Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants which have largely fallen out of favor for the treatment of depression. However, their use is on the rise in the treatment of neurodegenerative diseases and they are still used in cases of refractory depression.
MAOI toxicity can occur in the following three ways:
All three mechanisms produce similar symptoms and signs, which stem from an excess of catecholaminergic neurotransmitters (see Pathophysiology). Clinical features include hypertension, tachycardia, tremors, seizures, and hyperthermia. (See Presentation.)
Because of the potential for severe toxicity and lack of effective antidotes, recognition of the disease, withdrawal of offending agents and aggressive decontamination is very important in patients with MAOI toxicity. Control of hyperthermia and fluid therapy are paramount. (See Treatment.)
Monoamine neurotransmitters (eg, epinephrine, norepinephrine, dopamine, serotonin) are stored in vesicles at the pre-synaptic nerve terminals and released through the plasma membrane into the synaptic cleft. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve and metabolized by intracellular monoamine oxidase (MAO) or destroyed by catechol-o-methyl transferase (COMT) in the synaptic cleft.
MAO has two isoforms: MAO-A and MAO-B. MAO-A is found primarily in the liver, gastrointestinal (GI) tract, and monoaminergic neurons. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are largely metabolized by MAO-A in the liver. Ingested monoamines, such as tyramine, are metabolized by MAO-A in the GI tract and liver.[1] This shields the body from foods with high levels of tyramine, which have to potential to cause adrenergic hyperstimulation. This protective property of MAO-A is critical to the understanding of the most common cause of MAOI toxicity, drug-food interaction. The other isoform, MAO-B, is found primarily in the basal ganglia of the central nervous system and platelets.[2]
One of the prevailing theories of depression is that its clinical features are related to decreased concentration of these neurotransmitters at the synapse.[3] To address this, pharmaceuticals have been developed that either block the reuptake of neurotransmitters (eg, cyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs]) or interfere with the breakdown of the reabsorbed monoamines within the nerve terminal (monoamine oxidase inhibitors [MAOIs]).[4]
First-generation MAOIs, such as phenelzine, isocarboxazid and tranylcypromine, are nonselective inhibitors. Second- and third-generation MAOIs tend to be specific inhibitors of either MAO-A or MAO-B. Specific MAO-A inhibitors are not commonly used, but have been studied in the treatment of depression. Specific MAO-B inhibitors have been studied in the treatment of both depression and neurodegenerative disorders. They are thought to have a better safety profile, as MAO-A activity in the gut is not inhibited. However, the selectivity of even the new MAOIs is dose related.[1]
Monoamine oxidase is responsible for the deactivation of monoamines such as epinephrine, norepinephrine, dopamine, serotonin and tyramine. When the inhibitory effects of MAOIs are amplified by overdose, drug-drug interactions, or drug-food interactions, the resulting increase of active monoamines are directly responsible for the manifestations of MAOI toxicity.
In a pure MAOI overdose, the ability of the neuron to degrade monoamines is severely diminished. As a result, the storage and release of monoamines is greatly increased. This effect can be potentiated or even enhanced by an additional property of MAOIs: even at therapeutic doses, MAOIs indirectly cause a release of norepinephrine into the synaptic space. Depending on the dose of the exposure, a hyperadrenergic crisis may ensue; 5 mg/kg of a non-selective MAOI can be life-threatening.[1] This occurs uncommonly. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion but generally occur within 24 hours. These patients require prolonged close monitoring to prevent significant morbidity.
MAOI toxicity can be seen when an MAOI is combined with any drug that increases the synthesis, release, or effect of monoamines or decreases the metabolism or reuptake of monoamines. For a detailed list, see Causes.
The combination of an MAOI with a drug that increases serotonin levels can result in serotonin toxicity. This disease entity is similar to an adrenergic crisis from MAOI toxicity, but also features hyperreflexia and autonomic instability when severe. This constellation of symptoms is called serotonin syndrome.
Delayed presentations of MAOI toxicity are common, ranging from several hours to 24 hours for maximal toxicity, but symptoms can also be seen within minutes. Though MAOIs interact unfavorably with many medications, fatalities are rare with supportive care.[1]
The most common MAOI toxicity results from interaction with tyramine-containing foods. When MAO found in the gut and liver (type A) is inhibited, ingested tyramine indirectly causes an amplification of adrenergic activity. It is usually rapid in onset, occurring within 15-90 minutes after ingestion. Most symptoms resolve in 6 hours. Fatalities are rare, but have been reported due to complications from hypertensive emergencies. See Causes for a detailed list of tyramine-containing foods.
MAOIs are absorbed well orally and peak plasma concentrations are reached within 2-3 hours. These drugs have a relatively large volume of distribution (1-5 L/kg) and are highly protein bound. They are metabolized by oxidation and acetylation in the liver and are excreted in the urine.
The two isoforms of MAO have different affinities for specific neurotransmitters. MAO-A is the primary metabolizer of norepinephrine. Dopamine and tyramine can be metabolized equally by MAO-A and MAO-B.[2]
MAOIs bind irreversibly at their sites of action (moclobemide is an exception). By this binding, they are eliminated from circulation and, since they do not recirculate afterwards, their effects are not determined by their concentration in the blood. As it takes 2-3 weeks for enough new MAO to be synthesized, MAOIs have clinical effects for that amount of time after the last dose has been ingested. Third-generation MAOIs (not available in the United States) are reversible inhibitors and exist in a competitive equilibrium.[5]
MAOIs absorbed through the gastrointestinal tract bind significantly to MAO in the gut mucosa and liver, producing a significant first pass effect. Thus, to produce their clinically desired effect in the central nervous system (CNS), MAOIs must be given in high enough doses to reach centrally-located MAO. A transdermal preparation of a selective MAO-B inhibitor, selegiline, appears to produce antidepressant effects with a significantly reduced risk for dietary-induced toxicity by bypassing the first pass effect of gut and hepatic MAOI effects.[6, 7] At the lowest effective dosage of 6 mg/day, selegiline can be used without dietary modification.[8]
United States
Reported exposures to MAOIs have decreased by more than 60% over the past 25 years. By year, the American Association of Poison Control Centers has reported the following number of cases involving MAOIs:
Depending on the year, 40%-50% of these cases were single exposures to MAOIs, with the remainder of the cases involving co-exposures. Death due to MAOI exposure is rare, with about one case reported per year over the past 10 years (including cases with both single and multiple exposures).
In 2015, there were 90 single exposures to MAOIs reported. Adults accounted for 71 cases, and 62 were known to be unintentional. Two cases (both involving tranylcypromine) had major outcomes. No deaths occurred due to single exposure to MAOIs in 2015. However, tranylcypromine was indicated as the primary cause of death in one case with multiple exposures.[16]
The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAO has been found to play a central role in the pathogenesis of Alzheimer disease, and MAOIs are currently being studied as potential neuroprotective agents.[17] If they prove effective for that purpose, their use—and episodes of toxicity—may well increase.
Severe toxicity is manifested by hyperthermia, seizures, respiratory depression, and CNS depression. Hypotension, cardiovascular collapse, and death may ensue but this is rare with supportive care. (See Epidemiology)
All patients who are starting treatment with a monoamine oxidase inhibitor (MAOI) should receive extensive education regarding the potential for interactions with tyramine-containing foods and with other drugs. Patients should be encouraged to have all of their prescription and nonprescription drugs dispensed from one pharmacy so that an accurate medication profile can be maintained.
The patient history is of vital importance to the diagnosis of monoamine oxidase inhibitor (MAOI) toxicity. Because many of the signs and symptoms are nonspecific, a careful history of all prescription medications, ove-the-counter drugs, supplements, and dietary items must be obtained. Additionally, because the effects of many MAOIs (including all of the ones available in the United States) are irreversible and restoration of MAO activity takes 2-3 weeks,[1] , a history of past medications should be obtained as well.
The most common MAOIs that a provider should be familiar with are phenelzine, tranylcypromine, isocarboxazid, and selegiline. Reversible inhibitors of MAO are available in Europe (eg, brofaromine, cimoxatone, clorgyline, lazabemide, moclobemide). Other common agents that have MAOI-like activity and have been reported to cause serotonin syndrome include St. John's wort, methylene blue, and linezolid.[18, 19, 20, 21, 22] . For a more complete list, see Causes.
In many cases, a significant latent period occurs between exposure and the maximal of clinical effects. Early mild symptoms include irritability, anxiety, flushing, sweating, and headache. As the episode continues, a patient may complain of fever, agitation, diplopia, and restlessness. If the toxicity progresses further, severe symptoms include seizures, confusion, hallucinations, altered mental status, and coma.
As with any ingestion, the possibility of self-harm exists and a detailed psychiatric history should be taken as well.
Patients with MAOI overdoses or interactions present with excessive catecholamine stimulation toxidromes. Late in the course, the patient may become hypotensive and comatose. Clinical manifestations can be classified into mild, moderate, and severe.
A peculiar nystagmus has been reported in cases of overdose. Rapid jerking movement of the eyes as if watching a tennis or ping pong match—termed "ping pong gaze"[23, 24] or opsoclonus—has been reported in severe MAOI intoxication.
Mild signs include agitation, diaphoresis, tachycardia, and mild temperature elevation. Signs of moderate toxicity include altered mental status, tachypnea, vomiting, dysrhythmias, hyperthermia, and hypertension, which can be critically severe and precipitate rhabdomyolysis, myocardial infarction, intracranial hemorrhage, renal failure, and other hypertensive emergency complications. Severe signs include the following:
Monoamine oxidase inhibitors (MAOIs) can interact with foods that contain tyramine and with a variety of drugs. Any drug that is serotoninergic or releases catecholamines may precipitate life-threatening events in individuals who are taking MAOIs or have taken MAOIs in the preceding weeks.[1]
Tyramine-containing foods associated with MAOI interactions include the following:
Meperidine is probably the most infamous of medications known to produce significant toxicity when administered to an individual taking an MAOI. Meperidine produces a release of serotonin, which can precipitate a potentially fatal outcome.
In 1984, an MAOI-meperidine interaction changed physician training in the United States. Libby Zion was a young woman admitted to a major hospital with fever, agitation, and jerking motions. There is a great deal of controversy about the historical information, but it is clear that she had been receiving an MAOI. Either this was not known or the interaction risk was not appreciated by the young resident physician who ordered meperidine for the patient's shaking, which resulted in severe hyperpyrexia and her eventual death. This case led to the modern emphasis on shorter work hours for resident physicians and greater supervision by senior physicians.[25]
Other drugs that may interact with MAOIs include the following:
See the list below:
Prehospital care for MAOI toxicity may include the following:
Because of the potential for severe toxicity and lack of antidotes, aggressive decontamination is important, as follows:
Frequent measurements of temperature is recommended. If the patient is hyperthermic, decreasing the temperature rapidly (within 20-30 min) is imperative. Considerations include the following:
Fluid therapy is of paramount importance. Patients may be significantly dehydrated from hyperthermia.
Treating the associated hypertension is usually not necessary and may actually be dangerous, because it may exacerbate the eventual hypotensive phase. If antihypertensive therapy is deemed necessary, use of a short-acting antihypertensive agent, such as nitroprusside, nitroglycerine, or phentolamine, is advisable. Avoid beta-blockers because they leave unopposed alpha stimulation.
Intravenous benzodiazepines are useful for agitation and seizure control. They also may help control the hypertension.
Hospital admission is recommended in a patient with a tyramine reaction if symptoms do not resolve within 6 hours of onset or if it was an intentional MAOI overdose.
Consult the regional poison control center or a local medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) to obtain additional information and patient care recommendations. Critical care management may be required for cardiovascular complications.
Pharmaceutical agents should be used after the patient is adequately hydrated. Choose medications that have a short half-life and are easily titratable because of the rapid changes in cardiovascular status that may occur from a drug-food interaction, drug-drug interaction, or overdose involving a monoamine oxidase inhibitor (MAOI).
Clinical Context: Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min of ingesting poison.
Alternate use of cathartic and monitor for active bowel sounds.
Useful for limiting systemic burden of the ingested substance, especially if administered within 1-4 h of ingestion.
Clinical Context: Produces vasodilation and increases inotropic activity of the heart. At higher doses, may exacerbate myocardial ischemia by increasing the heart rate.
Clinical Context: Relaxes vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production, resulting in a decreased blood pressure.
May administer bolus of 12.5-25 mcg before continuous infusion.
Initial infusion rate of 10-20 mcg/min may be increased 5-10 mcg/min, q5-10 min until desired clinical or hemodynamic response is achieved.
Infusion rates of 500 mcg/min have occasionally been required.
Clinical Context: Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Clinical Context: Sedative hypnotic with short onset of effects and relatively long half-life.
By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Clinical Context: Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.
Clinical Context: Cyproheptadine is a first-generation antihistamine with antiserotonergic and anticholinergic properities. Its effectiveness in patients with a serotonergic crisis due to MAOI-toxicity has not been proven, but could be useful as an adjunctive treatment to hydration and benzodiazepines. It is dosed at 12 mg orally with 2 mg orally every two hours as needed for symptomatic control.
Used as a third-line treatment for MAOI-induced serotonin toxicity after the interventions listed above. [2]
Because toxicity may be delayed in onset, admit the patient and observe in a monitored setting. Maintain vigilance regarding recrudescence of fever and ongoing fluid requirements.
Patients should recover without sequelae if no adverse reactions occur, such as renal failure, stroke, or refractory hypotension.