過減少DA分解提高前額葉皮層等區(qū)域的DA水平[42]，并具有神經(jīng)保護(hù)的作用[43]。近期一項(xiàng)針對伴原發(fā)陰性癥狀精神分裂癥的隨機(jī)雙盲對照研究結(jié)果顯示，雷沙吉蘭能有效輔助治療原發(fā)陰性癥狀，對意志缺乏患者的療效尤為顯著[44]。

5.3 抗精神病藥聯(lián)合磷酸二酯酶抑制劑

磷酸二酯酶具有特異性水解細(xì)胞內(nèi)第二信使的功能，5-磷酸二酯酶抑制劑西地那非通過提高環(huán)磷酸鳥苷等第二信使的濃度，選擇性改善NMDA受體功能，從而治療精神分裂癥陰性癥狀[45]。然而，由于研究設(shè)計(jì)及評估工具的不同，Goff等[46]的一項(xiàng)隨機(jī)對照研究并未顯示西地那非對精神分裂癥有效，但隨后的另一項(xiàng)隨機(jī)雙盲對照研究結(jié)果顯示，與安慰劑相比，西地那非能顯著改善陰性癥狀[45]。目前西地那非治療精神分裂癥的研究有限，仍需進(jìn)一步探索其在陰性癥狀治療中的價(jià)值。

另外，除上述藥物之外，僅個(gè)別研究顯示其他藥物，如拉莫三嗪[47]、葉酸和維生素B12[48]輔助治療陰性癥狀有效，仍需更多的臨床研究進(jìn)一步證實(shí)。

6 小結(jié)與展望

陰性癥狀作為精神分裂癥核心癥狀之一，其生物學(xué)機(jī)制復(fù)雜，目前仍缺乏有效的靶向性治療方法，是影響預(yù)后的主要不利因素。非典型抗精神病藥自20世紀(jì)70年代問世以來，曾一度被認(rèn)為是精神分裂癥藥物治療的革命性突破，但經(jīng)過長期的臨床驗(yàn)證，其治療陰性癥狀的療效并沒有預(yù)期那么好，目前多藥物聯(lián)合治療越來越受到青睞。本綜述總結(jié)了可能對陰性癥狀有效的新型藥物，目前此類藥物的臨床研發(fā)主要聚焦于5-HT、谷氨酸和炎性因子等方面。雖然本綜述未涉及非藥物干預(yù)，但這類治療值得單獨(dú)評估，因?yàn)檫@些方法可能會進(jìn)一步提高藥物治療的效果。隨著越來越多的新型治療藥物和方法的問世，陰性癥狀的治療將越來越全面，精神分裂癥患者的社會功能及預(yù)后將得到進(jìn)一步改善。

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(本文編輯：唐雪莉)

Review of pharmacotherapy advance in schizophrenic negative symptoms

PanHui1,2,DuXiangdong2*

(1.TheThirdPeople'sHospitalofChangshuCity,Changshu215500,China; 2.SuzhouPsychiatryHospital,Suzhou215000,China*Correspondingauthor:DuXiangdong,E-mail:xiangdong-du@163.com)

Negative symptom is one of the core symptoms of schizophrenia and is a main adverse factor which effects schizophrenic prognosis, as there is no effective treatment now. According to various biological mechanisms, clinical researches mainly focus on the effects of used antipsychotics alone as well as combined with antidepressants, anxiolytics, glutamate compounds and anti-inflammatory drugs on negative symptoms currently.This review summarized the common drug therapies for negative symptoms and analyzed the effects of different therapies, which may provide references for the clinical treatment of negative symptoms.

Schizophrenia; Negative symptom; Pharmacotherapy

R749.3

A

10.11886/j.issn.1007-3256.2017.04.021

2016-09-08)