Moclobemide

Moclobemide
Moclobemide
Systematic (IUPAC) name
4-chloro-N-(2-morpholin-4-ylethyl)benzamide
Clinical data
Trade names Aurorix
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy cat. B3(AU)
Legal status Rx-only; not a controlled substance
Routes oral
Pharmacokinetic data
Bioavailability 60% after first dose, >80% after first week of treatment
Metabolism Liver
Half-life 1 to 2 hours
Excretion renally/in urine
Identifiers
CAS number 71320-77-9 YesY
ATC code N06AG02
PubChem CID 4235
DrugBank APRD00603
ChemSpider 4087 YesY
UNII PJ0Y7AZB63 YesY
KEGG D02561 YesY
ChEMBL CHEMBL86304 YesY
Chemical data
Formula C13H17ClN2O2 
Mol. mass 268.739 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Moclobemide (sold as Aurorix, Manerix) is a monoamine oxidase inhibitor (MAOI) drug primarily used to treat depression and social anxiety. Although clinical trials with the medicine began in 1977, it is not approved for use in the United States. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company.

Contents

Pharmacology

Moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA),[1] a type of monoamine oxidase inhibitor (MAOI), and acts on serotonin, norepinephrine (noradrenaline), and dopamine.[2] Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines.[3] The MAO inhibition of moclobemide wears off within 24 hours.[4] Moclobemide is chemically unrelated to irrversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine.[5] Moclobemide produces several active metabolites that are weaker at inhibiting MAO-A than the parent compound; at least one active metabolite is a potent inhibitor of MAO-B,[6] but due to the very low levels of the MAO-B inhibiting active metabolite that occurs in humans moclobemide is considered to be a selective MAO-A inhibitor.[7]

Depressed people show improved sleep, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.[8] A small study found the oppsite happens in healthy men, a slight suppression of REM occurs; also it was found that cortisol levels may be elevated by moclobemide.[9] Moclobemide also has neuroprotective properties in it's demonstrated anti-hypoxia effects.[10] Additionally moclobemide has cognitive enhancing properties.[11]

Platelet MAO levels are not significantly affected by moclobemide, possibly because it is a reversible MAOI.[12] A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B),[13] blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs).

Moclobemide should not generally be taken concurrently with other antidepressants, because of the likelihood of significant drug interactions. Some very specific regimens may combine moclobemide with a tricyclic or SSRI antidepressant. A washout period of two days is necessary when switching to a tricyclic antidepressant, and for SSRIs, a washout period of at least four to five half-lives is required.

Pharmacokinetics

Moclobemide is rapidly absorbed. Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is 1 to 2 hours.[14][15] Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver by 3 enzymes, CYP2C19, CYP2D6 and CYP1A2.[16] Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours.[17] The main metabolites are the N-oxide Ro 12-5637 and lactam derivative Ro 12-8095;[18] active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation.[19] About 44 percent of the drug is lost due to the first pass effect through the liver.[20] Age and renal status do not affect the pharmacokinetics of moclobemide; however impaired hepatic function slows down the elimination of moclobemide.[21]

Steady state concentrations are established after one week of three times daily dosing. It has been suggested that changes in dose should not be made with a gap of no less than a week.[22] Moclobemide has good pentration across the blood brain barrier with peak plasma levels within the central nervous system occuring 2 hours after administration.[23]

Animal toxicology

  • Acute toxicity: The oral LD50 values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 for mice is 730 mg/kg and for rats 1,300 mg/kg. In dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness.
  • Chronic toxicity: In an 18-months-study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of weight, and with 250 mg/kg mildly elevated Alkaline phosphatase and Gamma-GT. Studies in dogs revealed no toxicity relevant for humans. No evidence for a possible hepatic or cardiovascular toxicity was found.

Uses

  • Depression; most experience exists with major depression according to DSM-III,[24] with both endogenous and non-endogenous depression responding; in addition moclobemide has a fast onset of action compared to other antidepressants and is significantly more tolerable than the tricyclic antidepressants.[25] Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly.[26]

Similar to other MAOI's, reversible MAOI's such as moclobemide may also be effective in a range of other psychiatric disorders.[27]

In efficacy studies for the treatment of major depressive disorder, moclobemide has been found to be significantly more effective than placebo, as effective as the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and somewhat less effective than the older, irreversible MAOIs phenelzine and tranylcypromine. In terms of tolerability, however, moclobemide was found to be comparable to the SSRIs and better tolerated than the TCAs and older MAOIs.[28] A 52 week followup of 102 people on moclobemide found that the therapeutic effects were retained with long-term use as well as safe and well tolerated.[29]

Contraindications and cautions

Contraindications:

  • Hypersensitivity to moclobemide
  • States of severe confusion
  • Concomitant treatment with selegiline
  • Concomitant treatment with clomipramine
  • Concomitant treatment with SSRIs. After termination of SSRI treatment, moclobemide should not be used until four to five half-lives of the SSRI have elapsed (five weeks in the case of fluoxetine and two weeks otherwise).
  • Combination treatment with pethidine (Interaction may be fatal)
  • Combination treatment with dextromethorphan
  • Pediatric patients (no sufficient data exists)

Caution: Individuals who have liver impairment may require dose reduction of about one half or one third.[21]

  • Patients with schizophrenia (psychosis may exacerbate, longterm treatment with neuroleptics should be continued.)
  • Patients with hyperthyroidism (overfunction of the thyroid gland) and phaeochromocytoma. Hypertensive reactions are possible, therefore treatment with moclobemide cannot be recommended.
  • Patients with uncontrolled hypertension
  • Patients with bipolar disorder.

Pregnancy and lactation

The doses of moclobemide are very low and therefore it has been concluded that moclobemide is unlikely to have any adverse affect on a suckling baby.[30]

Side effects

Side effects with moclobemide are minimal and mostly consist of some nausea and dizziness in a small number of people at the start of therapy. The tolerability of moclobemide is similar in woman and men and it is also well tolerated in the elderly.[31] Moclobemide has been found to be superior to tricyclic antidepressants in terms of side effects, especially anticholinergic side effects which are low with moclobemide; cardiovascular adverse effects are also lower with moclobemide compared to tricyclic antidepressants.[24] Adverse effects on cognition, which are a particular concern in the elderly, are minimal and infact evidence suggests that moclobemide may actually enhance cognition, especially memory. Compared to trazadone there is significantly less of an impairment on vigilence.[32] Research has found evidence that moclobemide may be able to counter cholinergic induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.[33] Liver toxicity does not occur with moclobemide. Moclobemide has a similar efficacy profile compared to other antidepressants but is very significantly superior in terms of tolerance and safety profile.[34] Moclobemide has little effect on psychomotor functions.[35] Other side effects include, restlessness, paraesthesias, nausea and sleep disturbances[36] such as difficulty falling asleep.[37]

Moclobemide is relatively well-tolerated. Severe side effects are infrequent. The side effect profile is as follows:

  • Blood and blood-forming-organs: Isolated cases of bone-marrow-damage.
  • Allergic Reactions/Hypersensitivity: Occasionally isolated urticaria without other symptoms, isolated cases of anaphylaxis involving urticaria, angioedema, asthma, and rapid fall in blood pressure.
  • Psychiatric Reactions: Occasionally insomnia and agitation,[38] increased anxiety; infrequent are confusion (readily reversible after termination of treatment) and nervousness. Preexisting schizophrenia may exacerbate under moclobemide therapy (see under Cautions).
  • Central and Peripheral Nervous System: Occasionally headache,[39] and vertigo, infrequent peripheral neuropathy, rarely seizures. Moclobemide may impair the capability of the patient to drive or operate machinery, because it can cause vertigo, headache or rarely seizures.
  • Eyes: Infrequent is blurred vision.
  • Cardiovascular: Changes in blood pressure (hypertension, hypotension) are infrequent.
  • Gastro-Intestinal Tract: Nausea[24] and dry mouth, infrequently stomach upset, heartburn, diarrhea, and obstipation.
  • Skin: Occasionally rash, pruritus and redness of skin.
  • Breast: Rarely breast enlargement and secretion of milk in both sexes (due to elevated prolactin levels).

Withdrawal

Withdrawal of moclobemide, causes a rebound in REM Sleep.[9]

Agitated patients or patients with suicidal thoughts

Moclobemide has no sedative properties. Therefore, agitated patients or those with suicidal thoughts should receive sedative/anxiolytic treatment with benzodiazepines or neuroleptics during the initial phase of treatment. It can be advisable to hospitalize such patients until remission is stable.

Interactions

Moclobemide has less interactions than the irreversible MAOI's. Cimetidine however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended.[40] There is little increase in the effects of alcohol when combined with moclobemide[40] and infact moclobemide causes a reduction in alcohol related impairments.[35]

  • Other MAO-Inhibitors, SSRIs, SNRIs, clomipramine, selegiline, pethidine/meperidine, dextromethorphan, tramadol and MDMA: Development of serotonin syndrome, which may be fatal, is possible. MAOIs, in general, interfere with the metabolism of SSRIs.
  • Opiates: Moclobemide potentiates the analgesic action of opiates.
  • Sympathomimetics: Risk of serious hypertensive crisis. Combination therapy is not recommended.
  • Cimetidine: Metabolization of moclobemide is reduced; dosage of moclobemide should be reduced to 1/3 to 1/2 of the normal dose.
  • Antidepressants without serotonergic action: Moclobemide treatment is possible after a latent period of 48 hours. The moclobemide dose should not exceed 300 mg daily during the first week.
  • Benzodiazepines: Moclobemide doubles the half-life of diazepam and the active metabolite nordiazepam. The diazepam dose should be reduced accordingly.

Dietary advice

Irreversible MAOI's can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly-acting sympathomimetic amines such as tyramine. This is sometimes referred to as the 'cheese effect'. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as mocobemide have a much different side effect profile in this regard.[41] Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietry restrictions, none experienced a tyramine-mediated hypertensive reaction.[31] As the pressor effect of moclobemide is so low, a strict diet is not necessary, in contrast to irreversible MAOIs.[34] However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution.[42] No significant rise in blood pressure occurs when moclobemide is combined with tyramine containing foods unlike irreversible MAOI's which cause a severe rise in blood pressure.[43] The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs.[44] Nevertheless, the patient should avoid excessive consumption of foods containing tyramine (e.g. cheddar cheese, fava beans, chianti wine) in order to avoid a rise in blood pressure.

Dosage

  • Depression: The initial dose is 300 mg daily in 2 or 3 divided doses. In cases of severe or resistant depression the dose can be increased to 600 mg daily. One week should elapse before the dose is escalated, because bioavailability increases during the first week. The treatment should be continued for 4 to 6 weeks, before a determination regarding the success of moclobemide treatment is made.
  • Social anxiety disorder: The recommended dose is 600 mg daily in 2 or 3 divided doses. Treatment is usually started with 300 mg daily on the first 3 days. The treatment should be continued for at least 3 to 4 weeks, before the therapeutic gain is determined. Physician and patient should be aware that the therapeutic prospects of moclobemide treatment in patients with chronic alcoholism are bad. As social phobia is a chronic disease, it can be advisable to treat patients on a long-term basis. In clinical studies moclobemide proved to be an efficient drug for maintenance.

Dosage in patients with liver or renal disease

Impairment of renal function does not alter metabolization or elimination of the drug. The dose does not need to be reduced.

Patients with significantly reduced liver function should receive 1/3 to 1/2 of the normal dose.

Overdose

Intoxications with moclobemide as single agent are usually mild with reversible CNS disturbances and irritations of the GI tract. Patients with mixed intoxications (e.g. with other CNS active drugs) may show severe or life-threatening symptoms and should be hospitalized. Treatment is largely symptomatic and should be aimed at maintenance of the vital functions.

History

The discovery of moclobemide as an antidepressant came about after it was initially investigated as a possible lipid lowering drug.[45] Subsequent research found that moclobemide was far superior to tricyclic antidepressants in terms of side effects, being well tolerated in elderly patients.[31]

References

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  2. ^ Nair, N. P.; S. K. Ahmed, N. M. Kin (November 1993). "Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide". Journal of Psychiatry & Neuroscience (Ontario: Canadian Psychiatric Association) 18 (5): 214–225. PMC 1188542. PMID 7905288. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1188542. Retrieved 27 May 2009. 
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  • moclobemide — noun A drug used to treat depression and social anxiety …   Wiktionary

  • moclobemide — n. an antidepressant drug that reversibly inhibits the enzyme monoamine oxidase. The adverse effects of existing MAO inhibitor, which include severe reactions when cheese or other tyramine containing foods are eaten by patients taking them, are… …   Medical dictionary

  • moclobemide — n. an antidepressant drug that reversibly inhibits the enzyme monoamine oxidase. The adverse effects of irreversible MAO inhibitors, which include severe hypertensive reactions when cheese or other tyramine containing foods are eaten by patients… …   The new mediacal dictionary

  • Моклобемид (Moclobemide) — антидепрсссант, обратимо угнетающий действие фермента моноамина оксидазы. Отрицательное воздействие на существование МАО ингибиторов, проявляющееся в сильных аллергических реакциях на сыр и другие тираминсодержащие продукты питания, употребляемые …   Медицинские термины

  • 71320-77-9 — Moclobémide Moclobémide Général Nom IUPAC 4 chloro N (2 (4 morpholinyl)éthyl)benzamide …   Wikipédia en Français

  • C13H17ClN2O2 — Moclobémide Moclobémide Général Nom IUPAC 4 chloro N (2 (4 morpholinyl)éthyl)benzamide …   Wikipédia en Français

  • Moclamine — Moclobémide Moclobémide Général Nom IUPAC 4 chloro N (2 (4 morpholinyl)éthyl)benzamide …   Wikipédia en Français

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