Citalopram transporters

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

It is perhaps not surprising that, even after taking into account pharmacokinetic differences between these drugs, the therapeutic doses of the SSRIs do not parallel their Ki for inhibition of 5-HT reuptake. For instance, citalopram is about a thousand times more selective than fluoxetine for inhibition of 5-HT uptake, and yet their clinically effective doses are similar. In short, not only is their selectivity for the 5-HT transporter in vitro a poor predictor of their efficacy in vivo but it has to be questioned whether any of these compounds actually work by blocking 5-HT uptake alone. 

Arias, B., Catalan, R. et al. (2003). 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study. /. Clin. Psychopharmacol, 23(6), 563-7. 

Barker, E. L., Perlman, M. A., Adkins, E. M Houlihan, W. J., Pristupa, Z. B Niznik, H. B and Blakely, R. D. (1998) High affinity recognition of serotonin transporter antagonists defined by species-scanning mutagenesis. An aromatic residue in transmembrane domain I dictates species-selective recognition of citalopram and mazindol. J. Biol. Chem. 273, 19459-19468. 

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a... 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

Plate 6.2 A patient has received two PET scans with [nC]DASB (3-amino-4-[(2-dlmethylaminomethyl) phenylsulfanyll benzonitrilet. a tracer selective for the serotonin transporter. The first was obtained prior to treatment and the sec raid after treatment with citalopram, 20 mg/day for 4 weeks. Tracer uptake has been reduced in the striatum by approximately 90l ot suggesting that 80 o of the serotonin transporters are occupied by citalopram with that level of exposure (Meyer etal, 2001)... 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

The affinities and transporter selectivities of experimental agents were assessed in brain tissue of adult cynomolgus or rhesus monkeys (Macaca fasicularis or Macaca mulatto). Caudate-putamen was the source of the dopamine and serotonin transporters. The dopamine transporter affinity was measured with [3H]WIN 35428 ([3H]CFT), while the serotonin transporter was measured with [3H]citalopram. Testing data are provided in Table 2. 

Table 2 Binding affinities data of selected experimental agents as inhibitors of [3H]WIN 35428 binding to the dopamine transporter and [3H]citalopram binding to the serotonin transporter in adult cynomolgus or rhesus monkeys...

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

R-citalopram may interfere with the binding of S-citalopram at the serotonin transporter... 

Escitalopram oxalate is the 5-enantiomer of citalopram (5). The therapeutic activity of citalopram resides in the 5-isomer and escitalopram binds with high affinity to the human serotonin transporter R-citalopram is about 30-fold less potent. The half-life of escitalopram is 27-32 hours. Citalopram and escitalopram have negligible effects on CYP isozymes. 

Wiborg, O. and Sanchez, C. (2003) R-Citalopram decreases the association of [ Hj-S-citalopram with the human serotonin transporter by an allosteric mechanism. European... 

I Recent evidence that escitalopram may be more effective, or have an earlier onset of action, than citalopram and have equal efficacy to venlafaxine. This is attributed to escitalopram binding to both the re-uptake site and an allosteric site causing conformational change in the 5-HT transporter and enhancing re-uptake blockade. R-enantiomer blocks this effect. This is not seen with other SSRIs. These are mostly company data so claims need independent verification. 

Escitalopram is the S-enantiomer of citalopram that binds with high affinity and selectivity to the human SERT equivalent to ( )-citalopram. It has been reported that nearly all the activity resides in the S-enantiomer and that R-citalopram actually counteracts the action of the S-enantiomer (59,60). Studies show that escitalopram exhibits twice the activity of citalopram and is at least 27 times more potent than the R-enantiomer. The R-enantiomer inhibits the S-enantiomer at the transporter (59,60). Escitalopram s mechanism of action is common to the SSRIs. 

Furthermore the authors showed that the dissociation kinetics of H-citalopram in membrane preparations of human platelets and human brain (putamen) both appeared to be affected differently by different 5-HT uptake inhibitors at 200 micromolar concentration. For instance 5-HT, clovoxamine and fluvoxamine had no effect on the dissociation half life while indalpine shortened and other 5-HT uptake inhibitors prolonged the dissociation half life of H-citalopram in both transporter preparations [24],... 

Citalopram a disubstituted racemic l-(3-dimethylaminopropyl)-l-phenyl-isobenzofuran derivative (fig. 7) is a highly selective and potent inhibitor of the 5-HT transporter in vitro as well as in vivo. Citalopram is used in clinical practice as an antidepressant. 

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