Vasiliu Octavian
Department of Psychiatry, Dr.Carol Davila University Emergency Central Military Hospital, Bucharest, Romania.
Front Pharmacol. 2022 Jun 14;13:884143. doi: 10.3389/fphar.2022.884143. eCollection 2022.
Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4-6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients' response rate.
抑郁症的治疗管理目前存在重要局限性，其低疗效体现在即使经过多次抗抑郁药试验后仍有很高的无反应率。在接受4至6周抗抑郁药试验的重度抑郁症患者中，几乎三分之二无法达到缓解，其中超过30%的患者被认为对治疗耐药。在双相抑郁症中，如果我们分析其高自杀率、添加抗抑郁药时出现治疗引发的情感转换的风险、高治疗耐药率（高达25%）以及与这些发作相关的严重功能障碍，情况同样不容乐观。因此，需要新的治疗药物以及新的抑郁症发病机制模型。目前绝大多数已获批的抗抑郁药都基于单胺假说，尽管利用不同神经递质途径的新药最近已获美国食品药品监督管理局（FDA）批准。布雷沙诺龙，一种别孕烯醇酮类似物，就是这类新抗抑郁药的一个例子，它获批用于产后抑郁症激发了人们对新一代神经甾体和γ-氨基丁酸（GABA）能调节剂的探索，这类药物具有更简便的给药方式和更好的耐受性。食欲素受体拮抗剂在II期试验中也被广泛研究用于包括抑郁症在内的不同精神疾病。基于临床前和临床研究中已证实的炎症与情绪障碍之间的关联，环氧化酶2抑制剂和生物疗法等抗炎药物也在抑郁症患者中进行研究。此外，新一代基于单胺的研究性药物也在重度抑郁症患者中进行探索，范围从三重再摄取抑制剂到非典型抗精神病药物。总之，单相和双相抑郁症的新治疗方法有望出现，因为在近七十年后，很明显应该针对新的发病途径来提高这些患者的反应率。
