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Drugs

, Volume 52, Issue 3, pp 450–474 | Cite as

Moclobemide

An Update of its Pharmacological Properties and Therapeutic Use
  • Bret Fulton
  • Paul Benfield
Drug Evaluation

Abstract

Synopsis

Unlike older monoamine oxidase inhibitors, which irreversibly and non-selectively bind monoamine oxidase (MAO), moclobemide is a reversible and selective inhibitor of the MAO-A isozyme. Moclobemide only weakly potentiates the pressor response induced by tyramine or other indirectly acting sympathomimetics; therefore, there is no need to avoid dietary tyramine or over-the-counter decongestants with moclobemide as there is with older MAO inhibitors.

Recent clinical trials and meta-analyses have confirmed the efficacy of moclobemide in the treatment of depressive disorders. Moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and nonselective, irreversible MAO inhibitors. Long term follow-up studies of 6 to 12 months’ duration have demonstrated that the antidepressant efficacy of moclobemide is maintained. Moclobemide, given alone or in combination with another antidepressant, has shown some efficacy in patients with refractory depression; however, comparative trials are required to confirm these findings. Data are also available to show clinical efficacy of moclobemide in the management of social phobia.

Comparative studies have established that moclobemide is better tolerated at therapeutic dosages and has less toxicity in overdose than TCAs and nonselective, irreversible MAO inhibitors. Moclobemide lacks the anticholinergic, sedative and cardiovascular effects associated with many of the older antidepressants. Compared with SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects than the SSRIs and has not been reported to interfere with sexual function.

In summary, recent data which confirm and extend its comparative therapeutic efficacy and low potential for adverse effects have established moclobemide as an effective treatment in depressive disorders. The drug is also effective in patients with a primary diagnosis of social phobia. Its lack of adverse anticholinergic, cardiovascular, cognitive and psychomotor effects makes moclobemide a particularly useful option in the elderly or patients with cardiac disease.

Pharmacodynamic Properties

The in vitro binding of moclobemide to monoamine oxidase (MAO)-A is weak but >167-fold more selective than for the MAO-B isozyme. However, its ex vivo activity against -A is more pronounced, perhaps indicating the existence of an as yet unidentified, more active metabolite. The ex vivo binding of moclobemide to MAO-A was demonstrated to be reversible, with recovery of enzyme activity within 16 hours. This is in contrast to older MAO inhibitors, which nonselectively and irreversibly bind to both MAO-A and MAO-B isozymes.

The effects of moclobemide on monoamine metabolism and/or activity of monoaminergic neurons have been indirectly demonstrated in humans by reductions in plasma levels of the catecholamine metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol and the serotonin (5-hydroxytryptamine) metabolite 5-hydroxyindoleacetic acid. In vitro, moclobemide has no appreciable affinity for muscarinic, dopaminergic, seroto-nergic, adrenergic, H1-histaminergic, benzodiazepine or opioid receptors.

In oral tyramine pressor tests moclobemide enhanced the hypertensive re-sponse to oral tyramine approximately 8- and 16-fold less than tranylcypromine and phenelzine, respectively. In addition, the pressor response induced by tyramine returned to baseline within 3 days of discontinuing moclobemide, whereas baseline sensitivity did not return until 4 and 8 weeks after discontinuing tranyl-cypromine and phenelzine, respectively.

In contrast to other antidepressants, moclobemide has minimal effect on REM sleep and is reported to have no effect on, or to improve, sleep continuity in depressed patients. Unlike tricyclic antidepressants (TCAs), moclobemide has no reported effect on cognitive or psychomotor function.

Pharmacokinetic Properties

After single-dose oral administration, moclobemide is almost completely absorbed; however, oral bioavailability ranges from 44 to 69% because of substantial first-pass metabolism. After multiple doses, moclobemide is associated with increased bioavailability (>80%), possibly due to saturation of first-pass metabolism. Moclobemide is approximately 50% bound to plasma proteins and the volume of distribution ranges from 76 to 134L.

Moclobemide is rapidly and extensively metabolised to at least 19 different metabolites, two of which have moderate MAO-A inhibitory activity. The elimination half-life of moclobemide is approximately 1 to 2 hours and the drug is primarily excreted renally as metabolites. Age and renal function are reported to have no significant effect on the pharmacokinetics of moclobemide; however, elimination is impaired in patients with hepatic dysfunction.

Therapeutic Efficacy

Recent clinical trials and meta-analyses in patients with depressive disorders have confirmed that moclobemide generally has similar efficacy to TCAs, selective serotonin reuptake inhibitors (SSRIs), the MAO inhibitor tranylcypromine and maprotiline. Although results from a meta-analysis indicate that moclobemide is as effective as clomipramine, this was not the case in patients with severe depression when dosages of moclobemide of 400 mg/day or less were used. Data from meta-analyses also indicate that moclobemide has similar efficacy to TCAs when patients are classified according to severity of disease or when symptom clusters (psychic, somatic, retardation, agitation) of the Hamilton Depression Rating Scale (HDRS) are examined separately.

In studies comparing moclobemide 300 to 600 mg/day with fluoxetine 20 to 40 mg/day, the percentage of patients who responded to treatment (≥50% reduction in HDRS scores or either a ≥50% reduction in HDRS score or a final HDRS score <10) was similar (range 47 to 72% and 48 to 77%, respectively). One study reported that moclobemide and fluoxetine were associated with similar improvements in quality-of-life parameters after treatment for up to 12 weeks.

Long term follow-up studies have reported that moclobemide retains its antidepressant efficacy over treatment periods of up to 12 months. In elderly patients, moclobemide was generally at least as effective as comparator antidepressants and more effective than placebo. The use of moclobemide in patients with depression that is refractory to standard therapy is primarily limited to noncomparative studies. Preliminary data indicate that combination of moclobemide with a TCA or SSRI may be effective in these patients (although the coadministration of moclobemide with antidepressants with serotonergic properties should be undertaken only with great caution).

Moclobemide has been shown to be effective in the management of social phobia. Comparative 16-week data indicate moclobemide (approximately 580 mg/day) to be as effective as phenelzine (approximately 70 mg/day) in this disorder. In a subsequent study, moclobemide 600 mg/day was associated with significant global improvement relative to placebo on the Liebowitz Social Phobia Scale and on all subscales of the Clinical Impression of Change for social phobia after 12 weeks. Long-term data are also available from a nonblind trial to show clinical efficacy of moclobemide 600 to 750 mg/day over a 2-year period.

Tolerability

Based on pooled data from clinical trials involving over 1600 patients, the frequency of the most common adverse effects did not significantly differ between moclobemide and placebo. Only dizziness, nausea and insomnia/sleep disturbance were reported more frequently in moclobemide-treated patients than placebo recipients.

Moclobemide generally lacks the adverse effects associated with antidepressant drugs which bind to muscarinic (dry mouth, constipation, blurred vision, urinary retention), α1-adrenergic (hypotension) and histaminergic (sedation) receptors. In comparative trials with TCAs, moclobemide was associated with a lower frequency of adverse effects, primarily related to a lower propensity to produce anticholinergic and sedative effects. Moclobemide had a similar overall tolerability to SSRIs. However, SSRIs tended to cause more gastrointestinal adverse effects than moclobemide.

Moclobemide has a relatively low frequency of adverse effects during long term treatment and is reported to be as well tolerated in the elderly as in younger patients.

In cases of overdose when moclobemide was the sole ingestant, most symptoms have been relatively mild and reversible. However, several fatal cases of serotonin syndrome have been reported after multidrug overdose involving moclobemide in combination with clomipramine, citalopram or fluoxetine.

Drug Interactions

Although moclobemide has been combined with serotonin reuptake inhibitors in clinical trials without evidence of the serotonin syndrome, there have been isolated case reports of this occurring when moclobemide was combined with clomipramine or fluoxetine at therapeutic dosages. Thus, these drugs should be used together only with great caution. Similarly, pethidine (meperidine) or dextro-methorphan (both of which have serotonergic properties) should be avoided in patients receiving moclobemide.

Moclobemide has no reported interaction with directly acting sympathomimetic agents. Data indicate that the drug may be used with caution in combination with low dosages of indirectly acting sympathomimetics. The elimination of moclobemide is significantly reduced when it is coadministered with cimetidine.

Dosage and Administration

Moclobemide may be initiated at full therapeutic dosages of 300 to 450 mg/day. The maximum recommended dosage is 600 mg/day. Dietary restrictions are not required but consumption of large amounts of tyramine-rich food should be avoided. Washout periods when switching between moclobemide and other antidepressants are not required. Dosage adjustments are not needed in patients with renal dysfunction; however, moclobemide dosages should be reduced by one-third to one-half in patients with hepatic dysfunction.

Keywords

Fluoxetine Fluvoxamine Social Phobia Tyramine Clomipramine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Bret Fulton
    • 1
  • Paul Benfield
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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