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Antidepressant treatment alters both suicide-candidate gene expression levels and mitochondrial bioenergetic function
1Department of Forensic Sciences, Graduate School of Science and Engineering, Hacettepe University, 06800 Beytepe, Ankara, Türkiye; Department of Interdisciplinary Forensic Sciences, Institute of Health Sciences, Ankara University, 06620 Mamak, Ankara, Türkiye.
Background:
Although antidepressants are widely used in treatment of depression and suicidality, treatment-emergent suicidality remains a critically important concern. Mitochondrial dysfunction and microglial dysregulation have been implicated in depression and suicidal behavior. Similarly, certain candidate genes have been reported to display altered expression profiles in suicide victims. However, data remain highly limited regarding concurrent antidepressant-induced alterations in microglial bioenergetics and suicide-candidate gene expression levels.
Methods:
After exposing HMC3 cells to four frequently used antidepressants, we investigated the changes in; cell viability by MTT assay, suicide-candidate gene (GRIK2 and PLSCR4) expression levels via RT-PCR method, and levels of SIRT1, PGC-1α, and TFAM proteins by western blotting. Intracellular ATP and ROS levels were measured using colorimetric assays.
Results:
Our results revealed that GRIK2 was up-regulated by Amitriptyline, Sertraline, and Trazodone, but remained unaffected by Paroxetine. PLSCR4 was up-regulated by Amitriptyline, Paroxetine, and Trazodone, but not by Sertraline. Sertraline, Amitriptyline, and Trazodone caused significant decreases in ATP and PGC-1α levels, while ROS levels remained unchanged. Conversely, Paroxetine exerted a protective effect on intracellular ATP and PGC-1α levels.
Conclusions:
Sertraline, Amitriptyline, and Trazodone exerted significant decreases in ATP and PGC-1α levels, suggesting an increase in treatment-emergent suicidality risk due to a potential increase in microglial activity, while Paroxetine exerted a protective effect. The most prominent finding was that the antidepressants decreasing ATP and PGC-1α levels, simultaneously, induced suicide-candidate gene expression profiles which are also indicative of an increase in treatment-emergent suicidality risk. Despite a decrease in ATP and PGC-1α levels induced by three antidepressants, ROS levels remained unchanged, suggesting a potential oxidative stress-independent bioenergetic impairment. Collectively, these results suggest a clear correlation between PGC-1α levels and suicide-candidate gene expression profiles regarding the ultimate change in the treatment-emergent suicidality risk.
