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Reboxetine is a selective noradrenaline (norepinephrine) reuptake inhibitor, the first drug of a new antidepressant class.
Most clinical studies of reboxetine were of 4 to 8 weeks’ duration and are published in summary papers; only a few trials have been published in full. This prevents accurate determination of the efficacy and tolerability of reboxetine because data are limited for some studies. Nevertheless, reboxetine (usually 4 to 10 mg/day) generally has significantly greater efficacy than placebo, similar efficacy to the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) fluoxetine and appears at least as effective as the tricyclic antidepressants desipramine and imipramine. Some evidence suggests that, compared with fluoxetine, reboxetine may be more effective in severely depressed patients and at improving social behaviour. This requires confirmation, as do limited long term data suggesting that reboxetine may prevent relapse in patients who respond to short term therapy.
Reboxetine recipients generally have a lower incidence of dry mouth and blurred vision than desipramine recipients and are less likely to experience dry mouth, somnolence, hypotension-related symptoms and tremor than patients treated with imipramine, according to short term tolerability data. Compared with fluoxetine, reboxetine causes fewer events typical of SSRIs (nausea and related symptoms and diarrhoea) and less somnolence but is associated with more anticholinergictype events, paraesthesia, flushing and hypotension. Constipation, urinary hesitancy or retention, hypertension and rash are reported more frequently with long term reboxetine therapy than with placebo. Urinary retention or hesitancy in males is the only event that is more common with long term than with short term reboxetine therapy in placebo-controlled trials.
Conclusions: In summary, reboxetine is the first of a new class of antidepressants, the selective noradrenaline reuptake inhibitors. As reported predominantly in summary papers, reboxetine appears to be at least as effective as the tricyclic antidepressants desipramine and imipramine and similar in efficacy to the SSRI fluoxetine after short term therapy. Reboxetine may also improve social functioning, an important corollary of depression. However, clarification of this point, and of its comparative efficacy and tolerability and ability to prevent relapse is required in fully reported and well designed trials before its role can be established definitively. Nevertheless, with its selective mechanism of action and acceptable tolerability profile, reboxetine can be considered a promising new agent for the treatment of depression.
Reboxetine is a selective inhibitor of noradrenaline reuptake. It inhibits noradrenaline reuptake in vitro to a similar extent to the tricyclic antidepressant desmethylimipramine. Reboxetine does not affect dopamine or serotonin reuptake and it has low in vivo and in vitro affinity for adrenergic, muscarinic, cholinergic, histaminergic, dopaminergic and serotonergic receptors. However, reboxetine has been associated with anticholinergic-type adverse events in clinical trials.
Studies in animal models have demonstrated the antidepressant activity of reboxetine.
In healthy volunteers, psychomotor performance and cognitive function were not affected by single doses of reboxetine 0.5 to 4mg with or without alcohol (the recommended dosage of reboxetine is 4mg twice daily). In addition, EEG recordings and volunteers’ subjective ratings indicated that reboxetine ≤4mg, alone or with alcohol, did not cause significant sedation. This contrasted with the CNS impairment seen with amitriptyline 25mg alone or plus alcohol.
Maximum plasma concentrations of reboxetine are reached about 2.5 hours after an oral dose in healthy volunteers. Reboxetine has linear pharmacokinetics over the dose range studied (single oral doses of 2 to 5mg) and steady-state plasma concentrations are reached within about 5 days of starting therapy. Reboxetine is ≈98% bound to plasma proteins, predominantly α1-acid glycoprotein, but its potential for interaction with other highly bound drugs has not been determined.
Reboxetine is metabolised via oxidation of the morpholine ring, O-dealkylation of the ethoxyphenoxy ring and hydroxylation. Preliminary evidence suggests that it is unlikely that the cytochrome P450 (CYP) 2D6 isoenzyme is involved in the metabolism of reboxetine, and reboxetine appears to inhibit CYP2D6 only at high concentrations. In contrast, reboxetine appears to be metabolised by the CYP3A4 isoenzyme, and compounds that decrease the activity of this isoenzyme are likely to increase plasma concentrations of reboxetine. It is unclear whether reboxetine inhibits CYP3A4. A study in healthy volunteers suggests that coadministration of reboxetine and lorazepam does not cause clinically significant changes to the pharmacokinetics of either drug.
Reboxetine has a relatively short elimination half-life (t1/2) of 12.5 hours in healthy volunteers and is therefore given twice daily. Only 9% of the administered dose is excreted unchanged in the urine.
Elderly individuals (mean age 81 years) appear to have higher plasma concentrations, a longer t1/2, and reduced renal clearance of reboxetine than younger individuals (age 21 to 39 years); similar effects were observed in individuals with renal impairment. Patients with alcoholic liver disease had approximately 2-fold increases in area under the plasma concentration-time curve (AUC) and t1/2, compared with healthy volunteers after the same dose of reboxetine, although pharmacokinetic parameters were not affected by the severity of liver disease.
To date, most studies assessing the efficacy of reboxetine in patients with depression have been published only in summary papers lacking peer review and full details of methodology and results.
In short term (4- to 8-week) placebo-controlled clinical trials, the proportion of reboxetine recipients whose Hamilton Depression Rating Scale score was reduced by ≥50% ranged from 56 to 74%, a significantly superior response to that with placebo in most studies.
Reboxetine was at least as effective as the tricyclic antidepressants desipramine and imipramine in a total of 4 double-blind randomised studies that each included at least 200 outpatients or hospitalised patients; 1 trial included elderly patients only.
Reboxetine had equivalent antidepressant efficacy to the SSRI fluoxetine in 2 well designed clinical trials, one of which was placebo-controlled. However, reboxetine was significantly more effective than fluoxetine in a pooled subgroup analysis of severely depressed patients from the 2 comparisons. Reboxetine improved social motivation and behaviour, assessed using the newly-developed Social Adaptation Self-Evaluation Scale, to a greater extent than fluoxetine in the placebo-controlled study, but not in the other comparison between reboxetine and fluoxetine that did not include a placebo group.
Preliminary results from a placebo-controlled trial and 2 noncomparative studies (all patients had responded to short term reboxetine therapy) also suggest that reboxetine may be effective for the prevention of relapse. Remission rates were similar for reboxetine and both imipramine and fluoxetine in the only trials with active comparators to report this parameter.
Reboxetine is likely to have a similar onset of action to other antidepressants (2 to 3 weeks) on the basis of available data.
Most tolerability data for reboxetine are provided by a summary paper of both published and previously unpublished trials.
Pooled data from placebo-controlled studies in a total of 746 patients showed that anticholinergic-type events (dry mouth, constipation and urinary hesitancy or retention), increased sweating, insomnia, impotence in male patients, tachycardia and vertigo occurred significantly more frequently with reboxetine than with placebo. Reboxetine does not appear to cause ECG abnormalities in the short term, apart from tachycardia in some adult and elderly patients and occasional atrial and ectopic beats in the elderly. However, in the long term, tachycardia and hypertension appear to be more frequent with reboxetine than with placebo; the cardiovascular effects of reboxetine have not been specifically assessed.
The overall incidence of adverse events with short term reboxetine is similar to that with desipramine, imipramine and fluoxetine. However, dry mouth, tremor, somnolence and hypotension are more common with imipramine than with reboxetine, and blurred vision and dry mouth are experienced more frequently with desipramine than with reboxetine. SSRI-related events (nausea and diarrhoea) and somnolence are more common with fluoxetine than with reboxetine, whereas anticholinergic-type events (constipation, dry mouth, urinary retention or hesitancy), paraesthesia, flushing and hypotension are more frequently reported with reboxetine than with fluoxetine.
Constipation, urinary hesitancy or retention, hypertension and rash are more common with long term reboxetine therapy than with placebo. Urinary retention or hesitancy in males was the only event that had a greater incidence with long term than with short term reboxetine therapy in placebo-controlled trials.
Data from 2 studies (interim results only were available for 1 trial) suggest that the tolerability profile of reboxetine in the elderly is similar to that in younger patients.
In a clinical trial, nausea, fatigue and headache were experienced by patients taking reboxetine at dosages higher than those recommended (up to a dosage of 20 mg/day). There are no published reports of patients taking very large doses of reboxetine. Reboxetine has not been associated with clinically relevant changes in laboratory parameters.
Dosage and Administration
The recommended initial oral dosage of reboxetine is 4mg twice daily in adults and 2mg twice daily in the elderly. The dosage can be increased to 10 mg/day in adults and 6 mg/day in the elderly if the response to therapy is incomplete after 3 to 4 weeks. Dosage adjustments are recommended for patients with severe renal impairment and those with hepatic insufficiency.
KeywordsAdis International Limited Fluoxetine Imipramine Desipramine Clinical Global Impression
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