Pharmacology of Serotonin Uptake Inhibitors: Focus on Fluvoxamine Pavel D. Hrdina Departments of Pharmacology and Psychiatry, and Institute of Mental Health Research, University of Ottawa, Ottawa, Canada Selective serotonin uptake inhibitors comprise a from suicide victim/depressives in comparison with relatively new class of clinically effective antidepressants controls. In other post-mortem studies, a significant increase that are chemically distinct from tricyclics. They share a was found in the number of 5-HT2 receptors in the brains of common feature - a selective and potent inhibition of suicide victims or depressed subjects (Stanley et al 1983; neuronal uptake of serotonin (5-HT, 5-hydroxytryptamine) Yates et al 1990). Serotonin uptake has been found to be and have no or very weak effects on neuronal uptake of decreased and the number of [3H]imipramine sites reduced norepinephrine (NE). More importantly, they lack a signifi- in blood platelets of depressed patients (Tuomisto and cant affinity to various neurotransmitter receptor systems in Tukiainen 1976; Briley et al 1980). Whether these markers the brain and, in contrast to tricyclic antidepressants, they reflect the functional state of the serotonin uptake system in do not possess significant sedative, anticholinergic and/or the brain is at present unknown. Finally, clinical observa- cardiovascular effects. On the other hand, they all tions also indicate that the precursor of serotonin, L- potentiate the pharmacological effects of serotonin and its tryptophan, particularly in conjunction with an MAO precursor, 5-hydroxytryptophan. Fluvoxamine, now being inhibitor can be an effective treatment for depression introduced into the clinical practice, has some metabolic (Coppen et al 1963). and pharmacokinetic features that distinguish this drug Tricyclic antidepressants, the main drugs in the treatment from other compounds in this class. The purpose of this of depressive illness, are known to block the neuronal article is to review the preclinical pharmacological effects uptake of two major biogenic amines, norepinephrine and of selective serotonin uptake inhibitors with a focus on serotonin. In addition, these drugs exert a significant effect fluvoxamine and to compare them with those of representa- on several neurotransmitter receptors (including adrenergic, tive tricyclic antidepressants. cholinergic and histaminergic) and many of their side effects There is now considerable evidence available to indicate are thought to be related to this property of the tricyclic that impaired functioning of the central serotonergic system drugs. The inhibition of norepinephrine and serotonin was is involved in the pathogenesis of at least some types of thought to be responsible for the antidepressant action of depressive illness (Asberg et al 1976a). This evidence stems these compounds. This has led to the development of the from clinical observations that the level of the main 'biogenic amine hypothesis' of affective disorders which serotonin metabolite, 5-HIAA in the cerebrospinal fluid is suggests that depression may be due to a lack of nore- significantly decreased in a subgroup of depressive patients pinephrine and/or serotonin in some critical parts of the who exhibit suicidal behaviour (Asberg et al 1976b). brain. However, the delayed onset of the clinical antidepres- Furthermore, the density of presynaptic uptake sites for sant effect with tricyclic antidepressants was difficult to serotonin (labelled by [3H]imipramine) has been reported explain in the view of the fact that the inhibition of amine to be decreased in some (Stanley et al 1982; Perry et al uptake occurs shortly after drug administration. In addition, 1983), but not all, studies of post-mortem brain samples some newer, clinically effective antidepressants (e.g. mianserin) do not inhibit the uptake of either norepinephrine or serotonin. The amine hypothesis of affective disorders Address reprint requests to: Dr. P.D. Hrdina, Dept. of Pharmacology, needed a critical evaluation (see Baldessarini, 1975). University of Ottawa, 451 Smyth Rd., Rm 3131, Ottawa, Canada K1H 8M5 Subsequent studies have shown that after chronic treatment J Psychiatr Neurosci, VoL 16, No. 2 (Suppl. 1), 1991 July 1991 Pharmacology ofSerotonin Uptake Inhibitors I1I with almost all clinically effective antidepressants, a down inhibitors. The compound has a molecular weight of 434 (as regulation of B-adrenergic receptors and of responsiveness maleate), is sparingly soluble in water, freely soluble in of adenylate cyclase to norepinephrine occurs, regardless of ethanol and chloroform and practically insoluble in the effect of drugs used in the uptake of monoamines diathylether. In humans and animals, fluvoxamine is well (Vetulani et al 1974; Sulser 1983). It is now believed that absorbed after oral administration. It is metabolized entirely after the initial block of neuronal re-uptake, adaptive in the liver by two metabolic pathways: oxidative demethyla- changes in the neuronal networks have to take place in order tion (major) and deamination (minor) to more than ten to give expression to the antidepressant effect. metabolites, out of which nine have been identified in the urine (Overmars et al 1983). They are all excreted by the Table 1 kidney. After a single oral administration, almost the whole Serotonin uptake inhibitors used as antidepressants. dose (94%) is eliminated from the body within 48 hours (DeBree et al 1983). The two major metabolites of fluvox- Alaproclate Fluoxetine amine are without significant pharmacological activity when Citalopram Fluvoxamine compared to parent compound, although one of the major Clomipramine Indalpine metabolites (the carboxylic acid derivative) shows some Clovoxamine Paroxetine inhibition of serotonin uptake (Claassen 1983). The bioavail- Femoxetine Sertraline ability of fluvoxamine was shown to be about 60% (in dogs) and the binding to plasma proteins about 77%, compared to 85-90% for imipramine and 95% for fluoxetine (Claassen Serotonin Uptake Inhibitors 1983; Kaye et al 1989). Side-effects of the commonly used tricyclic antidepres- sants (sedative, hypotensive, anticholinergic, cardiac) have been a limiting factor in their clinical use particularly in N certain of cardiovascularly .CH3 subgroups patients (elderly, CH2-CH2-CH2-H" compromised). During the last two decades there has been a CH3 considerable effort to develop compounds which would have a relatively selective effect on the serotonergic system Clomipramine without concomitant interaction with a variety of neurotrans- mitter receptor systems and would be free of undesirable side F3C..a4~-C..CH2-CH2-CH2-CH2-0-CH3 effects. A new group of compounds has emerged from this search: selective serotonin uptake inhibitors. They have little N or no effect on the uptake of norepinephrine or dopamine and O-CH2-CH2-NH2 have been shown to be clinically effective antidepressants (Asberg et al 1985). They include compounds listed in Table Fluvoxamine 1. The aim of this article is to review the pharmacology of this class of compounds with special focus on the new, recently introduced member of this family, fluvoxamine, and to compare some aspects of preclinical and clinical pharma- cology of main representatives of this class, fluoxetine, F30- HCH2CH2NHCH3 clomipramine and paroxetine that either are, or may in the near future, become available for clinical use in Canada. Fluoxetine Inspection of the chemical structure of serotonin uptake H inhibitors, presented in Fig. 1, reveals that these compounds are chemically different from tricyclic antidepressants and from each other. They have some common structural features V- CH20/ and a halogen substituent is an important determinant of the potency and selectivity for serotonin uptake inhibition. Metabolism of Fluvoxamine F Fluvoxamine (LUVOX) is a compound that belongs to a Paroxetine new chemical series, the 2-aminoethyl oximethers of aralkylketones. It is chemically unrelated to any of the Fig. 1: Molecular structure of some selective serotonin existing antidepressants or selective serotonin uptake uptake inhibitors. 12 Journal ofPsychiatry & Neuroscience Supplement I Vol. 16, No. 2,1991 Table 2 Interaction with Serotonergic Mechanisms Inhibition of serotonin (5-HT) and norepinephrine (NE) uptake in vitro (rat hypothalamus) by selective serotonin The functional consequence of inhibiting neuronal uptake inhibitors and imipramine. serotonin uptake is an increased synaptic concentration of serotonin. The acute effects of serotonin uptake inhibitors Ki(nM) are believed to be due to activation of serotonergic Drug 5-HT NE NE/5-HT mechanisms. These include potentiation of the effects of serotonin and its presursors, induction (in conjunction with Imipramine 100 65 0.65 MAO inhibitors) of a serotonin produced behavioral Clomipramine 7.4 96 13 syndrome and serotonin mediated effects on REM sleep and Fluoxetine 25 500 20 food consumption. Fluvoxamine 6.2 1100 180 Paroxetine 1.1 350 320 Table 3 Ki is the concentration of drugs that produces 50% inhibition of [3H]5-HT Inhibition of monoamine uptake in synaptosomes from or ['H]NE uptake. rat hypothalamus ex vivo after oral administration of (Adapted from Johnson 1989) selective serotonin uptake inhibitors and imipramine. Selectivity for Serotonin Uptake Inhibition ED50(mg/kg) Drug 5-HT NE The main pharmacological effect of fluvoxamine is the inhibition of neuronal uptake of serotonin. The selectivity of Imipramine >30 10 fluvoxamine to inhibit the neuronal re-uptake