[Viloxazine. Aspects of the therapeutic effect of the antidepressive agent viloxazine (Vivalan ICI) in the opinion of practicing neurologists].
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Pharmacological comparison of the potential antidepressant UP 614-04 with viloxazine and imipramine; behavioral studies.
1. Several behavioral tests were used to compare the pharmacological activity of the potential antidepressant UP 614-04 with those of viloxazine and imipramine. 2. Orally-administered UP 614-04, like viloxazine, reduced locomotor activity in mice, and, like viloxazine and imipramine, it antagonized the hypothermia or ptosis induced by reserpine or tetrabenazine and the hypothermia induced by a high dose of apomorphine. 3. UP 614-04 antagonized oxotremorine-induced hypothermia, and to a lesser extent, oxotremorine-induced tremors, indicating that it possesses some CNS anticholinergic activity. 4. Both imipramine and viloxazine were more potent than UP 614-04 in potentiating yohimbine toxicity in mice. 5. Orally-administered UP 614-04 potentiated d-amphetamine-induced stereotypy to a greater extent than viloxazine, but to a lesser extent than imipramine. 6. Intraperitoneally-injected UP 614-04 was much more potent than viloxazine in increasing tryptamine convulsive potential in rats, indicating that it might exert an inhibitory action on monoamine oxidase. 7. These results indicate that UP 614-04 has a behavioral profile that is consistent with an antidepressant action, but that it differs from imipramine and viloxazine.
Animals↗
Clinical profile and serum concentration of viloxazine as compared to amitriptyline.
The antidepressive effect of viloxazine (300 mg/d) was investigated during three weeks in 41 patients with depressive syndromes requiring drug-treatment against amitriptyline (150 mg/d), using a controlled double-blind design. Viloxazine differs from amitriptyline by selective inhibition of norepinephrine re-uptake, whereas amitriptyline acts also on serotonin re-uptake. Psychopathological changes were documented by means of the Hamilton Depression Rating Scale, the Bf-S (v. Zerssen), the AMDP-System, and videotaped recordings. Besides routine clinical-chemical tests, the serum concentrations of viloxazine and partly of amitriptyline were determined. Repeated EEG-recordings were evaluated by spectral analysis. The number of global responders and non-responders -- defined according to the final HDRS-scores -- was equally distributed between the two drug-groups. The AMDP-evaluation suggests that viloxazin has a somewhat more marked and more rapid effect on symptoms of retardation, whereas amitriptyline acts predominantly on depressive mood, disturbances of sleep and vital feelings. The EEG-profile of both drugs was similar to the spectral changes seen under tricyclic antidepressants, through only the viloxazine-induced changes reached statistical significance on the 10th and 20th day, the variability of the EEG-recordings being greater in the amitriptyline group. The viloxazine blood levels showed a remarkably low inter- and intraindividual variance. Steady state was reached at day 5 at the latest. Amitriptyline serum concentrations still increased between the 10th and the 21st day. The average blood concentration of viloxazine was higher in the responder- than in the non-responder-group.
Adult↗
Blood level studies with viloxazine hydrochloride in man.
1 The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, (ICI 58,834, Vivalan), have been investigated in four separate studies. 2 In Study 1, blood levels were measured over a period of 24 h after single doses of viloxazine hydrochloride from 10-100 mg (expressed as base). In Study 2, blood levels were measured over 24 h, during which three single doses of viloxazine hydrochloride (80 mg, expressed as base) were given 4 h apart. In Study 3, blood samples and urine and faeces were collected for 96 h after doses of 40 and 100 mg of [14C] viloxazine hydrochloride (40 muCi). In Study 4, 1 h blood levels were measured at weekly intervals during a comparative clinical trial in which viloxazine was given at a dose of 100 mg four times a day. 3 The half-life of the drug is in the range 2-5 h with maximum blood levels occurring in 1-4 h of the oral dose. Maximum blood levels are proportional to the oral dose given over the range studied (0.76(mug/ml)/(mg/kg)). The drug is very well absorbed orally, only 2% being found in faeces. Repeated dosing at 4 hourly intervals leads to slightly higher blood levels after the second, but not subsequent, doses. No accumulation was seen from week to week in depressed patients. No regular sex difference was seen in the pharmacokinetic characteristics of viloxazine hydrochloride but two females in one study did show a markedly higher maximum blood level and apparently longer half-life than the males. 4 It is concluded that viloxazine is rapidly and almost totally absorbed after an oral dose, and has a shorter half-life than the tricyclic antidepressants; therapy with it should be easily controllable.
Adult↗
An evidence for the central serotoninergic activity of viloxazine.
The effects of viloxazine on the flexor reflex of the hind limb of the spinal rat and the blood pressure in the pithed rat were studied. Viloxazine (1--16 mg/kg) stimulated the hind limb flexor reflex in the dose-dependent manner. This effect of viloxazine was inhibited by serotonin receptor blockers, cyproheptadine, danitracen and metergoline, and by serotonin uptake blocking agents imipramine and clomipramine. H22/54, an inhibitor of serotonin synthesis, was much less active in this respect. Desipramine, a noradrenaline uptake inhibitor, had no effect on the stimulatory action of viloxazine. Viloxazine (similarly as serotonin) elevated blood pressure in the pithed rat. This action of viloxazine was abolished by cyproheptadine but potentiated by pargyline, an inhibitor of MAO. It is suggested that viloxazine may facilitate the serotonergic transmission in the central nervous system.
Animals↗
A double blind comparison of viloxazine and amitryptyline in involutional and endogenous depression.
Thirty-two hospitalized patients with either endogenous (n = 15) or involutional (n = 17) depression were entered into a double blind study to compare the effectiveness and acceptability of viloxazine with amitriptyline. The severity of the depression was assessed before starting treatment and at day 7, 14 and 28 using the Hamilton Rating Scale. Spontaneously reported side effects were recorded. Patients received viloxazine 50 mg three times a day during the first week followed by 100 mg three times a day during the next three weeks or amitriptyline 25 mg three times a day during the first week followed by 50 mg three times a day during the following three weeks. Viloxazine and amitriptyline were equally effective in endogenous depression, but viloxazine was significantly more effective than amitriptyline in patients with involutional depression. Nausea and vomiting were the main side effect of viloxazine during early treatment necessitating the withdrawal of two patients. Anticholinergic side effects were reported during amitryptyline treatment, but were absent in patients on viloxazine. It is concluded that viloxazine is an effective antidepressant and particularly useful in the treatment of involutional depression.
Amitriptyline↗
Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial.
Antidepressant efficacy and tolerability of citalopram and viloxazine were compared under double-blind conditions during the first two weeks of treatment with slow drop infusion, followed by oral administration for the rest of the six week trial period. The 62 severely depressed and hospitalised patients included in the intention-to-treat analysis had a mean age of 45 years (range 23 to 70 years). About two thirds of the patients were female. Thirty patients were allocated to the citalopram and 32 patients to the viloxazine group. The mean MADRS total score at baseline was 34 in both groups and decreased to 12.3 in the citalopram and to 16.9 in the viloxazine group after 14 days of infusion. On day 42 (end point) the scores dropped to 6.7 in the citalopram and to 13.1 in the viloxazine group respectively. The group differences reached the level of significance at both time points (p < 0.05) in favour of citalopram. The analysis of treatment emergent adverse events based on the UKU scale showed a higher frequency of nausea on day 14 and constipation at study end in the viloxazine group (p < 0.05) whereas reported weight gain (day 21) and concentration difficulty (day 21) were more frequently seen in the citalopram group (p < 0.05). Standard laboratory investigations and ECG analyses did not show clinically relevant abnormalities. It is concluded that antidepressant treatment with citalopram infusion followed by oral citalopram may be more efficacious than a corresponding treatment schedule with viloxazine.
Administration, Oral↗
Clinical pharmacology of viloxazine hydrochloride.
Plasma concentrations of viloxazine were determined in twenty depressed inpatients during 4 weeks of treatment with progressively increasing dosage. Viloxazine plasma levels varied markedly during the day, due to the short half-life of the drug. Plasma levels rose to peak values after 7-10 days of treatment and then decreased, perhaps due to enzymatic induction by viloxazine. A negative linear correlation was found between the plasma concentration of viloxazine and its clinical effect, with the best clinical improvement in patients whose plasma concentration was 20-500 ng/ml at 7 a.m. Performance in psychomotor tests (visual reaction time and ring of Pierron was improved in many patients after treatment and was correlated with the plasma viloxazine level and the Hamilton Rating score. Assessment of viloxazine effects of electroencephalogram showed a decrease in EEG amplitude in the eight clinically improved patients.
Depressive Disorder↗
A placebo controlled trial of viloxazine with and without tranquillizers in depressive illness.
Two double-blind four-way crossover studies are reported, comparing the antidepressant effect of 14-day courses of: viloxazine, viloxazine with a tranquillizer either perphenazine or diazepam or tranquillizer alone, against a placebo. In one study the antidepressant effect of viloxazine at a dose of 150 mg daily was statistically greater than that of placebo, whilst in the second study viloxazine was statistically superior to diazepam (15 mg daily). In depressed patients with a clear anxiety component, viloxazine alone seemed preferable to a combination with a tranquillizer as such a combination did not produce an enhanced clinical effect and the incidence of side-effects was possibly increased. Viloxazine was generally well tolerated and side-effects, when they occurred, were generally a mild upper gastro-intestinal disturbance.
Depressive Disorder↗
Inhibition of monoamine oxidase by viloxazine in rats.
Biochemical and pharmacological investigations about the effect of the antidepressant drug viloxazine (Vivalan) on catecholamine metabolism in rats led to the following results: Viloxazine exerts a dose and time dependent inhibition of monoamine oxidase activity of brain and liver mitochondrial fraction and tissue homogenates of hypothalamus, heart, liver, and adrenal glands, both in vitro and after oral and parenteral administration in vivo. Consequently, an increase in catecholamine concentrations in brain of rats could be observed after pretreatment with viloxazine. In addition brain serotonin concentrations rose and 5-hydroxy-indoleacetic acid was diminished. However, characterization of inhibition of monoamine oxidase activity by viloxazine in vitro revealed: Compared to the specific inhibitors clorgyline for MAO-A- and pargyline for MAO-B-activity, viloxazine was a very weak inhibitor both for MAO-A and MAO-B in vitro. The type of inhibition was competitive and reversible. From the presented results and the results obtained by other laboratories it is concluded that inhibition of monoamine oxidase activity by viloxazine, although clearly demonstrated in animal experiments, may not be the only mechanism for an antidepressant action of the drug in man.
Animals↗
A study of the interaction of viloxazine with theophylline.
The effect of viloxazine on the pharmacokinetics of theophylline was studied in eight healthy volunteers. Theophylline 200 mg/day (théophylline Bruneau 100 mg tablets) was administered on day 1; after a 3-day washout period, viloxazine 300 mg/day (Vivalan 100 mg tablets) was administered orally from days 5 to 7. On day 8, theophylline 200 mg and viloxazine 100 mg were concomitantly administered. The pharmacokinetic parameters of theophylline alone and after coadministration of viloxazine were determined. Viloxazine significantly increased the plasma concentrations (p less than 0.01) and the area-under-the-curve values (p less than 0.01) of theophylline and decreased its body clearance (p less than 0.05). Our results suggest that the dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is prescribed.
Adult↗
Modification of cortical neuron responses to acetylcholine by viloxazine.
Viloxazine, an antidepressant with no peripheral antiacetylcholine activity, was capable of reducing responses of single cortical neurons to acetylcholine. Acetylcholine responses could also be potentiated by viloxazine. Both potentiation and reduction by viloxazine were often seen in the same study, reduction of responses invariably preceding potentiation. These results suggest that viloxazine may have selective effects on central cholinergic receptors. Responses of cortical neurons to monoamines could also be potentiated by viloxazine although it has little effect on monoamine uptake. These results are compatible with the idea that potentiation of monoamine responses may occur by a postsynaptic mechanism.
Acetylcholine↗
The effect of viloxazine on drug-induced inhibition of food intake in the rat.
In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7.5 mg kg-1 viloxazine, while 40 mg kg-1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.
Amphetamine↗
Carbamazepine-viloxazine interaction in patients with epilepsy.
In six depressed epileptic patients stabilised on carbamazepine therapy, addition of the antidepressant agent viloxazine (300 mg/day for three weeks) induced a marked (average 55%) increase in steady-state plasma carbamazepine concentration. The concentration of the active metabolite carbamazepine-10,11-epoxide also increased during viloxazine therapy, but to a lesser extent (16%). In three patients, these effects were associated with symptoms of carbamazepine intoxication, which regressed rapidly when plasma carbamazepine and carbamazepine-10,11-epoxide levels returned to baseline values after discontinuation of viloxazine. In a seventh patient, viloxazine had to be discontinued after only two weeks because of severe side effects associated with a striking elevation of carbamazepine and carbamazepine 10,11-epoxide levels (by 197% and 137% respectively). Although viloxazine appears to be one of the few antidepressants which can be used safely in patients with epilepsy these results indicate that the drug should be prescribed with great caution in subjects treated with carbamazepine. The mechanism of the interaction probably involves inhibition of the metabolism of both carbamazepine and its active epoxide metabolite.
Adult↗
Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction.
The effect of viloxazine (150-300 mg daily for 21 days) on plasma phenytoin levels at steady state was examined in 10 epileptic patients stabilised on a fixed phenytoin dosage. After starting viloxazine treatment, plasma phenytoin concentrations increased by 37% on average (range 7-94%) from a mean value of 18.8 micrograms/ml at baseline to a mean value of 25.7 micrograms/ml during the last week of combined therapy. In four patients the rise in plasma phenytoin was associated with the development of signs of phenytoin toxicity. Discontinuation of viloxazine resulted in return of plasma phenytoin towards baseline values and disappearance of the clinical symptoms. The mechanism of interaction probably involves inhibition of phenytoin metabolism by viloxazine. Careful monitoring of plasma phenytoin levels is recommended in patients treated with phenytoin who need to be started on viloxazine therapy.
Adult↗
Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities.
The effects of viloxazine, a clinically effective antidepressant, on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake and various related pharmacological activities were determined and compared to those of the tricyclic antidepressants desimipramine, imipramine, and amitriptyline. Viloxazine inhibitied [3H]NA uptake in the mouse and rat heart, being maximally about one half as potent as imipramine with a similar onset, but shorter duration of action than imipramine. The drug did not inhibit [3H]NA uptake in rat medulla or hypothalamus in contrast to desimipramine and imipramine, but it did alter [3H]NA metabolites in a similar manner. Viloxazine, like desimipramine, was a weak blocker of mouse brain 5-HT uptake, but differed from desimipramine as it poteniated 5-HT-mediated functions in the mouse and rat, as did imipramine and amitriptyline, the latter drugs being relatively potent blockers of 5-HT uptake. Viloxazine potentiated the L-DOPA behavioural syndrome in the mouse, antagonized reserpine-induced ptosis and hypothermia in the mouse, and inhibited gastric acid secretion in the rat, but was less potent than the tricyclic antidepressants. No appreciable in vivo inhibition of monoamine oxidase (EC 1.4.3.4.) activity in the mouse was exhibited. Like imipramine, the drug potentiated the ocular effects of L-adrenaline in the rabbit. It was similar to imipramine in potency in potentiating the apomorphine-induced gnawing in the mouse. The drug antagonized oxotremorine-induced hypothermia in the mouse but differed from the tricyclic antidepressants in not exhibiting the anticholinergic effects of blocking the tremors, salivation and lacrimation. Thus, viloxazine exhibits activities related to the biogenic amines both similar to and different from the tricyclics desimipramine, imipramine, and amitriptyline. These actions appear to be of relevance with respect to the antidepressant action of this drug.
Amitriptyline↗
Viloxazine (Vivalan ICI) in depression: results of a field trial of 276 patients in neuropsychiatric practice.
276 ambulatory depressed patients were entered into a multicentered clinical study to assess the effectiveness and acceptability of viloxazine. Results from global assessment by the trialist showed that viloxazine monotherapy produced a good response in 83% of patients. Improvement has been seen in all grades of depression including the sad-depressed, inhibited-apathetic and masked-depressed syndrome. Only 38 patients did not improve on viloxazine and even including 46 withdrawals because of insufficient efficacy and/or side-effects, the clinical response with viloxazine exceeded by far the rate of spontaneous remission expected in depressive illness, thus reducing a major objection against open studies like this. This study also confirmed the rapid onset of drug effect; since as early as after 1 week of treatment, statistically significant improvements were seen even in severe forms of depression. As to the unwanted effects of therapy, viloxazine was again favourably assessed by trialists. Nausea and vomiting were the main side-effects reported and accounted for withdrawal in 8% of the original 276 patients. As expected from previous findings no change in cardiovascular function was observed. So it can be concluded from this open trial, that VIVALAN ICI is an effective antidepressant for use in out-patients. It produces a fairly rapid onset of action and has been generally well tolerated.
Adolescent↗
Relationship between blood and cerebrospinal levels of the antidepressant agent viloxazine.
Viloxazine levels in blood and CSF have been measured following acute and chronic dosing in depressed patients. Blood profiles confirm previous findings that viloxazine is rapidly absorbed and eliminated with a half-life of 4.5 h. Viloxazine crosses the blood-brain barrier and concentrations in CSF remain virtually unchanged over a ten hour period post administration. Viloxazine does not accumulate in CSF on chronic administration. The fact that CSF levels do not reflect concentrations in blood has significant implications on any attempt to correlate the clinical efficacy and the pharmacokinetic behaviour of an antidepressant agent.
Adult↗