What is a SERT Inhibitor?
A SERT (Serotonin Transporter) inhibitor is a drug that blocks the serotonin transporter protein, preventing the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron, thereby increasing serotonin availability in the brain. 1
Mechanism of Action
SERT inhibitors work by binding to the serotonin transporter (SERT) and blocking the reuptake of serotonin at the synaptic cleft, which increases serotonin availability in the synapse. 1 This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors, which heightens serotonergic neuronal firing rates and increases serotonin release. 1
The mechanism involves a multistep process that explains the delayed onset of therapeutic effects (typically 2-6 weeks) seen with SERT inhibitor treatment. 1 The drug must first block the transporter, then allow time for receptor adaptations to occur before clinical benefits emerge. 1
Primary Classes of SERT Inhibitors
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are drugs that selectively inhibit serotonin reuptake in the brain and enhance serotonin function. 2 These medications have only very weak effects on norepinephrine and dopamine neuronal reuptake. 3
Common SSRIs include:
- Sertraline: The FDA label confirms it blocks the uptake of serotonin into human platelets and is a potent and selective inhibitor of neuronal serotonin reuptake. 3
- Fluoxetine: The most activating SSRI due to its receptor profile and very long half-life. 1
- Escitalopram and citalopram: Preferred in older adults due to lower rates of adverse effects. 4
- Paroxetine: Has more anticholinergic effects than other SSRIs due to muscarinic receptor binding. 1
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
SNRIs inhibit the reuptake of both serotonin and norepinephrine in the brain, enhancing both serotonin and norepinephrine function. 2 These medications combine robust serotonin transporter inhibition with various degrees of norepinephrine transporter inhibition. 2
Examples include venlafaxine and duloxetine. 2
Clinical Applications
SERT inhibitors are first-line pharmacological treatments for multiple conditions:
- Social anxiety disorder: SSRIs are suggested as first-line treatment, with venlafaxine (SNRI) as an alternative. 2
- Depression: SSRIs and SNRIs represent established first-line treatments. 5
- Visceral pain syndromes: SNRIs can reduce perception of pain at different levels of the brain-gut axis, though SSRIs are unlikely to directly improve visceral pain because they do not block norepinephrine reuptake. 2
- Erythromelalgia: SNRIs like venlafaxine and sertraline have shown variable success in treatment. 2
Important Clinical Considerations
Serotonin syndrome risk increases when SERT inhibitors are combined with other serotonergic medications, including certain opioids (levorphanol, meperidine, fentanyl, methadone, tapentadol, tramadol), MAO inhibitors, triptans, ondansetron, and St. John's wort. 2 This potentially fatal condition is characterized by neuroexcitatory symptoms, autonomic dysfunction, and neuromuscular abnormalities. 2
Discontinuation symptoms are more common with shorter-acting SSRIs (paroxetine, fluvoxamine, sertraline) than with longer-acting ones like fluoxetine due to their different half-lives. 1
The pharmacokinetics show that SSRIs like escitalopram reach equilibrium in neuronal cytoplasm within seconds to minutes, while simultaneously accumulating in lipid membranes by 18-fold or more. 6 Regional differences in SERT occupancy occur throughout the brain, with higher occupancy in regions like the subgenual cingulate, amygdala, and raphe nuclei—areas commonly associated with antidepressant response. 7