吡格列酮作为增效剂治疗双相障碍抑郁发作的疗效研究及机制探索

Depressive episodes of bipolar disorder often dominate the course of bipolar disorder and are associated not only with suffering but also with functional impairment, suicide and other causes of excess mortality. Compare to unipolar depression, bipolar depression was considered to be more refractory, with less favorable response to antidepressants and having a high risk of switching to mania during treatment with antidepressants. The effectiveness of existing options based on the monoaminergic systems is still far from optimal, more and more scientist focus on the the identification of novel mechanisms for treating bipolar depression. As the ability to regulate metabolism and reduce inflammation has been well documented, the antidepressant effect of peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist pioglitazone has been noted gradually. We intended to conducted a double-blind placebo controlled, perspective study, 80 patients with bipolar disorder depression will be recruited according to the 1:1 ratio of concomitant metabolic syndrome or not, randomized and underwent 8-week pioglitazone or placebo adjunctive therapy to their original medications. The primary efficacy measure was the change from baseline to Week 8 on the Hamilton depression rating scale-17 (HAMD-17) total score. The study’s primary objective was to evaluate the adjunctive effect and safety of pioglitazone in patients with bipolar depression. The secondary objective was to determine if metabolic syndrome and the levels of inflammatory factors predicted treatment outcome, and try to explore the underlying mechanisms of bipolar depression.

双相抑郁往往在双相障碍的病程中占据主导位置，带给患者巨大的痛苦及疾病负担。较单相抑郁，其更具难治性特点，且抗抑郁药物治疗期间存在转躁风险，使其治疗成为精神科面临的一大挑战。鉴于基于单胺理论假说的现有治疗手段难以取得满意疗效，其新的病因机制假说已成为研究热点。基于代谢紊乱、炎性反应假说的过氧化物酶体增殖物激活受体-γ（PPAR-γ）的激动剂——吡格列酮的抗抑郁作用也逐渐引起关注。本课题拟进行一项随机双盲、安慰剂对照的前瞻性研究，按照是否伴有代谢综合征匹配入组80例双相抑郁患者，随机化后进入吡格列酮或安慰剂增效治疗组，以17项汉密尔顿抑郁量表评分（HAMD-17）作为评估指标，治疗8周，完成疗效及安全性评估，并完成炎性因子水平测定。本研究有望初步明确吡格列酮对于双相抑郁患者是否安全有效，探索代谢综合征、炎性因子水平对于预后的影响，为个体化治疗提供依据，并探索其可能的发病机制。

双相情感障碍是一种严重且发病率较高的精神疾病，然而其病理生理机制尚不明确。有研究表明免疫炎性变化在情感障碍的病理生理机制中发挥重要作用，既往研究发现双相情感障碍患者存在外周免疫炎性信号的升高，然而结果有限且不一致。本研究计划通过检测外周炎性细胞因子来初步探索双相情感障碍的免疫炎性状态，通过比较双相情感障碍患者不同疾病阶段炎性因子水平的变化以期了解不同的情绪状态对炎性水平的影响。另外本研究在已有研究报告的差异炎性因子基础上，扩大对炎性因子探索范围比如增加趋化因子，以期为未来相关研究提供更多目标炎性细胞因子。本研究共计筛选199例符合ICD-10双相情感障碍诊断的患者，根据汉密尔顿抑郁评估量表（HAMD）、Young躁狂评定量表（YMRS）选取处于双相抑郁期受试者36例，双相躁狂期受试者40例，以及处于缓解期的受试者32例，根据性别、年龄、体重指数匹配32例正常对照。通过定量蛋白芯片法检测所有受试者血清中40种炎性细胞因子水平。通过双相情感障碍受试者与健康对照组炎性因子水平比较，发现14个炎性因子在双相情感障碍患者中存在下调：IL-16、MCSF、IL-1α、PDGF-BB、CCL3、TNF RI、CCL4、IL-1ra、CXCL13、IL-4、CCL24、CCL15、IL-8、IL-1β。而分别比较抑郁期、躁狂期及缓解期受试者与正常对照之间炎性因子水平变化，发现在以上三个疾病组中均存在部分炎性因子水平的下调，如：IL-16、MCSF、IL-1α、CCL3、CCL4。而抑郁期受试者相较躁狂期及缓解期受试者，存在部分炎性因子水平的增高。以上结论与双相情感障碍存在免疫炎性激活的预期不符，提示双相情感障碍炎性机制可能并非单纯的免疫激活，其复杂性仍有待进一步的研究证实。另外本研究筛选出部分差异炎性因子如IL-16、MCSF、CCL3、CCL4，均在既往研究中涉及较少，可作为以后免疫炎性机制相关研究的新的目标因子选择。