Selective serotonin reuptake inhibitors in affective disorders — I. Basic pharmacology

Abstract

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. 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 serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT 2c , also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, 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 metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs.

Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay

“…However, dosage may not correlate well with circulating SSRI levels, given differences in metabolism arising from, for example, metabolic gene polymorphisms. 39 Furthermore, the usually effective minimum dose of each SSRI produces comparable effects on the degree of serotonin reuptake inhibition, a surrogate for efficacy. 40 Third, assessment of individual SSRI formulations was unfeasible, because few women used SSRIs during pregnancy.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…Several lines of research converge to make the 5-HTT gene (termed SLC6A4; solute carrier family 6, member 4) a prime candidate gene for studies on the aetiology of depression: (a) the role of serotonin in the regulation of mood, activity, sleep and appetite, 63 (b) the development of depression-like features in animals after disruption of the 5-HTT function in the neonatal period, 24 (c) the efficacy of 5-HTT pharmacological inhibition to alleviate depression, 64 (d) the provocation of depressive symptom relapse by depletion of the serotonin precursor tryptophan. 65 Several polymorphisms in the SLC6A4 gene have been described, including a variable number tandem repeat in exon 2, 66 a restriction fragment-length polymorphism in the 3 0 untranslated region, 67 and a variable number tandem repeat polymorphism in the 5 0 promotor region, termed the 5-HTT gene-linked polymorphic region (5-HTTLPR).…”

From Galactorrhea to Osteopenia: Rethinking Serotonin–Prolactin Interactions

“…With the exception of fluoxetine, SSRIs generally have little interaction with postsynaptic 5-HT receptors and are mainly thought to work through this presynaptic mechanism. While several SSRIs differentially interact with other neurotransmitter systems (Goodnick and Goldstein, 1998;Hyttel, 1984;Tatsumi et al, 1997), including dopamine (sertraline) and norepinephrine (paroxetine) stimulation of PRL likely involves serotonergic mechanisms, since all SSRIs have been implicated in hyperprolactinemia, regardless of their effects on these other transmitter systems (Attenburrow et al, 2001;Bronzo and Stahl, 1993;Spigset and Mjorndal, 1997;Cowen and Sargent, 1997;Peterson, 2001;Morrison et al, 2001). …”