The sertraline metabolite, desmethylsertraline, may be implicated in adverse outcomes reported after gestational sertraline use: insights from a study in zebrafish

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Abstract
Background: Sertraline (SER) is a selective serotonin reuptake inhibitor (SSRI) prescribed for depression, including during pregnancy. Existing literature suggests a potential association between gestational SER use and cardiac and neurodevelopmental anomalies in exposed offspring. This study evaluated the relative impacts of SER and its metabolite desmethylsertraline (DES) on the proteome during early development. Methods: Zebrafish embryos and larvae were exposed to individual treatments of translated umbilical cord-blood equivalent concentrations of SER or DES during early developmental stages. Quantified activity tracking and protein expression levels of serotonin transporter (SERT) were used to confirm a significant SSRI effect in exposed larvae. A whole-larvae proteomic analysis was conducted using a label-free quantitative liquid chromatography-mass spectrometry approach. Protein identification was performed using zebrafish and human protein databases. Results: Apparent therapeutic SSRI effect of exposure doses of SER and DES was confirmed in zebrafish larvae, by reduced activity levels, as well as decreased SERT. DES, but not SER, resulted in several differentially regulated proteins, identified in both the zebrafish and human databases. The results from the two databases correlated and aligned with an increased risk for cardiovascular and neurodevelopmental dysregulation. Conclusion: Proteomic data suggest that DES, rather than SER, at physiologically relevant doses, may be responsible for adverse clinical outcomes reported after gestational SSRI use. Current data positions larval zebrafish as a possible tool for assessment of long-term risk after gestational SER use, as well as a drug development tool in this context. Clinical trial number: N/A.
Funding Information
  • Universiteit Stellenbosch

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