SELECTIVE SEROTONIN REUPTAKE INHIBITORS IN AFFECTIVE-DISORDERS - I - BASIC PHARMACOLOGY

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluox etine, fluvoxamine, paroxetine and sertraline, are the result of ratio nal research to find drugs that were as effective as the tricyclic ant idepressants but with fewer safety and tolerability problems. The SSRI s selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of pote nt serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disor ders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotoni n reuptake inhibition varies amongst this group, as does the selectivi ty for serotonin relative to noradrenaline and dopamine reuptake inhib ition. The relative potency of sertraline for dopamine reuptake inhibi tion differentiates it pharmacologically from other SSRIs. Affinity fo r neuroreceptors, such as sigma1, muscarinic and 5-HT2c, also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paro xetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active me tabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in th eir half-lives, linear versus non-linear pharmacokinetics, effect of a ge on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacok inetic differences underly the increasingly apparent important clinica l differences amongst the SSRIs.