Comparison of the Effects of Antidepressants and Their Metabolites on ...

Cellular and Molecular Neurobiology, Vol. 19, No. 4, 1999

Comparison of the Effects of Antidepressants and Their Metabolites on Reuptake of Biogenic Amines and on Receptor Binding Connie Sańchez1,2 and John Hyttel1 Received December 17, 1996; accepted February 20, 1997 SUMMARY 1. The present survey compares the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. The following antidepressants were included in the study: the tricyclic antidepressants amitriptyline, dothiepin, and lofepramine and the atypical antidepressant bupropion, which all have considerable market shares in the UK and/or US markets; the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the recently approved antidepressants venlafaxine and nefazodone. 2. Amitriptyline has similar in vitro reuptake inhibitory potencies for 5-HT and NA, whereas the metabolite nortriptyline is preferentially a NA reuptake inhibitor. Both amitriptyline and nortriptyline are also 5-HT2 receptor antagonists. 3. Dothiepin has equipotent 5-HT and NA reuptake inhibitory activity, whereas northiaden shows a slight selectivity for NA reuptake inhibition. Dothiepin and northiaden are also 5-HT2 receptor antagonists. The slow elimination rate of northiaden (36–46 hr) compared to dothiepin (14–24 hr) suggests that northiaden contributes significantly to the therapeutic effect of dothiepin. 4. Lofepramine is extensively metabolized to desipramine. Desipramine plays an important role in the antidepressant activity of lofepramine, as the plasma elimination half-life of lofepramine (4–6 hr) is much shorter than that of desipramine (24 hr). Both compounds are potent and selective inhibitors of NA reuptake. 5. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are potent 5-HT reuptake inhibitors, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity. Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective and the metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound and has an extremely long half-life (7–15 compared to 1–3 days). Thus the metabolite plays an important role for the therapeutic effect of fluoxetine. Fluoxetine is also a 5HT2C receptor antagonist. Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline, but demethylsertraline has a very long half-life (62–104 hr) compared to the parent compound (24 hr) and it might play a role in the therapeutic effects of sertraline. Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram, and the elimination half-lives are approximately 1.5 and 2 days, respectively. 6. Bupropion and hydroxybupropion are weak inhibitors of biogenic amine reuptake. The mechanisms of action responsible for the clinical effects of bupropion are not fully 1 2

Pharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Copenhagen, Denmark. To whom correspondence should be addressed. 467 0272-4340/99/0800-0467$16.00/0  1999 Plenum Publishing Corporation

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Sańchez and Hyttel understood, but it has been suggested that both dopaminergic and noradrenergic components play a role and that the hydroxybupropion metabolite contributes significantly to the antidepressant activity. 7. Venlafaxine and O-demethylvenlafaxine are weak inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to one. O-Demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively), and it is likely that it contributes to the overall therapeutic effect of venlafaxin. 8. Nefazodone and 움-hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors. Both compounds are also 5-HT2 receptor antagonists. Both parent compound and metabolite have short elimination half-lives. KEY WORDS: antidepressants; metabolites; biogenic amine reuptake inhibition; receptor binding; in vitro.

INTRODUCTION Effective antidepressant treatment has been available for the last 30–40 years. The first tricyclic antidepressant (TCA), imipramine, and the first monoamine oxidase inhibitor (MAOI), iproniazid, were introduced in the late 1950s. In particular, the TCAs are still being used extensively as antidepressant treatment, whereas the MAOIs are used less extensively. However, selective serotonin reuptake inhibitors (SSRIs) have gained extensive use in many countries during the last decade. During all these years much research effort has been put into identifying antidepressants with an improved efficacy and, in particular, with improved side-effect profiles compared to those of the first generation of antidepressants. The efficacy has not been improved so far, whereas the side-effect profile has been markedly improved in the new antidepressants. Antidepressants are classified according to chemical structures and pharmacological properties of the parent compound (i.e., tricyclic, tetracyclic, bicyclic, and monocyclic monoamine reuptake inhibitors and MAOIs). However, a considerable number of the antidepressant compounds are metabolized into pharmacologically active substances. Depending on their potency, efficacy, selectivity, half-life, and quantity, the activity of these metabolites may have an important impact on the net in vivo effect of a given drug. The present survey compares and discusses the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. In this context, by principal metabolites we mean metabolites that are produced in large quantities in the first-pass metabolism or are accumulated in the organism after repeated treatment due to substantially longer half-lives than the mother substance. Drugs being used in the clinic in either the United Kingdom or the United States were considered for inclusion in the present survey (Table I). Among these drugs, two criteria have been applied for selection; for the older drugs a market share of 5% or more in at least one of the two countries was required, whereas the five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, all were included irrespective of market shares. Furthermore, the recently approved antidepressants venlafaxine and nefazodone were included in the survey.

Antidepressants and Metabolites, Biogenic Amines, and Receptors

469

CHEMICAL STRUCTURE AND PHARMACOKINETICS OF ANTIDEPRESSANTS AND THEIR MAIN METABOLITES The chemical structures of the parent compounds and their principal metabolites are summarized in Fig. 1. Table I summarizes the names of the selected antidepressants and their principal metabolites, as well as their plasma half-lives in humans. Many biogenic amine reuptake inhibitors contain a tertiary or secondary amino group, and the principal route of metabolism is N-demethylation of these groups to form demethyl metabolites. These structures may undergo further biotransformations (e.g., oxidation), but in general these metabolites are biologically inactive. Amitriptyline was one of the first TCAs to be used in the clinic and it is still being used in a large number of patients. Amitriptyline is a tertiary amine and it is metabolized by N-demethylation to nortriptyline, which is the major active metabolite (Fig. 1). Numerous other metabolites with pharmacological activity are formed as well, i.e., 10-hydroxyamitriptyline, 10-hydroxynortriptyline, and demethylnortriptyline (Ishida et al., 1984; Burch et al., 1984). The maximum plasma concentration after oral administration of amitriptyline is reached within 2–3 hr, and the plasma half-lives in man of amitriptyline and its major metabolite, nortriptyline, are 12-36 and 22-88 hours, respectively (Schulz et al., 1985; Braithwaite, 1978). Dothiepin is the most frequently prescribed TCA in the United Kingdom. It is a tertiary amine and has a close structural similarity to amitriptyline (Fig. 1). Dothiepin is rapidly absorbed after oral administration, with maximum plasma concentrations within 2–4 hr. Three major metabolites are produced in humans, i.e., demethylation to northiaden and oxidation of the sulfur atom to dothiepin sulfoxide or northiaden sulfoxide (Yu et al., 1986). Dothiepin sulfoxide is produced in slightly larger quantities than the other two metabolites (Goodnick, 1994). Dothiepin has a plasma elimination half-life humans of 14–24 hr, and the three metabolites have somewhat longer half-lives: i.e., northiaden, 36–46 hr; dothiepin sulfoxide, 23–26 hr; and northiaden sulfoxide, 24–34 hr (Maguire et al., 1981; Goodnick, 1994). Lofepramine (Fig. 1) is a TCA with a close structural similarity to imipramine. It is extensively metabolized (more than 70%) to the tricyclic secondary amine, desipramine, both in rat and in humans (Plym Forshell, 1977). A smaller quantity of lofepramine is metabolized to demethyllofepramine. Both desipramine and demethyllofepramine are further metabolized to demethyldesipramine, and desipramine is also metabolized to 2-hydroxydesipramine. Lofepramine is rapidly absorbed after oral administration, with the maximum plasma concentration 1 hr after administration. The plasma elimination half-life of lofepramine is short (4–6 hr), whereas that of desipramine is considerably longer (approximately 24 hr) (Plym Forshell et al., 1976; Stern et al., 1985). The fact that the plasma elimination half-life of lofepramine is much shorter than that of desipramine suggests that desipramine is accumulated during repeated treatment. This also suggests that desipramine plays an important role in the antidepressant activity of lofepramine, or even that lofepramine is acting like a prodrug for desipramine. However, lofepramine has been found to be less cardiotoxic than desipramine and amitriptyline in a study of electrocardiographic changes after intravenous injection to rat (Sjo¨gren, 1987). A comparison

Paroxetine (3S-trans)-3-[(1,3-Benzodioxol-5-yloxy)methyl-4-(4-fluorophenyl)piperidine Sertraline (1S-cis)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1naphthalenamine

SSRIs Fluoxetine (⫾)-3-[(4-Trifluoromethyl)phenoxy]-N-methyl-3-phenyl-1propanamine

Lofepramine 1-(4-Chlorophenyl)-2-[[3-(10,11-dihydro-5H-dibenz[b,f ]azepin-5yl)propyl]amino]ethanone

Dothiepin (Z)-3-Dibenzo[b,e]thiepin-11(6H)-ylidene-N,N-dimethyl-1propanamine

TCAs Amitriptyline 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,Ndimethyl-1-propanamine

Parent compound

Norfluoxetine (⫾)-3-[(4-Trifluoromethyl)phenoxy]-3-phenyl-1-propanamine None

Desipramine 10,11-Dihydro-N-methyl-5H-dibenz[b,f ]azepine-5-propanamine

Northiaden (Z)-3-Dibenzo[b,e]thiepin-11(6H)-ylidene-N-methyl-1-propanamine Dothiepin sulfoxide (Z)-3-Dibenzo[b,e]thiepin-11(6H)-ylidene-N,N-dimethyl-1propanamine-S-oxide Northiaden sulfoxide (Z)-3-Dibenzo[b,e]thiepin-11(6H)-ylidene-N-methyl-1-propanamineS-oxide

Nortriptyline 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-Ndimethyl-1-propanamine

Main metabolite

Table I. Antidepressants: Their Main Metabolites and Plasma Half-Lives in Humans

Approx. 24

Approx. 24

168–360

24–72

Approx. 24

4–6

24–34

23–26

36–46

14–24

22–88

12–36

T1/2 in human (hr)

Nefazodone 2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one

Venlafaxine 1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

Others Bupropion 1-(3-Chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone

Fluvoxamine (E)-5-Methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone-O-(2aminoethyl)oxime Citalopram 1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3dihydroisobenzofuran-5-carbonitrile

움-Hydroxynefazodone 2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-(2-hydroxyethyl)2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one

O-Demethylvenlafaxine 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol

Hydroxybupropion 1-(3-Chlorophenyl)-2-[(1,1-hydroxymethylethyl)amino]-1-propanone Threohydrobupropion 1-(3-Chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanol

Demethylcitalopram (1-(4-Fluorophenyl)-1-[3-(methylamino)propyl]-1,3dihydroisobenzofuran-5-carbonitrile

Demethylsertraline (1S-cis)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1naphthalenamine None

1.5–4

2–4

Approx. 11

Approx. 5

9–27

15–22

10–21

Approx. 48

Approx. 33

10–16

62–104

472

Sańchez and Hyttel

Fig. 1. Chemical structures of the parent compounds and their principal metabolites.

of the effects of lofepramine and amitriptyline on blood pressure and heart rate in healthy volunteers also suggested a more favorable profile of lofepramine than other TCAs, but no direct comparison with desipramine was performed in this study (Stern et al., 1985). In the late 1980s fluoxetine was the first SSRI to be approved for treatment of depressive disorder and it is by now the most prescribed antidepressant in the world. Structurally, fluoxetine (Fig. 1) is classified as a monocyclic antidepressant. Fluoxetine is absorbed relatively slow after oral administration, with the maximum plasma concentration after 6–8 hr (Goodnick, 1994). Fluoxetine is metabolized by N-demethylation to norfluoxetine in both rat and human (Caccia et al., 1990;


473

Fig. 1. (Continued).

Lemberger et al., 1985). After repeated oral doses the metabolite is present in equal amounts as the parent compound, but the plasma elimination half-lives of fluoxetine and norfluoxetine differ markedly. In humans, plasma elimination half-lives of parent compound and metabolite are 1–3 and 7–15 days, respectively (Lemberger et al., 1985). The other SSRIs, citalopram, fluvoxamine, paroxetine, and sertraline, are structurally unrelated to fluoxetine (Fig. 1). Paroxetine is a phenylpiperazine derivative; it is metabolized in both rat and human by oxidation at the methylenedioxy bridge, and a substantial number of metabolites have been identified (Haddock et al., 1989). However, all metabolites are reported to be devoid of pharmacological activity (Haddock et al., 1989; Kaye et al., 1989). The plasma elimination half-life of paroxetine in humans is about 24 hr, and maximum concentrations are reached within 5 hr (Kaye et al., 1989).

474


Fig. 1. (Continued).

Sertraline is structurally classified as bicyclic antidepressant (Fig. 1). Like most other monoamine reuptake inhibitors, sertraline is metabolized by N-demethylation (to produce demethylsertraline) (Koe et al., 1983). Sertraline is absorbed relatively slowly after oral administration, with the maximum plasma concentration after 6–8 hr. The plasma elimination half-life of sertraline is approximately 24 hr, whereas that of the metabolite is considerably longer, 62–104 hr (Warrington, 1991; Goodnick, 1994). The ratio between plasma concentrations of demethylsertraline and sertraline is of the order of 2 : 1 under steady-state conditions. Fluvoxamine is structurally classified as a monocyclic antidepressant (Fig. 1). It is extensively metabolized in the liver and at least 11 metabolites have been identified in the urine (Claasen, 1983; Overmars et al., 1983). However, all of these metabolites are pharmacologically inactive. The plasma elimination half-life of fluvoxamine in humans is 10–16 hr and the maximum plasma concentration is reached within 2–8 hr (de Bree et al., 1983).


475

Citalopram is a bicyclic phthalane derivative (Fig. 1). It is metabolized by Ndemethylation and N-oxide formation. The principal metabolite of citalopram is demethylcitalopram; a second and minor metabolite of citalopram is didemethylcitalopram (Hyttel, 1982). The maximum plasma concentration of citalopram is reached within 2–4 hr, and plasma elimination half-lives of citalopram and the demethyl metabolite in humans are approximately 1.5 and 2 days, respectively (Fredricson Overø, 1982; Baumann and Larsen, 1995). Bupropion is an aminoketone antidepressant which is described as an atypical antidepressant (Fig. 1). It was marketed in the United States in the late 1980s. It is rapidly absorbed after oral administration (maximum concentration, 1–2 hr), and it is extensively metabolized by oxidative side chain cleavage in both rodents and humans (Posner et al., 1985; Schroeder, 1983; Welch et al., 1987; Goodnick, 1994). The major metabolites of bupropion are hydroxybupropion and threohydrobupropion (Fig. 1) (Ferris and Cooper, 1993). Furthermore, a minor metabolite, erythrohydrobupropion, is formed (Goodnick, 1994). The plasma half-lives of bupropion and the two major metabolites in humans are of the order of 10–21, 15–22, and 9–27 hr, respectively (Goodnick, 1994; Ascher et al., 1995). Venlafaxine is a bicyclic phenylethylamine and its major metabolite in humans is O-demethylvenlafaxine (Muth et al., 1991; Howell et al., 1993) (Fig. 1). Furthermore, venlafaxine is metabolized into two minor metabolites, N-demethylvenlafaxine and N,O-didemethylvenlafaxine (Muth et al., 1991). The plasma elimination half-life of venlafaxine in humans is relatively short, i.e., 5 hr, and the maximum concentration is achieved within 2 hours. The plasma elimination half-life of Odemethylvenlafaxine is considerably longer, i.e., approximately 11 hr (Muth et al., 1991). Nefazodone is a phenoxyethyltriazolinophenylpiperazine that is structurally related to trazodone. The primary metabolites are 움-hydroxynefazodone and triazolenedione, and a third and minor metabolite of nefazodone is m-chlorophenylpiperazine (mCPP) (Eison et al., 1990; Mayol et al., 1994; Taylor et al., 1995). The latter is also a metabolite of trazodone. Triazolenedione is considered of minor importance compared to 움-hydroxynefazodone because it is a weak 5-HT2A receptor antagonist and is otherwise pharmacologically inactive (Taylor et al., 1995). The elimination half-lives of nefazodone and 움-hydroxynefazodone in humans are 2–4 and 1.5–4 hr, respectively (Goldberg, 1995).

METHODS USED TO ASSESS IN VITRO EFFECTS ON BIOGENIC AMINE ACTIVITY AND RECEPTOR AFFINITIES The following methods were used for previously unpublished results of the present study. Inhibition of 3H-5-HT reuptake in synaptosomes from rat brain minus cerebellum, inhibition of 3H-noradrenaline (NA) reuptake in rat cortical synaptosomes and inhibition of 3H-DA reuptake in rat striatal synaptosomes were determined as described by Hyttel (1982). Inhibition of 3H-8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) binding to 5-HT1A receptors in membranes from rat brain minus cerebellum and inhibition of 3H-ketanserin binding to 5-HT2A recep-

476


tors in membranes from rat cortex were determined as described by Hyttel et al. (1988). Inhibition of 3H-mesulergine binding to a cloned rat 5-HT2C receptor expressed in 3T3 cells was determined as described by Bøgesø et al. (1995). Inhibition of 3H-SCH 23390 binding to DA D1 receptors in rat striatal membranes was determined as described by Hyttel (1982), and inhibition of 3H-spiperone binding to DA D2 receptors in rat striatal membranes was determined as described by Hyttel (1987). Inhibition of 3H-prazosin binding to 움1-adrenoceptors in membranes from whole rat brain was determined as described by Hyttel and Larsen (1985), inhibition of 3H-idazoxan binding to 움2-adrenoceptors in membranes from rat brain cortex was determined as described by Megens et al. (1986), and inhibition of 3H-dihydroalprenolol binding to 웁-adrenoceptors in membranes from rat cortex was determined as described by Hyttel et al. (1984). Inhibition of 3H-mepyramine binding to histamine H1 receptors in membranes from rat brain minus cerebellum was determined ¨ gren (1984). Inhibition of 3H-quinyclidinyl benzilate as described by Hall and O (QNB) binding to muscarinic cholinergic receptors in membranes from rat whole brain was determined as described by Meier et al. (1996). Table II summarizes the radioactive ligands and brain areas that were used to study receptor binding and functional activity on biogenic amines in the present study and other studies that are referred to in Tables III–VI. Furthermore, literature references are included in Table II.

FUNCTIONAL EFFECTS ON CATECHOLAMINE REUPTAKE SYSTEMS Table III shows the in vitro and in vivo reuptake inhibitory potencies of the selected antidepressants and their major metabolites and Fig. 2 illustrates the 5HT/NA selectivity ratios. The TCA amitriptyline has similar reuptake inhibitory potencies for 5-HT and NA, whereas its metabolite nortriptyline is preferentially a NA reuptake inhibitor, with a selectivity ratio of more than 150. Similar 5-HT/NA selectivity ratios were observed in vivo, measured as potentiation of 5-HTP-induced 5-HT syndrome and reversal of tetrabenazine-induced ptosis in mice, respectively (Table III). Compared to the 5-HT and NA reuptake inhibitory potencies, the DA reuptake inhibition appears to be of minor importance for both compounds. The TCA dothiepin and its metabolite northiaden sulfoxide show equipotent effects as regards 5-HT and NA reuptake inhibition, whereas the metabolite, northiaden, shows a slight selectivity for NA reuptake inhibition compared to 5-HT reuptake inhibition (Table III). Dothiepin sulfoxide has very weak reuptake inhibitory effects at all three sites. The NA reuptake inhibitory activity of both dothiepin and northiaden is also reflected in vivo, where both compounds reverse tetrabenazine-induced ptosis in mice. Actually, the in vivo potency of northiaden is higher than that of dothiepin (Table III). These results and the fact that northiaden is eliminated at a slower rate than dothiepin suggest that northiaden probably contributes significantly to the therapeutic effect of dothiepin (Heal et al., 1992). Both lofepramine and the metabolite desipramine are potent and selective inhibitors of NA reuptake and have only minor effects on 5-HT and DA reuptake


477

Table II. Overview of Methods Used for Determination of Monoamine Reuptake Inhibitory Potencies and Receptor Binding Affinities Target Reuptake inhibition 5-HT

Ligand

3

H-5-HT

NA

3

DA

3

H-NA

H-DA

Tissuea or cell line

Brain synaptosomes Cortical synaptosomes Hypothalamus Striatum Cortical synaptosomes Hypothalamic synaptosomes Striatal synaptosomes Cortical synaptosomes

Receptor binding 5-HT1 5-HT1A

3 3

H-5-HT H-8-OHDPAT

Cortex Brain minus cerebellum Hippocampus

5-HT2A

3

H-Ketanserin

Cortex

5-HT2C

3

H-Mesulergine

DA D1 DA D2

3

H-SCH 23399 H-Spiroperidol

NA 움1

3

H-WB 4101

3T3 cells Bovine choroid plexus Striatum Striatum Striatum Brain homogenate Cortex

H-Idazoxane

Cortex

3

H-Prazosin

3

NA 움2

3

3

H-Clonidine H-Dihydroalprenolol

NA 웁

3

Cholinergic Muscarine

3

Histamine H1

3

H-QNB

3

H-QNB H-Mepyramine

3

H-Pyrilamine

a

Rat brain tissue if not stated otherwise.

Cortex Cortex Brain homogenate Striatum Brain homogenate Brain homogenate

Reference(s)

Hyttel, 1982, 1994 Muth et al., 1986; Eison et al., 1990 Ascher et al., 1995 Koe et al., 1983 Hyttel, 1982, 1994; Muth et al., 1986 Eison et al., 1990; Ascher et al., 1995; Koe et al., 1983 Hyttel, 1982, 1994; Ascher et al., 1995; Koe et al., 1983 Muth et al., 1986

Ferris et al., 1983 Hyttel et al., 1988; Hyttel, 1994 Heal et al., 1992; Eison et al., 1990 Hyttel et al., 1988; Hyttel, 1994 Bøgesø et al., 1995 Taylor et al., 1986 Hyttel, 1982, 1994 Hyttel, 1987, 1994 Muth et al., 1986 Hyttel and Larsen, 1985; Hyttel, 1994 Muth et al., 1986; Eison et al., 1990 Megens et al., 1986; Hyttel, 1994 Eison et al., 1990 Hyttel et al., 1984, Eison et al., 1990; Hyttel, 1994 Meier et al., 1996 Muth et al., 1986 ¨ gren, 1984; Hall and O Hyttel, 1994 Muth et al., 1986

Compound

움-Hydroxynefazodone

O-Demethylvenlafaxine

Hydroxybupropion Threohydrobupropion

Demethylcitalopram

Demethylsertraline

Norfluoxetine

Desipramine

Northiaden Dothiepin sulfoxide Northiaden sulfoxide

Nortriptyline

Major metabolite

NA 24a 3.4a 70* b 25* b 4,912* b 1,948* b 2.7a 0.83a 370a 580a 81a 160a 4,600i 620a 6,100a 740a 1,400 7,000g 16,000g 640c 1,160c 110d 376d

5-HT 39a 570a 78* b 192* b 5,402* b 534* b 880a 200a 6.8a 3.8a 0.29a 0.19a 450i 3.8a 1.8a 14a 19,000 105,000g 67,000g 210c 180c 68d 165d

DA 5,300a 3,500a 5,185* b 2,539* b 77,387* b 58,727* b 3,300a 9,100a 5,000a 4,300a 5,100a 48a 3,800i 42,000a 40,000a 28,000a 570 23,000g 47,000g 2,800 13,400c 470d

b

Hyttel (1994). Heal et al. (1992). c Muth et al. (1986, 1991). d Eison et al. (1990). e Hyttel et al. (1992). f Reversal of reserpine-induced ptosis in mice, p.o. administration (Taylor et al., 1986). g Ascher et al. (1995). h mg/kg, p.o. i Koe et al. (1983).

a

Nefazodone

Venlafaxine

Bupropion

Fluvoxamine Citalopram

Paroxetine Sertraline

Fluoxetine

Lofepramine

Dothiepin

Amitriptyline

Reuptake inhibition in vivo, IC50 or K* i (nM)

96

13

18a 1.8a 170e 130

37f 39f

29

⬎92a ⬎99a ⬎120e ⬎140

⬎54a ⬎54a

1.9a 1.6a ⬎29a

88a ⬎130a 88a 0.63a 5.4a

20a 2.9a 65h 9.8h

NA

17a 89a

5-HT

Reuptake inhibition in vivo, ED50 (애mol/kg, s.c.)

Table III. Biogenic Amine Reuptake Inhibitory Potencies in Vitro of Antidepressants and Their Metabolites Expressed as IC50 or K* i Values, and in Vivo 5-HT and NA Reuptake Inhibition Measured as Potentiation of 5-HTP-Induced 5-HT Syndrome and Reversal of Tetrabenazine-Induced Ptosis in Mice, Respectively (Method Described by Hyttel et al., 1992).

478 Sańchez and Hyttel


479

Table IV. Affinities for 5-HT Receptor Subtypes Receptor binding affinity, IC50 or K*i (nM) Compound

Metabolite

Amitriptyline Nortriptyline Dothiepin Northiaden Dothiepin sulfoxide Northiaden sulfoxide Lofepramine Desipramine Fluoxetine Norfluoxetine Paroxetine Sertraline Demethylsertraline Fluvoxamine Citalopram Demethylcitalopram Bupropion Hydroxybupropion Threohydrobupropion Venlafaxine

5-HT1A

5-HT2A

19,000 2,800 4,004* b 2,623* b ⬎10,000* b ⬎10,000* b ⬎10,000 3,300 79,000a 79,000a ⬎100,000a 100,000a

11 72 152* b 141* b ⬎10,000* b ⬎10,000* b 1,200 560 710a 2,500 18,000a 8,500a

⬎100,000a 15,000a 41,000a ⬎100,000

12,000a 5,600a 6,200a ⬎100,000d

⬎10,000

⬎10,000

1,000 589c

10 34c

5-HT2C 8.0 19

160 20,000 20,000a 6,700a 630a 1,400 ⬎100,000 40,000

O-Demethylvenlafaxine Nefazodone Hydroxynefazodone

72 1,070* e

a

Hyttel (1994). Heal et al. (1992). c Eison et al. (1990). d 3 H-SPI. e Taylor et al. (1995). b

inhibition. Thus lofepramine exerts its therapeutic effect mainly by facilitation of noradrenergic neurotransmission, and due to the fast plasma elimination rate of lofepramine and the slow rate of the metabolite desipramine, it is very likely that despramine is the principal drug responsible for the therapeutic effect. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are all potent 5-HT reuptake inhibitors in vitro as well as in vivo, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity (Table III). However, the 5-HT/NA selectivity ratios vary considerably between SSRIs (Fig. 2). Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective compound among the SSRIs (Fig. 2). The metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound, whereas the opposite is the case for O-demethylated sertraline and O-demethylated citalopram (Fig. 2). Because of the extremely long halflife of norfluoxetine compared to fluoxetine (Table I), it is likely that the metabolite plays an important role in the therapeutic effect of fluoxetine. Actually, fluoxetine is a racemic mixture of (R)- and (S)-fluoxetine, but both enantiomers are selective 5-HT reuptake inhibitors (Wong et al., 1985). In contrast, the (S)-enantiomer of

Compound

b

Metabolite

움-Hydroxynefazodone

O-Demethylvenlafaxine

Hydroxybupropion Threohydrobupropion

Demethylcitalopram

Demethylsertraline

Norfluoxetine

Desipramine

Northiaden Dothiepin sulfoxide Northiaden sulfoxide

Nortriptyline

Hyttel (1994). Heal et al. (1992). c Muth et al. (1986, 1991). d Eison et al. (1990). e 3 H-Piflutixol.

a

Nefazodone

Venlafaxine

Bupropion

Fluvoxamine Citalopram

Paroxetine Sertraline

Fluoxetine

Lofepramine

Dothiepin

Amitriptyline

1,500

⬎10,000

⬎10,000a 22,000a 32,000a 43,000e

500 4,400 10,000a 22,000a 15,000a 6,300a

81 210

DA D1

⬎10,000 ⬎1,000c 180

66,000a 33,000a 53,000a ⬎10,000

6,700 6,100 32,000a 13,000a 52,000a 24,000a

850 2,300

DA D2

⬎10,000 ⬎1,000c 42 145d

4,800a 1,600a 1,500a 16,000

69 120 419* b 950* b 9,660* b ⬎10,000* b 620 260 14,000a 15,000a 19,000a 2,800a

움1

1,200 2,490d

⬎10,000

1,900a 18,000a 23,000a ⬎100,000

8,900a 1,800a

340 710 12* b 15* b 267* b 272* b 2,100 1,700 2,800a

움2

Receptor binding affinity, IC50 or K* i (nM)

Table V. Affinities for DA D1 and DA D2 Receptors and 움1⫺ , 움2⫺ , and 웁-Adrenoceptors

웁

24,000 ⬎1,000d

89,000a ⬎100,000a ⬎10,000a ⬎100,000

⬎10,000 1,700 18,000a ⬎1,000a 35,000a 14,000a

14,000 13,000

480 Sańchez and Hyttel


481

Table VI. Affinities for Cholinergic Muscarinic and Histamine H1 Receptors Receptor binding affinity, IC50 or K*i (nM) Compound

Metabolite

Amitriptyline Nortriptyline Dothiepin Northiaden Dothiepin sulfoxide Northiaden sulfoxide Lofepramine Desipramine Fluoxetine Norfluoxetine Paroxetine Sertraline

Musc 8.9 53 26* b 110* b 2,512 b 5,478* b 300 170 3,100a 3,400a 210a 1,100a

Hist1 8.3 61 4* b 25* b 105* b 936* b 1,000 260 3,200a 11,000a 19,000a 10,000a

Demethylsertraline Fluvoxamine Citalopram Demethylcitalopram Bupropion Hydroxybupropion Threohydrobupropion Venlafaxine O-Demethylvenlafaxine Nefazodone Hydroxynefazodone

34,000a 5,600a 14,000a 49,000

11,000a 350a 1,700a

⬎10,000c ⬎10,000c 19,000 ⬎1,000* d

⬎10,000c ⬎1,000c 370 240* d

a

Hyttel (1994). Heal et al. (1992). Muth et al. (1986, 1991). d Taylor et al. (1995). b c

norfluoxetine was found to be a considerably more potent 5-HT reuptake inhibitor than the (R)-enantiomer (Fuller et al., 1992). Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline (Fig. 2 and Table III), but demethylsertraline has a very long half-life compared to the parent compound and is consequently present at higher concentrations in plasma in humans than the parent compound (Table I). Thus it is possible that demethylsertraline plays a role in the therapeutic effects of sertraline (Koe et al., 1983). A recent study comparing the in vivo effects of sertraline and demethylsertraline on extracellular 5-HT in striatum measured by microdialysis techniques and on inhibition of 5-HT mediated neuronal firing in the dorsal raphe´ nucleus suggest a very low in vivo potency of demethylsertraline (Sprouse et al., 1996). Citalopram is also a racemic mixture, and the pharmacological activities of citalopram and demethylcitalopram reside in the (S)-enantiomers (Hyttel et al., 1992). Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram and has only very weak activity in vivo (Table III). The ratio between in vitro 5-HT and NA reuptake inhibition suggests a reuptake selectivity comparable to that of fluoxetine. Bupropion and its major metabolites are weak inhibitors of biogenic amine reuptake (Table III). There is in vitro selectivity for DA and NA reuptake inhibition

482


Fig. 2. Selectivity ratio between in vitro 5-HT and NA reuptake inhibitory potencies of antidepressants and principal metabolites.

relative to the 5-HT reuptake inhibitory potency of bupropion. Bupropion is also a weak DA reuptake inhibitor in acute in vivo tests, where it shows a weak stimulatory effect at high doses measured as increased locomotor activity (Martin et al., 1990). The mechanisms of action responsible for the clinical effects of bupropion are not fully understood, and it has been suggested that both dopaminergic and noradrenergic components play a role (Martin et al., 1990; Ascher et al., 1995). Based on studies of bupropion and its metabolites in animal models, it has been suggested that the metabolites, in particular, the hydroxybupropion metabolite, may contribute significantly to the antidepressant activity of bupropion (Martin et al., 1990). Hydroxybupropion had a similar potency to that of bupropion in the forced swim test in mice and in the inhibition of reserpine-induced hypothermia (Martin et al., 1990). Both venlafaxine and O-demethylvenlafaxine are relatively weak in vitro inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to 1 (Fig 2). In spite of the low in vitro potency, venlafaxine is a moderately potent 5-HT and NA reuptake inhibitor in vivo (Table III). The O-demethyl metabolite has in vivo


483

potencies that are comparable to those of the parent compound (Muth et al., 1991). Furthermore, O-demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively; Table I) and is, consequently, found at a higher concentration in plasma than the parent compound. Thus it is very likely that O-demethylvenlafaxine contributes significantly to the overall therapeutic effect of venlafaxine. The minor N-demethylated and N,O-didemethylated metabolites are both weak 5-HT and NA reuptake inhibitors and are not expected to contribute significantly to the therapeutic effect (Muth et al., 1991). Venlafaxine is a racemic mixture of (S)- and (R)-venlafaxine. The (R)-enantiomer inhibits both 5-HT and NA reuptake (in vitro selectivity ratio, approximately 0.25), while the (S)-enantiomer preferentially inhibits 5-HT reuptake (in vitro selectivity ratio, approximately 0.03) (Muth et al., 1991). Nefazodone and 움-hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors in vitro. In the present study, nefazodone is also a very weak 5-HT reuptake inhibitor in vivo (Table III). This apparent lack of 5-HT reuptake inhibition in vivo in animal models agrees with former findings but is contradictory to the potency in platelets in vitro and ex vivo (reviewed and discussed by Taylor et al., 1995). Nefazodone has a seven and four times, respectively, weaker DA reuptake inhibitory potency compared to its 5-HT- and NA-reuptake inhibition in vitro.

SEROTONERGIC RECEPTOR MECHANISMS In general, the selected antidepressants and their metabolites have low affinities (in the micromolar concentration range) for 5-HT1A receptors, whereas the affinities for 5-HT2A and 5-HT2C receptors vary from compound to compound. In a number of studies chronic antidepressant treatment of animals as well as humans has been shown to induce subsensitivity of 5-HT1A receptors (Newman et al., 1993). This adaptive desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal raphe´ nucleus is suggested to play an important role in the time lag between the acutely induced facilitation of serotonergic neurotransmission after SSRI treatment and the onset of antidepressant activity (e.g., reviews by Blier and de Montigny; Artigas et al., 1996). It has been hypothesized that the antidepressant effect can be accelerated by blockade of 5-HT1A receptors, and much research activity is ongoing to study these mechanisms in further detail. Both amitriptyline and its main metabolite, nortriptyline, have an appreciable affinity for 5-HT2 receptors and are nonselective with respect to 5-HT2A and 5-HT2C subtypes (Table IV). In vivo, this is reflected in rats as a relatively potent antagonism of head shakes induced by the serotonergic agonist quipazine (ED50 ⫽ 1.7 and 1.6 mg/kg, respectively). Similarly, dothiepin and the demethylated metabolite, northiaden, have a considerable affinity for 5-HT2 receptors. These 5-HT2 receptor antagonistic properties might play a role in the antidepressant activity of these TCAs. Several studies of cortical brain tissue from depressed patients suggest an enhanced 5-HT2 receptor number and function in depression (e.g., Mann et al., 1986; Hrdina et al., 1993). Animal studies of 5-HT2 receptor number and/or function after chronic TCA treatment have demonstrated a decrease in 5-HT2 receptor

484


function. However, selective inhibition of 5-HT2 receptors does not appear to be sufficient for achieving an antidepressant effect. Clinical studies of the selective 5HT2A/2C receptor antagonist, ritanserin, have shown relatively weak antidepressant activity (for references see Pinder and Wieringa, 1993), and clinical development of the compound has been given up. An increase in serotonergic neurotransmission and, consequently, stimulation of other serotonin receptor subtypes (e.g., postsynaptic 5-HT1A receptors) appear to be required. These mechanisms probably contribute significantly to the therapeutic effects of the recently approved antidepressant drug nefazodone. However, nefazodone does not seem to be superior to conventional antidepressant treatment in terms of the efficacy and onset of antidepressant action, but the side-effect profile is favorable compared to TCAs. Interestingly, long-term receptor stimulation (by administration of agonist or SSRI) as well as long-term receptor blockade has produced 5-HT2 receptor down-regulation (e.g., Eison et al., 1989; Buckholtz et al., 1988; Leysen et al., 1986). A recently published study of the two selective 5-HT2C receptor agonists, Ro 60-0175 and Ro 60-0332, in the rat anhedonia model suggests that these compounds have antidepressant activity (Moreau et al., 1996). One possible explanation of these apparently contradictory results could be that functional interactions between 5-HT2C receptors and other receptor systems (e.g., 5-HT1A receptors) are involved (reviewed by Borsini, 1994). Among the SSRIs, fluoxetine shows some affinity for 5-HT2C receptors, whereas its affinity for 5-HT2A receptors is considerably weaker (Table IV). The metabolite, norfluoxetine, has only a weak affinity for both 5-HT2 receptor subtypes. The affinity of fluoxetine for 5-HT2C receptors relative to the 5-HT reuptake inhibitory potency is 24 in the present study (ratio between IC50 values). A further increase in serotonergic neurotransmission appears to be required. Whether this is relevant for the therapeutic effect in humans remains to be established. A recently published study on the effect of fluoxetine on phosphoinositide hydrolysis measured in rat choroid plexus suggested that fluoxetine is a 5-HT2C antagonist. It cannot be excluded that this 5HT2C receptor antagonistic property of fluoxetine interacts with the 5-HT reuptake inhibitory activity and affects the net effect on serotonergic activity and, in this way, plays a role in the antidepressant activity of fluoxetine (Palvimaki et al., 1996). The same study also demonstrated weak 5-HT2C receptor antagonistic activity of norfluoxetine and citalopram. The combined antagonism of 5-HT2 receptors and inhibition of 5-HT reuptake is suggested to be the mechanism of action responsible for the antidepressant activity of nefazodone. Nefazodone has a somewhat higher affinity for 5-HT2A receptors compared to 5-HT2C receptors [ratio of 7 in the present study, Table IV; ratio of 3 (Taylor et al., 1995)]. Actually, the ratio between affinity data for 5-HT2C receptors for fluoxetine and nefazodone is only about 2 in the present study (Table IV), whereas fluoxetine has a markedly lower affinity for 5HT2A receptors and is about 10 times more potent on in vitro 5-HT reuptake inhibition. Although the affinity data are not directly comparable, 움-hydroxynefazodone appears to have in vitro selectivity for 5-HT2A receptors compared to 5-HT2C receptors (Table IV). CATECHOLAMINERGIC RECEPTOR MECHANISMS The affinities for DA D1 receptors and DA D2 receptors are generally weak for the selected antidepressants, although amitriptyline shows some affinity for DA


485

D1 receptors (Table V). Amitriptyline facilitates DA receptor mediated effects in vivo, shown as potentiation of apomorphine-induced gnawing behavior in mice [ED50 ⫽ 27 애mol/kg, s.c. (unpublished observation)]. It might be questioned whether a direct effect on the DA receptor plays an important role for the net effect of amitriptyline. It is a general finding that chronic treatment with antidepressants, including TCAs and SSRIs, facilitates dopaminergic neurotransmission, and studies of brains from depressed patients suggest a decreased DA turnover in depression (e.g., review by Brown and Gershon, 1993). Recent in vivo microdialysis studies in rats have demonstrated that facilitation of 5-HT-induced neurotransmission increases the extracellular DA level in prefrontal cortex (Iyer and Bradberry, 1996; Ichikawa and Meltzer, 1995). This mechanism is more likely to be involved in the effect of antidepressants on DA rather than a direct drug effect on DA receptors. The role of DA receptors in relation to depression and whether the antidepressantinduced facilitation of DA neurotransmission can be ascribed to induction of subsensitivity of presynaptic DA receptors or supersensitivity of postsynaptic DA receptors are still a matter for discussion (Brown and Gershon, 1993; Weiss et al., 1996). The cardiovascular side effects (e.g., orthostatic hypotension) and also the sedative effects of TCAs are related to their antagonism of 움1-adrenenoceptors, and lack of this effect has been an important issue in the development of new antidepressant drugs. SSRIs and their main metabolites all have negligible affinities for 움1-adrenoceptors (Table V), and bupropion and venlafaxine and the corresponding metabolites are devoid of affinity for 움1-adrenoceptors (Table V). Nefazodone and 움-hydroxynefazodone have a relatively high affinity for 움1-adrenoceptors (Table V), but functional in vivo studies (e.g., inhibition of NA-induced lethality and attenuation of NA agonist-induced pressor effect in rats) have failed to demonstrate significant effects (Taylor et al., 1986, 1995). It can only be speculated whether this lack of effect may be ascribed to selectivity for a particular 움1-adrenoceptor subtype, as a clear relationship between cardiovascular effects and 움1-adrenoceptor subtypes remains to be established until selective compounds are available. Dothiepin and northiaden have a relatively high affinity for 움2-adrenoceptors, and the other two metabolites, dothiepin sulfoxide and northiaden sulfoxide, have a weak affinity. Facilitation of noradrenergic neurotransmission by selective blockade of presynaptically situated 움2-adrenoceptors has been a research strategy for developing antidepressant drugs for many years, but with limited success so far (for references see Pinder and Wieringa, 1993). It cannot be excluded that 움2adrenoceptor antagonistic effects of dothiepin and northiaden are contributing to the therapeutic effects. Clinical studies of the 움2-adrenoceptor antagonist, idazoxane, did suggest antidepressant activity (Pinder and Wieringa, 1993), but the compound has not been developed as an antidepressant drug. Mianserin and the recently approved antidepressant, mirtazapine, both have potent 움2-adrenoceptor antagonistic properties (de Boer, 1996). The findings that long-term treatment with many, but not all, antidepressants can down-regulate the number of 웁-adrenoceptors and/or their function in animals and that the time course resembles that of clinical improvement in depressed patients have led to the hypothesis that 웁-adrenoceptor down-regulation is important for achieving antidepressant effect. Studies of different types of blood cells from depressed patients suggest that 웁-adrenoceptors are functionally desensitized (e.g.,

486


Halper et al., 1988). Studies of postmortem brain tissue from depressed patients that had committed suicide suggest a decreased number of 웁-adrenoceptors (De Paermentier et al., 1990). A few 웁-adrenoceptor agonists (i.e., clenbuterol and salbutamol) were studied in the clinic at the beginning of the 1980s (Simon et al., 1984). The compounds did show antidepressant activity but did not offer major advantages in terms of a faster onset of action. None of the antidepressants and metabolites discussed in the present survey have a significant affinity for 웁-adrenoceptors (Table V).

ANTICHOLINERGIC AND ANTIHISTAMINERGIC ACTIVITY The characteristic anticholinergic side effects (e.g., dry mouth, constipation, blurred vision) and sedation due to antihistaminergic effects of the TCAs have been practically eliminated in the new antidepressant drugs. Among the TCAs in the present survey, amitriptyline and dothiepin have the highest in vitro affinities for muscarinic cholinergic receptors and histamine H1 receptors and are antagonists in functional in vitro preparations (e.g., isolated ileum from rat), whereas their corresponding metabolites have weaker affinities (Table VI). Lofepramine and desipramine have rather weak affinities for these two receptors types (Table VI) and show corresponding weak antagonistic activity in functional in vitro assays. Paroxetine has a weak affinity for muscarinic cholinergic receptors, and citalopram and nefazodone and 움-hydroxynefazodone have a weak in vitro affinity for histamine H1 receptors (Table VI). However, this is reflected neither in functional in vitro assays nor in vivo.

CONCLUSION The present survey of a number of the most frequently prescribed TCAs and the new-generation antidepressant drugs and their metabolites clearly shows that the pharmacological activity of the metabolites is an important factor for the overall therapeutic effect of many drugs. The impact that the metabolites exert on the therapeutic effects may be ascribed to their potency and/or their pharmacokinetic properties compared to those of the parent compounds.

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