Gurvich Artem, Begemann Martin, Dahm Liane, Sargin Derya, Miskowiak Kamilla, Ehrenreich Hannelore
Clinical Neuroscience, Max Planck Institute of Experimental Medicine.
Bipolar Disord. 2014 Dec;16(8):881-8. doi: 10.1111/bdi.12223. Epub 2014 Jun 25.
Over 12% of patients with bipolar disorder exhibit rapid cycling. The underlying biological mechanisms of this extreme form of bipolar disease are still unknown. This study aimed at replicating and extending findings of our previously published case report, where an involvement of prostaglandin synthesis-related genes in rapid cycling was first proposed.
Psychopathological follow-up of the reported case was performed under cessation of celecoxib treatment. In a prospective observational study, patients with bipolar disorder (n = 47; of these, four had rapid cycling) or with monopolar depression (n = 97) were recruited over a period of three years. Repeated psychopathology measurements were conducted using standard instruments. Peripheral blood mononuclear cells (PBMC) were obtained during as many consecutive episodes as possible and processed for mRNA isolation and quantitative real-time reverse transcriptase polymerase chain reaction for prostaglandin D2 synthase (PTGDS), aldo-ketoreductase family 1, member C3 (AKR1C3), cyclooxygenase-2 (PAN means all splice variants) (COX2PAN ), prostaglandin-endoperoxide synthase 2 (PTGS2), and purinergic receptor P2X, ligand-gated ion channel 7 (P2RX7).
The follow-up of our original case of a patient with rapid cycling who had shown impressive psychopathological improvement under celecoxib revealed complete loss of this effect upon discontinuation of the COX2 inhibitor. Episode-specific gene expression measurements in PBMC of four newly recruited rapid cycling patients confirmed the higher expression of PTGDS in depressive compared to manic phases. Additionally, higher relative expression of PTGS2/COX2PAN was found. No comparable alterations were observable in samples available from the remaining 43 patients with bipolar disorder and the 97 monopolar depressed patients, emphasizing the advantages of the rapid cycling condition with its rapid and frequent shifts for identification of gene expression changes.
This study supports a role for prostaglandins in rapid cycling and advocates the cyclooxygenase cascade as a treatment target in this condition.
超过12%的双相情感障碍患者表现出快速循环。这种极端形式的双相情感障碍的潜在生物学机制仍然未知。本研究旨在重复并扩展我们之前发表的病例报告的结果，该报告首次提出前列腺素合成相关基因与快速循环有关。
在塞来昔布治疗停止的情况下，对报告病例进行精神病理学随访。在一项前瞻性观察研究中，在三年时间里招募了双相情感障碍患者（n = 47；其中4例有快速循环）或单相抑郁症患者（n = 97）。使用标准工具进行重复的精神病理学测量。在尽可能多的连续发作期间获取外周血单个核细胞（PBMC），并进行处理以分离mRNA，并对前列腺素D2合成酶（PTGDS）、醛糖还原酶家族1成员C3（AKR1C3）、环氧化酶-2（所有剪接变体）（COX2PAN）、前列腺素内过氧化物合酶2（PTGS2）和嘌呤能受体P2X、配体门控离子通道7（P2RX7）进行定量实时逆转录聚合酶链反应。
对我们最初报告的一例快速循环患者的随访显示，在塞来昔布治疗下该患者的精神病理学有显著改善，但停用COX2抑制剂后这种效果完全消失。对4例新招募的快速循环患者的PBMC进行发作特异性基因表达测量，证实与躁狂期相比，抑郁期PTGDS的表达更高。此外，还发现PTGS2/COX2PAN的相对表达更高。在其余43例双相情感障碍患者和97例单相抑郁症患者的样本中未观察到类似变化，这突出了快速循环状态因其快速频繁的转变在识别基因表达变化方面的优势。
本研究支持前列腺素在快速循环中的作用，并主张将环氧化酶级联反应作为这种情况下的治疗靶点。
