Abstract Objectives Although lithium (Li) remains a first-line treatment for bipolar disorder (BD), its exact mechanisms of action are still heavily debated. Because neurosteroid (NS) dysregulation plays a critical role in psychiatric disorders, this study looked into whether some of lithium’s effects are mediated through altering intracellular NS levels. Methods We assessed the effects of Li (0.5–25 mM) on SH-SY5Y cell viability over 24–72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Following this, we measured intracellular NS levels at specific doses and durations via LC-MS/MS. Results While 0.5–2.5 mM Li treatments preserved cell viability, doses ≥5 mM markedly reduced it (p<0.05). At a 1 mM non-toxic dose (24 h), we noted a significant buildup in pregnenolone, progesterone, 17-OH progesterone, and dehydroepiandrosterone (DHEA) (p<0.05). Conversely, treating cells with 25 mM Li spiked pregnenolone but significantly depleted androstenedione (p<0.05), and it drove up dehydroepiandrosterone sulfate (DHEAS) across all time points. Conclusions In conclusion, Li distinctly alters neurosteroidogenesis in a dose and time-dependent manner. Although preliminary, these in vitro findings offer remarkable insights, suggesting that NS pathways might mediate lithium’s clinical efficacy, warranting further comprehensive studies.
Fenangi et al. (2026) studied this question.