19.01.6 Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors (MAOIs) fall into two categories, the irreversible non-selective MAOIs (phenelzine) which bind covalently to both MAO-A and MAO-B, and the reversible inhibitor of MAO-A (moclobemide) which binds selectively to MAO-A. In depressed individuals their efficacy is similar to TCAs, although MAOIs are possibly more effective for atypical depression. These drugs inhibit the activity of monoamine oxidase enzymes (which function to maintain low cytoplasmic monoamine concentrations), preventing breakdown of the monoamines. This increase in the cytoplasmic pool of monoamines, without affecting vesicular stores, increases spontaneous leakage of monoamines into the synapse and extracellular space. Consequently, noradrenaline and serotonin (and dopamine) availability is enhanced to act on pre- and post-synaptic receptors. After many weeks of administration, MAOIs downregulate -adrenoceptors and 5-HT₂ receptors, similar to TCAs. They also consistently downregulate α₁-adrenoceptors and postsynaptic 5-HT₁ receptors. Like TCA’s, MAOIs downregulate presynaptic ₂-adrenoceptors and 5-HT₁ autoreceptors, which control noradrenaline and serotonin release, thus monoamine release is facilitated.

MAOIs cause fewer side/adverse effects than TCAs. They still have a propensity to cause nausea, insomnia, hypotension, dizziness, and disturbances of libido and potency, however they cause fewer anticholinergic side effects (dry mouth, blurred vision, urinary retention etc.). Nonetheless the usefulness of irreversible MAOIs has been limited by their interaction with sympathomimetic agents such as tyramine in foods. This can create a hypertensive crisis, the so-called “cheese-reaction”, which may be fatal and requires strict adherence to dietary guidelines. The RIMA, moclobemide, is much safer than the irreversible MAOIs due to its selectivity for MAO-A.