While the primary mode of action of TCAs was thought to be inhibition of NE reuptake, a reassessment of the actions of the diverse antihistamines on the reuptake of various biogenic amines, especially 5HT, led to the hypothesis that an increase in brain noradrenergic function caused the energizing and motor stimulating effects of the TCAs, but that an increase in 5HT function was responsible for their mood-elevating effects.42 Structural analogs of diphenhydramine were sought as novel antidepressants. The phenoxyphenylpropylamine pharmacophore was used to identify fluoxetine (1), the first SSRI.33 The phenomenal success of fluoxetine (1) as an antidepressant led to the identification of other SSRIs, e.g., paroxetine (2), citalopram (34), fluvoxamine (3), and sertraline (35).
Most SSRIs are aryl or aryloxalkylamines. Within this chemical genus, fluoxetine (1), citalopram (34), and zimelidine (36) are racemates, and sertraline and paroxetine are separate enantiomers. The (S)-enantiomers of citalopram (escitalopram) and of fluoxetine (norfluoxetine) are relatively more potent at SERT (Table 9). Structure-activity relationships (SARs) are not well established for SSRIs, although the para-CF3 substituent of fluoxetine is critical for potency as removal and substitution at the ortho-position of a methoxy group yields nisoxetine (37), a highly selective NE uptake (NET) inhibitor.
The potency for SERT inhibition varies amongst this group, as does the selectivity for 5HT relative to NE and DA reuptake inhibition. The relative potency of sertraline for DA reuptake inhibition differentiates it from other SSRIs (Table 9). Affinity for neurotransmitter receptors such as sigma1, muscarinic, and 5HT2C also differs widely (Table 7). Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Fluoxetine has a long-acting and pharmacologically active metabolite, with high affinity for the
5HT2C receptor. Other important clinical differences among the SSRIs include differences in their half-lives, linear versus nonlinear PK, effect of patient age on their clearance, and their potential to inhibit drug metabolizing CYP isoenzymes. These differences underly the increasingly apparent important clinical differences among the SSRIs (Table 8).
Of the very limited comparative clinical data available, a meta-analysis of 20 short-term comparative studies of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) showed no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. The most common adverse reactions to the SSRIs, according to FDA and MHRA websites, were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache, tremor, discontinuation reactions, and sexual dysfunction; Table 7).
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