Monoamine Oxidase Inhibitor Toxicity

Etiology

There are three ways in which MAOI toxicity can occur: drug-food interaction, overdose, or drug-drug interactions.

1. The most common MAOI toxicity involves the interaction with tyramine-containing foods. When MAO found in the gut and liver is inhibited, dietary tyramine indirectly causes an amplification of adrenergic activity. Food rich in tyramine includes aged cheeses, aged/picked/smoked meats, beer, wine, yeast extracts, ginseng, sauerkraut, and avocado. 
2. MAOIs have a low therapeutic index. Ingestion of 2 mg/kg of a first generation, non-selective MAOI inhibitors such as isocarboxazid, phenelzine, or tranylcypromine has the potential for severe toxicity. MAOI overdose may see a delay in symptoms of several hours or more.
3. MAOI toxicity can be seen when a MAOI is combined with any drug that increases the synthesis, release, and effect or decreases the metabolism or reuptake of monoamines. These drugs include but are not limited to, dextromethorphan, linezolid, methylene blue, selective serotonin reuptake inhibitors, serotoninergic agents, and tramadol [2] [3] [4] [5].

Epidemiology

There has been a 60% decrease in cases of MAOI exposures in the United States over the last 25 years. In 2015, only 208 cases of MAOI exposures were reported to poison control centers. Single exposures to MAOIs accounted for 90 of the cases. Adults accounted for 71 of these cases, and 28 cases were intentional ingestions. Death due to MAOI exposure is rare, with about one case reported per year over the past decade (including cases with both single and multiple exposures) [6] [7] [8] [5]. 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. MAOIs are currently being studied as potential neuroprotective agents [9]. If they prove to be an effective treatment and rates of prescribing increase, then the incidence of toxicity has the potential to increase as well.

Pathophysiology

The toxic effects of MAOIs are observed when their inhibitory effects on monoamine oxidase are compounded by drug-food interactions, overdose or drug-drug interactions. Without MAO to break down epinephrine, norepinephrine, dopamine, serotonin, and tyramine, the storage, and release of these monoamines are increased. Increased adrenergic tone produces findings of tachycardia, hyperthermia, myoclonus, hypertension, and agitation (see below for a more comprehensive list of findings). The time course can range from minutes for a drug-food interaction to several hours in a pure MAOI overdose.

Histopathology

There are no clinically relevant histopathologic findings in MAOI toxicity.

Toxicokinetics

MAOIs have high oral bioavailability and plasma concentrations peak within two to three hours. They irreversibly bind monoamine oxidase (except for moclobemide), removing the drug from circulation and making blood concentrations not indicative of effect. It takes two to three weeks to synthesize enough new monoamine oxidase, so clinical effects of MAOIs may last for that amount of time. MAOIs are metabolized in the liver and excreted by the kidneys.

History and Physical

Though many of the symptoms of MAOI toxicity are nonspecific, much of the suspicion for MAOI toxicity will come from the patient history. A complete list of medications, supplements, both current and recently discontinued, should be obtained as there can be significant latency between ingestions and development of symptomatology. Signs of MAOI toxicity are non-specific as well. Mild signs include agitation, diaphoresis, tachycardia and mild temperature elevation. Signs of moderate disease include altered mental status, tachypnea, vomiting, dysrhythmias, hyperthermia, and hypertension. Severe signs include severe hyperthermia, seizures, central nervous system (CNS) depression, coma, cardiorespiratory depression, muscle rigidity and myoclonus. Though similar to other hyperthermic toxidromes, there are a few ways in which MAOI toxicity can be distinguished. MAOI toxicity can present with diaphoresis whereas an anticholinergic syndrome should have dry skin. Additionally, MAOI toxicity is much more likely to present with generalized or ocular clonus than neuroleptic malignant syndrome. A "ping-pong" gaze has also been described in MAOI toxicity [10].

Evaluation

Physicians primarily diagnose patients with a history and physical examination. Frequent measurements of temperature are recommended. Electrolytes and lactic acid should be obtained in patients in which MAOI toxicity is suspected. Salicylate, acetaminophen and alcohol levels should be obtained in any patient in which intentional overdose is suspected as should a pregnancy test in any woman of child bearing age. MAOI levels are not clinically useful. Radiologic tests are not useful for the evaluation of MAOI toxicity.

Treatment / Management

As with any patient with a potentially toxic ingestion, treatment starts with the assessment of the patient’s airway, breathing, and circulation as well as the interventions to maintain a patent airway, adequate ventilation, and circulation. Patients may be significantly dehydrated due to hyperthermia and should be given intravenous fluids. Treat seizures and/or agitation with benzodiazepines.

Cyproheptadine can be considered a third-line treatment after hydration and benzodiazepines. Cyproheptadine is a first-generation antihistamine with anticholinergic and antiserotonergic effects. Its effectiveness has not been proven, but the typical dosing is 12 mg by mouth (or nasogastric/orogastric tube) with additional 2 mg doses every two hours as needed for symptomatic control.

If the time of ingestion was within one hour, activated charcoal could be considered by either emergency medical services during transport or by emergency department providers. The patient’s airway may need to be secured before charcoal administration. Gastric lavage should be considered in a patient with a life-threatening ingestion. There are no antidotes for MAOI toxicity. Hemodialysis is ineffective in removing the drug from the body.

Rapid correction of hyperthermia is vital. Cooling by evaporative heat loss (wetting skin and creating air flow with fans) is an effective treatment. If the patient has signs of severe MAOI toxicity, covering the body with ice or immersing the patient in an ice bath may be necessary. Antipyretics likely will not be adequate treatment.

Patients may present hypertensive, but treatment specifically for hypertension is usually not necessary. If needed, a short-acting agent such as nitroprusside or phentolamine is suggested as beta-blockers may result in unopposed alpha stimulation.

Hospital admission and observation is recommended for any patient with symptoms persisting more than six hours. Consulting the regional poison control center or another medical toxicologist is advised for further recommendations.

Differential Diagnosis

• Acute respiratory distress syndrome

• Amphetamine toxicity

• Anticholinergic toxicity

• Antidepressant toxicity

• Cocaine toxicity

• Heatstroke

• Hypertensive emergencies

• Hyperthyroidism

• Neuroleptic malignant syndrome

• Withdrawal syndrome