Moclobemide: A Review of its Pharmacological Properties and Therapeutic Use in Depressive Illness

Abstract

Synopsis Moclobemide is a reversible and selective inhibitor of the enzyme monoamine oxidase (MAO) subtype A with a broad spectrum of antidepressant activity. Controlled clinical studies suggest that the short term clinical efficacy of moclobemide is significantly superior to that of placebo, and comparable to that of the tricyclic antidepressants clomipramine, amitriptyline, imipramine and desipramine, the irreversible MAO inhibitor tranylcypromine and the second-generation antidepressants maprotiline, mianserin and fluvoxamine in the treatment of major depressive illness. Moclobemide appears to be equally effective in endogenous and nonendogenous depression, producing marked amelioration of clinical features of psychomotor retardation and depressed mood. Moclobemide is well tolerated, being largely devoid of the anticholinergic adverse effects, symptomatic postural hypotension and weight gain variously associated with the tricyclic antidepressants and irreversible MAO inhibitors, and appears considerably safer on overdosage than the tricyclic and second generation antidepressants. Moreover, moclobemide offers the advantage over the older, irreversible MAO inhibitors of causing only minimal potentiation of the pressor response to dietary tyramine (the so-called ‘cheese effect’). Consequently, the risk of potentially fatal hypertensive crisis, a major deterrent to the wider acceptance of these earlier compounds, is substantially reduced with moclobemide, and the need for dietary precautions is minimised. With its efficacy against endogenous and nonendogenous depression, relatively rapid onset of antidepressant activity, and absence of carry-over effects on treatment withdrawal, moclobemide is likely to make an important contribution to the treatment of major depressive illness. Its favourable tolerability profile, safety on overdosage and beneficial effect on age-related cognitive impairment may be of particular value in the elderly and those with concurrent physical illness. Pharmacodynamic Properties Moclobemide is a selective, potent and reversible inhibitor of MAO-A, devoid of significant affinity for central neurotransmitter binding sites or inhibitory effects on central monamine biosynthesis, reuptake or release. The moclobemide-induced changes in brain monoamine levels are consistent with its short-lasting inhibitory action on MAO-A. In humans, moclobemide increases plasma prolactin levels (an effect presumably mediated via central serotonergic mechanisms) but has no apparent effect on sympathoadrenal function or plasma melatonin levels. At therapeutic doses of 300 to 600 mg/day, moclobemide produces minimal (≈ 2- to 4-fold) potentiation of the pressor response to intravenous tyramine, and, in comparison with the irreversible MAO inhibitors, only slight (4- to 7-fold) potentiation of that to oral tyramine under fasting conditions. On coadministration with food, at least 150mg tyramine was required to produce a clinically relevant increase in systolic blood pressure (30mm Hg) in healthy volunteers receiving moclobemide 600 mg/day. Moclobemide has a less marked suppressant effect on rapid eye movement sleep than the irreversible MAO inhibitors, and its antidepressant action is characterised by an improvement in the quality and pattern of sleep. Therapeutic doses of moclobemide did not influence vigilance or short/long term memory in volunteers but attenuated the scopolamine-induced impairment of cognitive function. Pharmacokinetic Properties Following virtually complete (> 95%) absorption from the gastrointestinal tract, moclobemide undergoes extensive (but apparently saturable) first-pass hepatic metabolism, resulting in an oral bioavailability ranging from ≈ 45 to 60% on single-dose administration and ≈ 85% on multiple dosing. In patients with depression, steady-state plasma moclobemide concentrations on multiple oral dosing were significantly correlated with dose. Moclobemide displays a large volume of distribution (≈ 75 to 95L) on oral administration, suggesting extensive tissue distribution. Clearance of moclobemide is almost exclusively due to hepatic metabolism; the identified metabolites display at best only modest MAO-A inhibitory activity, although comparison of ex vivo and in vitro findings suggests the presence of active, but as yet unidentified, metabolites. Moclobemide obeys first-order elimination kinetics; the parent compound has a short elimination half-life (1 to 2 hours) and a relatively high systemic clearance (0.5 to 1.0 L/min). Multiple oral dosing results in a reduction in the drug’s hepatic clearance, suggesting auto-inhibition or metabolite-mediated inhibition of moclobemide metabolism. While the absorption and elimination kinetics of moclobemide are not significantly modified by advanced age or renal impairment, hepatic dysfunction or coadministration with cimetidine result in decreased systemic clearance of moclobemide. Therapeutic Use Moclobemide 150 to 600 mg/day displayed significantly superior efficacy to placebo on short term (4- to 6-week) administration to patients with major depression, as reflected by achievement of clinical response criteria [⩾ 50% reduction in total Hamilton Depression Rating Scale (HDRS) scores] in 60 to 70% of moclobemide recipients vs 30% of placebo recipients. The drug proved equally effective in endogenous and nonendogenous depression, showing the most pronounced ameliorative effects on features of psychomotor retardation and depressed mood. Dose-finding studies suggested a tentative dose-response relationship over the therapeutic range of 100 to 600 mg/day. In randomised, double-blind, but predominantly non-placebo-controlled studies, moclobemide 150 to 600 mg/day demonstrated a similar antidepressant profile and overall therapeutic equivalence to the tricyclic antidepressants amitriptyline 125 to 250 mg/day, desipramine 50 to 175 mg/day, clomipramine 75 to 200 mg/day and imipramine 75 to 200 mg/day in major depression and dysthymic disorder, with approximately 60 to 70% of patients satisfying response criteria (⩾ 50% reduction in total HDRS score) over a 4- to 12-week treatment period. The onset of the antidepressant action of moclobemide 300 to 600 mg/day (day 10) occurred significantly earlier than that of clomipramine 100 to 200 mg/day (day 13). While moclobemide 150 to 600 mg/day appeared to be of comparable overall efficacy to the second-generation antidepressants maprotiline 75 to 225 mg/day, mianserin 75 to 150 mg/day and fluvoxamine 100 to 200 mg/day in major depression, its action was primarily activating, whereas that of the second-generation antidepressants tended to be more anxiolytic (fluvoxamine) or soporific (maprotiline). Preliminary indications suggest that moclobemide 100 to 350 mg/day is of at least comparable efficacy to the irreversible MAO inhibitor tranylcypromine 10 to 30 mg/day in endogenous depression, and that moclobemide 450 mg/day has a more marked and rapid antidepressant action than the reversible but relatively nonselective MAO-A inhibitor toloxatone 1000 mg/day, showing a significant advantage over the latter in normalising disrupted sleep patterns. Meta-analysis of pooled controlled comparative data indicates that moclobemide is equally effective in the various subtypes of unipolar and bipolar depression, agitated and retarded depression, endogenous and nonendogenous depression, as well as in melancholic and non-melancholic depression. Tolerability and Safety On short term (⩾ 12 weeks) administration at doses of up to 600 mg/day moclobemide has proved to be almost as well tolerated as placebo in patients with depression, with only nausea occurring significantly more frequently on active treatment (10 vs 5%). Moclobemide had no consistent, clinically relevant effect on heart rate or systemic blood pressure; hypertensive episodes were infrequent (0.7%) and in the majority of eases were related to pre-existing labile hypertension rather than to dietary factors, while postural hypotension was no more common with moclobemide (1%) than with placebo. The drug appeared to be equally well tolerated in elderly and younger patients. Moclobemide displayed superior overall tolerability to the tricyclic antidepressants, primarily on the basis of its relative lack of anticholinergic effects (dry mouth, blurred vision, constipation), less pronounced postural changes in blood pressure, and minimal weight gain. Additionally, moclobemide appeared to be devoid of the central excitatory effects (agitation, restlessness, irritability and insomnia) associated with the irreversible MAO inhibitors. Moclobemide displays considerably less toxicity on overdosage than the tricyclic and second-generation antidepressants. Moclobemide overdoses of up to 20g were associated with severe drowsiness and disorientation, but no life-threatening respiratory or cardiovascular depression or neurological sequelae, and there were no residual complications on recovery. Dosage and Administration Moclobemide is administered orally at a full therapeutic dose of 300 to 450 mg/day, in 2 or 3 divided doses, from the outset of treatment; subsequent upward dose titration to a maximum of 600 mg/day may be performed from the second week of therapy onwards. Moclobemide dosage reduction is warranted in the presence of hepatic dysfunction, or if the drug is coadministered with cimetidine. Moclobemide should be taken at the end of a meal to minimise any possible risk of hypertensive responses to dietary tyramine. Although dietary restriction is unnecessary, patients should be advised to avoid consumption of large amounts of tyramine-rich foods (e.g. mature cheese) at any one meal. The combined use of moclobemide with pethidine or dextromethorphan is contraindicated. © 1992, Adis International Limited. All rights reserved.