Comparative pharmacology of selective serotonin re-uptake inhibitors (SSRIs)

Abstract

Tricyclic antidepressants (TCAs) affect a series of neurotransmitter functions. The uptake of noradrenaline (NA) and serotonin (5-HT) is inhibited to a varying degree. Many of the TCAs potently inhibit a series of neurotransmitter receptors. A series of newer antidepressants preferentially increases 5-HT transmission by inhibiting 5-HT uptake. Selective serotonin re-uptake inhibitors (SSRIs) are those which have a high potency ratio of 5-HT-uptake inhibition as compared to NA-uptake inhibition, together with slight or no effect on other uptake mechanisms, neurotransmitter receptors, enzymes, etc. The marketed SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline all fulfil the above-mentioned criteria. Paroxetine is the most potent 5-HT-uptake inhibitor, whereas citalopram is the most selective. In general, the rank order of selectivity is equal in in vitro studies, in biochemical in vivo studies and in behavioural studies. Potency and selectivity for 5-HT uptake do not coincide. In contrast to TCAs, most of which inhibit receptors for acetylcholine, histamine, NA, 5-HT or DA, most SSRIs neither bind to nor inhibit these receptors. Likewise, monoamine oxidase (MAO) is not inhibited by these drugs. Citalopram, fluoxetine and sertraline are metabolized to compounds possessing similar properties as the parent drugs, whereas this is not the case with the metabolites of fluvoxamine and paroxetine. Upon repeated administration the potency and selectivity of SSRIs are maintained. Although repeated treatment with TCAs and electroconvulsive shocks leads to changes in receptor number and pharmacological responsiveness, e.g. down-regulation of β-adrenoceptors and down-regulation of 5-HT2-mediated function, no consistent changes are seen after prolonged treatment with SSRIs. Since SSRIs show antidepressant effect, this receptor regulation seems not to be a prerequisite for clinical antidepressant activity.