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.
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Abbreviations
- 3-NP:
-
3-Nitropropionic acid
- 4-HNE:
-
4-Hydroxy-nonenal
- 5-HT:
-
Serotonin
- 5-HTT:
-
Serotonin transporter
- 8-oxo-dG:
-
8-Oxo-2-deoxyguanosine
- ACR:
-
Acrolein
- BDNF:
-
Brain-derived neurotrophic factor
- CAT:
-
Catalase
- CIS:
-
Chronic isolation stress
- CIT:
-
Citalopram
- CMS:
-
Chronic mild stress
- CREB:
-
CAMP response element binding protein
- CUS:
-
Chronic unpredictable stress
- DA:
-
Dopamine
- DNA:
-
Deoxyribonucleic acid
- eNOS:
-
Endothelial nitric oxide synthase
- ESC:
-
Escitalopram
- FLX:
-
Fluoxetine
- FST:
-
Forced-swim test
- FVX:
-
Fluvoxamine
- GPX:
-
Glutathione peroxidase
- GR:
-
Glutathione reductase
- GSH:
-
Reduced glutathione
- GSSG:
-
Oxidized glutathione
- GST:
-
Glutathione-sulfotransferase
- H2O2 :
-
Hydrogen peroxide
- HO·:
-
Hydroxyl
- HO-1:
-
Hemoxygenase 1
- HPA:
-
Hypothalamic–pituitary–adrenal
- iNOS:
-
Inducible nitric oxide synthase
- Keap1:
-
Kelch-like ECH-associated protein 1
- LPS:
-
Lipopolysaccharide
- MAOIs:
-
Monoamine oxidase inhibitors
- MDA:
-
Malondialdehyde
- MDD:
-
Major depressive disorder
- MPO:
-
Myeloperoxidase
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- NA:
-
Noradrenaline
- NEA:
-
Non-enzymatic antioxidants
- nNOS:
-
Neuronal nitric oxide synthase
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- O2·− :
-
Superoxide
- OS:
-
Oxidative stress
- PC:
-
Protein carbonyls
- PRX:
-
Paroxetine
- ROS:
-
Reactive oxygen species
- RS:
-
Restraint stress
- SNRIs:
-
Serotonin–noradrenaline reuptake
- SOD:
-
Superoxide-dismutase
- SRT:
-
Sertraline
- SSRIs:
-
Selective serotonin reuptake inhibitors
- StAR:
-
Steroidogenic acute regulatory protein
- TAC:
-
Total antioxidant capacity
- TAS:
-
Total antioxidant status
- TCAs:
-
Tricyclic antidepressants
- TST:
-
Tail suspension test
- XO/XDH:
-
Xanthine oxidase/xanthine dehydrogenase
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Ștefan, MG., Kiss, B., Gutleb, A.C. et al. Redox metabolism modulation as a mechanism in SSRI toxicity and pharmacological effects. Arch Toxicol 94, 1417–1441 (2020). https://doi.org/10.1007/s00204-020-02721-6
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DOI: https://doi.org/10.1007/s00204-020-02721-6