Neurotransmitter Selectivity: Lexapro vs Zoloft
Lexapro (escitalopram) is the most serotonin-selective antidepressant available, with minimal effect on dopamine or norepinephrine reuptake, while Zoloft (sertraline) has moderate affinity for the dopamine transporter in addition to its serotonin effects. 1
Primary Neurotransmitter Targets
Escitalopram (Lexapro)
- Escitalopram demonstrates the highest selectivity for the serotonin transporter (SERT) among all SSRIs, with a binding affinity (Ki) of 1.1-2.1 nmol/L 1, 2
- It has minimal effect on dopamine or norepinephrine reuptake, making it highly serotonin-specific 3, 1
- Escitalopram is approximately 30-fold more potent than its R-enantiomer at the serotonin transporter 1
Sertraline (Zoloft)
- Sertraline binds to the serotonin transporter as its primary target, but unlike escitalopram, it possesses moderate affinity (Ki <50 nmol/L) for the dopamine transporter 1
- This dopaminergic activity distinguishes sertraline from escitalopram and may contribute to its moderately activating profile 4
- Sertraline has less effect on metabolism of other medications compared to some SSRIs, but more drug interaction potential than escitalopram 5, 6
Unique Allosteric Mechanism of Escitalopram
Escitalopram functions as an "allosteric serotonin reuptake inhibitor" rather than a pure SSRI, which represents a mechanistic difference from sertraline 7, 8:
- Escitalopram binds to both the orthosteric (primary) site and an allosteric (secondary) site on the serotonin transporter 8, 2
- Through allosteric binding, escitalopram decreases its own dissociation rate from the primary binding site, potentially enhancing its therapeutic effect 8
- This dual binding mechanism may explain why escitalopram produces greater increases in extracellular serotonin levels compared to other SSRIs at equipotent doses 2
Secondary Receptor Interactions
Escitalopram
- Higher affinity for sigma receptors (sigma1 and sigma2; Ki = 200-430 nmol/L) compared to other SSRIs, which may contribute to antidepressant and anxiolytic effects 2
- Minimal affinity for H1 histaminergic receptors (Ki ≥2000 nmol/L) and alpha1-adrenergic receptors (Ki ≥2000 nmol/L) 2
- Less effect on CYP450 isoenzymes, resulting in lower propensity for drug interactions 6
Sertraline
- Moderate dopamine transporter affinity distinguishes it from escitalopram 1
- Moderate drug interaction issues compared to escitalopram's minimal interaction profile 7
- Well-tolerated overall with neutral activation/sedation profile 5
Clinical Activation Profile Differences
Sertraline is characterized as "moderately activating" while escitalopram is not specifically categorized as activating 4:
- Fluoxetine is the most activating SSRI, sertraline is moderately activating, and paroxetine is the least activating 4
- Sertraline can be dosed morning or evening, reflecting its neutral activation/sedation profile 5
- Both medications can cause initial nervousness, insomnia, and agitation as class effects 5
Common Pitfalls
- Do not assume all SSRIs have identical neurotransmitter profiles—the dopamine transporter affinity of sertraline and the allosteric mechanism of escitalopram represent clinically meaningful differences 7, 1
- Escitalopram's superior serotonin selectivity translates to fewer off-target effects and drug interactions 6, 7
- When polypharmacy is necessary, escitalopram's minimal CYP450 effects make it advantageous over sertraline 6