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 relatively new class of clinically effective antidepressants that are chemically distinct from tricyclics. They share a common feature - a selective and potent inhibition of neuronal uptake of serotonin (5-HT, 5-hydroxytryptamine) and have no or very weak effects on neuronal uptake of norepinephrine (NE). More importantly, they lack a significant affinity to various neurotransmitter receptor systems in the brain and, in contrast to tricyclic antidepressants, they do not possess significant sedative, anticholinergic and/or cardiovascular effects. On the other hand, they all potentiate the pharmacological effects of serotonin and its precursor, 5-hydroxytryptophan. Fluvoxamine, now being introduced into the clinical practice, has some metabolic and pharmacokinetic features that distinguish this drug from other compounds in this class. The purpose of this article is to review the preclinical pharmacological effects of selective serotonin uptake inhibitors with a focus on fluvoxamine and to compare them with those of representative tricyclic antidepressants. There is now considerable evidence available to indicate that impaired functioning of the central serotonergic system is involved in the pathogenesis of at least some types of depressive illness (Asberg et al 1976a). This evidence stems from clinical observations that the level of the main serotonin metabolite, 5-HIAA in the cerebrospinal fluid is significantly decreased in a subgroup of depressive patients who exhibit suicidal behaviour (Asberg et al 1976b). Furthermore, the density of presynaptic uptake sites for serotonin (labelled by [3H]imipramine) has been reported to be decreased in some (Stanley et al 1982; Perry et al 1983), but not all, studies of post-mortem brain samples Address reprint requests to: Dr. P.D. Hrdina, Dept. of Pharmacology, University of Ottawa, 451 Smyth Rd., Rm 3131, Ottawa, Canada K1H 8M5 J Psychiatr Neurosci, VoL 16, No. 2 (Suppl. 1), 1991
from suicide victim/depressives in comparison with controls. In other post-mortem studies, a significant increase was found in the number of 5-HT2 receptors in the brains of suicide victims or depressed subjects (Stanley et al 1983; Yates et al 1990). Serotonin uptake has been found to be decreased and the number of [3H]imipramine sites reduced in blood platelets of depressed patients (Tuomisto and Tukiainen 1976; Briley et al 1980). Whether these markers reflect the functional state of the serotonin uptake system in the brain is at present unknown. Finally, clinical observations also indicate that the precursor of serotonin, Ltryptophan, particularly in conjunction with an MAO inhibitor can be an effective treatment for depression (Coppen et al 1963). Tricyclic antidepressants, the main drugs in the treatment of depressive illness, are known to block the neuronal uptake of two major biogenic amines, norepinephrine and serotonin. In addition, these drugs exert a significant effect on several neurotransmitter receptors (including adrenergic, cholinergic and histaminergic) and many of their side effects are thought to be related to this property of the tricyclic drugs. The inhibition of norepinephrine and serotonin was thought to be responsible for the antidepressant action of these compounds. This has led to the development of the 'biogenic amine hypothesis' of affective disorders which suggests that depression may be due to a lack of norepinephrine and/or serotonin in some critical parts of the brain. However, the delayed onset of the clinical antidepressant effect with tricyclic antidepressants was difficult to explain in the view of the fact that the inhibition of amine uptake occurs shortly after drug administration. In addition, some newer, clinically effective antidepressants (e.g. mianserin) do not inhibit the uptake of either norepinephrine or serotonin. The amine hypothesis of affective disorders needed a critical evaluation (see Baldessarini, 1975). Subsequent studies have shown that after chronic treatment
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Pharmacology of Serotonin Uptake Inhibitors
July 1991
with almost all clinically effective antidepressants, a down regulation of B-adrenergic receptors and of responsiveness of adenylate cyclase to norepinephrine occurs, regardless of the effect of drugs used in the uptake of monoamines (Vetulani et al 1974; Sulser 1983). It is now believed that after the initial block of neuronal re-uptake, adaptive changes in the neuronal networks have to take place in order to give expression to the antidepressant effect.
Table 1 Serotonin uptake inhibitors used as antidepressants. Alaproclate Citalopram
Clomipramine Clovoxamine Femoxetine
Fluoxetine Fluvoxamine Indalpine Paroxetine Sertraline
Serotonin Uptake Inhibitors
inhibitors. The compound has a molecular weight of 434 (as maleate), is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diathylether. In humans and animals, fluvoxamine is well absorbed after oral administration. It is metabolized entirely in the liver by two metabolic pathways: oxidative demethylation (major) and deamination (minor) to more than ten metabolites, out of which nine have been identified in the urine (Overmars et al 1983). They are all excreted by the kidney. After a single oral administration, almost the whole dose (94%) is eliminated from the body within 48 hours (DeBree et al 1983). The two major metabolites of fluvoxamine are without significant pharmacological activity when compared to parent compound, although one of the major metabolites (the carboxylic acid derivative) shows some inhibition of serotonin uptake (Claassen 1983). The bioavailability 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 1983; Kaye et al 1989).
Side-effects of the commonly used tricyclic antidepressants (sedative, hypotensive, anticholinergic, cardiac) have
been a limiting factor in their clinical use particularly in certain subgroups of patients (elderly, cardiovascularly compromised). During the last two decades there has been a considerable effort to develop compounds which would have a relatively selective effect on the serotonergic system without concomitant interaction with a variety of neurotransmitter receptor systems and would be free of undesirable side effects. A new group of compounds has emerged from this search: selective serotonin uptake inhibitors. They have little or no effect on the uptake of norepinephrine or dopamine and have been shown to be clinically effective antidepressants (Asberg et al 1985). They include compounds listed in Table 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 pharmacology of main representatives of this class, fluoxetine, clomipramine and paroxetine that either are, or may in the near future, become available for clinical use in Canada. Inspection of the chemical structure of serotonin uptake 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 and a halogen substituent is an important determinant of the potency and selectivity for serotonin uptake inhibition.
N
.CH3
CH2-CH2-CH2-H"
CH3
Clomipramine F3C..a4~-C..CH2-CH2-CH2-CH2-0-CH3 N
O-CH2-CH2-NH2
Fluvoxamine
F30-
HCH2CH2NHCH3
Fluoxetine H
V-
CH20/
Metabolism of Fluvoxamine F
Fluvoxamine (LUVOX) is a compound that belongs to a chemical series, the 2-aminoethyl oximethers of aralkylketones. It is chemically unrelated to any of the existing antidepressants or selective serotonin uptake
Paroxetine
new
Fig. 1: Molecular structure of some selective serotonin uptake inhibitors.
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Vol. 16, No. 2,1991
Journal ofPsychiatry & Neuroscience Supplement I
Table 2 Inhibition of serotonin (5-HT) and norepinephrine (NE) uptake in vitro (rat hypothalamus) by selective serotonin uptake inhibitors and imipramine.
Drug
Imipramine Clomipramine Fluoxetine Fluvoxamine Paroxetine
Ki(nM) 5-HT
NE
100 7.4 25 6.2 1.1
65 96 500 1100 350
NE/5-HT 0.65 13 20 180 320
Ki is the concentration of drugs that produces 50% inhibition of [3H]5-HT or ['H]NE uptake. (Adapted from Johnson 1989)
Interaction with Serotonergic Mechanisms The functional consequence of inhibiting neuronal serotonin uptake is an increased synaptic concentration of serotonin. The acute effects of serotonin uptake inhibitors are believed to be due to activation of serotonergic mechanisms. These include potentiation of the effects of serotonin and its presursors, induction (in conjunction with MAO inhibitors) of a serotonin produced behavioral syndrome and serotonin mediated effects on REM sleep and food consumption.
Table 3 Inhibition of monoamine uptake in synaptosomes from rat hypothalamus ex vivo after oral administration of selective serotonin uptake inhibitors and imipramine.
ED50(mg/kg)
Selectivity for Serotonin Uptake Inhibition The main pharmacological effect of fluvoxamine is the inhibition of neuronal uptake of serotonin. The selectivity of fluvoxamine to inhibit the neuronal re-uptake in vitro by synaptosomes from rat hypothalamus is illustrated in Table 2. The Ki of fluvoxamine for inhibition of serotonin uptake is 180 times lower than its Ki for inhibition of norepinephrine uptake. Fluvoxamine appears to be a more selective and potent inhibitor of serotonin uptake than fluoxetine and clomipramine, but is less potent and selective than paroxetine. It is important, however, to demonstrate that the selectivity of the compound to inhibit serotonin uptake is maintained after in vivo administration. Fluvoxamine administered in vivo produces an 80% inhibition of 5-HT uptake by rat brain synaptosomes 30 minutes after administration. In comparison, imipramine in a similar dose produces only 50% inhibition of serotonin neuronal uptake (Claassen 1983). Table 3 compares the relative potency and selectivity of serotonin uptake inhibitors on 5-HT and norepinephrine uptake measured 'ex vivo' and shows that fluvoxamine maintains its selectivity for serotonin uptake after in vivo administration. Fluvoxamine was also shown to significantly decrease platelet serotonin uptake in patients treated with the drug (Wood et al 1983; Nathan et al 1990). The selectivity of serotonin uptake inhibitors can also be demonstrated by their ability to potentiate behaviors mediated by serotonin and norepinephrine, respectively. Table 4 compares the activity of fluvoxamine, clomipramine and imipramine in potentiating the 5-hydroxytryptophaninduced hyperactivity syndrome in rodents (Ortman 1984) pretreated with an MAO inhibitor and in antagonizing the tetrabenazine effect thought to be mediated through norepinephrine. The ratio of ED50 of fluvoxamine needed to potentiate 5-hydroxytryptophan and to antagonize tetrabenazine effect was 0.34 compared to 7 for clomipramine and 26 for imipramine (Claassen 1983).
Drug
5-HT
NE
Imipramine Fluoxetine Fluvoxamine Paroxetine
>30 7 23 1.9
10 >30 >30 >30
'Forms an active metabolite that has a higher potency for NE uptake inhibition than the parent compound (Adapted from Johnson 1989)
Hormonal Effects Serum concentration of prolactin in animals as well as in humans, is increased by serotonergic stimuli (Clemens et al, 1977; Fuller, 1981). Fluvoxamine was shown to stimulate prolactin secretion in rats (Fig 2) and to significantly potentiate the prolactin releasing effect of 5-hydroxytryptophan (Cella et al 1983). These endocrine effects of acute fluvoxamine administration are compatible with activation of 5-HT neurotransmission. In humans, fluvoxamine alone does not produce an increased prolactin secretion and plasma levels. However, it potentiates significantly the effect of tryptophan stimulation on prolactin release (Price et al 1990).
Serotonin Mediated Behavioral Syndrome Several directly acting serotonin agonists or a combination of a serotonin precursor with an inhibitor of monoamine oxidase and/or an inhibitor of serotonin uptake, produce in rats the serotonin behavioral syndrome consisting of forepaw threading, head weaving, hind limb abduction, body tremor, compulsive movements, piloerection and salivation (Ortmann, 1984). This behavioral syndrome results from an intense stimulation of central
13
Pharmacology of Serotonin Uptake Inhibitors
July 1991
Saline Saline
Fluvoxamine 5-HTP
Saline k
9 8 7 6 5
5-HTP
*4.
*"
T~
S/B
T
I
3 2
0
TF
0
30
45
0
30
45
0
30
45
0
30
45
Time (min)
Fig. 2: Effect of fluvoxamine (25 mg/kg ip) on plasma levels of prolactin in rats treated with 5-hydroxytryptophan. S/B = ratio between stimulated and baseline prolactin levels. * = difference vs time 0; (Adapted from Cella et al 1983).
serotonin receptors. Serotonin uptake inhibitors (eg. fluvoxamine) alone do not elicit this syndrome, but they potentiate the 5-hydroxytryptophan induced head twitch in mice to an extent which correlates with their 5-HT uptake inhibiting potencies (Ortmann et al 1980) and produce the serotonin behavioral syndrome when given in conjunction with monoamine oxidase inhibitors. Fluvoxamine was about twice as potent as clomipramine in potentiating the 5-HTP induced behavioral syndrome in mice (Table 4).
Reduction of Serotonin Turnover One of the consequences of serotonin uptake inhibition is increased activity of this neurotransmitter on both postand presynaptic receptors. Administration of serotonin uptake inhibitors results, probably via a negative feedback mechanism and autoreceptor stimulation, in reduction of serotonin turnover rate as measured by decreases in the level of its major metabolite, 5-HIAA (Claassen 1977; Macro and Meek 1979), and in an inhibition of spontaneous firing rate of n. raphe dorsalis neurons in rats (Dresse and ScuveeMorreau 1984). an
+
=
difference vs corresponding values in 5-HTP treated rats.
effect appears (Montgomery 1989). Serotonin uptake inhibitors can also produce anti-nociceptive effects and can potentiate an analgesic effect of some opioid analgesic drugs (Hynes and Fuller 1982) as well as the 5-hydroxytryptophan induced myoclonus in animals (Green and Heal 1985). Fluvoxamine in a dose of 200 mg/day was shown to reduce REM sleep time as well as the time spent in stages 3 and 4 of sleep, and to extend REM sleep latency in depressive subjects (Berger et al 1986).
Table 4 Potentiation of monoamine-mediated effects in vivo (mice) by some selective serotonin uptake inhibitors and imipramine. Drug
Imipramine3 Clomipramine3 Fluvoxamine
ED50oral (mg/kg) 5-HTP' Antag of TBZ (NE)2 Ratio
135 84 36
5.2 12 107
26 7 0.34
Other Effects Serotonin uptake inhibitors alone, or in combination with a serotonin precursor, produce a decrease in food intake in rats (Yen et al 1987; LUVOX 1990). The doses at which weight loss is seen in humans tend to be rather higher than the minimum dose at which an antidepressant
'Dose of the test drug that potentiates to 50% of the maximal score the 5HTP induced behavioral syndrome. 2Dose of the test drug that reduced the tetrabenazine induced ptosis to half of that of the controls. 3Forms in vivo an active metabolite that inhibits NE uptake. (Adapted from Claassen 1983)
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Journal ofPsychiatry & Neuroscience Supplement I
Interaction with Neurotransmitter Receptors Many of the side effects of tricyclic antidepressants have been related to their ability to interact with various neurotransmitter receptors in the brain (Hall and Ogren 1981; Richelson and Nelson 1984; Wander et al 1986). For instance, sedative effects, increased appetite and postural hypotension have been related to their affinity for central and peripheral a] adrenergic receptors. Dyskinesia with some of the tricyclic antidepressants has been ascribed to the affinity of some of these drugs to dopamine D2 receptor sites in the brain. The undesirable anticholinergic side effects present with most tricyclic antidepressants result from the affinity of these compounds for the muscarinic receptors. The sedative effect and drowsiness produced by tricyclics and possibly the weight gain which is seen with these compounds (Feighner and Cohn 1985), could be related to the effect of these compounds on histamine H1 receptors in the brian.
Table 5
Affinity of selective serotonin uptake inhibitors and imipramine for neurotransmitter receptors in rat brain.
Drug
IC50 value for displacement (nM) I al a2 5-HT2 D2 MUSC
Imipramine
300
N
N
180
Clomipramine
117
N
N
150
N
N
5000
N
N
N
N
>5000
Fluoxetine Fluvoxamine
Paroxetine
2700 400 700
N N
160 N
N
N
VoL 16, No. 2, 1991
In contrast to tricyclic antidepressants, fluvoxamine has no antihistaminic effect, no sedative effect, does not inhibit monoamine oxidase (Lapierre et al 1983), does not have an amphetamine-like stimulating effect and has very little or no parasympatholytic activity (Claassen et al 1983; Wilson et al 1983). At high doses (over 60 mg/kg) it has shown in animal studies, a tendency to induce seizures. Physical dependence liability has not been demonstrated for this compound at doses up to 90 mg/kg per day in monkeys (LUVOX 1990). Furthermore, in contrast to tricyclic antidepressants, fluvoxamine at therapeutic doses lacks significant effects on the cardiovascular system (Roos 1983). A single dose of fluvoxamine did not affect heart rate or blood pressure in healthy volunteers (Wilson et al 1983). Repeated administration (for 9 days) of fluvoxamine had little or no effect on ECG or blood pressure and produced only a slight decrease in heart rate (Robinson and Doogan 1982).
Drug Interactions In combination with MAO inhibitors, fluvoxamine produces an increase in serotonin mediated effects (Claassen et al 1983). In contrast to some tricyclic antidepressants, fluvoxamine produces no interaction with the antihypertensive effect of guanethidine or a-methyldopa (LUVOX 1990). However, it may prolong the elimination of some drugs metabolized by the oxidation pathway in the liver. This could be an important consideration when fluvoxamine is taken simultaneously with drugs that have a narrow therapeutic index, such as warfarin and phenytoin. In fact, fluvoxamine was shown to increase plasma levels of warfarin by 65%. It also produced a 5-fold increase in plasma levels of simultaneously administered propranolol (LUVOX 1990).
Toxicity
1000 7700
N = no effect in conc. < 10000 nM (Adapted from Claassen 1983 and Schmidt et al 1988)
As shown in Table 5, the selective serotonin re-uptake inhibitors, fluoxetine, fluvoxamine and paroxetine, lack a significant affinity to al, cc2, B-adrenergic, 5-HT2, dopamine D2 or muscarinic cholinergic receptors in the brain (Wong et al 1983: Nelson et al 1989; Schmidt et al 1988). This is most likely the reason why they do not show the above mentioned side effects typical for tricyclic antidepressants. The selectivity of specific 5-HT uptake inhibitors (eg. paroxetine) for the serotonin uptake sites and serotonergic innervation in the brain has also been demonstrated in autoradiographic studies (Hrdina et al 1990).
In animal experiments, fluvoxamine in doses which are near to lethal doses, produced acute toxic effects including ataxia, mydriasis, bradypnea and convulsions. The oral LD50 of the compound is more than 2 g/kg in rats and more than 500 mg/kg in dogs. Emesis in dogs has occurred at doses higher than 25 mg/kg. In these cases, a haemorrhage of intestinal mucosa has been observed on the biopsy (LUVOX 1990). Chronic toxic effects of fluvoxamine in rodents include a decrease in body weight gain, decreases in serum lipids and increases in liver lipids that were similar to those produced with comparable doses of imipramine and amitriptyline. After high doses, an increase in fatty vacuolation of hepatocytes was noted. Finally, in dogs at doses 60 mg/kg per day and higher, there was ataxia, anorexia and, in some cases, convulsions (LUVOX 1990).
Pharmacology of Serotonin Uptake Inhibitors
July 1991
Table 6 Pharmacokinetic parameters of some selective serotonin uptake inhibitors and imipramine. Parameter
Imipramine Fluvoxamine Fluoxetine Paroxetine (40 MG) (125 MG) (100 MG) 139
Cmax (ng/ml)
4.2
tmax (hr)
27
31-87 1.5-8
tl/2(hr)
13
17-22
Bioavail. (%)
50
60
Prot. bind.(%)
85-90
77
6.4 43 (140)
20.6
95
(Adapted from Hrdina et al 1981; Bergstrom et al 1988 and Kaye et al 1989)
Differences in Metabolism and Kinetics: Impact on Clinical Therapy The pharmacokinetic parameters of fluvoxamine and of some other serotonin uptake inhibitors in comparison with those of imipramine are reported in Table 6. In healthy volunteers, peak plasma levels following a single oral dose of 100 mg of fluvoxamine were observed 1.5 to 8 hours
15
after the dose and were comparable to those seen after imipramine. The half-life of fluvoxamine is between 17 and 22 hours. This is within the range of the half-life of tricyclic antidepressants, but much shorter than the halflife of fluoxetine and particularly of its demethylated metabolite, norfluoxetine. The consequences of the effects of metabolism and kinetics on the selectivity and duration of action of some serotonin uptake inhibitors are shown in Table 7. Clomipramine is metabolized in the body to its main active metabolite, desmethylclomipramine (de Cuyper et al 1983), which, in contrast to the parent compound is a much more potent inhibitor of norepinephrine than serotonin uptake. Thus, the metabolism of clomipramine to desmethylclomipramine results in a loss of selectivity of the parent compound for the inhibition of serotonin uptake. On the other hand, fluoxetine which is also metabolized to an active compound, norfluoxetine (Bergstrom et al 1988), maintains its selectivity for serotonin uptake inhibition because norfluoxetine is just as effective an inhibitor of serotonin uptake as is its parent compound, (Schmidt et al 1988). However, the duration of action of the drug increases significantly with the formation of the active metabolite, norfluoxetine, whose half-life is approximately 140 hours. In the case of fluvoxamine, the metabolites are inactive, without a significant effect on serotonin or norepinephrine uptake. Fluvoxamine metabolism thus does not change either the selectivity or
Table 7 Effect of metabolism and kinetics on the selectivity and duration of action of some clinically used serotonin uptake inhibitors.
Drug Clomipramine
5-HT Uptake +++
NE Uptake +
Duration -
Consequence Loss of
selectivity
Desmethylclomipramine
+
+++
Fluoxetine
+++
+
Nofluoxetine
+++
+
Fluvoxamine
+++
+
Inact. metabolites
(+)
-
Increased duration
-
No change in selectivity or duration
16
the duration of the action of the drug. The clinical effects of fluvoxamine are therefore more predictable than those of clomipramine and a downward adjustment of its dose is simpler than with fluoxetine. Table 8 Effect of repeated administration of serotonin uptake inhibitors and imipramine on the density of betaadrenergic receptors, NE-coupled adenylate cyclase and the number of 5-HT2 receptors in rat brain.
Drug
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Journal of Psychiatry & Neuroscience Supplement I
Density of Adenylate Cyclase Number of [B-adrenergic Activity 5-HT2 Receptors
Receptors (Rat Brain)
Block of 5-HT uptake + Availability of 5-HT in the Synapse
+ 4 Action on 5-HT Receptors
Acute Effects
* In 5-HT Turnover & Firing Rate Desensitization of Presynaptic Receptors On Terminals Somatodendritic
Imipramine
Normal Firing Rate Clomipramine
+
+
Fluoxetine
0(+)
0
0(+)
Fluvoxamine
0
+
0
Paroxetine
0
4 5- HT Release and Neurotransmission
|Therapeutic Effect|
+
+ decrease; + increase; 0 no change (Adapted from Nelson et al 1989)
Fig. 3: Chain of events in the serotonergic neurotransmission after administration of serotonin uptake inhibitors.
Possible Mode of Antidepressant Action Down regulation of B-adrenergic receptors has been considered to be a crucial event in adaptive changes during the chronic administration of antidepressant treatments (Sulser 1983). However, the selective serotonin uptake inhibitors, fluvoxamine and paroxetine which are clinically effective antidepressants, do not produce a down regulation of B-adrenergic receptors after repeated treatment in animals (Table 8), although fluoxetine was found to reduce the number of beta-adrenergic receptors in frontal cortex (Nelson et al 1989). Fluvoxamine though, was shown to produce a down regulation in the responsiveness of adenylate cyclase to norepinephrine. These findings cast some doubt on the postulate that B-adrenergic receptor down regulation is an essential component of antidepressant efficacy. It could be however, that adaptive changes in receptor systems other than B-adrenergic could be an integral part of changes which occur after repeated administration of serotonin uptake inhibitors and which would be essential for the antidepressant activity of these compounds. For example, both fluoxetine and paroxetine were reported to produce a down regulation of 5-HT2 receptors after repeated administration (Wong and Bymaster 1980, Nelson et al 1989).
The mechanism by which serotonin uptake inhibitors produce their antidepressant effect is at present unclear. One possible chain of events occurring after repeated administration of these drugs has been suggested by de Montigny and his coworkers (de Montigny and Aghajanian 1978; Blier et al 1987). According to this concept, illustrated in Fig. 3, the block of the 5-HT uptake by these compounds would lead to the increased availability of serotonin in the synapse and to acute manifestation of the increased action on 5-HT synapses, both presynaptically and postsynaptically. Dynamic changes would then include a decrease in 5-HT turnover and firing rate. With time, the increased availability of serotonin in the synaptic gap and at the receptor sites would lead to desensitization of presynaptic serotonin receptors either on the cell bodies (somatodendritic receptors) or on the terminals. This in turn, would bring the firing rate back to normal and would increase the serotonin release and serotonin neurotransmission, which may be translated in a therapeutic antidepressant effect. These adaptive changes however, might be just one step in the chain of events which occur between the primary manifestation of the effect of those compounds, that is inhibition of the uptake of serotonin and between the onset of the clinical therapeutic effect. The notion that the brain monoamine
July 1991
Pharmacology ofSerotonin Uptake Inhibitors
systems are targets for the action of some antidepressants does not necessarily mean that the abnormal functioning of these systems is a primary factor in the pathogenesis of affective disorders. The perturbation of brain neuronal systems could well be a result of other hitherto unrecognized disturbances. Nevertheless, a better understanding of the neurobiological basis of the action of antidepressants might help us in unravelling the disturbances in brain function that are the biological basis of depression.
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Journal ofPsychiatry & Neuroscience Supplement )
Luvox: Product Monograph (1990) McNeil Pharmaceutical (Canada) Ltd., Stouffville, Ontario, Canada. Marco EJ, Meek JL (1979) The effects of antidepressants on serotonin turnover in discrete regions of rat brain. Naunyn Schmiedeberg Arch Pharmacol 306:75-79. Montgomery SA (1989) New antidepressants and 5-HT uptake inhibitors. Acta Psychiatry Scand 80(Suppl 350):107-116. Nathan RS, Perel JM, Pollock BG, Kupfer DJ (1990) The role of neuropharmacologic selectivity in antidepressant action: Fluvoxamine versus desipramine. J Clin Psychiatr
51:367-72. Nelson DR, Thomas DR, Johnson AM (1989) Pharmacological effects of paroxetine after repeated administration to animals. Acta Psychiatr Scand 80(Suppl 350):21-3. Ortmann R (1984) The 5-HT syndrome in rats as a tool for the screening of psychoactive drugs. Drug Dev Res 4:593-606. Ortmann R, Waldmeier PC, Radeke E, Felner A, DeliniStula A (1980) The effects of 5HT uptake-and MAO-inhibitors on L-5-HTP-induced excitation in rats. Naunyn Schmiedeberg 's Arch Pharmacol 311:185-92. Overmars H, Scherpenisse PM, Post LC (1983) Fluvoxamine maleate: metabolism in man. Eur J Drug Metab Pharmacokinet 8:259-80. Perry EK, Marshall EF, Blessed G, Tomlison BE, Perry RH (1983) Decreased imipramine binding in the brains of patients with depressive illness. Br J Psychiatry 142:188-92. Price LH, Charney DS, Delgado PL, Anderson GM, Heninger GR (1989) Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan. Arch Gen Psychiatry 46:625-31. Richelson E, Nelson A (1984) Antagonism by antidepressants of neurotransmitter receptors in normal human brain in vitro. J Pharmacol Exp Ther 230:94-102. Robinson JF, Doogan DP (1982) A placebo controlled study of the cardiovascular effects of fluvoxamine and clorosamine in human volunteers. Br J Clin Pharmacol 14:805-8. Roos JC (1983) Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressants and fluvoxamine. Br J Clin Pharmacol 15:439S-45S. Schmidt MJ, Fuller, RW, Wong T (1988) Fluoxetine, a highly selective serotonin reuptake inhibitor: A review of preclinical studies. Br J Psychiatry 153(Suppl 3):40-6.
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Stanley M, Virgilio J, Gershon S (1982) Tritiated imipramine binding sites in frontal cortex of suicides. Science 216:337-9. Stanley M, Mann JJ (1983) Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1:214-6. Sulser F (1983) Deamplification of noradrenergic signal transfer by antidepressants: a unified catecholamineserotonin hypothesis of affective disorders. Psychopharmacol Bull 19:300-4. Tuomisto J, Tukiainen E (1976) Decreased uptake of 5hydroxytryptamine in blood platelets from depressed patients. Nature (Lond) 252:596-8. Vetulani J, Dingell JV, Sulser F (1974) Effect of chronic treatment with desipramine (DMI) and iprindole (IP) on the norepinephrine (NE) sensitive adenylate cyclase system in slices of the rat limbic forebrain(LFS). Pharmacologistl6:287. Wander TJ, Nelson A, Okazaki H, Richelson E (1986) Antagonism by antidepressants of serotonin SI and S2 receptors of normal human brain in vitro. Eur J Pharmacol 132:115-21. Wilson WH, Higano H, Papadatos Y, Kelwala S, Ban TA (1983) A double-blind placebo-controlled study to compare the autonomic effects of fluvoxamine with those of amitriptyline and doxepin in healthy volunteers. Br J Clin Pharmacol 15:385S-92S. Wong DT, Bymaster FP (1980) Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine. Res Commun Chem Pathol Pharmacol 32:4151. Wong DT, Bymaster FP, Reid LR, Threlkeld PG (1983) Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. Biochem Pharmacol 32:1287-93. Wood K, Swade C, Abou-Saleh M, Milln P, Coppen A (1983) Drug plasma levels and platelet 5-HT uptake inhibition during long-term treatment with fluvoxamine or lithium in patients with affective disorders. Br J Clin Pharmacol 15:365S-8S. Yates M, Leake A, Candy JM, Fairbairn AF, McKeith IG, Ferrier IN (1990) 5-HT2 receptor changes in major depression. Biol Psychiatry 27:489-96. Yen TT, Wong DT, Bemis KG (1987) Reduction of food consumption and body weight of normal and obese mice by chronic treatment with fluoxetine, a serotonin reuptake inhibitor. Drug Dev Res 10:37-45.
Selective serotonin uptake inhibitors comprise a relatively new class of clinically effective antidepressants that are chemically distinct from tricyclics. They share a common feature - a selective and potent inhibition of neuronal uptake of serotonin (5-HT, 5-hydroxytryptamine) and have no or very weak effects on neuronal uptake of norepinephrine (NE). More importantly, they lack a significant affinity to various neurotransmitter receptor systems in the brain and, in contrast to tricyclic antidepressants, they do not possess significant sedative, anticholinergic and/or cardiovascular effects. On the other hand, they all potentiate the pharmacological effects of serotonin and its precursor, 5-hydroxytryptophan. Fluvoxamine, now being introduced into the clinical practice, has some metabolic and pharmacokinetic features that distinguish this drug from other compounds in this class. The purpose of this article is to review the preclinical pharmacological effects of selective serotonin uptake inhibitors with a focus on fluvoxamine and to compare them with those of representative tricyclic antidepressants. There is now considerable evidence available to indicate that impaired functioning of the central serotonergic system is involved in the pathogenesis of at least some types of depressive illness (Asberg et al 1976a). This evidence stems from clinical observations that the level of the main serotonin metabolite, 5-HIAA in the cerebrospinal fluid is significantly decreased in a subgroup of depressive patients who exhibit suicidal behaviour (Asberg et al 1976b). Furthermore, the density of presynaptic uptake sites for serotonin (labelled by [3H]imipramine) has been reported to be decreased in some (Stanley et al 1982; Perry et al 1983), but not all, studies of post-mortem brain samples Address reprint requests to: Dr. P.D. Hrdina, Dept. of Pharmacology, University of Ottawa, 451 Smyth Rd., Rm 3131, Ottawa, Canada K1H 8M5 J Psychiatr Neurosci, VoL 16, No. 2 (Suppl. 1), 1991
from suicide victim/depressives in comparison with controls. In other post-mortem studies, a significant increase was found in the number of 5-HT2 receptors in the brains of suicide victims or depressed subjects (Stanley et al 1983; Yates et al 1990). Serotonin uptake has been found to be decreased and the number of [3H]imipramine sites reduced in blood platelets of depressed patients (Tuomisto and Tukiainen 1976; Briley et al 1980). Whether these markers reflect the functional state of the serotonin uptake system in the brain is at present unknown. Finally, clinical observations also indicate that the precursor of serotonin, Ltryptophan, particularly in conjunction with an MAO inhibitor can be an effective treatment for depression (Coppen et al 1963). Tricyclic antidepressants, the main drugs in the treatment of depressive illness, are known to block the neuronal uptake of two major biogenic amines, norepinephrine and serotonin. In addition, these drugs exert a significant effect on several neurotransmitter receptors (including adrenergic, cholinergic and histaminergic) and many of their side effects are thought to be related to this property of the tricyclic drugs. The inhibition of norepinephrine and serotonin was thought to be responsible for the antidepressant action of these compounds. This has led to the development of the 'biogenic amine hypothesis' of affective disorders which suggests that depression may be due to a lack of norepinephrine and/or serotonin in some critical parts of the brain. However, the delayed onset of the clinical antidepressant effect with tricyclic antidepressants was difficult to explain in the view of the fact that the inhibition of amine uptake occurs shortly after drug administration. In addition, some newer, clinically effective antidepressants (e.g. mianserin) do not inhibit the uptake of either norepinephrine or serotonin. The amine hypothesis of affective disorders needed a critical evaluation (see Baldessarini, 1975). Subsequent studies have shown that after chronic treatment
I1I
Pharmacology of Serotonin Uptake Inhibitors
July 1991
with almost all clinically effective antidepressants, a down regulation of B-adrenergic receptors and of responsiveness of adenylate cyclase to norepinephrine occurs, regardless of the effect of drugs used in the uptake of monoamines (Vetulani et al 1974; Sulser 1983). It is now believed that after the initial block of neuronal re-uptake, adaptive changes in the neuronal networks have to take place in order to give expression to the antidepressant effect.
Table 1 Serotonin uptake inhibitors used as antidepressants. Alaproclate Citalopram
Clomipramine Clovoxamine Femoxetine
Fluoxetine Fluvoxamine Indalpine Paroxetine Sertraline
Serotonin Uptake Inhibitors
inhibitors. The compound has a molecular weight of 434 (as maleate), is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diathylether. In humans and animals, fluvoxamine is well absorbed after oral administration. It is metabolized entirely in the liver by two metabolic pathways: oxidative demethylation (major) and deamination (minor) to more than ten metabolites, out of which nine have been identified in the urine (Overmars et al 1983). They are all excreted by the kidney. After a single oral administration, almost the whole dose (94%) is eliminated from the body within 48 hours (DeBree et al 1983). The two major metabolites of fluvoxamine are without significant pharmacological activity when compared to parent compound, although one of the major metabolites (the carboxylic acid derivative) shows some inhibition of serotonin uptake (Claassen 1983). The bioavailability 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 1983; Kaye et al 1989).
Side-effects of the commonly used tricyclic antidepressants (sedative, hypotensive, anticholinergic, cardiac) have
been a limiting factor in their clinical use particularly in certain subgroups of patients (elderly, cardiovascularly compromised). During the last two decades there has been a considerable effort to develop compounds which would have a relatively selective effect on the serotonergic system without concomitant interaction with a variety of neurotransmitter receptor systems and would be free of undesirable side effects. A new group of compounds has emerged from this search: selective serotonin uptake inhibitors. They have little or no effect on the uptake of norepinephrine or dopamine and have been shown to be clinically effective antidepressants (Asberg et al 1985). They include compounds listed in Table 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 pharmacology of main representatives of this class, fluoxetine, clomipramine and paroxetine that either are, or may in the near future, become available for clinical use in Canada. Inspection of the chemical structure of serotonin uptake 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 and a halogen substituent is an important determinant of the potency and selectivity for serotonin uptake inhibition.
N
.CH3
CH2-CH2-CH2-H"
CH3
Clomipramine F3C..a4~-C..CH2-CH2-CH2-CH2-0-CH3 N
O-CH2-CH2-NH2
Fluvoxamine
F30-
HCH2CH2NHCH3
Fluoxetine H
V-
CH20/
Metabolism of Fluvoxamine F
Fluvoxamine (LUVOX) is a compound that belongs to a chemical series, the 2-aminoethyl oximethers of aralkylketones. It is chemically unrelated to any of the existing antidepressants or selective serotonin uptake
Paroxetine
new
Fig. 1: Molecular structure of some selective serotonin uptake inhibitors.
12
Vol. 16, No. 2,1991
Journal ofPsychiatry & Neuroscience Supplement I
Table 2 Inhibition of serotonin (5-HT) and norepinephrine (NE) uptake in vitro (rat hypothalamus) by selective serotonin uptake inhibitors and imipramine.
Drug
Imipramine Clomipramine Fluoxetine Fluvoxamine Paroxetine
Ki(nM) 5-HT
NE
100 7.4 25 6.2 1.1
65 96 500 1100 350
NE/5-HT 0.65 13 20 180 320
Ki is the concentration of drugs that produces 50% inhibition of [3H]5-HT or ['H]NE uptake. (Adapted from Johnson 1989)
Interaction with Serotonergic Mechanisms The functional consequence of inhibiting neuronal serotonin uptake is an increased synaptic concentration of serotonin. The acute effects of serotonin uptake inhibitors are believed to be due to activation of serotonergic mechanisms. These include potentiation of the effects of serotonin and its presursors, induction (in conjunction with MAO inhibitors) of a serotonin produced behavioral syndrome and serotonin mediated effects on REM sleep and food consumption.
Table 3 Inhibition of monoamine uptake in synaptosomes from rat hypothalamus ex vivo after oral administration of selective serotonin uptake inhibitors and imipramine.
ED50(mg/kg)
Selectivity for Serotonin Uptake Inhibition The main pharmacological effect of fluvoxamine is the inhibition of neuronal uptake of serotonin. The selectivity of fluvoxamine to inhibit the neuronal re-uptake in vitro by synaptosomes from rat hypothalamus is illustrated in Table 2. The Ki of fluvoxamine for inhibition of serotonin uptake is 180 times lower than its Ki for inhibition of norepinephrine uptake. Fluvoxamine appears to be a more selective and potent inhibitor of serotonin uptake than fluoxetine and clomipramine, but is less potent and selective than paroxetine. It is important, however, to demonstrate that the selectivity of the compound to inhibit serotonin uptake is maintained after in vivo administration. Fluvoxamine administered in vivo produces an 80% inhibition of 5-HT uptake by rat brain synaptosomes 30 minutes after administration. In comparison, imipramine in a similar dose produces only 50% inhibition of serotonin neuronal uptake (Claassen 1983). Table 3 compares the relative potency and selectivity of serotonin uptake inhibitors on 5-HT and norepinephrine uptake measured 'ex vivo' and shows that fluvoxamine maintains its selectivity for serotonin uptake after in vivo administration. Fluvoxamine was also shown to significantly decrease platelet serotonin uptake in patients treated with the drug (Wood et al 1983; Nathan et al 1990). The selectivity of serotonin uptake inhibitors can also be demonstrated by their ability to potentiate behaviors mediated by serotonin and norepinephrine, respectively. Table 4 compares the activity of fluvoxamine, clomipramine and imipramine in potentiating the 5-hydroxytryptophaninduced hyperactivity syndrome in rodents (Ortman 1984) pretreated with an MAO inhibitor and in antagonizing the tetrabenazine effect thought to be mediated through norepinephrine. The ratio of ED50 of fluvoxamine needed to potentiate 5-hydroxytryptophan and to antagonize tetrabenazine effect was 0.34 compared to 7 for clomipramine and 26 for imipramine (Claassen 1983).
Drug
5-HT
NE
Imipramine Fluoxetine Fluvoxamine Paroxetine
>30 7 23 1.9
10 >30 >30 >30
'Forms an active metabolite that has a higher potency for NE uptake inhibition than the parent compound (Adapted from Johnson 1989)
Hormonal Effects Serum concentration of prolactin in animals as well as in humans, is increased by serotonergic stimuli (Clemens et al, 1977; Fuller, 1981). Fluvoxamine was shown to stimulate prolactin secretion in rats (Fig 2) and to significantly potentiate the prolactin releasing effect of 5-hydroxytryptophan (Cella et al 1983). These endocrine effects of acute fluvoxamine administration are compatible with activation of 5-HT neurotransmission. In humans, fluvoxamine alone does not produce an increased prolactin secretion and plasma levels. However, it potentiates significantly the effect of tryptophan stimulation on prolactin release (Price et al 1990).
Serotonin Mediated Behavioral Syndrome Several directly acting serotonin agonists or a combination of a serotonin precursor with an inhibitor of monoamine oxidase and/or an inhibitor of serotonin uptake, produce in rats the serotonin behavioral syndrome consisting of forepaw threading, head weaving, hind limb abduction, body tremor, compulsive movements, piloerection and salivation (Ortmann, 1984). This behavioral syndrome results from an intense stimulation of central
13
Pharmacology of Serotonin Uptake Inhibitors
July 1991
Saline Saline
Fluvoxamine 5-HTP
Saline k
9 8 7 6 5
5-HTP
*4.
*"
T~
S/B
T
I
3 2
0
TF
0
30
45
0
30
45
0
30
45
0
30
45
Time (min)
Fig. 2: Effect of fluvoxamine (25 mg/kg ip) on plasma levels of prolactin in rats treated with 5-hydroxytryptophan. S/B = ratio between stimulated and baseline prolactin levels. * = difference vs time 0; (Adapted from Cella et al 1983).
serotonin receptors. Serotonin uptake inhibitors (eg. fluvoxamine) alone do not elicit this syndrome, but they potentiate the 5-hydroxytryptophan induced head twitch in mice to an extent which correlates with their 5-HT uptake inhibiting potencies (Ortmann et al 1980) and produce the serotonin behavioral syndrome when given in conjunction with monoamine oxidase inhibitors. Fluvoxamine was about twice as potent as clomipramine in potentiating the 5-HTP induced behavioral syndrome in mice (Table 4).
Reduction of Serotonin Turnover One of the consequences of serotonin uptake inhibition is increased activity of this neurotransmitter on both postand presynaptic receptors. Administration of serotonin uptake inhibitors results, probably via a negative feedback mechanism and autoreceptor stimulation, in reduction of serotonin turnover rate as measured by decreases in the level of its major metabolite, 5-HIAA (Claassen 1977; Macro and Meek 1979), and in an inhibition of spontaneous firing rate of n. raphe dorsalis neurons in rats (Dresse and ScuveeMorreau 1984). an
+
=
difference vs corresponding values in 5-HTP treated rats.
effect appears (Montgomery 1989). Serotonin uptake inhibitors can also produce anti-nociceptive effects and can potentiate an analgesic effect of some opioid analgesic drugs (Hynes and Fuller 1982) as well as the 5-hydroxytryptophan induced myoclonus in animals (Green and Heal 1985). Fluvoxamine in a dose of 200 mg/day was shown to reduce REM sleep time as well as the time spent in stages 3 and 4 of sleep, and to extend REM sleep latency in depressive subjects (Berger et al 1986).
Table 4 Potentiation of monoamine-mediated effects in vivo (mice) by some selective serotonin uptake inhibitors and imipramine. Drug
Imipramine3 Clomipramine3 Fluvoxamine
ED50oral (mg/kg) 5-HTP' Antag of TBZ (NE)2 Ratio
135 84 36
5.2 12 107
26 7 0.34
Other Effects Serotonin uptake inhibitors alone, or in combination with a serotonin precursor, produce a decrease in food intake in rats (Yen et al 1987; LUVOX 1990). The doses at which weight loss is seen in humans tend to be rather higher than the minimum dose at which an antidepressant
'Dose of the test drug that potentiates to 50% of the maximal score the 5HTP induced behavioral syndrome. 2Dose of the test drug that reduced the tetrabenazine induced ptosis to half of that of the controls. 3Forms in vivo an active metabolite that inhibits NE uptake. (Adapted from Claassen 1983)
14
Journal ofPsychiatry & Neuroscience Supplement I
Interaction with Neurotransmitter Receptors Many of the side effects of tricyclic antidepressants have been related to their ability to interact with various neurotransmitter receptors in the brain (Hall and Ogren 1981; Richelson and Nelson 1984; Wander et al 1986). For instance, sedative effects, increased appetite and postural hypotension have been related to their affinity for central and peripheral a] adrenergic receptors. Dyskinesia with some of the tricyclic antidepressants has been ascribed to the affinity of some of these drugs to dopamine D2 receptor sites in the brain. The undesirable anticholinergic side effects present with most tricyclic antidepressants result from the affinity of these compounds for the muscarinic receptors. The sedative effect and drowsiness produced by tricyclics and possibly the weight gain which is seen with these compounds (Feighner and Cohn 1985), could be related to the effect of these compounds on histamine H1 receptors in the brian.
Table 5
Affinity of selective serotonin uptake inhibitors and imipramine for neurotransmitter receptors in rat brain.
Drug
IC50 value for displacement (nM) I al a2 5-HT2 D2 MUSC
Imipramine
300
N
N
180
Clomipramine
117
N
N
150
N
N
5000
N
N
N
N
>5000
Fluoxetine Fluvoxamine
Paroxetine
2700 400 700
N N
160 N
N
N
VoL 16, No. 2, 1991
In contrast to tricyclic antidepressants, fluvoxamine has no antihistaminic effect, no sedative effect, does not inhibit monoamine oxidase (Lapierre et al 1983), does not have an amphetamine-like stimulating effect and has very little or no parasympatholytic activity (Claassen et al 1983; Wilson et al 1983). At high doses (over 60 mg/kg) it has shown in animal studies, a tendency to induce seizures. Physical dependence liability has not been demonstrated for this compound at doses up to 90 mg/kg per day in monkeys (LUVOX 1990). Furthermore, in contrast to tricyclic antidepressants, fluvoxamine at therapeutic doses lacks significant effects on the cardiovascular system (Roos 1983). A single dose of fluvoxamine did not affect heart rate or blood pressure in healthy volunteers (Wilson et al 1983). Repeated administration (for 9 days) of fluvoxamine had little or no effect on ECG or blood pressure and produced only a slight decrease in heart rate (Robinson and Doogan 1982).
Drug Interactions In combination with MAO inhibitors, fluvoxamine produces an increase in serotonin mediated effects (Claassen et al 1983). In contrast to some tricyclic antidepressants, fluvoxamine produces no interaction with the antihypertensive effect of guanethidine or a-methyldopa (LUVOX 1990). However, it may prolong the elimination of some drugs metabolized by the oxidation pathway in the liver. This could be an important consideration when fluvoxamine is taken simultaneously with drugs that have a narrow therapeutic index, such as warfarin and phenytoin. In fact, fluvoxamine was shown to increase plasma levels of warfarin by 65%. It also produced a 5-fold increase in plasma levels of simultaneously administered propranolol (LUVOX 1990).
Toxicity
1000 7700
N = no effect in conc. < 10000 nM (Adapted from Claassen 1983 and Schmidt et al 1988)
As shown in Table 5, the selective serotonin re-uptake inhibitors, fluoxetine, fluvoxamine and paroxetine, lack a significant affinity to al, cc2, B-adrenergic, 5-HT2, dopamine D2 or muscarinic cholinergic receptors in the brain (Wong et al 1983: Nelson et al 1989; Schmidt et al 1988). This is most likely the reason why they do not show the above mentioned side effects typical for tricyclic antidepressants. The selectivity of specific 5-HT uptake inhibitors (eg. paroxetine) for the serotonin uptake sites and serotonergic innervation in the brain has also been demonstrated in autoradiographic studies (Hrdina et al 1990).
In animal experiments, fluvoxamine in doses which are near to lethal doses, produced acute toxic effects including ataxia, mydriasis, bradypnea and convulsions. The oral LD50 of the compound is more than 2 g/kg in rats and more than 500 mg/kg in dogs. Emesis in dogs has occurred at doses higher than 25 mg/kg. In these cases, a haemorrhage of intestinal mucosa has been observed on the biopsy (LUVOX 1990). Chronic toxic effects of fluvoxamine in rodents include a decrease in body weight gain, decreases in serum lipids and increases in liver lipids that were similar to those produced with comparable doses of imipramine and amitriptyline. After high doses, an increase in fatty vacuolation of hepatocytes was noted. Finally, in dogs at doses 60 mg/kg per day and higher, there was ataxia, anorexia and, in some cases, convulsions (LUVOX 1990).
Pharmacology of Serotonin Uptake Inhibitors
July 1991
Table 6 Pharmacokinetic parameters of some selective serotonin uptake inhibitors and imipramine. Parameter
Imipramine Fluvoxamine Fluoxetine Paroxetine (40 MG) (125 MG) (100 MG) 139
Cmax (ng/ml)
4.2
tmax (hr)
27
31-87 1.5-8
tl/2(hr)
13
17-22
Bioavail. (%)
50
60
Prot. bind.(%)
85-90
77
6.4 43 (140)
20.6
95
(Adapted from Hrdina et al 1981; Bergstrom et al 1988 and Kaye et al 1989)
Differences in Metabolism and Kinetics: Impact on Clinical Therapy The pharmacokinetic parameters of fluvoxamine and of some other serotonin uptake inhibitors in comparison with those of imipramine are reported in Table 6. In healthy volunteers, peak plasma levels following a single oral dose of 100 mg of fluvoxamine were observed 1.5 to 8 hours
15
after the dose and were comparable to those seen after imipramine. The half-life of fluvoxamine is between 17 and 22 hours. This is within the range of the half-life of tricyclic antidepressants, but much shorter than the halflife of fluoxetine and particularly of its demethylated metabolite, norfluoxetine. The consequences of the effects of metabolism and kinetics on the selectivity and duration of action of some serotonin uptake inhibitors are shown in Table 7. Clomipramine is metabolized in the body to its main active metabolite, desmethylclomipramine (de Cuyper et al 1983), which, in contrast to the parent compound is a much more potent inhibitor of norepinephrine than serotonin uptake. Thus, the metabolism of clomipramine to desmethylclomipramine results in a loss of selectivity of the parent compound for the inhibition of serotonin uptake. On the other hand, fluoxetine which is also metabolized to an active compound, norfluoxetine (Bergstrom et al 1988), maintains its selectivity for serotonin uptake inhibition because norfluoxetine is just as effective an inhibitor of serotonin uptake as is its parent compound, (Schmidt et al 1988). However, the duration of action of the drug increases significantly with the formation of the active metabolite, norfluoxetine, whose half-life is approximately 140 hours. In the case of fluvoxamine, the metabolites are inactive, without a significant effect on serotonin or norepinephrine uptake. Fluvoxamine metabolism thus does not change either the selectivity or
Table 7 Effect of metabolism and kinetics on the selectivity and duration of action of some clinically used serotonin uptake inhibitors.
Drug Clomipramine
5-HT Uptake +++
NE Uptake +
Duration -
Consequence Loss of
selectivity
Desmethylclomipramine
+
+++
Fluoxetine
+++
+
Nofluoxetine
+++
+
Fluvoxamine
+++
+
Inact. metabolites
(+)
-
Increased duration
-
No change in selectivity or duration
16
the duration of the action of the drug. The clinical effects of fluvoxamine are therefore more predictable than those of clomipramine and a downward adjustment of its dose is simpler than with fluoxetine. Table 8 Effect of repeated administration of serotonin uptake inhibitors and imipramine on the density of betaadrenergic receptors, NE-coupled adenylate cyclase and the number of 5-HT2 receptors in rat brain.
Drug
Vol. 16, No. 2,1991
Journal of Psychiatry & Neuroscience Supplement I
Density of Adenylate Cyclase Number of [B-adrenergic Activity 5-HT2 Receptors
Receptors (Rat Brain)
Block of 5-HT uptake + Availability of 5-HT in the Synapse
+ 4 Action on 5-HT Receptors
Acute Effects
* In 5-HT Turnover & Firing Rate Desensitization of Presynaptic Receptors On Terminals Somatodendritic
Imipramine
Normal Firing Rate Clomipramine
+
+
Fluoxetine
0(+)
0
0(+)
Fluvoxamine
0
+
0
Paroxetine
0
4 5- HT Release and Neurotransmission
|Therapeutic Effect|
+
+ decrease; + increase; 0 no change (Adapted from Nelson et al 1989)
Fig. 3: Chain of events in the serotonergic neurotransmission after administration of serotonin uptake inhibitors.
Possible Mode of Antidepressant Action Down regulation of B-adrenergic receptors has been considered to be a crucial event in adaptive changes during the chronic administration of antidepressant treatments (Sulser 1983). However, the selective serotonin uptake inhibitors, fluvoxamine and paroxetine which are clinically effective antidepressants, do not produce a down regulation of B-adrenergic receptors after repeated treatment in animals (Table 8), although fluoxetine was found to reduce the number of beta-adrenergic receptors in frontal cortex (Nelson et al 1989). Fluvoxamine though, was shown to produce a down regulation in the responsiveness of adenylate cyclase to norepinephrine. These findings cast some doubt on the postulate that B-adrenergic receptor down regulation is an essential component of antidepressant efficacy. It could be however, that adaptive changes in receptor systems other than B-adrenergic could be an integral part of changes which occur after repeated administration of serotonin uptake inhibitors and which would be essential for the antidepressant activity of these compounds. For example, both fluoxetine and paroxetine were reported to produce a down regulation of 5-HT2 receptors after repeated administration (Wong and Bymaster 1980, Nelson et al 1989).
The mechanism by which serotonin uptake inhibitors produce their antidepressant effect is at present unclear. One possible chain of events occurring after repeated administration of these drugs has been suggested by de Montigny and his coworkers (de Montigny and Aghajanian 1978; Blier et al 1987). According to this concept, illustrated in Fig. 3, the block of the 5-HT uptake by these compounds would lead to the increased availability of serotonin in the synapse and to acute manifestation of the increased action on 5-HT synapses, both presynaptically and postsynaptically. Dynamic changes would then include a decrease in 5-HT turnover and firing rate. With time, the increased availability of serotonin in the synaptic gap and at the receptor sites would lead to desensitization of presynaptic serotonin receptors either on the cell bodies (somatodendritic receptors) or on the terminals. This in turn, would bring the firing rate back to normal and would increase the serotonin release and serotonin neurotransmission, which may be translated in a therapeutic antidepressant effect. These adaptive changes however, might be just one step in the chain of events which occur between the primary manifestation of the effect of those compounds, that is inhibition of the uptake of serotonin and between the onset of the clinical therapeutic effect. The notion that the brain monoamine
July 1991
Pharmacology ofSerotonin Uptake Inhibitors
systems are targets for the action of some antidepressants does not necessarily mean that the abnormal functioning of these systems is a primary factor in the pathogenesis of affective disorders. The perturbation of brain neuronal systems could well be a result of other hitherto unrecognized disturbances. Nevertheless, a better understanding of the neurobiological basis of the action of antidepressants might help us in unravelling the disturbances in brain function that are the biological basis of depression.
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