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Pharmacological Properties History

First generation ► tricyclic antidepressants (► TCAs), particularly ► clomipramine, are potent inhibitors of the serotonin transporter, but these agents have a wide range of effects on various neurotransmitter receptors, resulting in a substantial side effect burden. Although zimelidine was the first SSRI to receive approval as an antidepressant in Europe, plans to launch it in the United States were abandoned when several cases of Guillain-Barre syndrome were reported. ► Fluoxetine became the first SSRI to be licensed in the United States in 1987, and paved the way for an attack on stigma and under-detection of

► depression, with an expectation that greater safety and tolerability would be associated with superior treatment outcomes (Kramer 1999). Although this proved not to be the case, it heralded the beginning of a new era in drug development for the treatment of MDD. Over the next decade a whole class of SSRI antidepressants emerged as first line agents for the treatment of MDD, accounting for 60% of prescribed antidepressants in the U.S. Medicaid program (Chen et al. 2008; Healy 1999).

Mechanism of Action

As their name implies, the SSRIs selectively block ► serotonin (5HT) reuptake. This occurs through inhibitory actions on the Na+/K+ adenosine triphosphatase-dependent carrier on presynaptic neurons. Among the six available SSRIs, ► citalopram, ► escitalopram and

► paroxetine are the most potent blockers of 5HT reup-take. Some SSRIs have additional ► antagonist effects on neurotransmitter receptors (Table 1). For example, par-oxetine and citalopram have moderate anticholinergic effects and sertraline blocks presynaptic dopamine receptors. Escitalopram is a stereoisomer of citalopram and has been shown to exert actions at both the primary binding sites for the serotonin transporter, and also on secondary

► allosteric binding sites, a property not shared by other SSRIs (Sanchez 2006).

There is also evidence from position emission tomography (► PET) using a ligand for the serotonin transporter, that 80% or greater occupancy of the transporter occurs with citalopram, paroxetine, and sertraline at standard doses, and no additional binding occurs at higher doses (Meyer 2007). These findings are based on only a small sample of depressed patients, and the SSRIs were not examined across a wide range of doses.

The SSRIs, like their predecessors the TCAs, inhibit neurotransmitter reuptake almost immediately, but often take 2-3 weeks to exert clinically meaningful benefit.

SSRIs and Related Compounds. Table 1. Mechanism of action and indications for six available SSRIs.

Drug

Mechanism of action

Indications

Citalopram

5HT blockade; mild NE blockade; Post receptor blockade: ACH; H1, DA and alpha-1 (weak blockade)

MDD; panic disorder

Escitalopram

5HT blockade; mild NE blockade

MDD; GAD; panic disorder

Fluoxetine

5HT blockade; mild NE blockade; mild post DA receptor blockade

MDD; OCD; bulimia nervosa; panic disorder

Fluvoxamine

5HT blockade; mild NE blockade

MDD; OCD

postsynaptic receptor blockade: ACH

MDD; panic disorder; SAD; GAD; OCD; PTSD; premenstrual dysphoric disorder

Sertraline

5HT blockade; mild NE blockade; Post receptor blockade: alpha-1; presynaptic receptor blockade: DA

MDD; OCD; panic disorder; PTSD; SAD; premenstrual dysphoric disorder

NE = norepinephrine;ACH = acetylcholine;H1 = histamine 1;DA = dopamine;MDD = major depressive disorder;GAD = generalized anxiety disorder, OCD = obsessive compulsive disorder;PTSD = posttraumatic stress disorder;SAD = social anxiety disorder

NE = norepinephrine;ACH = acetylcholine;H1 = histamine 1;DA = dopamine;MDD = major depressive disorder;GAD = generalized anxiety disorder, OCD = obsessive compulsive disorder;PTSD = posttraumatic stress disorder;SAD = social anxiety disorder

This has been linked to down regulation of the 5HT1A terminal autoreceptors. In addition, SSRIs, like other antidepressants, stimulate ► neurogenesis, particularly in the CA3 layer of the ► hippocampus after 2-3 weeks of exposure. Animal models of depression using stress paradigms show suppression of neurogenesis which is reversed by antidepressants (Schmidt and Duman 2007).

► Pharmacokinetics

The SSRIs are generally well absorbed and not affected by food administration, with the exception of sertraline, where food can increase levels of the drug in plasma. They are metabolized by hepatic microsomal enzymes that are part of the ► cytochrome P450 system, particularly the CYP2D6 isoenzyme, although the 2C9, 2C19 and 3A4 isoenzymes are also substrates for several SSRIs (Table 2) (Kennedy et al. 2007).

SSRIs and Related Compounds. Table 2. Pharmacokinetic profile of SSRIs.

Drug

% Bioavailability

Metabolism

Active metabolites

Half life (hours)

Citalopram

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