Fluvoxamine

Abstract

Synopsis: Fluvoxamine¹ is a new antidepressant which potently and specifically inhibits neuronal reuptake of serotonin. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from facilitation of serotoninergic neurotransmission as a result of reuptake inhibition. Studies suggest that fluvoxamine has overall therapeutic efficacy comparable with that of imipramine and clomipramine in depressive illness. It causes fewer anticholinergic-type and cardiovascular side effects than the tricyclic antidepressants but it is associated with a higher incidence of nausea and vomiting. Elderly patients also respond well to fluvoxamine. Studies are now required to compare fluvoxamine with other second generation antidepressants and to establish whether some types of depressive illness respond more readily to fluvoxamine than other agents. Thus, in patients with depressive illness, fluvoxamine offers a suitable alternative to tricyclic antidepressants and may be especially valuable in patients with concomitant cardiovascular disease, and those unresponsive to or unable to tolerate tricyclic antidepressants. Pharmacodynamic Properties: Fluvoxamine facilitates serotoninergic neurotransmission through potent and selective inhibition of presynaptic serotonin reuptake. This effect has been demonstrated in brain tissues of rodents following both in vitro application and in vivo administration. Thus, serotonin turnover in rat forebrain was reduced after a single dose of fluvoxamine, and in the raphé nuclei the intraneuronal and extraneuronal concentrations of serotonin decreased and increased, respectively. Furthermore, the spontaneous firing rate of raphé neurons decreased. Fluvoxamine also potentiates the behavioural syndrome induced by 5-hydroxytryptophan in mice. In contrast, experiments designed to demonstrate facilitation of noradrenergic neurotransmission showed that it was generally inactive, and in common with several other specific inhibitors of serotonin uptake fluvoxamine had very little in vitro affinity for α₁ α₂ β₃ dopamine₂, histamine₁, serotonin₁, serotonin₂ or muscarinic receptors. Fluvoxamine does not inhibit monoamine oxidase. Studies in animals and man indicate that fluvoxamine may be less likely to produce adverse cardiovascular effects than some other antidepressant agents. In addition, receptor binding data and the results of various in vitro and in vivo experiments in animals suggest that fluvoxamine is unlikely to cause anticholinergic side effects. Fluvoxamine did not cause sedation in rodents, and pharmacoelectroencephalogram recordings and psychometric tests in healthy humans suggest that it is less sedative than imipramine. Pharmacokinetic Properties: Following oral administration to healthy volunteers fluvoxamine is well absorbed and peak plasma concentrations are reached within 2 to 8 hours after ingestion. About 10 days’ administration is required to attain steady-state plasma concentrations. Studies in rats indicate rapid and wide distribution to most organs. Extrapolation from studies in dogs suggests that the volume of distribution in man should be in excess of 5 L/kg. Fluvoxamine is 77% bound to plasma proteins. Over 90% of a dose of fluvoxamine is recovered in urine in the form of at least 11 metabolites. The initial elimination half-life of fluvoxamine is about 2 hours but a second elimination phase with a half-life of nearly 15 hours occurs. The pharmacokinetic profile of fluvoxamine appears to be unaffected in elderly subjects. Therapeutic Trials: In single or divided daily dosages of between 50 and 300mg, fluvoxamine has been shown to possess antidepressant activity in open and placebo-controlled studies of patients with depressive illness. Individual therapeutic trials have generally been of short duration, although some patients have been followed up for 12 months of successful therapy. In one study, mean Hamilton Rating Scale scores were reduced by 50 and 86% after 1 and 3 months’ treatment, respectively. In comparative studies with certain tricyclic agents fluvoxamine has generally displayed equivalent therapeutic efficacy. When compared with imipramine, Hamilton Rating Scale scores were reduced by 50 to 60% after 6 weeks’ treatment with either of the active medications compared with a reduction of 32% after placebo. However, several studies reported unusually low therapeutic responses to either fluvoxamine or imipramine in comparison with placebo. In studies comparing fluvoxamine with clomipramine, improvements in Hamilton Rating Scale scores were about 65% after 4 weeks’ treatment with either drug. In contrast with the tricyclic agents, fluvoxamine has the advantage of seldom causing anticholinergic side effects. However, gastrointestinal side effects occur more frequently with fluvoxamine than with the tricyclic agents. Elderly patients have generally responded to and tolerated fluvoxamine as well as the general patient population. Studies comparing fluvoxamine with some of the other, newer, antidepressants (such as mianserin and trazodone) are now required. Side Effects: Nausea and vomiting (37% of patients) were the most frequently occurring fluvoxamine-related side effects in placebo-controlled comparative studies with imipramine. Somnolence, dry mouth and headache also occurred in over 20% of patients. In comparison with imipramine, fluvoxamine was associated with a notably lower incidence of dry mouth and other symptoms of anticholinergic activity (such as sweating and abnormal accommodation) and a higher incidence of nausea, vomiting, anorexia and headache. Approximately 12% of patients could not tolerate fluvoxamine and withdrew from treatment. Fluvoxamine does not appear to adversely affect the cardiovascular system of otherwise healthy depressed patients, neither did administration of a single dose to patients with mild forms of cardiovascular disorders. Preliminary data from a few patients who have taken an overdosage of fluvoxamine suggest that it may be free of the cardiac toxicity associated with overdosages of tricyclic antidepressants. However, overdosages of fluvoxamine have not occurred in patients with pre-existing cardiovascular disease. Thus, the absence of cardiovascular effects in such patients following therapeutic dosage regimens or overdosages remain to be clarified. Dosage and Administration: The currently recommended dosage regimen for fluvoxamine is that patients should commence treatment on a dose of 100 mg/day for 1 week which should, thereafter, be adjusted according to symptomatic response and/or the emergence of side effects. Patients are usually maintained on between 50 and 300mg daily and there is some evidence to suggest that administration as a single evening dose may cause fewer side effects.