How SSRIs Work
SSRIs work by selectively blocking the serotonin transporter (SERT) at presynaptic nerve endings, which prevents serotonin reuptake from the synaptic cleft and increases serotonin availability in the synapse. 1
Primary Mechanism of Action
SSRIs inhibit the serotonin transporter (SERT), blocking reuptake of serotonin at the synaptic cleft, which increases synaptic serotonin concentration. 2, 1, 3
This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors on the presynaptic neuron, which heightens serotonergic neuronal firing rates and increases serotonin release over time. 1
The multistep process—initial reuptake blockade followed by autoreceptor desensitization—explains why therapeutic effects are delayed by 3-6 weeks despite immediate increases in synaptic serotonin levels. 1, 4
Dual Sites of Action
SSRIs increase serotonin signaling through two distinct SERT-mediated mechanisms: local uptake inhibition at nerve terminals and disruption of inhibitory feedback at the dorsal raphe nucleus (DRN). 4
SERT inhibition in the DRN disrupts modulatory mechanisms that normally suppress serotonin neuron firing, causing frequency-dependent facilitation of serotonin release at distant terminal sites. 4
This amplification of terminal serotonin release occurs independently of local uptake changes and requires SERT expression, demonstrating that SSRIs enhance serotonin release by inhibiting uptake at locations distal to the terminal release site. 4
Receptor Selectivity Profile
SSRIs have no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors, which distinguishes them from tricyclic antidepressants and explains their more favorable side effect profile. 3
The exception is paroxetine, which has more anticholinergic effects than other SSRIs due to muscarinic receptor binding. 1
Chronic SSRI administration downregulates brain norepinephrine receptors, similar to other effective antidepressants, despite SSRIs having only very weak effects on norepinephrine neuronal reuptake. 3
Clinical Implications of Mechanism
The requirement for sustained serotonin elevation to achieve therapeutic effects is demonstrated by tryptophan depletion studies: depleting serotonin in patients with depression or panic disorder in remission on SSRIs causes relapse, confirming that increased synaptic serotonin levels are necessary for SSRI efficacy. 5
SSRIs are effective across the full spectrum of anxiety disorders, depression, obsessive-compulsive disorder, panic disorders, and other conditions because serotonergic neurotransmission mediates multiple functions including mood, aggression, sexual behavior, and pain. 6, 7
The therapeutic efficacy of SSRIs likely involves plasticity in multiple brain systems downstream of serotonergic inputs, not just the immediate increase in serotonin levels. 4
Important Caveats
SSRIs do not inhibit monoamine oxidase, which differentiates their mechanism from MAOIs. 3
Clinical signs of SSRI overdose result from excessive serotonin in the central nervous system (serotonin syndrome), manifesting as nausea, vomiting, mydriasis, hypersalivation, hyperthermia, ataxia, tremors, muscle rigidity, and seizures at higher doses. 8
All SSRIs can potentially cause serotonin syndrome when combined with other serotonergic medications (MAOIs, tramadol, dextromethorphan, certain stimulants), regardless of their receptor binding profiles. 1