Depression’s link to serotonin dysregulation is well-known. The monoamine theory posits that depression results from impaired serotonin activity, leading to the development of antidepressants targeting serotonin levels. However, their limited efficacy suggests a more complex cause. Recent studies highlight mitochondria as key players in depression’s pathophysiology. Mounting evidence indicates that mitochondrial dysfunction significantly correlates with major depressive disorder (MDD), underscoring its pivotal role in depression. Exploring the serotonin-mitochondrial connection, our study investigated the effects of chronic serotonin treatment on induced-pluripotent stem cell-derived astrocytes and neurons from healthy controls and two case study patients. One was a patient with antidepressant non-responding MDD (“Non-R”) and another had a non-genetic mitochondrial disorder (“Mito”). The results revealed that serotonin altered the expression of genes related to mitochondrial function and dynamics in neurons and had an equalizing effect on calcium homeostasis in astrocytes, while ATP levels seemed increased. Serotonin significantly decreased cytosolic and mitochondrial calcium in neurons. Electrophysiological measurements evidenced that serotonin depolarized the resting membrane potential, increased both sodium and potassium current density and ultimately improved the overall excitability of neurons. Specifically, neurons from the Non-R patient appeared responsive to serotonin in vitro, which seemed to improve neurotransmission. While it is unclear how this translates to the systemic level and AD resistance mechanisms are not fully elucidated, our observations show that despite his treatment resistance, this patient’s cortical neurons are responsive to serotonergic signals. In the Mito patient, evidence suggested that serotonin, by increasing excitability, exacerbated an existing hyperexcitability highlighting the importance of considering mitochondrial disorders in patients with MDD, and avoiding serotonin-increasing medication. Taken together, our findings suggested that serotonin positively affects calcium homeostasis in astrocytes and increases neuronal excitability. The latter effect must be considered carefully, as it could have beneficial or detrimental implications based on individual pathologies.

众所周知，抑郁症与血清素失调有关。单胺理论认为抑郁症是由血清素活性受损引起的，从而导致针对血清素水平的抗抑郁药物的开发。然而，它们有限的功效表明了更复杂的原因。最近的研究强调线粒体是抑郁症病理生理学的关键参与者。越来越多的证据表明线粒体功能障碍与重度抑郁症（MDD）显着相关，强调了线粒体在抑郁症中的关键作用。为了探索血清素与线粒体的联系，我们的研究调查了长期血清素治疗对来自健康对照组和两名案例研究患者的诱导多能干细胞衍生的星形胶质细胞和神经元的影响。一名患者患有抗抑郁药无反应MDD（“Non-R”），另一名患者患有非遗传性线粒体疾病（“Mito”）。结果显示，血清素改变了与线粒体功能和神经元动力学相关的基因表达，并对星形胶质细胞中的钙稳态具有平衡作用，而 ATP 水平似乎有所增加。血清素显着降低神经元中的细胞质和线粒体钙。电生理学测量证明，血清素可以使静息膜电位去极化，增加钠和钾电流密度，并最终提高神经元的整体兴奋性。具体来说，来自非 R 患者的神经元在体外似乎对血清素有反应，这似乎改善了神经传递。虽然尚不清楚这如何转化为全身水平，并且 AD 抵抗机制尚未完全阐明，但我们的观察表明，尽管该患者存在治疗抵抗，但其皮质神经元对血清素信号有反应。在 Mito 患者中，有证据表明，血清素通过增加兴奋性，加剧了现有的过度兴奋性，这凸显了重度抑郁症患者考虑线粒体疾病并避免使用增加血清素的药物的重要性。综上所述，我们的研究结果表明，血清素对星形胶质细胞的钙稳态有积极影响，并增加神经元的兴奋性。必须仔细考虑后一种影响，因为它可能根据个体病理产生有益或有害的影响。