I. Introduction
Monoamine oxidase inhibitors (MAOIs) are a class of psychotropic drugs that inhibit the activity of monoamine oxidase enzymes (MAO-A and MAO-B) responsible for the metabolic breakdown of monoamines such as serotonin, norepinephrine, dopamine, and tyramine. Originally developed in the 1950s, MAOIs were among the first antidepressants introduced into clinical use. While their popularity waned with the advent of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), MAOIs remain valuable for treatment-resistant depression, atypical depression, and certain neurodegenerative disorders.
II. Monoamine Oxidase Enzymes
There are two isoforms of the MAO enzyme located in the outer mitochondrial membrane in neurons and peripheral tissues:
A. MAO-A
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Substrates: Serotonin, norepinephrine, dopamine, tyramine
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Distribution: Primarily in the gut, liver, and brain
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Inhibition leads to increased serotonergic and noradrenergic activity
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Associated with antidepressant effects
B. MAO-B
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Substrates: Dopamine, phenylethylamine
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Distribution: Mainly in the brain (especially striatum) and platelets
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Inhibition leads to increased dopaminergic activity
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Associated with neuroprotective effects in Parkinson’s disease
III. Classification of MAOIs
A. Based on Selectivity
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Non-selective (inhibit both MAO-A and MAO-B)
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Phenelzine
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Tranylcypromine
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Isocarboxazid
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Selective MAO-B Inhibitors
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Selegiline
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Rasagiline
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Safinamide
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B. Based on Reversibility
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Irreversible MAOIs (bind covalently to MAO)
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Phenelzine
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Tranylcypromine
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Selegiline
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Rasagiline
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Reversible MAOIs (RIMAs)
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Moclobemide (selective MAO-A inhibitor)
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IV. Mechanism of Action
MAOIs exert their therapeutic effects by inhibiting monoamine oxidase, preventing the breakdown of key neurotransmitters. The resulting increase in synaptic monoamine levels leads to improved mood, energy, motivation, and cognitive function.
Antidepressant Action:
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Increased serotonin, norepinephrine, and dopamine levels
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Enhanced monoaminergic transmission in limbic system, prefrontal cortex, and basal ganglia
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Alleviation of depressive symptoms, particularly in patients with atypical features or anxiety
Parkinson’s Disease Management (MAO-B Inhibitors):
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Increased dopamine levels in the striatum
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Slows progression of motor symptoms
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May offer neuroprotective effects
V. Approved MAOI Drugs and Clinical Uses
| Generic Name | Selectivity | Reversibility | Primary Indications |
|---|---|---|---|
| Phenelzine | Non-selective | Irreversible | Major Depressive Disorder (MDD), atypical depression |
| Tranylcypromine | Non-selective | Irreversible | MDD, treatment-resistant depression |
| Isocarboxazid | Non-selective | Irreversible | Depression |
| Moclobemide | Selective MAO-A | Reversible | Depression, social phobia (Europe, not FDA-approved in US) |
| Selegiline | Selective MAO-B | Irreversible | Parkinson’s disease, depression (transdermal only) |
| Rasagiline | Selective MAO-B | Irreversible | Parkinson’s disease |
| Safinamide | Selective MAO-B | Reversible | Parkinson’s disease |
VI. Formulations and Routes of Administration
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Oral tablets: All traditional MAOIs (phenelzine, tranylcypromine, etc.)
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Transdermal patch: Selegiline (Emsam®) — bypasses gut and first-pass metabolism, reduces dietary restrictions at low doses
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Extended-release: Some MAO-B inhibitors for Parkinson’s disease
VII. Pharmacokinetics
| Parameter | Typical MAOIs |
|---|---|
| Onset of action | 2–3 weeks |
| Half-life | Phenelzine: ~11.6 hrs; Tranylcypromine: ~2 hrs |
| Metabolism | Hepatic, via acetylation (phenelzine) or CYP enzymes |
| Elimination | Primarily renal and hepatic routes |
| Duration of MAO inhibition | Days to weeks (due to irreversible binding) |
VIII. Clinical Uses
A. Psychiatric Disorders
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Major Depressive Disorder, especially treatment-resistant
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Atypical Depression: Hypersomnia, hyperphagia, mood reactivity
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Panic disorder
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Social anxiety disorder
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Bulimia nervosa (off-label)
B. Neurological Disorders
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Parkinson’s Disease: Selegiline, rasagiline, safinamide
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May be used as monotherapy in early stages or as adjunct to levodopa
IX. Adverse Effects
| System | Common Adverse Effects |
|---|---|
| CNS | Insomnia, agitation, dizziness, headaches |
| Cardiovascular | Orthostatic hypotension, palpitations |
| GI | Nausea, dry mouth, constipation |
| Sexual dysfunction | Decreased libido, anorgasmia |
| Weight | Weight gain (especially with phenelzine) |
| Hypertensive crisis | Due to dietary tyramine intake (“cheese effect”) |
X. Dietary Restrictions and Tyramine Reaction
The "Cheese Effect"
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MAO-A in the gut degrades tyramine (found in aged cheese, cured meats, fermented foods)
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MAOI-induced MAO-A inhibition → tyramine accumulates → excess norepinephrine release → hypertensive crisis
Symptoms of Hypertensive Crisis:
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Sudden severe headache
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Palpitations, chest pain
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Sweating
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Nausea, vomiting
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Elevated blood pressure
Tyramine-Rich Foods to Avoid:
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Aged cheeses (e.g., cheddar, gouda)
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Cured meats (e.g., salami, pepperoni)
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Fermented products (e.g., sauerkraut, soy sauce)
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Draft beer, red wine
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Fava beans, miso
Selegiline patch at low doses may not require dietary restriction, but oral MAOIs do.
XI. Drug Interactions
MAOIs are associated with numerous dangerous and potentially fatal interactions:
| Class | Interaction |
|---|---|
| SSRIs, SNRIs, TCAs | Risk of serotonin syndrome |
| Meperidine, Tramadol, Dextromethorphan | Serotonin syndrome and seizures |
| Sympathomimetics (pseudoephedrine, phenylephrine) | Hypertensive crisis |
| Levodopa | Use cautiously; can cause severe hypertensive episodes |
| Buspirone | Risk of hypertensive crisis |
| Linezolid, methylene blue | Serotonergic toxicity; avoid use with MAOIs |
| Alcohol | CNS depression, exacerbates orthostatic hypotension |
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Mental status changes: agitation, confusion
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Autonomic instability: hyperthermia, tachycardia
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Neuromuscular abnormalities: tremor, clonus, hyperreflexia
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Can be life-threatening
XII. Contraindications
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Concurrent use of SSRIs, SNRIs, TCAs, or meperidine
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Recent use of other antidepressants (require 2–5 week washout)
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Pheochromocytoma
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Hepatic or renal dysfunction
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Cardiovascular disease (caution due to orthostatic hypotension)
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Tyramine-rich diet (for non-selective MAOIs)
XIII. Advantages and Limitations
| Advantages | Limitations |
|---|---|
| Effective in atypical or treatment-resistant depression | High burden of dietary and drug restrictions |
| Long history of use | Requires careful monitoring for hypertensive crisis |
| MAO-B inhibitors aid in Parkinson’s treatment | Not first-line due to safety concerns |
| Transdermal delivery improves tolerability | Still risk of serotonin syndrome with interactions |
XIV. Role in Modern Therapy
Although rarely first-line, MAOIs are critical for:
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Patients with refractory depression
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Those who do not respond to SSRIs, SNRIs, or atypical antipsychotics
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Parkinson’s disease management (particularly MAO-B inhibitors)
Newer formulations (e.g., selegiline patch) and reversible selective inhibitors (e.g., moclobemide) aim to minimize dietary and drug interactions while maintaining efficacy.
XV. Monitoring and Clinical Guidelines
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Blood pressure monitoring, especially when initiating therapy
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Tyramine education: Patients must be counseled clearly on dietary restrictions
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Medication review: Screen for interacting drugs
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Serotonin syndrome awareness: Particularly during initiation, switching, or combination therapy
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