Selective Serotonin Reuptake Inhibitors as Modulators of Mitochondrial Biogenesis and Function: A Systematic Review of the Evidence

Selective serotonin reuptake inhibitors (SSRIs) are a first line treatment for depressive and anxiety disorders. They function by selectively binding and blocking the serotonin transporter (SERT) and preventing reuptake of serotonin into the presynaptic terminal; however, the downstream changes and that determine the therapeutic effects remain largely unknown. There is growing evidence showing that serotonergic signalling and SERT blockade influences mitochondrial biogenesis and activity, suggesting that this may be an important downstream effect to consider in understanding the mechanism of action of these drugs. The aim of this study was to review the literature investigating mitochondrial biogenesis and activity as a result of SSRI treatment. Publications investigating SSRI treatment and mitochondrial function between 2007 and 2021 were identified by literature search using the PubMed database. Publications were categorised by whether mitochondrial biogenesis and activity was increased, decreased, restored following a disruption, or whether effects were mixed. Effects of SSRI treatment on mitochondrial biogenesis and function were dependent on the chosen dose and model. While cell culture based-studies showed mixed outcomes, the majority of animal studies showed that mitochondrial biogenesis and oxidative phosphorylation was increased, while oxidative stress was decreased. Collectively, the studies in this review suggest that SSRI treatment within the therapeutic dose range has the capacity to enhance mitochondrial biogenesis and function. Given that reduced oxidative capacity has been implicated in the pathophysiology of depressive and anxiety disorders, this may be important for understanding how SSRIs function to alleviate symptoms of these disorders.