A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike?

Abstract

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.

Fig. 1

A putative model showing that escitalopram, paroxetine, and sertraline interact with the primary (orthosteric) and allosteric binding sites at the SERT leading to differential increases in extracellular 5-HT levels. In each diagram, the SERT is shown to be located at serotonergic neurons and to have the primary and allosteric binding sites. (a) In the absence of inhibitor drugs, the SERT performs its transport function, which removes extracellular 5-HT; (b) SSRIs such as sertraline are not able to bind to the allosteric site, and thus their action in increasing extracellular 5-HT levels is only mediated through the primary site; (c) ASRIs such as escitalopram bind to both the primary and the allosteric sites. Allosteric site binding enhances their binding to the primary site, resulting in more pronounced increases in extracellular 5-HT levels and potentially signaling through SERT-interacting proteins (SIPs) (Sanchez et al., 2004; Zhong et al., 2012a, 2012b). ASRI, allosteric serotonin reuptake inhibitor; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor. Drawing is based on previously published diagrams by Zhong et al. (2012a), with permission.

Fig. 2

Increase in extracellular levels of 5-HT by escitalopram, paroxetine, and sertraline in relation to SERT occupancy in the rat. The ability of escitalopram, paroxetine, and sertraline to increase 5-HT levels in rat prefrontal cortex via SERT inhibition is shown. Rats in the microdialysis experiments were anesthetized and the drugs were administered by the subcutaneous route. SERT occupancy was measured by in-vivo binding using [³H]citalopram as radioligand. (a) Different 5-HT levels in the rat prefrontal cortex after treatment with escitalopram 0.5 mg/kg (n=8), paroxetine 0.33 mg/kg (n=7), and sertraline 3.1 mg/kg (n=6) to achieve 88–92% occupancies of the SERT. Data shown are averaged 5-HT levels by AUC (%×min); *P<0.05 compared with escitalopram. (b) Differential 5-HT level vs. SERT occupancy relationships for escitalopram, paroxetine, and sertraline. Data shown are averaged 5-HT levels as percentages of baseline; **P<0.01, ***P<0.001 compared with vehicle (Brennum et al., 2004). AUC, area under the curve; SERT, serotonin transporter.

Fig. 3

In-vivo measurements of the effects of escitalopram, paroxetine, and sertraline on muscarinic cholinergic and DAT activities in mice. The anticholinergic and DAT-inhibiting effects of escitalopram, paroxetine, and sertraline are shown in oxotremorine-induced hypothermia (a) and spontaneous locomotor activity (b, c) in mice. (a) The role of muscarinic cholinergic antagonism is assessed as antagonism of hypothermia induced by the muscarinic agonist oxotremorine. The test was conducted at room temperature and started at 11 a.m. Drug or vehicle was injected subcutaneously 30 min before oxotremorine. The rectal temperature was measured before drug and oxotremorine administration and after 30 min. Data were analyzed by analysis of variance; ***P<0.001 compared with vehicle+oxotremorine. (b) The role of dopamine reuptake inhibition by a single dose of escitalopram, paroxetine, or sertraline was assessed as stimulation of spontaneous locomotor activity. The test was conducted in cages equipped with infrared light sources and photocells and the number of light beam interruptions was used as measure of locomotor activity. The mice were placed individually in the test cages and were habituated for 30 min before administration of drug. The accumulated number of light beam interruptions recorded 60–120 min after drug administration was used as the measure of drug effect; ***P<0.001 compared with vehicle. (c) Multiple doses of sertraline were assessed for stimulation of spontaneous locomotor activity as in (b). Data were analyzed by analysis of variance; **P<0.01, ***P<0.001 compared with vehicle (Sanchez, 2002).