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==Pharmacology==
==Pharmacology==
[[File:Moclobemide 150 mg tablets.jpg|thumb|A picture of 150 mg tablets of the reversible [[MAOI]] drug moclobemide, brand name Aurorix.]]
[[File:Moclobemide 150 mg tablets.jpg|thumb|A picture of 150 mg tablets of the reversible [[MAOI]] drug moclobemide, brand name Aurorix.]]
Moclobemide is a [[benzamide]],<ref name="pmid8255982"/> derivative of [[morpholine]],<ref name="pmid7905288"/> which acts pharmacologically as a selective, [[reversible inhibitor of monoamine oxidase A]] (RIMA),<ref name="pmid8875133">{{cite journal |author=Fulton B, Benfield P |title=Moclobemide. An update of its pharmacological properties and therapeutic use |journal=Drugs |volume=52 |issue=3 |pages=450–74 |year=1996 |month=September |pmid=8875133 }}</ref> a type of monoamine oxidase inhibitor (MAOI), and increases levels of [[norepinephrine]] (noradrenaline), [[dopamine]], and especially [[serotonin]].<ref name="Nair">{{cite journal | last = Nair | first = N. P. | coauthors = S. K. Ahmed, N. M. Kin | year = 1993 | month = November | title = Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide | journal = Journal of Psychiatry & Neuroscience | volume = 18 | issue = 5 | pages = 214–225 | publisher = Canadian Psychiatric Association | location = Ontario | pmc = 1188542 | accessdate = 27 May 2009 | pmid=7905288 }}</ref><ref name="pmid1546143">{{cite journal |author=Haefely W, Burkard WP, Cesura AM, ''et al.'' |title=Biochemistry and pharmacology of moclobemide, a prototype RIMA |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S6–14 |year=1992 |pmid=1546143 }}</ref> in neuronal cells as well as in [[synaptic vesicles]]; [[extracellular]] levels also increase which results in increased [[monoamine]] receptor stimulation and suppression of [[REM sleep]], down regulation of [[3-adrenoceptors]]. There is also some evidence pointing towards moclobemide possessing [[neuroprotective]] properties.<ref name="pmid7905288"/> There is no cumulative effect of moclobemide centrally when taken long-term.<ref name="pmid7905288"/> With long-term use of moclobemide, there is a significant [[down-regulation]] of [[B-adrenoceptors]].<ref name="pmid7905288"/> Single or repeated dosing with 100-300 mg of moclobemide leads to a reduction in deaminated metabolites of [[amines]] such as [[3,4-dihydroxyphenylacetic acid]], [[3,4-dihydroxyphenylethylglycol]] as well as [[5-HIAA]]. Excretion of [[homovanillic acid]] and [[vanillylmandelic acid]] via urine is also reduced. There is also a temporary increase in [[prolactin]] during initial intake of 100-300 mg of moclobemide.<ref name="pmid7905288"/> However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.<ref name="pmid7519866">{{cite journal |author=Holford NH, Guentert TW, Dingemanse J, Banken L |title=Monoamine oxidase-A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor |journal=Br J Clin Pharmacol |volume=37 |issue=5 |pages=433–9 |year=1994 |month=May |pmid=7519866 |pmc=1364898 }}</ref>
Moclobemide is a [[benzamide]],<ref name="pmid8255982"/> derivative of [[morpholine]],<ref name="pmid7905288"/> which acts pharmacologically as a selective, [[reversible inhibitor of monoamine oxidase A]] (RIMA),<ref name="pmid8875133">{{cite journal |author=Fulton B, Benfield P |title=Moclobemide. An update of its pharmacological properties and therapeutic use |journal=Drugs |volume=52 |issue=3 |pages=450–74 |year=1996 |month=September |pmid=8875133 }}</ref> a type of monoamine oxidase inhibitor (MAOI), and increases levels of [[norepinephrine]] (noradrenaline), [[dopamine]], and especially [[serotonin]].<ref name="Nair">{{cite journal | last = Nair | first = N. P. | coauthors = S. K. Ahmed, N. M. Kin | year = 1993 | month = November | title = Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide | journal = Journal of Psychiatry & Neuroscience | volume = 18 | issue = 5 | pages = 214–225 | publisher = Canadian Psychiatric Association | location = Ontario | pmc = 1188542 | accessdate = 27 May 2009 | pmid=7905288 }}</ref><ref name="pmid1546143">{{cite journal |author=Haefely W, Burkard WP, Cesura AM, ''et al.'' |title=Biochemistry and pharmacology of moclobemide, a prototype RIMA |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S6–14 |year=1992 |pmid=1546143 }}</ref> in neuronal cells as well as in [[synaptic vesicles]]; [[extracellular]] levels also increase which results in increased [[monoamine]] receptor stimulation and suppression of [[REM sleep]], down regulation of [[3-adrenoceptors]]. There is also some evidence pointing towards moclobemide possessing [[neuroprotective]] properties.<ref name="pmid7905288"/> There is no cumulative effect of moclobemide centrally when taken long-term.<ref name="pmid7905288"/> With long-term use of moclobemide, there is a significant [[down-regulation]] of [[B-adrenoceptors]].<ref name="pmid7905288"/> Single or repeated dosing with 100-300 mg of moclobemide leads to a reduction in deaminated metabolites of [[amines]] such as [[3,4-dihydroxyphenylacetic acid]], [[3,4-dihydroxyphenylethylglycol]] as well as [[5-HIAA]]. Excretion of [[homovanillic acid]] and [[vanillylmandelic acid]] via urine is also reduced. There is also a temporary increase in [[prolactin]] during initial intake of 100-300 mg of moclobemide.<ref name="pmid7905288"/> L-dihydroxyphenylalanine is also reduced.<ref name="pmid8923574">{{cite journal |author=Radat F, Berlin I, Spreux-Varoquaux O, Elatki S, Ferreri M, Puech AJ |title=Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression. A double blind, randomized study |journal=Psychopharmacology (Berl.) |volume=127 |issue=4 |pages=370–6 |year=1996 |month=October |pmid=8923574 }}</ref> However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.<ref name="pmid7519866">{{cite journal |author=Holford NH, Guentert TW, Dingemanse J, Banken L |title=Monoamine oxidase-A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor |journal=Br J Clin Pharmacol |volume=37 |issue=5 |pages=433–9 |year=1994 |month=May |pmid=7519866 |pmc=1364898 }}</ref>


It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide.<ref name="pmid7905288"/> With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.<ref name="pmid1546145">{{cite journal |author=Dingemanse J, Berlin I, Payan C, Thiede HM, Puech AJ |title=Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S68–70 |year=1992 |pmid=1546145 }}</ref> The MAO inhibition of moclobemide lasts about 8-10 hours and wears off completely by 24 hours after dosing.<ref name="pmid7905288"/><ref name="pmid1546143"/> The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs [[phenelzine]] and approximately equivalent to [[tranylcypromine]] and [[isocarboxazid]].<ref name="pmid7905288"/>
It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide.<ref name="pmid7905288"/> With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.<ref name="pmid1546145">{{cite journal |author=Dingemanse J, Berlin I, Payan C, Thiede HM, Puech AJ |title=Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S68–70 |year=1992 |pmid=1546145 }}</ref> The MAO inhibition of moclobemide lasts about 8-10 hours and wears off completely by 24 hours after dosing.<ref name="pmid7905288"/><ref name="pmid1546143"/> The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs [[phenelzine]] and approximately equivalent to [[tranylcypromine]] and [[isocarboxazid]].<ref name="pmid7905288"/>

Revision as of 23:23, 1 January 2012

Moclobemide
Clinical data
Trade namesAurorix
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • AU: B3
Routes of
administration		oral
ATC code
Legal status
Legal status
  • Rx-only; not a controlled substance
Pharmacokinetic data
Bioavailability60% after first dose, >80% after first week of treatment
MetabolismLiver
Elimination half-life1 to 2 hours
Excretionrenally/in urine
Identifiers
  • 4-chloro-N-(2-morpholin-4-ylethyl)benzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.163.935 Edit this at Wikidata
Chemical and physical data
FormulaC13H17ClN2O2
Molar mass268.739 g/mol g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)C(=O)NCCN2CCOCC2
  • InChI=1S/C13H17ClN2O2/c14-12-3-1-11(2-4-12)13(17)15-5-6-16-7-9-18-10-8-16/h1-4H,5-10H2,(H,15,17) checkY
  • Key:YHXISWVBGDMDLQ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Moclobemide (sold as Aurorix[1] and Manerix[2]) is a reversible monoamine oxidase inhibitor (MAOI) drug primarily used to treat depression and social anxiety.[3] 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. No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine containing foods or pressor amine drugs, unlike the older non-selective irreversible MAOI's which cause a severe rise in blood pressure with such combination.[3] Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.[3]

Therapeutic uses

MAOI's such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes,[4] and has good long-term tolerabilty in terms of side effects.[5] Moclobemide has been found to be as effective as other potent antidepressants. Psychotic depression, unipolar endogenous depression, bipolar depression, depression with and without melancholia, retarded depression as well as agitated depression all respond to moclobemide,[6] as does neurotic depression, reactive depression. Unipolar endogenous depression is reported to have the best response to moclobemide therapy.[7][8] Individuals suffering from depression who are given moclobemide are twice as likely to improve on moclobemide than on placebo.[9] A concern of antidepressant adverse effects is sexual dysfunction, however moclobemide has actually been found to increase in libido and impaired erection, ejaculation and orgasm.[10] Cardiovascular toxicity is a concern with antidepressants such as tricyclic antidepressants as well as the irreversible MAOI's; when cardiovascular toxicity is a concern, SSRI's or the reversible MAOI's such as moclobemide are an option as they lack or have a significantly reduced level of cardiovascular toxicity in terms of adverse effect as well as in overdose.[11]

Tolerance does not seem to occur; research as found that moclobemide retains it's beneficial therapeutic properties in depression for at least a year.[12]

  • Depression; Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder,[13] 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.[14] Due to a very good safety profile and very low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression.[15] Reversed depressive symptoms such as hypersomnia, and increased appetite, and irritability in children and in adolescents may respond particularly well to moclobemide.[16]
    • Dysthymia; moclobemide has been found to be effective in the treatment and management of this depressive disorder.[17]
    • Agitated depression; The effectiveness of moclobemide in agitated depression is equivalent to that of imipramine and sedative antidepressants such as amitriptyline, mianserin and maprotiline. The therapeutic response in agitated depressive individuals is similar to that seen in non-agitated depression; however a past history of use of antidepressants reduces the chance of successful therapeutic response. The addition of a benzodiazepine to moclobemide therapy has not been found to be of benefit in this population group.[18]
    • Elderly; Reversible MAOI's such as moclobemide may have advantages in the treatment of depression associated with Alzheimer's disease due to its affect on noradrenaline.[19] Cognitive impairments have been found to improve in dementia sufferers when depression is treated with moclobemide.[6] Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly.[20] Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants.[21] 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.[22]
  • Social phobia; Moclobemide has been found to be effective for the treatment of social anxiety disorder in both short and long-term placebo controlled clinical trials.[23] Moclobemide, is as effective as other MAOI's in the treatment of social phobia,[24] however maximal benefits can take 8 - 12 weeks to manifest.[25]
  • Smoking cessation; Moclobemide has been tested in heavy dependent smokers against placebo based on the theory that tobacco smoking could be a form of self medicating of major depression,[26] and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of tobacco smoke. Moclobemide was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12 month follow-up the difference between the placebo group and the moclobemide group was no longer significant.[27]
  • Panic disorder; There is evidence that moclobemide is useful in the treatment and management of panic disorder.[6]
  • ADHD. Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.[6][6]
  • Migraine; Moclobemide has been reported to be effective in the treament of migraine.[28]

Similar to other MAOI's, reversible MAOI's such as moclobemide may also be effective in a range of other psychiatric disorders.[29][6] Menopausal flushing may also respond to moclobemide.[30] Moclobemide may also have benefit for some patient's with Parkinson's Disease by extending and enhancing the effects of l-dopa.[31]

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.[32] There is some evidence that moclobemide on it's own or in combination with other antidepressants such as SSRIs is also effective for treatment resistant depression and that the combination can be administered without the development of serotonin syndrome; however, further research is needed before such a combination can be recommended.[3][33] Follow-up studies has demonstrated that moclobemide retains it's therapeutic efficacy as an antidepressant for at least a year.[3]

People on irreversible MAOI's have to discontinue these antidepressants two weeks before general anesthesia, however, the use of moclobemide due to it's reversible nature, would allow such patients to possibly continue antidepressant therapy.[34][35]

A dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) test can be used to estimate who is likely to respond to moclobemide antidepressant therapy.[36]

Contraindications and cautions

Contraindications:

The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions.[37]

  • Hypersensitivity to moclobemide
  • States of severe confusion
  • While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietry restriction, the combination of seligiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine.[38] The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.[39]
  • Concomitant treatment with clomipramine
  • Concomitant treatment with SSRIs.[40] 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[40] (Interaction may be fatal)
  • Combination treatment with dextromethorphan
  • Pediatric patients (no sufficient data exists)

Caution:

Using moclobemide in combination with drugs which enhance serotonin require caution.[37] Individuals who have liver impairment may require dose reduction of about one half or one third.[41]

  • 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 in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse affect on a suckling baby.[2]

Side effects

The incidence of adverse events is not correlated with age, however adverse events occur more often in females than in males.[42] Moclobemide is regarded as a generally safe antidepressants and due to it's favourable side effect profile, it can be considered a first-line therapeutic antidepressant.[43] Side effects of moclobemide are exceptionally low,[15] with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide.[44] Many antidepressants have an adverse effect on sexual function, however, treatment with moclobemide has actually been found to improve sexual dysfunction.[45] Moclobemide does not have any adverse effect on cognitive abilities, thus there are no impairments of moclobemide therapy on memory, attention functions nor is ability to drive a motor vehicle affected adversely.[46] In fact moclobemide has been found to improve cognition, especially memory; this is relevant with regard to the elderly as adverse effects on cognition are of particular concern in this population. People with dementia and comorbid depression also show improvements in cognitive impairments; these improvements are unrelated to alleviation of depression. Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment. There is a mild impairment in psychometric performance in elderly people but none in younger people. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle.[47][2] The tolerability of moclobemide is similar in woman and men and it is also well tolerated in the elderly.[48] Moclobemide is tolerated to a similar degree to the SSRI antidepressants, although unlike SSRIs moclobemide does not cause sexual dysfunction and gastrointestinal disturbance is less common. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause anticholinergic, sedative or cardiovascular adverse effects[3] as well as not causing weight gain.[47]

Unlike the irreversible MAOI's there is no evidence of liver toxicity with moclobemide.[49] Moclobemide has a similar efficacy profile compared to other antidepressants but is significantly superior to the tricyclic antidepressants and the classic (unselective or irreversible) MAOI's, in terms of tolerance and safety profile.[50] Moclobemide has little effect on psychomotor functions.[51] Other side effects include, restlessness and paraesthesias.[52] Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg of higher, peripheral reaction time may be impaired.[53] Peripheral oedema has been associated with moclobemide.[54]

Some other side effects include, nausea, stimulation, migraine, disorientation, sedation, agitation and diarrhea. Over 80 percent of side effects are transient disappearing within 2 weeks of treatment.[55] tiredness, headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy.[56] A paradoxical worsening of depression has been reported in some individuals in several studies,[57] and reports of suicidal ideation and suicide as a adverse effect have been reported as a rare adverse effect of moclobemide.[58] Rarely seizures may occur.[59] Hypertension, has also been reported with moclobemide therapy.[60]

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: Preexisting schizophrenia may exacerbate under moclobemide therapy (see under Cautions).
  • Central and Peripheral Nervous System: infrequent peripheral neuropathy.
  • Eyes: Infrequent is blurred vision.
  • Cardiovascular: Changes in blood pressure such as hypotension are infrequent.
  • Gastro-Intestinal Tract: Dry mouth, infrequently stomach upset, heartburn, diarrhea, and constipation.
  • 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

Flu-like symptoms may be the predominant withdrawal symptom of moclobemide.[61] Withdrawal of moclobemide causes a rebound in REM Sleep.[2]

Moclobemide does not prevent withdrawal symptoms from serotonin reuptake inhibitors.[62]

Overdose

Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and nonselective, irreversible MAO inhibitors,[3] making it a safer antidepressant in the elderly or people with physical disorders.[47] .Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for in as well as outpatient use.[63] Intoxications with moclobemide as single agent are usually mild, however when combined with tricyclic or SSRI antidepressants the overdose much more toxic and potentially fatal.[64][65] Moclobemide, is prefered by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose.[66] 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.

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.[67] There is little increase in the effects of alcohol when combined with moclobemide[67] and, in fact, moclobemide causes a reduction in alcohol related impairments.[51] Moclobemide also interacts with pethidine/meperidine,[68] and dextropropoxyphene.[50] The combined use of moclobemide and selegiline, requires dietry restrictions as the combination can lead to increased sensitivity to the pressor effect of tyramine containing foods. Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects.[69]

Serotonin syndrome, a potentially fatal syndrome, has been reported when trazadone was abruptly replaced with moclobemide.[70] Taking at the same time or starting moclobemide too soon after discontinuing clomipramine, or other serotonin reuptake inhibitors, such as SSRI's may result in the development of a serotonin syndrome.[71][50] Cimetidine, causes a doubling of the blood plasma levels of moclobemide.[2]

  • Other MAO-Inhibitors, SNRIs, 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.
  • 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.[2] The reversible binding to MAO by moclobemide allows amines such as tyramine to displace moclobemide from MAO allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition.[72] 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.[48] As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs.[3] However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution.[73] The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs.[74] However, as a precaution moclobemide has been suggested to be post-prandially (taken on an empty stomach), to minimise even further the relatively small 'pressor effect' moclobemide possesses with regard to tyramine.[2]

Pharmacology

A picture of 150 mg tablets of the reversible MAOI drug moclobemide, brand name Aurorix.

Moclobemide is a benzamide,[40] derivative of morpholine,[2] which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA),[3] a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin.[75][76] in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of 3-adrenoceptors. There is also some evidence pointing towards moclobemide possessing neuroprotective properties.[2] There is no cumulative effect of moclobemide centrally when taken long-term.[2] With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors.[2] Single or repeated dosing with 100-300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100-300 mg of moclobemide.[2] L-dihydroxyphenylalanine is also reduced.[77] However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.[78]

It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide.[2] With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.[79] The MAO inhibition of moclobemide lasts about 8-10 hours and wears off completely by 24 hours after dosing.[2][76] The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.[2]

Moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks anticholinergic effects and ognitive impairments can be improved by moclobemide.[80] 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.[81] Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine.[82] In humans, the n-oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of MAO-A; other metabolites are significantly less potent than the parent compound.[2]

In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4 week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.[2] There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels.[2] Testosterone levels increase significantly with long-term use of moclobemide in depressed males.[2]

Moclobemide also has neuroprotective properties in it's demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to deprenyl, however, research is required to determine this.[2] Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.[83]

Platelet MAO levels are not significantly affected by moclobemide, possibly because it is a reversible MAOI.[84] Moclobemide has been reported to be a mixed MAO-A/MAO-B inhibitor in rats but in man, it has been reported to be a pure MAO-A inhibitor,[85] 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).

As MAO inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide.[2]

Pharmacokinetics

In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver.[86] 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 around 2 hours.[2][87] It is moderately bound to plasma proteins, especially albumin.[2] However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution.[86] 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; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2.[88] Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours.[89] The main metabolites are the N-oxide Ro 12-5637 formed via morpholine N-oxidation and lactam derivative Ro 12-8095 formed via morpholine C-oxidation;[90][91] 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.[92] About 44 percent of the drug is lost due to the first pass effect through the liver.[93] Age and renal status do not affect the pharmacokinetics of moclobemide; however impaired hepatic function slows down the elimination of moclobemide.[41] Food slows the absorption but does not affect the bioavailability of moclobemide.[2]

Steady state concentrations are established after one week.[86] It has been suggested that changes in dose should not be made with a gap of no less than a week.[94] Moclobemide has good pentration across the blood brain barrier with peak plasma levels within the central nervous system occuring 2 hours after administration.[95] Aging and renal function have little effect on the elimination of moclobemide.[96]

Age and renal function does not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide.[86]

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.

History

Irreversible MAOI antidepressants were discovered accidentally in the 1950's but their popularity declined as their toxicity especially their dangerous food interactions became apparent and rival the tricyclic antidepressants were discovered. Reversible MAOI's were developed in the hope that they would exert efficacy in depressive disorders but with less of the toxicity of the older irreversible compounds; moclobemide's discovery and marketing brought the renewed interest in MAOI's due to an absence of dangerous tyramine food interactions and potent antidepressant effects.[97][5] In 1992 moclobemide was launched onto the world markets.[98] Moclobemide was the first reversible MAO-A inhibitor to be widely marketed;[99] Moclobemide as well as other newer antidepressants such as the SSRIs lead to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.[100]

The discovery of moclobemide as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or antilipaemic properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally it's reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression.[101] Subsequent research found that moclobemide is well tolerated in elderly patients[48] and far superior to tricyclic antidepressants in terms of side effects/tolerability as well as being much safer in overdose; with regard to effectiveness in the treatment of depression, moclobemide was determined to be as effective as all major antidepressant drug classes. There is no need for dietary restrictions in contrast to people on irreversible MAOI's and apart from an important interaction with other serotonergic enhancing agents such as SSRI's and pethidine, there are few serious drug interactions; because of these benefits of moclobemide over existing antidepressant drugs, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'.[102][40] Moclobemide has been marketed in about 50 countries.[5] It is the only reversible MAOI in use in clinical practice.[2] The fact that moclobemide's pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of major depressive disorder.[2]

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Further reading

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