Killick Richard, Hooper Claudie, Fernandes Cathy, Elliott Christina, Aarsland Dag, Kjosavik Svein R, Østerhus Ragnhild, Williams Gareth
Centre for Healthy Brain Aging, IoPPN, King's College London, London SE5 9RT, UK.
IHU HealthAge, Gérontopôle, Department of Geriatrics, CHU Toulouse, 31059 Toulouse, France.
Cells. 2025 Apr 11;14(8):575. doi: 10.3390/cells14080575.
Lithium is prescribed as a mood stabilizer for bipolar disorder and severe depression. However, the mechanism of action of lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes, we generated the gene expression profile for acute lithium treatment of cortical neuronal cultures. We found that the lithium-associated transcription response harbors a significant component that is the reverse of that seen in human brain samples from patients with major depression, bipolar disorder, and a mouse model of depression. Interrogating publicly available drug-driven expression data, we found that cardiotonic steroids drive gene expression in a correlated manner to our acute lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.
锂被用作双相情感障碍和重度抑郁症的情绪稳定剂。然而，锂的作用机制尚不清楚，长期用药会产生严重的副作用。这促使人们寻找更安全的替代药物再利用候选药物。鉴于药物机制可能编码在转录变化中，我们生成了皮质神经元培养物急性锂处理的基因表达谱。我们发现，与锂相关的转录反应包含一个显著成分，该成分与重度抑郁症、双相情感障碍患者以及抑郁症小鼠模型的人脑样本中的情况相反。通过查询公开可用的药物驱动表达数据，我们发现强心甾类药物以与我们的急性锂谱相关的方式驱动基因表达。对挪威处方数据库中精神科用药队列的分析表明，强心甾类药物处方与锂处方的较低发生率相关。我们的转录和流行病学观察表明，强心甾类药物可能是锂的潜在再利用候选药物。这些观察结果促使开展一项对照试验，以在抑郁症背景下建立因果关系和真正的治疗益处。
