Pharmacodynamics
Moclobemide is a benzamide,[35] derivative of morpholine,[96] which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase-A (RIMA),[97] a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin[98][99] 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 beta-3 adrenergic receptors. Moclobemide's primary action is to disable MAO-A enzymes from decomposing norepinephrine, serotonin, and dopamine which results in a rising level of these neurotransmitters. Although it has been estimated that a single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase-A (MAO-A) and 20-30% of MAO-B,[100] studies evaluating brain occupancy of MAO-A enzymes have shown dosages of 600 mg to only inhibit 74% of MAO-A enzymes[101] and dosages in the 900–1200 mg range to inhibit slightly less MAO-A than phenelzine (Nardil) at 45–60 mg;[102] subsequently, it is highly plausible that reports of lower efficacy[103] could be largely or entirely the consequence of conservative dosage guidelines rather than the pharmacological properties of the drug. Previously, it was widely reported that both MAO-A and MAO-B enzymes were responsible for the metabolism of dopamine; however, new research suggests that MAO-B enzymes are involved in the generation of GABA and not the degradation of dopamine.[104] There is also some evidence of moclobemide possessing neuroprotective properties in rodent models.[98] There is no cumulative effect of moclobemide centrally when taken long-term.[98] With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors.[98] 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.[98] L-dihydroxyphenylalanine is also reduced.[105] Inhibition of the serotonin metabolite is less pronounced than the norepinephrine metabolite which suggests there are other major metabolic pathways for serotonin other than MAO-A.[106]
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.[98] With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.[107] The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing.[98][99] The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOI phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.[98]
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 cognitive impairments can be improved by moclobemide.[108] 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.[109] Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).[110]
Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine.[111] 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.[98]
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.[98] There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels.[98] Testosterone levels increase significantly with long-term use of moclobemide in depressed males.[112]
Moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to selegiline, however, research is required to determine this.[98] Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.[113]
Platelet MAO is of the MAO-B and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have MAO-B inhibiting properties.[114] 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,[115] 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).
MAO activity returns completely back to normal after 24 hours of the last dose, which allows for a quick switch to another antidepressant after the 24 hours.[98]
