Investigating the role of melatonin in bipolar disorder using transcriptomics.
Biorxiv : the Preprint Server for Biology
|September 15, 2025
Summary
Melatonin signaling gene dysregulation may contribute to bipolar disorder (BD) pathophysiology. This study identified potential melatoninergic therapeutic targets for BD, including GR-135531, and examined current BD drug effects on melatonin pathways.
Area of Science:
- Neuroscience
- Genomics
- Pharmacology
Background:
- Melatonin's role in bipolar disorder (BD) pathophysiology is unclear.
- Understanding melatonin's mechanisms in BD is crucial for novel therapeutic development.
Purpose of the Study:
- To investigate the therapeutic and mechanistic role of melatonin in BD using transcriptomics.
- To identify potential repurposing candidates for BD treatment among melatoninergic agents.
Main Methods:
- RNA sequencing (RNAseq) on post-mortem dorsolateral prefrontal cortex samples from individuals with and without BD.
- Gene set enrichment analysis (GSEA) to compare gene expression with melatonin-related gene lists.
- Analysis of RNAseq data from NT2-N cells treated with BD medications.
Main Results:
- Genes inhibiting melatonin signaling were upregulated in BD samples.
- Sex-specific downregulation of transcription factors regulating melatonin signaling was observed in BD.
- Quetiapine, valproate, lithium, and lamotrigine differentially altered melatonin-related gene expression, with quetiapine having the largest effect.
- Valproate upregulated genes involved in melatonin degradation.
- GR-135531 identified as a potential repurposing candidate for BD.
Conclusions:
- Dysregulation of melatonin-related genes is implicated in BD pathophysiology.
- Melatoninergic agents show potential as therapeutic candidates for bipolar disorder.
- Further research into melatonin-based therapies for BD is warranted.
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