How Celexa (Citalopram) Works
Celexa works by selectively blocking the reuptake of serotonin in the brain, which increases serotonin availability in the synaptic space and enhances serotonergic neurotransmission—this mechanism is responsible for its antidepressant effects. 1
Mechanism of Action
Citalopram potentiates serotonergic activity in the central nervous system by inhibiting neuronal reuptake of serotonin (5-HT), making it a highly selective serotonin reuptake inhibitor (SSRI). 1
The drug has minimal effects on norepinephrine and dopamine reuptake, distinguishing it from other antidepressants that affect multiple neurotransmitter systems. 1
Citalopram demonstrates very low affinity for other receptor systems including serotonin receptors (5-HT1A, 5-HT2A), dopamine receptors (D1, D2), adrenergic receptors (α1, α2, β), histamine H1 receptors, GABA receptors, muscarinic cholinergic receptors, and benzodiazepine receptors. 1
This high selectivity for serotonin reuptake inhibition, without significant binding to other receptors, explains why citalopram lacks the anticholinergic, sedative, and cardiovascular side effects commonly associated with tricyclic antidepressants. 1, 2
Pharmacological Selectivity
Citalopram is the most selective SSRI available, with a more specific pharmacological profile than other antidepressants in its class. 3, 4
The drug is a racemic mixture (50/50 split) of two enantiomers: S-citalopram (escitalopram) and R-citalopram. 1, 5
The S-enantiomer is primarily responsible for inhibiting serotonin reuptake, with an affinity for the serotonin transporter that is 30 to 40 times higher than the R-enantiomer. 5
Interestingly, the R-enantiomer can actually antagonize some of the therapeutic effects of the S-enantiomer by binding to an allosteric site on the serotonin transporter, which is why escitalopram (pure S-enantiomer) demonstrates superior efficacy compared to citalopram. 5
Clinical Implications of the Mechanism
Long-term treatment (14 days) in animal studies shows that tolerance to serotonin reuptake inhibition does not develop with citalopram. 1
In vitro studies demonstrate that citalopram is at least 8 times more potent than its metabolites (demethylcitalopram and didemethylcitalopram) in inhibiting serotonin reuptake, meaning the parent drug is responsible for the therapeutic effect. 1
The selective serotonergic mechanism makes citalopram effective not only for major depression but also for conditions involving serotonergic dysfunction, including anxiety disorders, panic disorder, obsessive-compulsive disorder, and premenstrual dysphoria. 6
Important Safety Consideration
- While the serotonergic mechanism provides therapeutic benefit, citalopram has dose-dependent effects on cardiac conduction (QT prolongation) that are unrelated to its primary mechanism of action, necessitating maximum dose limits of 40 mg/day in adults under 60 and 20 mg/day in adults 60 and older. 7