SSRI Mechanism of Action and Receptor Affinities

Primary Mechanism of Action

All SSRIs primarily inhibit the serotonin transporter (SERT), blocking reuptake of serotonin at the synaptic cleft, which increases serotonin availability, according to the American Academy of Child and Adolescent Psychiatry 1
This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors, heightening serotonergic neuronal firing rates and increasing serotonin release, as reported by the American Academy of Child and Adolescent Psychiatry 1
The multistep process explains the delayed onset of therapeutic effects seen with SSRI treatment, as noted by the American Academy of Child and Adolescent Psychiatry 1

Paroxetine has more anticholinergic effects than other SSRIs due to muscarinic receptor binding, which may impact treatment choices, according to Praxis Medical Insights 2
Fluoxetine is considered the most activating SSRI due to its receptor profile and very long half-life, which may benefit patients with fatigue but should be avoided in those with significant anxiety or insomnia, as suggested by Praxis Medical Insights 2
Sertraline is moderately activating but generally well-tolerated compared to other SSRIs, according to Praxis Medical Insights 2
Paroxetine is less activating but has more anticholinergic effects than other SSRIs, as reported by Praxis Medical Insights 2
Discontinuation symptoms are more common with shorter-acting SSRIs (paroxetine, fluvoxamine, sertraline) than with longer-acting ones (fluoxetine) due to their different half-lives, according to Praxis Medical Insights 2
All SSRIs can potentially cause serotonin syndrome when combined with other serotonergic medications, regardless of their receptor binding profiles, as warned by Praxis Medical Insights 2