Venlafaxine mechanism of action

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Dual Mechanism of Action: Serotonin and Norepinephrine Reuptake Inhibition

Venlafaxine is primarily known as a serotonin and norepinephrine reuptake inhibitor (SNRI). At lower doses, it selectively inhibits the reuptake of serotonin (5-HT), while at higher doses, it also inhibits norepinephrine (NE) reuptake, engaging both mechanisms sequentially as the dose increases 12. This dual action increases the levels of these neurotransmitters in the brain, which is believed to contribute to its antidepressant effects 124. Some studies also note a weak effect on dopamine reuptake .

Modulation of Monoamine Neurotransmitter Metabolism

Venlafaxine not only increases the levels of serotonin and norepinephrine but also helps correct imbalances in the metabolism of these neurotransmitters. It lowers the turnover of neurotransmitter metabolites, helping to restore the balance of serotonin, norepinephrine, and dopamine in the brain, which is important for its antidepressant function .

Molecular and Cellular Pathways: mTORC1, MAPK–ERK1/2, and PI3K–AKT

Recent research highlights that venlafaxine activates several important molecular pathways in the brain. It restores the function of the mTORC1 signaling cascade, which is involved in the brain’s response to stress and depression . Additionally, venlafaxine activates the MAPK–ERK1/2 and PI3K–AKT pathways in the hippocampus, which are linked to neuroplasticity and the antidepressant response .

Epigenetic Effects and Enzyme Modulation

Venlafaxine’s mechanism also involves epigenetic changes. It increases histone acetylation and modulates the expression of key enzymes like tyrosine hydroxylase and tryptophan hydroxylase in the hippocampus, which are involved in the synthesis of norepinephrine and serotonin, respectively. These changes help relieve anxiety- and depression-like behaviors in animal models .

Additional Mechanisms: Receptor Interactions and Neurochemical Effects

Venlafaxine’s effects on neurotransmitter levels can be influenced by other receptors. For example, blocking the 5-HT1A receptor can further increase serotonin levels when combined with venlafaxine, suggesting that receptor interactions can modulate its neurochemical effects .

Effects Beyond Depression: Cellular and Genetic Impact

Venlafaxine has been shown to affect cell survival and genetic material. It can induce apoptosis in certain cancer cells through specific signaling pathways, and in laboratory studies, it has shown dose-dependent effects on human genetic material, possibly by modifying epigenetic and DNA replication processes 610.

Conclusion

Venlafaxine’s mechanism of action is multifaceted. Its primary effect is the inhibition of serotonin and norepinephrine reuptake, but it also influences neurotransmitter metabolism, activates key molecular pathways, induces epigenetic changes, and interacts with various receptors. These combined actions contribute to its effectiveness as an antidepressant and may explain its benefits in treating a range of mood disorders.

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Most relevant research papers on this topic

Evidence of the dual mechanisms of action of venlafaxine.

Venlafaxine selectively inhibits serotonin uptake at low doses and both serotonin and norepinephrine uptake at high doses, with the latter also affecting the pressor response to tyramine.

Highly Cited

2000·

272citations

·A. Harvey et al.

Venlafaxine: a novel antidepressant that has a dual mechanism of action.

Venlafaxine is a new antidepressant that blocks serotonin and norepinephrine reuptake, has a relatively benign side-effect profile, and shows potential in moderate-to-severe depression and treatment-resistant depression.

Highly Cited

1996·

81citations

·James M. Andrews et al.

Antidepressant mechanisms of venlafaxine involving increasing histone acetylation and modulating tyrosine hydroxylase and tryptophan hydroxylase expression in hippocampus of depressive rats

Venlafaxine's antidepressant mechanism involves blocking histone deacetylation and increasing tyrosine and tryptophan hydroxylase expression in the hippocampus of depressed rats.

RCTAnimal StudyRigorous Journal

2019·

20citations

·Min Qiao et al.

Biochemical mechanism studies of venlafaxine by metabonomic method in rat model of depression.

Venlafaxine increases brain levels of serotonin and norepinephrine, correcting neurotransmitter metabolism disorders, and achieving antidepressed function.

Non-RCTAnimal Study

2013·

20citations

·S. Fenli et al.

Venlafaxine protects against chronic stress-related behaviors in mice by activating the mTORC1 signaling cascade.

Venlafaxine protects against chronic stress-related behaviors in mice by activating the mTORC1 signaling cascade, which is involved in its pharmacological mechanism.

Non-RCTAnimal StudyRigorous Journal

2020·

12citations

·Jin-liang Wang et al.

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

Venlafaxine shows potential as a melanoma therapy by inducing apoptosis in melanoma cells through the JNK1/2-Nur77 signaling pathway.

Non-RCTAnimal Study

2023·

6citations

·Ting Niu et al.

Venlafaxine exerts antidepressant effects possibly by activating MAPK–ERK1/2 and P13K–AKT pathways in the hippocampus

Venlafaxine's antidepressant effects may be mediated by activating MAPK-ERK1/2 and P13K-AKT pathways in the hippocampus.

RCTAnimal Study

2017·

23citations

·Peng Shen et al.

Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism

Venlafaxine increases noradrenaline in the rat frontal cortex, with its effects enhanced by 5-HT1A receptor antagonism.

Non-RCTAnimal StudyHighly Cited

1999·

75citations

·L. Dawson et al.

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction.

Venlafaxine induces oxidative stress and mitochondrial/lysosomal dysfunction in rat hepatocytes, with mitochondria and lysosomes being primary targets in cell damage.

In Vitro Study

2016·

51citations

·E. Ahmadian et al.

Venlafaxine’s effect on human genetic material: in vitro study

Venlafaxine exhibits dose-dependent cytogenetic activity in vitro, increasing Sister Chromatid Exchanges and diminishing Proliferation Rate Index and Mitotic Index levels in healthy human cultured lymphocytes.

2020·

2citations

·Georgios Demirtzoglou et al.

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