Redox metabolism modulation as a mechanism in SSRI toxicity and pharmacological effects

Abstract

Depressive disorders are amongst the greatest mental health challenges, with an increasing number of patients being diagnosed each year. Though it has not yet been fully elucidated, redox metabolism imbalances and oxidative stress seem to play a major role in the pathogenesis of depressive disorders. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants, considered to have a better tolerability. However, several adverse effects have been reported and the mechanisms involved in their pharmacological activity are not entirely understood. SSRIs have been shown to influence the redox metabolism, which could be involved in their toxicity and pharmacological effects. A comparative analysis of published in vivo and in vitro data regarding the activity of SSRIs on the redox metabolism pathways has been performed in this paper, with an emphasis on mechanistical aspects. Furthermore, a comparison between oxidative stress biomarker levels reported by different studies was attempted. The reviewed data point towards both pro-and antioxidant effects of SSRIs, dependent on tissue/cell type and dose/concentration, suggest a redox modulating potential of these compounds. In hepatic and testicular tissue, the majority of reviewed studies reported pro-oxidant effects, with possible implications towards the hepatotoxicity and sexual dysfunction that were reported following SSRI treatment; while in brain, the most common findings were antioxidant effects that could partially explain their antidepressant activity. However, given the heterogeneity of the reviewed data, further research is needed to fully understand the impact of SSRIs on redox metabolism and its implications.

Fluoxetine reduces organ injury and improves motor function after traumatic brain injury in mice

“…25 These alterations in immune cell activation may also contribute to their observed antiinflammatory properties. 26,27 Further studies will be needed to further elucidate the mechanism(s) for how SSRIs lead to reduced inflammation in TBI.…”

“…In fact, there is evidence that reduced immune cell activity and anti-inflammatory effects contribute to SSRI's antidepressant effects 25 . These alterations in immune cell activation may also contribute to their observed anti-inflammatory properties 26,27 . Further studies will be needed to further elucidate the mechanism(s) for how SSRIs lead to reduced inflammation in TBI.…”

Defining the nuanced nature of redox biology in post-traumatic stress disorder

“…Additionally, some medications are also known to inherently perturb the redox environment. The current recommended medications for PTSD patients include SSRIs, which are seen to directly influence some measurable redox markers such as 8-oxo-DG ( Ștefan et al, 2020 ; Jorgensen et al, 2022 ) . Blood pressure medications, such as statins and angiotensin II antagonists may also affect NADPH oxidases, which can alter O 2 •- production from these enzymes ( McCarty et al, 2015 ).…”

Fluoxetine Protects Retinal Ischemic Damage in Mice

“…The underlying mechanism involved in SSRI neuroprotection has not been clarified yet. These drugs can exert their neuroprotective effect apart from the effect on serotonin by acting on inflammation, oxidative stress, and microglia activation [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Several in vivo studies have demonstrated that fluoxetine (FLX) can be used as a neuroprotective agent in different models of neuronal damage [ 16 , 44 , 55 , 56 , 57 , 58 , 59 ].…”