Monoamine Oxidase Inhibitors (MAOIs)

Mechanism of Action

Monoamine oxidase (MAO) is an enzyme found in nearly all tissues that breaks down several key neurotransmitters, including serotonin, dopamine, and noradrenaline.

MAOIs inhibit this enzyme, leading to increased concentrations of these neurotransmitters within synaptic clefts, thereby improving mood and reducing symptoms of depression. This effect is greatest on serotonin and weakest with dopamine.

Recovery of MAO activity after use of MAOI takes many weeks, however is quicker with tranylcypromine.

There are two types of monoamine oxidase; A and B.

• Serotonin and noradrenaline are metabolised by MAO-A
• Dopamine and tyramine are metabolised by MAO-A and -B.

MAOIs are now used infrequently because of their potentially dangerous food and drug interactions

Cautions

MAOIs should be used cautiously in patients with epilepsy, as they may lower the seizure threshold. In individuals with diabetes, MAOIs can affect glycaemic control and may potentiate hypoglycaemia, necessitating closer blood glucose monitoring.

Postural (orthostatic) hypotension is a common adverse effect, particularly in older adults, increasing the risk of dizziness and falls. Patients should be counselled about rising slowly from sitting or lying positions.

As with other antidepressants, MAOIs have a delayed onset of action, and therapeutic benefit may not be apparent for several weeks. Patients should also be warned about the risk of withdrawal symptoms if treatment is stopped abruptly; gradual dose reduction is recommended.

There is a significant risk of serotonin syndrome, particularly when MAOIs are combined with other serotonergic medications. Strict adherence to washout periods when switching antidepressants is essential to reduce this potentially life-threatening complication.

Contraindications

MAOIs are contraindicated in patients with phaeochromocytoma, as inhibition of monoamine breakdown may precipitate hypertensive crises due to excess catecholamines.

They are also contraindicated in individuals with cerebrovascular disease or congestive heart failure, given the risk of significant blood pressure instability and hypertensive episodes.

Recent or concurrent use of other interacting medications is a major contraindication. MAOIs must not be used in patients who have recently taken tricyclic antidepressants (TCAs), carbamazepine, buspirone, SSRIs, SNRIs, or other MAOIs, due to the high risk of severe interactions including serotonin syndrome or hypertensive crisis. Appropriate washout periods must always be observed before initiating treatment.

Adverse Effects

Postural hypotension can occur, potentially due to dopamine accumulation within nerve terminals, which displaces noradrenaline and reduces sympathetic noradrenaline release. Conversely hypertensive crises’ can occur, especially when MAOIs are taken alongside tyramine-rich foods, which is explained below in the interactions section.

Gastrointestinal adverse effects include nausea, constipation and dry mouth. Furthermore neurological effects include dizziness, insomnia, headache, increased appetite and blurred vision.

Interactions

Severe interactions found with other antidepressants and tyramine rich foods has led to a decline in use of MAOIs. Interactions may be less severe with moclobemide, which is a reversible MAOI-A inhibitor, likely as there is still MAO-B activity.

1. Interaction with other antidepressants

• Do not start another antidepressant within 2 weeks of stopping an MAOI (or 3 weeks if starting clomipramine or imipramine
• This prevents serotonin syndrome, a potentially life-threatening condition caused by excess serotonergic activity
• If switching to an MAOI, an appropriate washout period must be observed based on the previous antidepressant’s half-life.

2. Interaction with tyramine rich foods; the cheese reaction

• MAO normally breaks down tyramine, a compound found in many aged or fermented foods.
• MAO inhibition allows tyramine to accumulate, causing displacement of noradrenaline, adrenaline, and dopamine from pre-synaptic storage vesicles and consequently release of these neurotransmitters results in severe hypertension, which may present as a headache and can lead to intracranial haemorrhage

Tyramine Rich Foods:

Patients should eat only fresh foods and avoid the following:

• Stale or aged protein foods
• Fermented, pickled, or smoked foods
• Mature or cooked cheeses
• Yeast extracts (Oxo, Bovril, Marmite)
• Liver, yoghurt, broad beans
• Chocolate
• Alcoholic and non-alcoholic beers, lagers, and wines
• Excessive tea and coffee

References

1. Onset of action of antidepressants | The BMJ
2. Antidepressant drugs | Treatment summaries | BNF | NICE
3. Nardil 15 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc)
4. Sub Laban T, Saadabadi A. Monoamine Oxidase Inhibitors (MAOI) [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539848/