Definitions

fetotoxicity

Moclobemide

Moclobemide (sold as Aurox, Manerix) is a 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.

Pharmacology

Moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA), a type of monoamine oxidase inhibitor (MAOI), and acts on epinephrine (adrenaline), norepinephrine (noradrenaline), serotonin, and dopamine. Unlike standard MAOIs, possible side effects do not include cardiovascular complications (hypertension) with encephalopathy, liver toxicity or hyperthermia.

A single 300mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), 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 as 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 2 to 4 hours. 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 2 enzymes, CYP2C19 and CYP2D6. Main metabolites are a lactam and a n-oxid; active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine).

Animal Toxicology

  • Acute Toxicity: The oral LD50-values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 (mouse) is 730mg/kg and LD50 (rat) is 1,300mg/kg. In dogs doses in exceed of 300mg/kg led to vomiting, salivation, ataxia, and drowsiness.
  • Chronic Toxicity: In an 18-months-study in rats with 10mg/kg no signs of chronic toxicity were noted, with 50mg/kg and 250mg/kg only a slight loss of weight, and with 250mg/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

In addition, moclobemide is occasionally used off-label mixed with the prototypical psychedelic dimethyltryptamine (DMT). Orally ingested DMT is inactive, as it is rapidly metabolized by gut monoamine oxidase enzymes, hence these enzymes must be temporarily inhibited in order for DMT to pass into the bloodstream intact. The combination of DMT-containing plants and the plant-based MAO-inhibiting harmala alkaloids (harmine, harmaline) is referred to as Ayahuasca, a sacred psychedelic brew used by several native tribes of South America in traditional spiritual ceremonies. Moclobemide serves a similar purpose to the harmala alkaloids and has been used in modern synthetic recapitulations of the Ayahuasca ritual.

Contraindications and Cautions

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

Pregnancy and Lactation

Animal models did not reveal any embryo- or fetotoxicity. Likewise, breastfed offspring showed normal development. In humans sufficient data is lacking. The concentration of moclobemide in maternal milk is quite low. However, moclobemide should only be given to pregnant or breastfeeding women if clearly indicated.

Side effects

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 increased anxiety; infrequent are confusion (readily reversible after termination of treatment), nervousness, and agitation. Preexisting schizophrenia may exacerbate under moclobemide therapy (see under Cautions).
  • Central and Peripheral Nervous System: Occasionally vertigo and headache, 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: Occasionally nausea and dry mouth, infrequently stomach upset, heartburn, diarrhea, and obstipation.
  • Liver: Occasionally elevated liver enzymes (asymptomatic) and rarely hepatitis.
  • Skin: Occasionally rash, pruritus and redness of skin.
  • Breast: Rarely breast enlargement and secretion of milk in both sexes (due to elevated prolactin levels).

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

  • Other MAO-Inhibitors, SSRIs, clomipramine, selegiline, pethidine, dextromethorphan and MDMA: Development of serotonergic 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 300mg 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

No special diet is necessary, in contrast to irreversible MAOIs. 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 300mg daily in 2 or 3 divided doses. In cases of severe or resistant depression the dose can be increased to 600mg 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 600mg daily in 2 or 3 divided doses. Treatment is usually started with 300mg 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.

References

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