What is the pathophysiology of Monoamine Oxidase Inhibitors (MAOIs) in adult patients with treatment-resistant depression?

Pathophysiology of Monoamine Oxidase Inhibitors (MAOIs)

MAOIs work by irreversibly or reversibly inhibiting the monoamine oxidase enzyme system, which prevents the oxidative deamination of monoamine neurotransmitters including serotonin, norepinephrine, and dopamine, thereby increasing their synaptic availability in the central nervous system. 1

Mechanism of Action

Enzyme Inhibition

• MAOIs block the monoamine oxidase enzyme complex, which is widely distributed throughout the body and normally degrades neurotransmitters 1
• The enzyme exists in two forms: MAO-A (which primarily metabolizes serotonin and norepinephrine) and MAO-B (which primarily metabolizes dopamine) 2
• Irreversible MAOIs (phenelzine, tranylcypromine, isocarboxazid) permanently inactivate the enzyme, requiring new enzyme synthesis for restoration of function 3
• Reversible MAOIs (moclobemide) and selective MAO-B inhibitors (selegiline) allow for competitive displacement and have different safety profiles 4, 3

Neurotransmitter Effects

• By preventing monoamine breakdown, MAOIs increase concentrations of serotonin, norepinephrine, and dopamine in neuronal synapses 2
• Phenelzine is extensively metabolized primarily by oxidation via monoamine oxidase itself, with 73% recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours 1
• The mean elimination half-life of phenelzine after a single 30 mg dose is 11.6 hours 1

Critical Pathophysiologic Consequences

Tyramine Interaction (Hypertensive Crisis)

• Under normal conditions, MAO-A in the gut and liver degrades dietary tyramine; when MAO-A is inhibited, as little as 8-10 mg of ingested tyramine can cause life-threatening blood pressure elevations 5
• Tyramine is a potent releaser of norepinephrine, and without MAO-A degradation, excessive norepinephrine accumulates and overstimulates postsynaptic adrenergic receptors 5
• Patients must avoid high-tyramine foods including aged cheeses, pickled herring, beer, wine, liver, yeast extract, dry sausage, fava beans, and excessive caffeine or chocolate 1

Serotonin Syndrome Risk

• MAOIs inhibit the destruction of serotonin, and when combined with other serotonergic agents (SSRIs, SNRIs, dextromethorphan, meperidine, tramadol), can cause potentially fatal serotonin syndrome 6, 1
• Serotonin syndrome manifests within 24-48 hours with mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia, rigidity), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 6
• Advanced symptoms include fever, seizures, arrhythmias, and unconsciousness that can lead to death 6
• At least 14 days must elapse between discontinuing an MAOI and starting a serotonergic agent (except fluoxetine, which requires 5 weeks due to its long half-life) 1

Sympathomimetic Drug Interactions

• MAOIs prevent the breakdown of catecholamines released by sympathomimetic drugs (phenylephrine, oxymetazoline, amphetamines), causing dangerous blood pressure elevations 5
• Patients must avoid both prescription sympathomimetics and over-the-counter decongestants 5

Clinical Implications

Therapeutic Window

• The clinical effects of MAOIs may result from MAO inhibition itself, other pharmacologic actions, or an interaction of both—the exact mechanism remains incompletely understood 1
• MAOIs are particularly effective for treatment-resistant depression, atypical depression with hypersomnia and hyperphagia, and anergic bipolar depression 4, 3

Safety Monitoring Requirements

• Patients require close monitoring for postural hypotension, which can occur in hypertensive, normotensive, and hypotensive patients 1
• Hypomania is the most consistently reported severe side effect, typically occurring in patients with coexisting hyperkinetic symptoms masked by depression 1
• MAOIs may cause excessive stimulation in schizophrenic patients and can precipitate manic switches in bipolar disorder 1
• Increased insulin sensitivity may occur in diabetic patients, requiring reduction of insulin or oral hypoglycemic doses 1

Contraindicated Combinations

• Absolute contraindications include concurrent use with other MAOIs, SSRIs, SNRIs, meperidine, dextromethorphan, buspirone, bupropion, sympathomimetic vasoconstrictors, and general anesthesia 1
• Patients must discontinue MAOIs at least 10 days before elective surgery requiring general anesthesia 1
• The combination of MAOIs with tryptophan causes behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, myoclonus, and hyperreflexia 1