腦源神經滋養因子信息路徑可能研發新型抗憂鬱藥物

Targeting Brain-derived Neurotrophic Factor (BDNF) Signaling Pathway as a Treatment Strategy for Depression

抗憂鬱藥通常是作為憂鬱症的第一線治療選擇。然而部分的憂鬱症病人對抗憂鬱藥治療反應不佳，而且抗憂鬱藥的療效通常需使用一段時間才出現，所以憂鬱症的藥物治療對精神科醫師仍然是很大的挑戰。近二十年來的研究為憂鬱症的神經營養假說提供了有力證據，壓力及憂鬱造成海馬的腦源神經滋養因子（BDNF）減少，治療回復這個腦區的腦源神經滋養因子，並且以這個信息路徑生成新的神經細胞。這個機轉可提供一種新的治療憂鬱症的方法，達到更快的療效及治療效果。這一方面的藥物目前在動物的研究已有不錯的抗鬱效果，包括能夠增加腦源神經滋養因子生成的藥物（半胱胺，溴氰菊酯，鋅，硫化氫，鎂，S 47445， TC G-1008，丁酸鈉，肌苷，薑黃素，利魯唑，紫羅蘭鹼），激發腦源神經滋養因子受體的藥物（二異黃酮，異氟醚）和增加腦源神經滋養因子／腦源神經滋養因子前驅物比率的藥劑（阿托伐他汀，齊留通）。這些藥劑需要進一步臨床測試評估其療效及副作用，期望透過憂鬱症的神經營養假說提供抗憂鬱藥物的發展一個嶄新的方向。

Major depressive disorder (MDD) is a common mental disorder accounting for significant morbidity and an increase in mortality worldwide. Antidepressants are often recommended as first-line treatment options in MDD patients. But the clinical management of depression with antidepressants remains a major concern for psychiatrists, and there is a need for more effective and quick onset antidepressants beyond the monoaminergic modulation. Studies in recent two decades have provided strong evidence for the neurotrophic hypothesis of MDD, suggesting that stress and antidepressant treatments exert opposing influences on the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. BDNF-mediated changes in adult hippocampal neurogenesis is critical for the therapeutic actions of antidepressant treatments. Therefore, up-regulation of BDNF signaling represents an intriguing opportunity to enhance response rates, and to have faster therapeutic onset in MDD. Those drugs that have received preclinical testing include agents that increase BDNF levels (cysteamine, deltamethrin, zinc, hydrogen sulfide, magnesium, S 47445, TC G-1008, sodium butyrate, inosine, curcumin, riluzole, and harmine), agents that activate BDNF receptors (7,8-dihydroxyflavone, and isoflurane), and agents that increase BDNF/proBDNF ratio (atorvastatin, and zileuton). The neurotrophic hypothesis of MDD may provide opportunity to develop faster and more efficient antidepressant drugs with higher response rates.