Review article
Pharmacokinetics of selective serotonin reuptake inhibitors

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Abstract

The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSRIs. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metabolism with high interindividual variability, whereby cytochrome P450 (CYP) isoenzymes play a major role. Therefore, resulting blood concentrations are highly variable between individuals. Except for N-demethylated fluoxetine, metabolites of SSRIs do not contribute to clinical actions. Therapeutically effective blood concentrations are unclear so far, although there is evidence for minimal effective and upper-threshold concentrations that should not be exceeded. Paroxetine and, to a lesser degree, fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and CYP2C19. This can give rise to drug-drug interactions that may have no effect, lead to intoxication, or improve the therapeutic response. These different pharmacokinetic properties of the five SSRIs, especially their drug-drug interaction potential, should be considered when selecting a distinct SSRI for treatment of depression or other disorders with a suggested dysfunction of the serotonergic system in the brain.

Introduction

In a manner similar to many psychotropic drugs, imipramine was the result of an accidental observation. It was first proposed as an antipsychotic drug. However, preclinical and clinical studies provided the first insight into the mechanisms likely to underlie therapeutic antidepressant actions, as well as the adverse reactions of imipramine and other tricyclic antidepressants (TCAs). Blockade of serotonin or noradrenaline uptake was related to antidepressant actions Wong et al. 1975, Fuller et al. 1975 and blockade of neurotransmitter receptors to their side effects. Among the latter are unpleasant, but harmless, reactions, such as dry mouth or sedation, and severe toxic reactions, such as cardiac arrest or delir Richelson 1994, Cusack et al. 1994, Owens et al. 1997. Biochemical research, therefore, looked for safer drugs that selectively or exclusively block monoamine uptake sites. The selective serotonin reuptake inhibitors (SSRIs) with high affinity to serotonin uptake sites, low affinity to noradrenaline uptake sites (Fig. 1), and very low affinity for neurotransmitter receptors were the result of these efforts (Frazer, 1997). SSRIs are thus the first class of rationally designed therapeutic drugs in psychiatry.

After the introduction of fluvoxamine, in Great Britain in 1983, fluoxetine became widely available, followed by paroxetine, citalopram, and sertraline (Preskorn, 1996a). Based on clinical trials, SSRIs are regarded as an alternative to TCAs. In some countries, they have even replaced TCAs as first-choice antidepressant medication Leonard & Tollefson 1994, Preskorn 1996a. With regard to therapeutic efficacy, SSRIs and TCAs are almost equipotent Bech 1988, Rickels & Schweizer 1990, Cole 1992. Due to the lack of receptor antagonism, SSRIs are almost devoid of life-threatening side effects, such as cardiotoxicity and CNS toxicity. SSRIs are safe De Jonghe & Swinkels 1992, Hotopf et al. 1996 and easy to handle (Leonard & Tollefson, 1994). In a Swedish survey consisting of 1202 reports describing adverse reactions to SSRIs, the most often reported events were neurological (22.4%), psychiatric (19.4%), and gastrointestinal (18%) symptoms (Spigset, 1999). The Swedish study was also aimed to assess possible risk factors associated with the occurrence of adverse events. It revealed differences in frequency and type of adverse reactions between male and female, old and young patients and between the different SSRIs.

Because of the advantageous safety profile of SSRIs, treatment of depression with antidepressant drugs could change from primarily hospitalized inpatients to outpatients (Lecrubier, 1992). Moreover, the use of SSRIs was extended from major depression to minor depression (Szegedi et al., 1997) and other psychiatric disorders that are also suggested to be associated with a dysfunctional state of the serotonin system. This includes anxiety (den Boer et al., 1995), obsessive-compulsive disorders Piccinelli et al. 1995, Leonard 1997, or premenstrual dysphoric disorders Redmond 1997, Gunasekara et al. 1998. Thus, the use of SSRIs is a rational, mechanism-based therapy.

In addition to higher safety of SSRIs, the pharmacology of the new drugs was first regarded as being less complex than for TCAs. The metabolism of TCAs leads to multiple metabolites with pharmacological properties that are different from that of the parent drug. Imipramine, for example, is a preferential serotonin reuptake inhibitor, whereas its N-demethylated metabolite desipramine primarily interacts with noradrenaline uptake sites. Clomipramine exerts marked anticholinergic activity; its 8-hydroxylated metabolite is almost devoid of anticholinergic activity, but still has serotonin uptake blocking activity. With the exception of norfluoxetine and perhaps desmethylcitalopram or desmethylsertraline, SSRI metabolites do not exhibit pharmacological properties that are relevant in vivo. Moreover, the three metabolites are also preferential inhibitors of the uptake of serotonin.

Thus, after the introduction of SSRIs, little attention was given to their pharmacokinetics in depressed patients being treated with SSRIs. This view has changed completely. Differences in the pharmacokinetics, especially in drug-drug interactions, are now the major selection criteria to use a distinct SSRI van den Berg 1995, Baumann 1996a, Brøsen 1996. Some SSRIs inhibit cytochrome P450 (CYP) isoenzymes Harvey & Preskorn 1996, Preskorn 1996b, a family containing more than 30 enzymes in humans that catalyze the oxidative metabolism of multiple drugs (Nelson et al., 1996; Gonzalez, 1992). The drug-drug interactions of SSRIs created a new estimation of a drug's pharmacokinetics in general for pharmacotherapy, since it became obvious that drug-drug interactions are not only a problem of SSRIs, but also of other drugs Preskorn & Magnus 1994, Harvey & Preskorn 1995, Shader et al. 1996, Nemeroff et al. 1996.

Because of the high relevance of differences in the pharmacokinetic properties of SSRIs for antidepressant drug therapy, this review describes pharmacokinetic abnormalities of the different SSRIs, such as nonlinear kinetics, gender differences, and age dependencies, and clinically relevant drug-drug interactions. Moreover, special attention is given to the current knowledge of therapeutically effective concentrations of SSRIs in blood, which so far is poorly documented in the literature.

Section snippets

Basic pharmacology

In most countries, fluoxetine was the first SSRI that became available for clinical use (Preskorn, 1996a). It is a racemic mixture of two enantiomers, whereby the S-enantiomer is ∼1.5 times more potent in the inhibition of serotonin reuptake than the R-enantiomer (Gram, 1994). The pharmacological difference between enantiomers is even more pronounced for the active metabolite norfluoxetine, with the S-enantiomer having ∼20 times higher reuptake blocking potency than the R-enantiomer (Fuller et

Basic pharmacology

Fluvoxamine facilitates serotonergic transmission by potent and selective inhibition of serotonin reuptake into presynaptic neurons (Fig. 1). The selectivity for blocking the uptake of serotonin is markedly higher than for norepinephrine or dopamine Richelson 1994, Hyttel 1993, Benfield & Ward 1986.

Basic pharmacokinetic properties

After oral application of fluvoxamine, more than 90% of the drug is absorbed van Harten 1995, DeVane & Gill 1997. Due to rapid and extensive hepatic first-pass biotransformation, the amount of

Basic pharmacology

Paroxetine is the most potent serotonin reuptake blocker clinically available, but has a lower selectivity for the serotonin reuptake site than either fluvoxamine or sertraline (Fig. 1). In addition, it blocks muscarinic acetylcholine receptors to almost the same degree as the TCAs imipramine or doxepin, and even more effectively than desipramine or maprotiline (Owens et al., 1997). In spite of this property, anticholinergic side effects are likely to be restricted to toxic doses of paroxetine

Basic pharmacology

Sertraline is the second most potent inhibitor of serotonin reuptake and the second most selective blocker of serotonin over noradrenaline uptake (Fig. 1). It is the only SSRI that binds to dopamine transporters (Richelson, 1994). With the exception of an α1-adrenoceptor blocking potential (Owens et al., 1997), the affinity of sertraline for neurotransmitter receptors is low and without clinical relevance. Since chronic administration of sertraline to rats attenuates phencyclidine-induced

Basic pharmacology

Citalopram has by far the highest selectivity for inhibiting serotonin reuptake (Fig. 1) over noradrenaline reuptake Owens et al. 1997, Baumann 1996a, Hyttel et al. 1995. It is marketed as a racemate, but its pharmacological effects are almost exclusively ascribed to the S-(+) enantiomer (Hyttel et al., 1992). The main metabolite of citalopram, measurable in plasma, is N-desmethylcitalopram, which is also an SSRI showing the same enantiomeric differential as its parent drug (Baumann & Larsen,

Synopsis

The various TCAs, the first generation of drugs that produce their antidepressant actions by inhibiting monoamine uptake, differ in their pharmacodynamic properties, especially with regard to side effects related to interactions with neurotransmitter receptors. The five SSRIs that are now available to treat depression or other disorders with a suggested dysfunctional serotonergic system exhibit similar therapeutic efficacies and similar adverse reaction profiles, in spite of a relatively wide

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