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Home , Clovoxamine, Indalpine

Pharmacology of Uptake Inhibitors: Focus on

Pavel D. Hrdina Departments of Pharmacology and Psychiatry, and Institute of Mental Health Research, University of Ottawa, Ottawa, Canada

Selective serotonin uptake inhibitors comprise a from suicide victim/depressives in comparison with relatively new class of clinically effective controls. In other post-mortem studies, a significant increase that are chemically distinct from . They share a was found in the number of 5-HT2 receptors in the brains of common feature - a selective and potent inhibition of suicide victims or depressed subjects (Stanley et al 1983; neuronal uptake of serotonin (5-HT, 5-hydroxytryptamine) Yates et al 1990). Serotonin uptake has been found to be and have no or very weak effects on neuronal uptake of decreased and the number of [3H] sites reduced (NE). More importantly, they lack a signifi- in blood platelets of depressed patients (Tuomisto and cant affinity to various neurotransmitter systems in Tukiainen 1976; Briley et al 1980). Whether these markers the brain and, in contrast to antidepressants, they reflect the functional state of the serotonin uptake system in do not possess significant sedative, anticholinergic and/or the brain is at present unknown. Finally, clinical observa- cardiovascular effects. On the other hand, they all tions also indicate that the precursor of serotonin, L- potentiate the pharmacological effects of serotonin and its , particularly in conjunction with an MAO precursor, 5-hydroxytryptophan. Fluvoxamine, now being inhibitor can be an effective treatment for depression introduced into the clinical practice, has some metabolic (Coppen et al 1963). and pharmacokinetic features that distinguish this Tricyclic antidepressants, the main in the treatment from other compounds in this class. The purpose of this of depressive illness, are known to block the neuronal article is to review the preclinical pharmacological effects uptake of two major biogenic amines, norepinephrine and of selective serotonin uptake inhibitors with a focus on serotonin. In addition, these drugs exert a significant effect fluvoxamine and to compare them with those of representa- on several neurotransmitter receptors (including adrenergic, tive tricyclic antidepressants. cholinergic and histaminergic) and many of their side effects There is now considerable evidence available to indicate are thought to be related to this property of the tricyclic that impaired functioning of the central serotonergic system drugs. The inhibition of norepinephrine and serotonin was is involved in the pathogenesis of at least some types of thought to be responsible for the action of depressive illness (Asberg et al 1976a). This evidence stems these compounds. This has led to the development of the from clinical observations that the level of the main 'biogenic amine hypothesis' of affective disorders which serotonin metabolite, 5-HIAA in the cerebrospinal fluid is suggests that depression may be due to a lack of nore- significantly decreased in a subgroup of depressive patients pinephrine and/or serotonin in some critical parts of the who exhibit suicidal behaviour (Asberg et al 1976b). brain. However, the delayed onset of the clinical antidepres- Furthermore, the density of presynaptic uptake sites for sant effect with tricyclic antidepressants was difficult to serotonin (labelled by [3H]imipramine) has been reported explain in the view of the fact that the inhibition of amine to be decreased in some (Stanley et al 1982; Perry et al uptake occurs shortly after drug administration. In addition, 1983), but not all, studies of post-mortem brain samples some newer, clinically effective antidepressants (e.g. ) do not inhibit the uptake of either norepinephrine or serotonin. The amine hypothesis of affective disorders Address reprint requests to: Dr. P.D. Hrdina, Dept. of Pharmacology, needed a critical evaluation (see Baldessarini, 1975). University of Ottawa, 451 Smyth Rd., Rm 3131, Ottawa, Canada K1H 8M5 Subsequent studies have shown that after chronic treatment

J Psychiatr Neurosci, VoL 16, No. 2 (Suppl. 1), 1991 July 1991 Pharmacology ofSerotonin Uptake Inhibitors I1I

with almost all clinically effective antidepressants, a down inhibitors. The compound has a molecular weight of 434 (as regulation of B-adrenergic receptors and of responsiveness maleate), is sparingly soluble in water, freely soluble in of adenylate cyclase to norepinephrine occurs, regardless of ethanol and chloroform and practically insoluble in the effect of drugs used in the uptake of monoamines diathylether. In humans and animals, fluvoxamine is well (Vetulani et al 1974; Sulser 1983). It is now believed that absorbed after oral administration. It is metabolized entirely after the initial block of neuronal re-uptake, adaptive in the liver by two metabolic pathways: oxidative demethyla- changes in the neuronal networks have to take place in order tion (major) and deamination (minor) to more than ten to give expression to the antidepressant effect. metabolites, out of which nine have been identified in the urine (Overmars et al 1983). They are all excreted by the Table 1 kidney. After a single oral administration, almost the whole Serotonin uptake inhibitors used as antidepressants. dose (94%) is eliminated from the body within 48 hours (DeBree et al 1983). The two major metabolites of fluvox- amine are without significant pharmacological activity when Fluvoxamine compared to parent compound, although one of the major Indalpine metabolites (the carboxylic acid derivative) shows some Clovoxamine inhibition 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 to 85-90% for imipramine and 95% for fluoxetine (Claassen Serotonin Uptake Inhibitors 1983; Kaye et al 1989). Side-effects of the commonly used tricyclic antidepres- sants (sedative, hypotensive, anticholinergic, cardiac) have been a limiting factor in their clinical use particularly in N certain of cardiovascularly .CH3 subgroups patients (elderly, CH2-CH2-CH2-H" compromised). During the last two decades there has been a CH3 considerable effort to develop compounds which would have a relatively selective effect on the serotonergic system Clomipramine without concomitant interaction with a variety of neurotrans- mitter receptor systems and would be free of undesirable side F3C..a4~-C..CH2-CH2-CH2-CH2-0-CH3 effects. A new group of compounds has emerged from this search: selective serotonin uptake inhibitors. They have little N or no effect on the uptake of norepinephrine or and O-CH2-CH2-NH2 have been shown to be clinically effective antidepressants (Asberg et al 1985). They include compounds listed in Table Fluvoxamine 1. The aim of this article is to review the pharmacology of this class of compounds with special focus on the new, recently introduced member of this family, fluvoxamine, and to compare some aspects of preclinical and clinical pharma- cology of main representatives of this class, fluoxetine, F30- HCH2CH2NHCH3 clomipramine and paroxetine that either are, or may in the near future, become available for clinical use in Canada. Fluoxetine Inspection of the chemical structure of serotonin uptake H inhibitors, presented in Fig. 1, reveals that these compounds are chemically different from tricyclic antidepressants and from each other. They have some common structural features V- CH20/ and a halogen substituent is an important determinant of the potency and selectivity for serotonin uptake inhibition. Metabolism of Fluvoxamine F Fluvoxamine (LUVOX) is a compound that belongs to a Paroxetine new chemical series, the 2-aminoethyl oximethers of aralkylketones. It is chemically unrelated to any of the Fig. 1: Molecular structure of some selective serotonin existing antidepressants or selective serotonin uptake uptake inhibitors. 12 Journal ofPsychiatry & Neuroscience Supplement I Vol. 16, No. 2,1991

Table 2 Interaction with Serotonergic Mechanisms Inhibition of serotonin (5-HT) and norepinephrine (NE) uptake in vitro (rat hypothalamus) by selective serotonin The functional consequence of inhibiting neuronal uptake inhibitors and imipramine. serotonin uptake is an increased synaptic concentration of serotonin. The acute effects of serotonin uptake inhibitors Ki(nM) are believed to be due to activation of serotonergic Drug 5-HT NE NE/5-HT mechanisms. These include potentiation of the effects of serotonin and its presursors, induction (in conjunction with Imipramine 100 65 0.65 MAO inhibitors) of a serotonin produced behavioral Clomipramine 7.4 96 13 syndrome and serotonin mediated effects on REM sleep and Fluoxetine 25 500 20 food consumption. Fluvoxamine 6.2 1100 180 Paroxetine 1.1 350 320 Table 3 Ki is the concentration of drugs that produces 50% inhibition of [3H]5-HT Inhibition of monoamine uptake in synaptosomes from or ['H]NE uptake. rat hypothalamus ex vivo after oral administration of (Adapted from Johnson 1989) selective serotonin uptake inhibitors and imipramine. Selectivity for Serotonin Uptake Inhibition ED50(mg/kg) Drug 5-HT NE The main pharmacological effect of fluvoxamine is the inhibition of neuronal uptake of serotonin. The selectivity of Imipramine >30 10 fluvoxamine to inhibit the neuronal re-uptake in vitro by Fluoxetine 7 >30 synaptosomes from rat hypothalamus is illustrated in Table 2. Fluvoxamine 23 >30 The Ki of fluvoxamine for inhibition of serotonin uptake is Paroxetine 1.9 >30 180 times lower than its Ki for inhibition of norepinephrine uptake. Fluvoxamine appears to be a more selective and 'Forms an active metabolite that has a higher potency for NE uptake potent inhibitor of serotonin uptake than fluoxetine and inhibition than the parent compound clomipramine, but is less potent and selective than (Adapted from Johnson 1989) paroxetine. It is important, however, to demonstrate that the selectivity of the compound to inhibit serotonin uptake is Hormonal Effects maintained after in vivo administration. Fluvoxamine administered in vivo produces an 80% inhibition of 5-HT Serum concentration of prolactin in animals as well as in uptake by rat brain synaptosomes 30 minutes after adminis- humans, is increased by serotonergic stimuli (Clemens et al, tration. In comparison, imipramine in a similar dose 1977; Fuller, 1981). Fluvoxamine was shown to stimulate produces only 50% inhibition of serotonin neuronal uptake prolactin secretion in rats (Fig 2) and to significantly (Claassen 1983). Table 3 compares the relative potency and potentiate the prolactin releasing effect of 5-hydroxytrypto- selectivity of serotonin uptake inhibitors on 5-HT and nore- phan (Cella et al 1983). These endocrine effects of acute pinephrine uptake measured 'ex vivo' and shows that fluvox- fluvoxamine administration are compatible with activation amine maintains its selectivity for serotonin uptake after in of 5-HT neurotransmission. In humans, fluvoxamine alone vivo administration. Fluvoxamine was also shown to signifi- does not produce an increased prolactin secretion and cantly decrease platelet serotonin uptake in patients treated plasma levels. However, it potentiates significantly the with the drug (Wood et al 1983; Nathan et al 1990). effect of tryptophan stimulation on prolactin release (Price The selectivity of serotonin uptake inhibitors can also be et al 1990). demonstrated by their ability to potentiate behaviors mediated by serotonin and norepinephrine, respectively. Serotonin Mediated Behavioral Syndrome Table 4 compares the activity of fluvoxamine, clomipramine and imipramine in potentiating the 5-hydroxytryptophan- Several directly acting serotonin agonists or a combi- induced hyperactivity syndrome in rodents (Ortman 1984) nation of a serotonin precursor with an inhibitor of pretreated with an MAO inhibitor and in antagonizing the monoamine oxidase and/or an inhibitor of serotonin effect thought to be mediated through nore- uptake, produce in rats the serotonin behavioral syndrome pinephrine. The ratio of ED50 of fluvoxamine needed to consisting of forepaw threading, head weaving, hind limb potentiate 5-hydroxytryptophan and to antagonize tetra- abduction, body tremor, compulsive movements, pilo- benazine effect was 0.34 compared to 7 for clomipramine erection and salivation (Ortmann, 1984). This behavioral and 26 for imipramine (Claassen 1983). syndrome results from an intense stimulation of central July 1991 Pharmacology ofSerotonin Uptake Inhibitors 13

Fluvoxamine Saline Saline 5-HTP Saline 5-HTP 9 k *4. 8 7 6 5 *" T S/B T~ I 3 2 TF

0 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; + = difference vs corresponding values in 5-HTP treated rats. (Adapted from Cella et al 1983).

serotonin receptors. Serotonin uptake inhibitors (eg. fluvox- effect appears (Montgomery 1989). Serotonin uptake amine) alone do not elicit this syndrome, but they potentiate inhibitors can also produce anti-nociceptive effects and can the 5-hydroxytryptophan induced head twitch in mice to an potentiate an analgesic effect of some analgesic extent which correlates with their 5-HT uptake inhibiting drugs (Hynes and Fuller 1982) as well as the 5-hydrox- potencies (Ortmann et al 1980) and produce the serotonin ytryptophan induced myoclonus in animals (Green and behavioral syndrome when given in conjunction with Heal 1985). Fluvoxamine in a dose of 200 mg/day was monoamine oxidase inhibitors. Fluvoxamine was about twice shown to reduce REM sleep time as well as the time spent as potent as clomipramine in potentiating the 5-HTP induced in stages 3 and 4 of sleep, and to extend REM sleep latency behavioral syndrome in mice (Table 4). in depressive subjects (Berger et al 1986). Reduction of Serotonin Turnover Table 4 Potentiation of monoamine-mediated effects in vivo (mice) One of the consequences of serotonin uptake inhibition is by some selective serotonin uptake inhibitors and an increased activity of this neurotransmitter on both post- imipramine. and presynaptic receptors. Administration of serotonin uptake inhibitors results, probably via a negative feedback Drug ED50oral (mg/kg) mechanism and autoreceptor stimulation, in reduction of Antag of TBZ Ratio serotonin turnover rate as measured by decreases in the level 5-HTP' (NE)2 of its major metabolite, 5-HIAA (Claassen 1977; Macro and Meek 1979), and in an inhibition of spontaneous firing rate Imipramine3 135 5.2 26 of n. raphe dorsalis neurons in rats (Dresse and Scuvee- Morreau 1984). Clomipramine3 84 12 7 Fluvoxamine 36 107 0.34 Other Effects 'Dose of the test drug that potentiates to 50% of the maximal score the 5- Serotonin uptake inhibitors alone, or in combination HTP induced behavioral syndrome. with a serotonin precursor, produce a decrease in food 2Dose of the test drug that reduced the tetrabenazine induced ptosis to half intake in rats (Yen et al 1987; LUVOX 1990). The doses at of that of the controls. which weight loss is seen in humans tend to be rather 3Forms in vivo an active metabolite that inhibits NE uptake. higher than the minimum dose at which an antidepressant (Adapted from Claassen 1983) 14 Journal ofPsychiatry & Neuroscience Supplement I VoL 16, No. 2, 1991

Interaction with Neurotransmitter Receptors In contrast to tricyclic antidepressants, fluvoxamine has no antihistaminic effect, no sedative effect, does not inhibit Many of the side effects of tricyclic antidepressants have monoamine oxidase (Lapierre et al 1983), does not have an been related to their ability to interact with various neuro- -like stimulating effect and has very little or no transmitter receptors in the brain (Hall and Ogren 1981; parasympatholytic activity (Claassen et al 1983; Wilson et al Richelson and Nelson 1984; Wander et al 1986). For 1983). At high doses (over 60 mg/kg) it has shown in animal instance, sedative effects, increased appetite and postural studies, a tendency to induce seizures. Physical dependence hypotension have been related to their affinity for central liability has not been demonstrated for this compound at and peripheral a] adrenergic receptors. Dyskinesia with doses up to 90 mg/kg per day in monkeys (LUVOX 1990). some of the tricyclic antidepressants has been ascribed to the Furthermore, in contrast to tricyclic antidepressants, fluvox- affinity of some of these drugs to dopamine D2 receptor sites amine at therapeutic doses lacks significant effects on the in the brain. The undesirable anticholinergic side effects cardiovascular system (Roos 1983). A single dose of fluvox- present with most tricyclic antidepressants result from the amine did not affect heart rate or blood pressure in healthy affinity of these compounds for the muscarinic receptors. volunteers (Wilson et al 1983). Repeated administration (for The sedative effect and drowsiness produced by tricyclics 9 days) of fluvoxamine had little or no effect on ECG or and possibly the weight gain which is seen with these blood pressure and produced only a slight decrease in heart compounds (Feighner and Cohn 1985), could be related to rate (Robinson and Doogan 1982). the effect of these compounds on histamine H1 receptors in the brian. Drug Interactions Table 5 In combination with MAO inhibitors, fluvoxamine Affinity of selective serotonin uptake inhibitors and produces an increase in serotonin mediated effects (Claassen imipramine for neurotransmitter receptors in rat brain. et al 1983). In contrast to some tricyclic antidepressants, fluvoxamine produces no interaction with the antihyperten- sive effect of or a- (LUVOX 1990). IC50 value for displacement (nM) However, it may prolong the elimination of some drugs Drug al a2 I 5-HT2 D2 MUSC metabolized by the oxidation pathway in the liver. This could be an important consideration when fluvoxamine is taken Imipramine 300 N N 180 2700 400 simultaneously with drugs that have a narrow therapeutic index, such as warfarin and phenytoin. In fact, fluvoxamine Clomipramine 117 N N 150 700 160 was shown to increase plasma levels of warfarin by 65%. It also produced a 5-fold increase in plasma levels of simulta- Fluoxetine N N N N neously administered (LUVOX 1990). Fluvoxamine 5000 N N N N N Toxicity Paroxetine N N >5000 1000 7700 In animal experiments, fluvoxamine in doses which are N = no effect in conc. < 10000 nM near to lethal doses, produced acute toxic effects including (Adapted from Claassen 1983 and Schmidt et al 1988) 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 As shown in Table 5, the selective serotonin re-uptake higher than 25 mg/kg. In these cases, a haemorrhage of inhibitors, fluoxetine, fluvoxamine and paroxetine, lack a intestinal mucosa has been observed on the biopsy (LUVOX significant affinity to al, cc2, B-adrenergic, 5-HT2, dopamine 1990). D2 or muscarinic cholinergic receptors in the brain (Wong et Chronic toxic effects of fluvoxamine in rodents include a al 1983: Nelson et al 1989; Schmidt et al 1988). This is most decrease in body weight gain, decreases in serum lipids and likely the reason why they do not show the above mentioned increases in liver lipids that were similar to those produced side effects typical for tricyclic antidepressants. The selec- with comparable doses of imipramine and . tivity of specific 5-HT uptake inhibitors (eg. paroxetine) for After high doses, an increase in fatty vacuolation of hepato- the serotonin uptake sites and serotonergic innervation in the cytes was noted. Finally, in dogs at doses 60 mg/kg per day brain has also been demonstrated in autoradiographic studies and higher, there was ataxia, anorexia and, in some cases, (Hrdina et al 1990). convulsions (LUVOX 1990). July 1991 Pharmacology ofSerotonin Uptake Inhibitors 15

Table 6 after the dose and were comparable to those seen after Pharmacokinetic parameters of some selective serotonin imipramine. The half-life of fluvoxamine is between 17 uptake inhibitors and imipramine. and 22 hours. This is within the range of the half-life of tricyclic antidepressants, but much shorter than the half- Parameter Imipramine Fluvoxamine Fluoxetine Paroxetine life of fluoxetine and particularly of its demethylated (125 MG) (100 MG) (40 MG) metabolite, norfluoxetine. The consequences of the effects of metabolism and Cmax (ng/ml) 139 31-87 27 kinetics on the selectivity and duration of action of some serotonin uptake inhibitors are shown in Table 7. tmax (hr) 4.2 1.5-8 6.4 Clomipramine is metabolized in the body to its main active metabolite, desmethylclomipramine (de Cuyper et al tl/2(hr) 13 17-22 43 (140) 20.6 1983), which, in contrast to the parent compound is a much more potent inhibitor of norepinephrine than serotonin Bioavail. (%) 50 60 uptake. Thus, the metabolism of clomipramine to desmethylclomipramine results in a loss of selectivity of Prot. bind.(%) 85-90 77 95 the parent compound for the inhibition of serotonin uptake. On the other hand, fluoxetine which is also metabolized (Adapted from Hrdina et al 1981; Bergstrom et al 1988 and to an active compound, norfluoxetine (Bergstrom et al Kaye et al 1989) 1988), maintains its selectivity for serotonin uptake inhibition because norfluoxetine is just as effective an Differences in Metabolism and Kinetics: Impact on inhibitor of serotonin uptake as is its parent compound, Clinical Therapy (Schmidt et al 1988). However, the duration of action of the drug increases significantly with the formation of the The pharmacokinetic parameters of fluvoxamine and of active metabolite, norfluoxetine, whose half-life is approx- some other serotonin uptake inhibitors in comparison with imately 140 hours. In the case of fluvoxamine, the those of imipramine are reported in Table 6. In healthy metabolites are inactive, without a significant effect on volunteers, peak plasma levels following a single oral dose serotonin or norepinephrine uptake. Fluvoxamine of 100 mg of fluvoxamine were observed 1.5 to 8 hours 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 5-HT Uptake NE Uptake Duration Consequence

Clomipramine +++ + - Loss of selectivity Desmethylclomipramine + +++

Fluoxetine +++ + - Increased duration Nofluoxetine +++ +

Fluvoxamine +++ + - No change in selectivity or duration Inact. metabolites (+) 16 Journal ofPsychiatry & Neuroscience Supplement I Vol. 16, No. 2,1991

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 Block of 5-HT uptake simpler than with fluoxetine. + Table 8 Availability of 5-HT in the Synapse Effect of repeated administration of serotonin uptake + inhibitors and imipramine on the density of beta- 4 Action on 5-HT Receptors Acute Effects adrenergic receptors, NE-coupled adenylate cyclase and the number of 5-HT2 receptors in rat brain. In 5-HT Turnover & Firing Rate Density of Adenylate Cyclase Number of * Drug [B-adrenergic Activity 5-HT2 Receptors Receptors Desensitization of Presynaptic Receptors (Rat Brain) On Terminals Somatodendritic Imipramine Normal Firing Rate Clomipramine + + Fluoxetine 0(+) 0 0(+) 4 5- HT Release and Neurotransmission Fluvoxamine 0 + 0 |Therapeutic Effect| Paroxetine 0 +

Fig. 3: Chain of events in the serotonergic neuro- + decrease; + increase; 0 no change transmission after administration of serotonin (Adapted from Nelson et al 1989) uptake inhibitors. Possible Mode of Antidepressant Action The mechanism by which serotonin uptake inhibitors Down regulation of B-adrenergic receptors has been produce their antidepressant effect is at present unclear. One considered to be a crucial event in adaptive changes during possible chain of events occurring after repeated administra- the chronic administration of antidepressant treatments tion of these drugs has been suggested by de Montigny and (Sulser 1983). However, the selective serotonin uptake his coworkers (de Montigny and Aghajanian 1978; Blier et inhibitors, fluvoxamine and paroxetine which are clinically al 1987). According to this concept, illustrated in Fig. 3, the effective antidepressants, do not produce a down regulation block of the 5-HT uptake by these compounds would lead to of B-adrenergic receptors after repeated treatment in animals the increased availability of serotonin in the synapse and to (Table 8), although fluoxetine was found to reduce the acute manifestation of the increased action on 5-HT number of beta-adrenergic receptors in frontal cortex synapses, both presynaptically and postsynaptically. (Nelson et al 1989). Dynamic changes would then include a decrease in 5-HT Fluvoxamine though, was shown to produce a down turnover and firing rate. With time, the increased avail- regulation in the responsiveness of adenylate cyclase to ability of serotonin in the synaptic gap and at the receptor norepinephrine. These findings cast some doubt on the sites would lead to desensitization of presynaptic serotonin postulate that B- down regulation is an receptors either on the cell bodies (somatodendritic essential component of antidepressant efficacy. It could be receptors) or on the terminals. This in turn, would bring the however, that adaptive changes in receptor systems other firing rate back to normal and would increase the serotonin than B-adrenergic could be an integral part of changes which release and serotonin neurotransmission, which may be occur after repeated administration of serotonin uptake translated in a therapeutic antidepressant effect. These inhibitors and which would be essential for the antidepres- adaptive changes however, might be just one step in the sant activity of these compounds. For example, both chain of events which occur between the primary manifesta- fluoxetine and paroxetine were reported to produce a down tion of the effect of those compounds, that is inhibition of regulation of 5-HT2 receptors after repeated administration the uptake of serotonin and between the onset of the clinical (Wong and Bymaster 1980, Nelson et al 1989). therapeutic effect. The notion that the brain monoamine July 1991 Pharmacology ofSerotonin Uptake Inhibitors 17

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