Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants whose mechanism of action is based on the inhibition of the enzyme monoamine oxidase, responsible for the degradation of key monoaminergic neurotransmitters: norepinephrine (NE), dopamine (DA), and serotonin (5-HT). Inhibiting this enzymatic activity increases the synaptic availability of these amines, enhancing their central effects.

MAOs are mitochondrial enzymes expressed in the central nervous system as well as in various peripheral tissues, including the liver and gastrointestinal tract. Two isoforms exist: MAO-A and MAO-B. MAO-A primarily degrades serotonin and norepinephrine, while MAO-B predominantly acts on dopamine, although functional overlap exists.

In clinical practice, MAOIs are classified based on three criteria:

• Type of enzyme binding: irreversible or reversible;
• Selectivity: non-selective inhibitors (MAO-A + MAO-B) or selective for one isoenzyme;
• Chemical structure: hydrazine derivatives (e.g., phenelzine) or non-hydrazine compounds (e.g., tranylcypromine).

Historically, MAOIs have been considered second-line antidepressants due to the risk of serious dietary and drug interactions. However, interest in their use has resurged with the introduction of safer, reversible, and selective formulations, commonly referred to as second-generation MAOIs.

First-generation MAOIs: irreversible and non-selective

First-generation MAOIs include agents such as phenelzine, tranylcypromine, and isocarboxazid. These compounds bind irreversibly and non-selectively to both MAO-A and MAO-B isoforms, resulting in prolonged enzyme inhibition that resolves only through endogenous synthesis of new enzyme (which may take up to 2 weeks).

Although effective in cases of severe or treatment-resistant depression, these drugs present several safety limitations:

• Food interactions with tyramine-rich items (e.g., aged cheeses, cured meats, red wine), potentially leading to hypertensive crises;
• Drug interactions with various agents (serotonin reuptake inhibitors, sympathomimetics, anesthetics), potentially life-threatening;
• Adverse effects such as orthostatic hypotension, insomnia, increased appetite, weight gain, sexual dysfunction, hepatotoxicity, and psychomotor agitation;
• Risk of serotonin syndrome when combined with SSRIs, SNRIs, TCAs, or triptans.

For these reasons, the use of first-generation MAOIs is now limited to selected cases, typically in specialized settings and under close monitoring. In specific clinical subtypes, such as atypical depression or treatment-resistant bipolar depression, they may still represent a valid therapeutic option.

Second-generation MAOIs: selective and reversible (RIMAs)

Second-generation MAOIs, also known as RIMAs (Reversible Inhibitors of Monoamine Oxidase A), bind reversibly and selectively to MAO-A. In Italy, moclobemide and toloxatone are currently available.

These agents offer several advantages over traditional MAOIs:

• Reduced risk of food interactions, as inhibition is competitive and non-persistent;
• Better tolerability, with fewer anticholinergic, sedative, and cardiovascular side effects;
• Absence of hepatic toxicity documented for both moclobemide and toloxatone;
• Comparable antidepressant efficacy to imipramine, with faster onset reported in some studies.

Their use is indicated in mild to moderate unipolar depression, anxious depression, and late-life depression, where increased selectivity and reversibility translate into greater safety.

The recommended dosage of moclobemide is generally between 300 and 600 mg/day, divided into 2–3 doses. Peak plasma concentration occurs within 30–60 minutes, and its half-life is short (1–3 hours), requiring frequent administration.

Selegiline and MAO-B: an emerging option in depression

Selegiline is a selective and irreversible MAO-B inhibitor, traditionally used in the treatment of Parkinson's disease due to its dopaminergic action. At low doses, it acts mainly on MAO-B, but at higher doses, it loses selectivity and inhibits MAO-A as well, thus exerting an antidepressant effect.

A transdermal formulation of selegiline, available in certain countries, bypasses the gastrointestinal tract and hepatic first-pass metabolism, significantly reducing the risk of tyramine interactions and enhancing safety. This formulation has proven effective in treatment-resistant depression with a favorable tolerability profile.

The observation that MAO-B activity increases with age has stimulated interest in the use of selegiline in late-life depression, particularly in cases involving cognitive symptoms or comorbid parkinsonian features.

Safe use of MAOIs: clinical strategies

Treatment with MAOIs—especially the irreversible types—requires specific precautions to prevent serious adverse events. Patients must receive detailed education regarding dietary and pharmacological interactions, avoiding tyramine-rich foods and serotonergic medications.

When switching from an SSRI/SNRI to an MAOI, a washout period of at least 2 weeks is required (up to 5 weeks for fluoxetine), to prevent serotonin syndrome. Likewise, transitioning from an MAOI to another antidepressant requires complete discontinuation and an appropriate interval.

During treatment, monitoring should include:

• Blood pressure (due to risk of hypertensive crises);
• Mental status and behavior (due to risk of manic activation or agitation);
• Liver function in patients on first-generation MAOIs;
• Drug interactions in polypharmacy contexts with newly introduced medications.

Final considerations

Although less commonly used today compared to other antidepressant classes, MAOIs retain a well-defined clinical role in the treatment of treatment-resistant major depression, atypical depression, and specific subgroups such as the elderly. Second-generation formulations (RIMAs) and transdermal selegiline offer safer and more manageable options, drastically reducing the historical risks associated with MAOIs.

In experienced hands, and with careful patient selection, MAOIs can represent a valuable therapeutic resource, especially when conventional strategies have failed. Their use, however, requires rigorous clinical monitoring and full patient cooperation.

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