What are the affinities of each Selective Serotonin Reuptake Inhibitor (SSRI) to different neurotransmitters?

SSRI Affinities to Different Neurotransmitters

SSRIs have varying affinities for serotonin transporters, with escitalopram showing the highest selectivity and potency, while other SSRIs demonstrate different binding profiles to norepinephrine, dopamine, and other neurotransmitter receptors, which explains their distinct clinical effects and side effect profiles. 1

Primary Mechanism of Action

• All SSRIs primarily inhibit the serotonin transporter (SERT), blocking reuptake of serotonin at the synaptic cleft, which increases serotonin availability 2
• This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors, heightening serotonergic neuronal firing rates and increasing serotonin release 2
• The multistep process explains the delayed onset of therapeutic effects seen with SSRI treatment 2

Comparative Serotonin Transporter Affinity

• Escitalopram has the highest selectivity and potency for the serotonin transporter (Ki = 1.1 nmol/L), making it approximately 30-fold more potent than R-citalopram 1
• Paroxetine has very high affinity for the serotonin transporter with minimal effects on other neurotransmitter systems 3
• Fluoxetine demonstrates potent serotonin reuptake inhibition (Ki = 1.4 nmol/L for R-fluoxetine) but with less selectivity than escitalopram 1
• Sertraline shows strong serotonin reuptake inhibition but also has moderate affinity for the dopamine transporter 1, 3
• Citalopram (racemic mixture) has lower potency compared to its S-enantiomer (escitalopram) 4
• Fluvoxamine demonstrates potent serotonin reuptake inhibition but with less selectivity than escitalopram 3

Norepinephrine Transporter Affinity

• Paroxetine has moderate affinity for the norepinephrine transporter (<50 nmol/L) 1
• Venlafaxine (an SNRI) inhibits both serotonin and norepinephrine transporters with a 30-fold difference in binding affinity, favoring serotonin 5
• Fluoxetine has minimal effects on norepinephrine reuptake 6, 3
• Escitalopram has minimal to no effect on norepinephrine neuronal reuptake 6
• Sertraline has minimal effect on norepinephrine reuptake 7
• Citalopram shows minimal effects on norepinephrine neuronal reuptake 8

Dopamine Transporter Affinity

• Sertraline has moderate affinity for the dopamine transporter (<50 nmol/L), which is unique among SSRIs 1
• Escitalopram has minimal to no effect on dopamine neuronal reuptake 6
• Fluoxetine has minimal effects on dopamine neuronal reuptake 7, 3
• Paroxetine has minimal effect on dopamine reuptake 3
• Citalopram shows minimal effects on dopamine neuronal reuptake 8

Other Receptor Affinities

• R-Fluoxetine uniquely possesses moderate affinity (Ki = 64 nmol/L) for the serotonin 2C receptor 1
• Paroxetine has more anticholinergic effects than other SSRIs due to muscarinic receptor binding 9
• Escitalopram has no or very low affinity for serotonergic (5-HT1-7), alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors 6
• Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, GABA, muscarinic cholinergic, and benzodiazepine receptors 8
• Sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors 7

Clinical Implications of Receptor Profiles

• 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 9
• Sertraline is moderately activating but generally well-tolerated compared to other SSRIs 9
• Paroxetine is less activating but has more anticholinergic effects than other SSRIs 9
• Escitalopram's high selectivity for serotonin transporters contributes to its favorable side effect profile 6, 1

Common Pitfalls and Caveats

• Discontinuation symptoms are more common with shorter-acting SSRIs (paroxetine, fluvoxamine, sertraline) than with longer-acting ones (fluoxetine) due to their different half-lives 9
• All SSRIs can potentially cause serotonin syndrome when combined with other serotonergic medications, regardless of their receptor binding profiles 9
• The halogen atoms present in all SSRIs are key determinants for their specificity for SERT, binding to a specific halogen-binding pocket 10
• Despite similar primary mechanisms, SSRIs have significant differences in their effects on CYP enzymes, leading to different drug interaction profiles 3