Pharmacology of Serotonin Uptake Inhibitors: Focus on Fluvoxamine

Pavel D. HrdinaDepartments of Pharmacology and Psychiatry, and Institute of Mental Health Research,

University of Ottawa, Ottawa, Canada

Selective serotonin uptake inhibitors comprise arelatively new class of clinically effective antidepressantsthat are chemically distinct from tricyclics. They share acommon feature - a selective and potent inhibition ofneuronal uptake of serotonin (5-HT, 5-hydroxytryptamine)and have no or very weak effects on neuronal uptake ofnorepinephrine (NE). More importantly, they lack a signifi-cant affinity to various neurotransmitter receptor systems inthe brain and, in contrast to tricyclic antidepressants, theydo not possess significant sedative, anticholinergic and/orcardiovascular effects. On the other hand, they allpotentiate the pharmacological effects of serotonin and itsprecursor, 5-hydroxytryptophan. Fluvoxamine, now beingintroduced into the clinical practice, has some metabolicand pharmacokinetic features that distinguish this drugfrom other compounds in this class. The purpose of thisarticle is to review the preclinical pharmacological effectsof selective serotonin uptake inhibitors with a focus onfluvoxamine and to compare them with those of representa-tive tricyclic antidepressants.

There is now considerable evidence available to indicatethat impaired functioning of the central serotonergic systemis involved in the pathogenesis of at least some types ofdepressive illness (Asberg et al 1976a). This evidence stemsfrom clinical observations that the level of the mainserotonin metabolite, 5-HIAA in the cerebrospinal fluid issignificantly decreased in a subgroup of depressive patientswho exhibit suicidal behaviour (Asberg et al 1976b).Furthermore, the density of presynaptic uptake sites forserotonin (labelled by [3H]imipramine) has been reportedto be decreased in some (Stanley et al 1982; Perry et al1983), 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

from suicide victim/depressives in comparison withcontrols. In other post-mortem studies, a significant increasewas found in the number of 5-HT2 receptors in the brains ofsuicide victims or depressed subjects (Stanley et al 1983;Yates et al 1990). Serotonin uptake has been found to bedecreased and the number of [3H]imipramine sites reducedin blood platelets of depressed patients (Tuomisto andTukiainen 1976; Briley et al 1980). Whether these markersreflect the functional state of the serotonin uptake system inthe brain is at present unknown. Finally, clinical observa-tions also indicate that the precursor of serotonin, L-tryptophan, particularly in conjunction with an MAOinhibitor can be an effective treatment for depression(Coppen et al 1963).

Tricyclic antidepressants, the main drugs in the treatmentof depressive illness, are known to block the neuronaluptake of two major biogenic amines, norepinephrine andserotonin. In addition, these drugs exert a significant effecton several neurotransmitter receptors (including adrenergic,cholinergic and histaminergic) and many of their side effectsare thought to be related to this property of the tricyclicdrugs. The inhibition of norepinephrine and serotonin wasthought to be responsible for the antidepressant action ofthese compounds. This has led to the development of the'biogenic amine hypothesis' of affective disorders whichsuggests that depression may be due to a lack of nore-pinephrine and/or serotonin in some critical parts of thebrain. However, the delayed onset of the clinical antidepres-sant effect with tricyclic antidepressants was difficult toexplain in the view of the fact that the inhibition of amineuptake occurs shortly after drug administration. In addition,some newer, clinically effective antidepressants (e.g.mianserin) do not inhibit the uptake of either norepinephrineor serotonin. The amine hypothesis of affective disordersneeded a critical evaluation (see Baldessarini, 1975).Subsequent studies have shown that after chronic treatment

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Pharmacology ofSerotonin Uptake Inhibitors

with almost all clinically effective antidepressants, a downregulation of B-adrenergic receptors and of responsivenessof adenylate cyclase to norepinephrine occurs, regardless ofthe effect of drugs used in the uptake of monoamines(Vetulani et al 1974; Sulser 1983). It is now believed thatafter the initial block of neuronal re-uptake, adaptivechanges in the neuronal networks have to take place in orderto give expression to the antidepressant effect.

Table 1Serotonin uptake inhibitors used as antidepressants.

Alaproclate FluoxetineCitalopram FluvoxamineClomipramine IndalpineClovoxamine ParoxetineFemoxetine Sertraline

Serotonin Uptake Inhibitors

Side-effects of the commonly used tricyclic antidepres-sants (sedative, hypotensive, anticholinergic, cardiac) havebeen a limiting factor in their clinical use particularly incertain subgroups of patients (elderly, cardiovascularlycompromised). During the last two decades there has been a

considerable effort to develop compounds which would havea relatively selective effect on the serotonergic systemwithout concomitant interaction with a variety of neurotrans-mitter receptor systems and would be free of undesirable sideeffects. A new group of compounds has emerged from thissearch: selective serotonin uptake inhibitors. They have littleor no effect on the uptake of norepinephrine or dopamine andhave been shown to be clinically effective antidepressants(Asberg et al 1985). They include compounds listed in Table1. The aim of this article is to review the pharmacology ofthis class of compounds with special focus on the new,

recently introduced member of this family, fluvoxamine, andto compare some aspects of preclinical and clinical pharma-cology of main representatives of this class, fluoxetine,clomipramine and paroxetine that either are, or may in thenear future, become available for clinical use in Canada.Inspection of the chemical structure of serotonin uptakeinhibitors, presented in Fig. 1, reveals that these compoundsare chemically different from tricyclic antidepressants andfrom each other. They have some common structural featuresand a halogen substituent is an important determinant of thepotency and selectivity for serotonin uptake inhibition.

Metabolism of Fluvoxamine

Fluvoxamine (LUVOX) is a compound that belongs to a

new chemical series, the 2-aminoethyl oximethers ofaralkylketones. It is chemically unrelated to any of theexisting antidepressants or selective serotonin uptake

inhibitors. The compound has a molecular weight of 434 (asmaleate), is sparingly soluble in water, freely soluble inethanol and chloroform and practically insoluble indiathylether. In humans and animals, fluvoxamine is wellabsorbed after oral administration. It is metabolized entirelyin the liver by two metabolic pathways: oxidative demethyla-tion (major) and deamination (minor) to more than tenmetabolites, out of which nine have been identified in theurine (Overmars et al 1983). They are all excreted by thekidney. After a single oral administration, almost the wholedose (94%) is eliminated from the body within 48 hours(DeBree et al 1983). The two major metabolites of fluvox-amine are without significant pharmacological activity whencompared to parent compound, although one of the majormetabolites (the carboxylic acid derivative) shows someinhibition of serotonin uptake (Claassen 1983). The bioavail-ability of fluvoxamine was shown to be about 60% (in dogs)and the binding to plasma proteins about 77%, compared to85-90% for imipramine and 95% for fluoxetine (Claassen1983; Kaye et al 1989).

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

FluoxetineH

V- CH20/

F

Paroxetine

Fig. 1: Molecular structure of some selective serotoninuptake inhibitors.

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Journal ofPsychiatry & Neuroscience Supplement I

Table 2Inhibition of serotonin (5-HT) and norepinephrine (NE)uptake in vitro (rat hypothalamus) by selective serotonin

uptake inhibitors and imipramine.

Ki(nM)Drug 5-HT NE NE/5-HT

Imipramine 100 65 0.65Clomipramine 7.4 96 13Fluoxetine 25 500 20Fluvoxamine 6.2 1100 180Paroxetine 1.1 350 320

Ki is the concentration of drugs that produces 50% inhibition of [3H]5-HTor ['H]NE uptake.(Adapted from Johnson 1989)

Selectivity for Serotonin Uptake Inhibition

The main pharmacological effect of fluvoxamine is theinhibition of neuronal uptake of serotonin. The selectivity offluvoxamine to inhibit the neuronal re-uptake in vitro bysynaptosomes from rat hypothalamus is illustrated in Table 2.The Ki of fluvoxamine for inhibition of serotonin uptake is180 times lower than its Ki for inhibition of norepinephrineuptake. Fluvoxamine appears to be a more selective andpotent inhibitor of serotonin uptake than fluoxetine andclomipramine, but is less potent and selective thanparoxetine. It is important, however, to demonstrate that theselectivity of the compound to inhibit serotonin uptake ismaintained after in vivo administration. Fluvoxamineadministered in vivo produces an 80% inhibition of 5-HTuptake by rat brain synaptosomes 30 minutes after adminis-tration. In comparison, imipramine in a similar doseproduces only 50% inhibition of serotonin neuronal uptake(Claassen 1983). Table 3 compares the relative potency andselectivity of serotonin uptake inhibitors on 5-HT and nore-pinephrine uptake measured 'ex vivo' and shows that fluvox-amine maintains its selectivity for serotonin uptake after invivo administration. Fluvoxamine was also shown to signifi-cantly decrease platelet serotonin uptake in patients treatedwith the drug (Wood et al 1983; Nathan et al 1990).

The selectivity of serotonin uptake inhibitors can also bedemonstrated by their ability to potentiate behaviorsmediated by serotonin and norepinephrine, respectively.Table 4 compares the activity of fluvoxamine, clomipramineand imipramine in potentiating the 5-hydroxytryptophan-induced hyperactivity syndrome in rodents (Ortman 1984)pretreated with an MAO inhibitor and in antagonizing thetetrabenazine effect thought to be mediated through nore-pinephrine. The ratio of ED50 of fluvoxamine needed topotentiate 5-hydroxytryptophan and to antagonize tetra-benazine effect was 0.34 compared to 7 for clomipramineand 26 for imipramine (Claassen 1983).

Interaction with Serotonergic Mechanisms

The functional consequence of inhibiting neuronalserotonin uptake is an increased synaptic concentration ofserotonin. The acute effects of serotonin uptake inhibitorsare believed to be due to activation of serotonergicmechanisms. These include potentiation of the effects ofserotonin and its presursors, induction (in conjunction withMAO inhibitors) of a serotonin produced behavioralsyndrome and serotonin mediated effects on REM sleep andfood consumption.

Table 3Inhibition of monoamine uptake in synaptosomes fromrat hypothalamus ex vivo after oral administration ofselective serotonin uptake inhibitors and imipramine.

ED50(mg/kg)Drug 5-HT NE

Imipramine >30 10Fluoxetine 7 >30Fluvoxamine 23 >30Paroxetine 1.9 >30

'Forms an active metabolite that has a higher potency for NE uptakeinhibition than the parent compound(Adapted from Johnson 1989)

Hormonal Effects

Serum concentration of prolactin in animals as well as inhumans, is increased by serotonergic stimuli (Clemens et al,1977; Fuller, 1981). Fluvoxamine was shown to stimulateprolactin secretion in rats (Fig 2) and to significantlypotentiate the prolactin releasing effect of 5-hydroxytrypto-phan (Cella et al 1983). These endocrine effects of acutefluvoxamine administration are compatible with activationof 5-HT neurotransmission. In humans, fluvoxamine alonedoes not produce an increased prolactin secretion andplasma levels. However, it potentiates significantly theeffect of tryptophan stimulation on prolactin release (Priceet al 1990).

Serotonin Mediated Behavioral Syndrome

Several directly acting serotonin agonists or a combi-nation of a serotonin precursor with an inhibitor ofmonoamine oxidase and/or an inhibitor of serotoninuptake, produce in rats the serotonin behavioral syndromeconsisting of forepaw threading, head weaving, hind limbabduction, body tremor, compulsive movements, pilo-erection and salivation (Ortmann, 1984). This behavioralsyndrome results from an intense stimulation of central

12 Vol. 16, No. 2,1991

Pharmacology ofSerotonin Uptake Inhibitors

5-HTPk *4.

30 45 0 30 45Time (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; + = difference vs corresponding values in 5-HTP treated rats.

(Adapted from Cella et al 1983).

serotonin receptors. Serotonin uptake inhibitors (eg. fluvox-amine) alone do not elicit this syndrome, but they potentiatethe 5-hydroxytryptophan induced head twitch in mice to an

extent which correlates with their 5-HT uptake inhibitingpotencies (Ortmann et al 1980) and produce the serotoninbehavioral syndrome when given in conjunction withmonoamine oxidase inhibitors. Fluvoxamine was about twiceas potent as clomipramine in potentiating the 5-HTP inducedbehavioral syndrome in mice (Table 4).

Reduction of Serotonin Turnover

One of the consequences of serotonin uptake inhibition isan increased activity of this neurotransmitter on both post-and presynaptic receptors. Administration of serotoninuptake inhibitors results, probably via a negative feedbackmechanism and autoreceptor stimulation, in reduction ofserotonin turnover rate as measured by decreases in the levelof its major metabolite, 5-HIAA (Claassen 1977; Macro andMeek 1979), and in an inhibition of spontaneous firing rateof n. raphe dorsalis neurons in rats (Dresse and Scuvee-Morreau 1984).

Other Effects

Serotonin uptake inhibitors alone, or in combinationwith a serotonin precursor, produce a decrease in foodintake in rats (Yen et al 1987; LUVOX 1990). The doses atwhich weight loss is seen in humans tend to be ratherhigher than the minimum dose at which an antidepressant

effect appears (Montgomery 1989). Serotonin uptakeinhibitors can also produce anti-nociceptive effects and canpotentiate an analgesic effect of some opioid analgesicdrugs (Hynes and Fuller 1982) as well as the 5-hydrox-ytryptophan induced myoclonus in animals (Green andHeal 1985). Fluvoxamine in a dose of 200 mg/day wasshown to reduce REM sleep time as well as the time spentin stages 3 and 4 of sleep, and to extend REM sleep latencyin depressive subjects (Berger et al 1986).

Table 4Potentiation of monoamine-mediated effects in vivo (mice)

by some selective serotonin uptake inhibitors andimipramine.

Drug ED50oral (mg/kg)5-HTP' Antag of TBZ (NE)2 Ratio

Imipramine3 135 5.2 26Clomipramine3 84 12 7Fluvoxamine 36 107 0.34

'Dose of the test drug that potentiates to 50% of the maximal score the 5-HTP induced behavioral syndrome.2Dose of the test drug that reduced the tetrabenazine induced ptosis to halfof that of the controls.3Forms in vivo an active metabolite that inhibits NE uptake.(Adapted from Claassen 1983)

SalineFluvoxamine Saline

Saline9

8

7

6

5S/B

3

2

0

I

5-HTP

T*"

T~

0 30 45

TF

0 0 30 45

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Journal ofPsychiatry & Neuroscience Supplement I

Interaction with Neurotransmitter Receptors

Many of the side effects of tricyclic antidepressants havebeen related to their ability to interact with various neuro-transmitter receptors in the brain (Hall and Ogren 1981;Richelson and Nelson 1984; Wander et al 1986). Forinstance, sedative effects, increased appetite and posturalhypotension have been related to their affinity for centraland peripheral a] adrenergic receptors. Dyskinesia withsome of the tricyclic antidepressants has been ascribed to theaffinity of some of these drugs to dopamine D2 receptor sitesin the brain. The undesirable anticholinergic side effectspresent with most tricyclic antidepressants result from theaffinity of these compounds for the muscarinic receptors.The sedative effect and drowsiness produced by tricyclicsand possibly the weight gain which is seen with thesecompounds (Feighner and Cohn 1985), could be related tothe effect of these compounds on histamine H1 receptors inthe brian.

Table 5Affinity of selective serotonin uptake inhibitors and

imipramine for neurotransmitter receptors in rat brain.

IC50 value for displacement (nM)Drug al a2 I 5-HT2 D2 MUSC

Imipramine 300 N N 180 2700 400

Clomipramine 117 N N 150 700 160

Fluoxetine N N N N

Fluvoxamine 5000 N N N N N

Paroxetine N N >5000 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-uptakeinhibitors, fluoxetine, fluvoxamine and paroxetine, lack asignificant affinity to al, cc2, B-adrenergic, 5-HT2, dopamineD2 or muscarinic cholinergic receptors in the brain (Wong etal 1983: Nelson et al 1989; Schmidt et al 1988). This is mostlikely the reason why they do not show the above mentionedside effects typical for tricyclic antidepressants. The selec-tivity of specific 5-HT uptake inhibitors (eg. paroxetine) forthe serotonin uptake sites and serotonergic innervation in thebrain has also been demonstrated in autoradiographic studies(Hrdina et al 1990).

In contrast to tricyclic antidepressants, fluvoxamine has noantihistaminic effect, no sedative effect, does not inhibitmonoamine oxidase (Lapierre et al 1983), does not have anamphetamine-like stimulating effect and has very little or noparasympatholytic activity (Claassen et al 1983; Wilson et al1983). At high doses (over 60 mg/kg) it has shown in animalstudies, a tendency to induce seizures. Physical dependenceliability has not been demonstrated for this compound atdoses up to 90 mg/kg per day in monkeys (LUVOX 1990).Furthermore, in contrast to tricyclic antidepressants, fluvox-amine at therapeutic doses lacks significant effects on thecardiovascular system (Roos 1983). A single dose of fluvox-amine did not affect heart rate or blood pressure in healthyvolunteers (Wilson et al 1983). Repeated administration (for9 days) of fluvoxamine had little or no effect on ECG orblood pressure and produced only a slight decrease in heartrate (Robinson and Doogan 1982).

Drug Interactions

In combination with MAO inhibitors, fluvoxamineproduces an increase in serotonin mediated effects (Claassenet al 1983). In contrast to some tricyclic antidepressants,fluvoxamine produces no interaction with the antihyperten-sive effect of guanethidine or a-methyldopa (LUVOX 1990).However, it may prolong the elimination of some drugsmetabolized by the oxidation pathway in the liver. This couldbe an important consideration when fluvoxamine is takensimultaneously with drugs that have a narrow therapeuticindex, such as warfarin and phenytoin. In fact, fluvoxaminewas shown to increase plasma levels of warfarin by 65%. Italso produced a 5-fold increase in plasma levels of simulta-neously administered propranolol (LUVOX 1990).

Toxicity

In animal experiments, fluvoxamine in doses which arenear to lethal doses, produced acute toxic effects includingataxia, mydriasis, bradypnea and convulsions. The oral LD50of the compound is more than 2 g/kg in rats and more than500 mg/kg in dogs. Emesis in dogs has occurred at doseshigher than 25 mg/kg. In these cases, a haemorrhage ofintestinal mucosa has been observed on the biopsy (LUVOX1990).

Chronic toxic effects of fluvoxamine in rodents include adecrease in body weight gain, decreases in serum lipids andincreases in liver lipids that were similar to those producedwith comparable doses of imipramine and amitriptyline.After high doses, an increase in fatty vacuolation of hepato-cytes was noted. Finally, in dogs at doses 60 mg/kg per dayand higher, there was ataxia, anorexia and, in some cases,convulsions (LUVOX 1990).

14 VoL 16, No. 2, 1991

Pharmacology ofSerotonin Uptake Inhibitors

Table 6Pharmacokinetic parameters of some selective serotonin

uptake inhibitors and imipramine.

Parameter Imipramine Fluvoxamine Fluoxetine Paroxetine(125 MG) (100 MG) (40 MG)

Cmax (ng/ml) 139 31-87 27

tmax (hr) 4.2 1.5-8 6.4

tl/2(hr) 13 17-22 43 (140) 20.6

Bioavail. (%) 50 60

Prot. bind.(%) 85-90 77 95

(Adapted from Hrdina et al 1981; Bergstrom et al 1988 andKaye et al 1989)

Differences in Metabolism and Kinetics: Impact onClinical Therapy

The pharmacokinetic parameters of fluvoxamine and ofsome other serotonin uptake inhibitors in comparison withthose of imipramine are reported in Table 6. In healthyvolunteers, peak plasma levels following a single oral doseof 100 mg of fluvoxamine were observed 1.5 to 8 hours

after the dose and were comparable to those seen afterimipramine. The half-life of fluvoxamine is between 17and 22 hours. This is within the range of the half-life oftricyclic antidepressants, but much shorter than the half-life of fluoxetine and particularly of its demethylatedmetabolite, norfluoxetine.

The consequences of the effects of metabolism andkinetics 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 activemetabolite, desmethylclomipramine (de Cuyper et al1983), which, in contrast to the parent compound is a muchmore potent inhibitor of norepinephrine than serotoninuptake. Thus, the metabolism of clomipramine todesmethylclomipramine results in a loss of selectivity ofthe parent compound for the inhibition of serotonin uptake.On the other hand, fluoxetine which is also metabolized

to an active compound, norfluoxetine (Bergstrom et al1988), maintains its selectivity for serotonin uptakeinhibition 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 ofthe drug increases significantly with the formation of theactive metabolite, norfluoxetine, whose half-life is approx-

imately 140 hours. In the case of fluvoxamine, themetabolites are inactive, without a significant effect on

serotonin or norepinephrine uptake. Fluvoxaminemetabolism thus does not change either the selectivity or

Table 7Effect of metabolism and kinetics on the selectivity and duration of action of some clinically used serotonin uptake

inhibitors.

Drug 5-HT Uptake NE Uptake Duration Consequence

Clomipramine +++ + - Loss ofselectivity

Desmethylclomipramine + +++

Fluoxetine +++ + - Increasedduration

Nofluoxetine +++ +

Fluvoxamine +++ + - No change inselectivityor duration

Inact. metabolites (+)

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Journal ofPsychiatry & Neuroscience Supplement I

the duration of the action of the drug. The clinical effectsof fluvoxamine are therefore more predictable than thoseof clomipramine and a downward adjustment of its dose issimpler than with fluoxetine.

Table 8Effect of repeated administration of serotonin uptake

inhibitors and imipramine on the density of beta-adrenergic receptors, NE-coupled adenylate cyclase and

the number of 5-HT2 receptors in rat brain.

Density of Adenylate Cyclase Number ofDrug [B-adrenergic Activity 5-HT2

Receptors Receptors(Rat Brain)

Imipramine

Clomipramine + +

Fluoxetine 0(+) 0 0(+)

Fluvoxamine 0 + 0

Paroxetine 0 +

+ decrease; + increase; 0 no change(Adapted from Nelson et al 1989)

Possible Mode of Antidepressant Action

Down regulation of B-adrenergic receptors has beenconsidered to be a crucial event in adaptive changes duringthe chronic administration of antidepressant treatments(Sulser 1983). However, the selective serotonin uptakeinhibitors, fluvoxamine and paroxetine which are clinicallyeffective antidepressants, do not produce a down regulationof B-adrenergic receptors after repeated treatment in animals(Table 8), although fluoxetine was found to reduce thenumber of beta-adrenergic receptors in frontal cortex(Nelson et al 1989).

Fluvoxamine though, was shown to produce a downregulation in the responsiveness of adenylate cyclase tonorepinephrine. These findings cast some doubt on thepostulate that B-adrenergic receptor down regulation is anessential component of antidepressant efficacy. It could behowever, that adaptive changes in receptor systems otherthan B-adrenergic could be an integral part of changes whichoccur after repeated administration of serotonin uptakeinhibitors and which would be essential for the antidepres-sant activity of these compounds. For example, bothfluoxetine and paroxetine were reported to produce a downregulation of 5-HT2 receptors after repeated administration(Wong and Bymaster 1980, Nelson et al 1989).

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 ReceptorsOn Terminals Somatodendritic

Normal Firing Rate

4 5- HT Release and Neurotransmission

|Therapeutic Effect|

Fig. 3: Chain of events in the serotonergic neuro-transmission after administration of serotoninuptake inhibitors.

The mechanism by which serotonin uptake inhibitorsproduce their antidepressant effect is at present unclear. Onepossible chain of events occurring after repeated administra-tion of these drugs has been suggested by de Montigny andhis coworkers (de Montigny and Aghajanian 1978; Blier etal 1987). According to this concept, illustrated in Fig. 3, theblock of the 5-HT uptake by these compounds would lead tothe increased availability of serotonin in the synapse and toacute manifestation of the increased action on 5-HTsynapses, both presynaptically and postsynaptically.Dynamic changes would then include a decrease in 5-HTturnover and firing rate. With time, the increased avail-ability of serotonin in the synaptic gap and at the receptorsites would lead to desensitization of presynaptic serotoninreceptors either on the cell bodies (somatodendriticreceptors) or on the terminals. This in turn, would bring thefiring rate back to normal and would increase the serotoninrelease and serotonin neurotransmission, which may betranslated in a therapeutic antidepressant effect. Theseadaptive changes however, might be just one step in thechain of events which occur between the primary manifesta-tion of the effect of those compounds, that is inhibition ofthe uptake of serotonin and between the onset of the clinicaltherapeutic effect. The notion that the brain monoamine

16 Vol. 16, No. 2,1991

July 1991 Pharmacology ofSerotonin Uptake Inhibitors 17

systems are targets for the action of some antidepressantsdoes not necessarily mean that the abnormal functioning ofthese systems is a primary factor in the pathogenesis ofaffective disorders.

The perturbation of brain neuronal systems could well bea result of other hitherto unrecognized disturbances.Nevertheless, a better understanding of the neurobiologicalbasis of the action of antidepressants might help us in unrav-elling the disturbances in brain function that are thebiological basis of depression.

REFERENCES

Asberg M, Thoren P, Traskman L, Bertilsson L, RingbergerV (1976) "Serotonin depression": A subgroup within theaffective disorders? Science 191:478-80.

Asberg M, Traskman L, Thoren P (1976) 5-HIAA in thecerebrospinal fluid - a biochemical suicide predictor?Arch Gen Psychiatry 33:1193-7.

Asberg M, Eriksson B, Matensson B, Traskman-Bendz L,Wagner A (1985) Therapeutic effects of serotonin uptakeinhibitors in depression. J Clin Psychiatry 47(Suppl 4):23-35.

Baldessarini RJ (1975) The basis for amine hypotheses inaffective disorders: a critical evaluation. Arch GenPsychiarty 32:1087-93.

Berger M, Emrich HM, Lund R, Riemann D, Lauer C(1986) Sleep EEG variables as course criteria andpredictors of antidepressant therapy withfluvoxamine/oxaprotiline. Adv Pharmacother 2:110-20.

Bergstrom RF, Lemberger L, Farid NA, Wolen RL (1988)Clinical pharmacology and pharmacokinetics of fluoxetine:A review. Brit J Psychiatry 153(Suppl 3):47-50.

Blier P, de Montigny C, Chaput Y (1987) Modifications ofthe serotonin system by antidepressant treatments:Implications for the therapeutic response in majordepression. J Clin Psychopharmacol 7:24S-35S.

Briley MS, Langer SZ, Raisman R, Sechter R, Zarifan E(1980) Tritiated imipramine binding sites are decreased inplatelets of untreated depressed patients. Science209:303-5.

Cella S, Penalva A, Locatelli V, Novelli D, Cocchi D,Muller EE (1983) Neuroendocrine studies with fluvox-amine: Animal data. Br J Clin Pharmacol 15:357S-63S.

Claassen V, Davies JE, Herrting G, Placheta P (1977)Fluvoxamine, a specific 5-hydroxytryptamine uptakeinhibitor. Br J Pharmacol 60:505-16

Claassen V (1983) Review of the animal pharmacology andpharmacokinetics of fluvoxamine. Br J Clin Pharmacol15:349S-55S.

Clemens JA, Sawyer BD, Cerimele B (1977) Furtherevidence that serotonin is a neurotransmitter involved inthe control of prolactin secretion. Endocrinology100:692-8.

Coppen A, Shaw DM, Ferrel JP (1963) Potentiation of theantidepressant effect of a monoamine oxidase inhibitor bytryptophan. Lancet 1:79-81.

DeBree H, Van der School ZB, Post LC (1983)Fluvoxamine maleate: Disposition in man. Eur J DrugMetab Pharmacokin 8:175-9.

de Cuyper HJA, van Praag HM, Mulder-Hajonides REM,Westenberg GM, de Zeeuw RA (1981). Pharmacokineticsof clomipramine in depressive patients. Psychiatry Res4:147-56.

de Montigny C, Aghajanian GK (1978) Long-term antide-pressant treatment increases responsivity of forebrainneurons to serotonin. Science 202:1303-6.

Dresse A, Scuvee-Morreau J (1984) The effects of variousantidepressants on the spontaneous firing rates of norad-renergic and serotonergic neurons. Clin Neuropharmacol7(Suppl 1):S312-9.

Feighner JP, Cohn JB (1985) Double-blind comparativetrials of fluoxetine and doxepin in geriatric patients withmajor depressive disorder. J Clin Psychiatry 46(3, sect2):20-5.

Fuller RW (1981) Serotonergic stimulation of pituitary-adrenocortical function in rats. Neuroendocrinology32:118-27.

Green AR, Heal DJ (1985) The effects of drugs on serotonin-mediated behavioural models. In: Neuropharmacology ofSerotonin Green AR (ed). Oxford: Oxford UniversityPress, 326-65.

Hall H, Ogren S-0 (1981) Effects of antidepressant drugs ondifferent receptors in the brain. Eur J Pharmacol 70:393-407.

Hrdina PD, Rovei V, Henry JF, Gomeni R, Forette F,Morselli P (1980) Psychopharmacology 70:29-34.

Hrdina PD, Foy B, Hepner A, Summers RJ (1990)Antidepressant binding sites in brain: Autoradiographiccomparison of [3H]paroxetine and [3H]imipramine local-ization and relationship to serotonin transporter.J Pharmacol Exp Ther 252:410-8.

Hynes MD, Fuller RW (1982) The effect of fluoxetine onmorphine analgesia, respiratory depression and lethality.Drug Dev Res 2:33-42.

Johnson AM (1989) An overview of the animal pharma-cology of paroxetine. Acta Psychiatr Scand 80(Suppl350): 14-20.

Kaye CM, Haddock RE, Langley PF, Mellows G, TaskerTCG, Zussman BD, Greb WH (1989) Acta PsychiatrScand 80(Suppl 350):60-75.

Lapierre YD, Rastogi RB, Singhal RL (1983) Fluvoxamineinfluences serotonergic system in the brain: neurochem-ical evidence. Neuropsychobiology 10:213-6.

18 Journal ofPsychiatry & Neuroscience Supplement ) Vol. 16, No. 2, 1991

Luvox: Product Monograph (1990) McNeil Pharmaceutical(Canada) Ltd., Stouffville, Ontario, Canada.

Marco EJ, Meek JL (1979) The effects of antidepressants onserotonin turnover in discrete regions of rat brain. NaunynSchmiedeberg Arch Pharmacol 306:75-79.

Montgomery SA (1989) New antidepressants and 5-HTuptake inhibitors. Acta Psychiatry Scand 80(Suppl350):107-116.

Nathan RS, Perel JM, Pollock BG, Kupfer DJ (1990) Therole of neuropharmacologic selectivity in antidepressantaction: Fluvoxamine versus desipramine. J Clin Psychiatr51:367-72.

Nelson DR, Thomas DR, Johnson AM (1989)Pharmacological effects of paroxetine after repeatedadministration to animals. Acta Psychiatr Scand80(Suppl 350):21-3.

Ortmann R (1984) The 5-HT syndrome in rats as a tool forthe screening of psychoactive drugs. Drug Dev Res4:593-606.

Ortmann R, Waldmeier PC, Radeke E, Felner A, Delini-Stula A (1980) The effects of 5HT uptake-andMAO-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 DrugMetab Pharmacokinet 8:259-80.

Perry EK, Marshall EF, Blessed G, Tomlison BE, Perry RH(1983) Decreased imipramine binding in the brains ofpatients with depressive illness. Br J Psychiatry 142:188-92.

Price LH, Charney DS, Delgado PL, Anderson GM,Heninger GR (1989) Effects of desipramine and fluvox-amine treatment on the prolactin response to tryptophan.Arch Gen Psychiatry 46:625-31.

Richelson E, Nelson A (1984) Antagonism by antidepres-sants of neurotransmitter receptors in normal human brainin vitro. J Pharmacol Exp Ther 230:94-102.

Robinson JF, Doogan DP (1982) A placebo controlled studyof the cardiovascular effects of fluvoxamine andclorosamine in human volunteers. Br J Clin Pharmacol14:805-8.

Roos JC (1983) Cardiac effects of antidepressant drugs. Acomparison of the tricyclic antidepressants and fluvox-amine. Br J Clin Pharmacol 15:439S-45S.

Schmidt MJ, Fuller, RW, Wong T (1988) Fluoxetine, ahighly selective serotonin reuptake inhibitor: A review ofpreclinical studies. Br J Psychiatry 153(Suppl 3):40-6.

Stanley M, Virgilio J, Gershon S (1982) Tritiated imipraminebinding sites in frontal cortex of suicides. Science216:337-9.

Stanley M, Mann JJ (1983) Increased serotonin-2 bindingsites in frontal cortex of suicide victims. Lancet 1:214-6.

Sulser F (1983) Deamplification of noradrenergic signaltransfer by antidepressants: a unified catecholamine-serotonin hypothesis of affective disorders.Psychopharmacol Bull 19:300-4.

Tuomisto J, Tukiainen E (1976) Decreased uptake of 5-hydroxytryptamine in blood platelets from depressedpatients. Nature (Lond) 252:596-8.

Vetulani J, Dingell JV, Sulser F (1974) Effect of chronictreatment with desipramine (DMI) and iprindole (IP) onthe norepinephrine (NE) sensitive adenylate cyclasesystem 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 S2receptors of normal human brain in vitro. Eur JPharmacol 132:115-21.

Wilson WH, Higano H, Papadatos Y, Kelwala S, Ban TA(1983) A double-blind placebo-controlled study tocompare the autonomic effects of fluvoxamine with thoseof amitriptyline and doxepin in healthy volunteers. Br JClin Pharmacol 15:385S-92S.

Wong DT, Bymaster FP (1980) Subsensitivity of serotoninreceptors after long-term treatment of rats withfluoxetine. Res Commun Chem Pathol Pharmacol 32:41-51.

Wong DT, Bymaster FP, Reid LR, Threlkeld PG (1983)Fluoxetine and two other serotonin uptake inhibitorswithout affinity for neuronal receptors. BiochemPharmacol 32:1287-93.

Wood K, Swade C, Abou-Saleh M, Milln P, Coppen A(1983) Drug plasma levels and platelet 5-HT uptakeinhibition during long-term treatment with fluvoxamineor lithium in patients with affective disorders. Br J ClinPharmacol 15:365S-8S.

Yates M, Leake A, Candy JM, Fairbairn AF, McKeith IG,Ferrier IN (1990) 5-HT2 receptor changes in majordepression. Biol Psychiatry 27:489-96.

Yen TT, Wong DT, Bemis KG (1987) Reduction of foodconsumption and body weight of normal and obese miceby chronic treatment with fluoxetine, a serotonin reuptakeinhibitor. Drug Dev Res 10:37-45.