Depression is a serious medical condition, typically treated by antidepressants. Conventional monotherapy can be effective only in 60-80% of patients, thus modern psychiatry deals with the challenge of new methods development. At the same moment, interactions between antidepressants and the occurrence of potential side effects raise serious concerns, which are even more exacerbated by the lack of relevant data on exact molecular mechanisms. Therefore, the aims of the study were to provide up-to-date information on the relative mechanisms of action of single antidepressants and their combinations. In this study, we evaluated the effect of single and combined antidepressants administration on mouse hippocampal neurons after 48 and 96 h in terms of cellular and biochemical features in vitro. We show for the first time that co-treatment with amitriptyline/imipramine + fluoxetine initiates in cells adaptation mechanisms which allow cells to adjust to stress and finally exerts less toxic events than in cells treated with single antidepressants. Antidepressants treatment induces in neuronal cells oxidative and nitrosative stress, which leads to micronuclei and double-strand DNA brakes formation. At this point, two different mechanistic events are initiated in cells treated with single and combined antidepressants. Single antidepressants (amitriptyline, imipramine or fluoxetine) activate cell cycle arrest resulting in proliferation inhibition. On the other hand, treatment with combined antidepressants (amitriptyline/imipramine + fluoxetine) initiates p16-dependent cell cycle arrest, overexpression of telomere maintenance proteins and finally restoration of proliferation. In conclusion, our findings may pave the way to better understanding of the stress-related effects on neurons associated with mono- and combined therapy with antidepressants.

中文翻译：

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与抑郁症治疗相关的神经元生死：药物及其与压力相关的结果之间的相互作用与单一或联合药物治疗有关。

抑郁症是一种严重的医学疾病，通常通过抗抑郁药治疗。传统的单一疗法仅对60-80％的患者有效，因此现代精神病学应对新方法开发的挑战。同时，抗抑郁药之间的相互作用和潜在副作用的出现引起了人们的严重关注，而缺乏确切的分子机制相关数据，则更加令人担忧。因此，该研究的目的是提供有关单一抗抑郁药及其组合的相对作​​用机理的最新信息。在这项研究中，我们根据体外细胞和生化特征评估了抗抑郁药的单一和联合给药对小鼠海马神经元的作用48和96小时后的效果。我们首次显示与阿米替林/丙咪嗪+氟西汀的共同治疗在细胞适应机制中启动，该机制使细胞能够适应压力并最终产生比单一抗抑郁药治疗的细胞更少的毒性事件。抗抑郁药治疗会在神经元细胞中诱导氧化和亚硝化应激，从而导致微核和双链DNA制动器形成。此时，在用单一和联合抗抑郁药治疗的细胞中引发了两种不同的机制事件。单一抗抑郁药（阿米替林，丙咪嗪或氟西汀）激活细胞周期阻滞，导致增殖抑制。另一方面，联合抗抑郁药（阿米替林/丙咪嗪+氟西汀）治疗可启动p16依赖性细胞周期阻滞，端粒维持蛋白的过表达并最终恢复增殖。总之，我们的发现可能为更好地理解与抗抑郁药单药或联合疗法对神经元的应激相关作用铺平了道路。