Venlafaxine Mechanism of Action
Venlafaxine inhibits the reuptake of both serotonin and norepinephrine in the central nervous system, with dose-dependent selectivity: at low therapeutic doses (≤75 mg/day) it acts primarily as a selective serotonin reuptake inhibitor, while at higher doses (≥150 mg/day) it blocks both serotonin and norepinephrine reuptake. 1, 2
Primary Mechanism
- Venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake 1
- The antidepressant action is believed to be associated with potentiation of neurotransmitter activity in the CNS through these reuptake inhibition properties 1
- Venlafaxine is somewhat more potent as an inhibitor of serotonin reuptake than norepinephrine reuptake in vitro, with comparable potency to tricyclic antidepressants for serotonin but less potent for norepinephrine 3
Dose-Dependent Pharmacology
- At 75 mg/day (minimal effective dose): Venlafaxine acts as a selective serotonin reuptake inhibitor, producing approximately 55% reduction in whole-blood serotonin after 1 week and 75% reduction after 4 weeks, with no significant norepinephrine reuptake blockade 2
- At 225-375 mg/day (higher doses): Venlafaxine acts as a dual serotonin and norepinephrine reuptake inhibitor, significantly attenuating the tyramine pressor response (indicating norepinephrine reuptake blockade) while maintaining serotonin reuptake inhibition 2
- In vivo microdialysis studies confirm that venlafaxine selectively inhibits serotonin uptake at low therapeutic doses and inhibits both serotonin and norepinephrine uptake at higher therapeutic doses 4
Receptor Profile and Lack of Anticholinergic Effects
- Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro 1
- This lack of receptor binding explains why venlafaxine has a side-effect profile similar to SSRIs rather than tricyclic antidepressants, avoiding anticholinergic, sedative, and cardiovascular effects associated with receptor blockade 1, 3
- Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity 1
Neurochemical Effects in the Brain
- Acute administration of venlafaxine (3-50 mg/kg) produces a dose-dependent increase in extracellular noradrenaline in the rat frontal cortex, but produces no significant increase in serotonin concentrations when given alone 5
- The lack of acute serotonin elevation is due to venlafaxine potently inhibiting dorsal raphe neuronal firing through a 5-HT1A-mediated negative feedback mechanism, similar to SSRIs 5
- When combined with a 5-HT1A antagonist (WAY100635), venlafaxine produces dose-dependent augmentation of extracellular serotonin concentrations, demonstrating that the 5-HT1A autoreceptor limits serotonin release despite reuptake blockade 5
Clinical Implications of Mechanism
- The dual mechanism at higher doses may explain venlafaxine's efficacy in treatment-resistant depression and potentially faster onset of action compared to SSRIs 6
- For hot flashes in breast cancer survivors, venlafaxine 75 mg/day produces a 61% reduction in hot flash score, with this dose representing the optimal balance of efficacy and tolerability 6
- The American Academy of Child and Adolescent Psychiatry notes that SNRIs like venlafaxine inhibit the reuptake of neuronal serotonin, norepinephrine, and dopamine and potentiate neurotransmitter activity in the central nervous system, though dopamine reuptake inhibition is weak 6
Important Caveats
- Unlike chronic treatment with selective serotonin or norepinephrine reuptake inhibitors, chronic venlafaxine treatment (21 days) does not reduce SERT or NET binding sites in rat brain, suggesting a different long-term adaptive mechanism compared to other antidepressants 7
- Venlafaxine's major metabolite ODV has comparable potency to the parent drug for inhibiting reuptake of either norepinephrine or serotonin in vitro, but is less potent in vivo 3