AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Neurotransmitters are generally monoamines. They are "manufactured," stored in vesicles in the nerve terminals, and then 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 monoamine oxidase (MAO) or destroyed by catechol-o-methyl transferase in the synaptic cleft. It is hypothesized that clinical depression is related to decreases in concentration of the neurotransmitters. For this reason, pharmaceutical research has produced drugs that can either block the reuptake of neurotransmitters (eg, cyclic antidepressants, newer selective serotonin reuptake inhibitors) or interfere with the breakdown of the reabsorbed monoamines within the nerve terminal (monoamine oxidase inhibitors [MAOIs]).¹

The 2 types of MAO are MAO-A and MAO-B. MAO-A is found primarily in the liver and gastrointestinal tract with some found in the monoaminergic neurons. MAO-A present in the liver is involved in the elimination of ingested monoamines such as dietary tyramine. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are inactivated when they pass through a liver rich in MAO-A. MAO-B, on the other hand, is found primarily in the brain and in platelets.

The older MAOIs, such as phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate), are considered nonselective inhibitors, while the newer MAOIs tend to be more specific inhibitors of either MAOI-A or MAOI-B. However, the selectivity is primarily dose related. Additionally, the older MAOIs bind irreversibly to the enzyme, while the newer products are bound reversibly in a competitive equilibrium.

Pathophysiology

Monoamine oxidase is responsible for the deactivation of active monoamines such as epinephrine, norepinephrine, dopamine, and serotonin. Such oxidases are present in a wide variety of body tissues. They control the concentration of monoamines in the nerve terminal. 

Two categories of MAOs exist: MAO-A and MAO-B. MAOIs are said to be specific for the two types, but such specificity seems to be somewhat dose dependent.

The widely prescribed MAOIs are rather unique in the fact that they bind irreversibly (moclobemide is an exception, since it is a reversible inhibitor) at their sites of action, are eliminated from circulation by such binding and, since they do not recirculate after such binding, their effects are not, strictly speaking, related to their blood levels. Additionally, MAOs are located in many tissues, including the gut wall. MAOIs absorbed through the gastrointestinal tract bind significantly to MAO in the gut mucosa and liver producing significant first pass effect. To be effective in the CNS, their location of clinically significant effect, they must be given in high enough concentration to reach plasma levels and thus brain levels, sufficient to produce binding centrally to MAO. MAO-A in the gut acts as a barrier to the absorption of tyramine, and thus ingestion of substances containing tyramine may produce significant toxicity.

Recently, a transdermal preparation of a "selective" MAO-B drug, selegiline, has appeared on the market, which by by-passing the first pass effect of gut and hepatic MAOI effects, appears to produce antidepressant effects with significantly reduced risk for dietary-induced toxicity.^{2, 3}

MAOI poisoning is classified into the following 3 subtypes:

• Actual poisoning from an overdose (uncommon)
• Drug-food interaction
• Drug-drug interaction

The symptoms and signs of all 3 categories are quite similar and represent the effects of excessive catecholamine neurotransmitters. MAOIs inhibit breakdown of the neurotransmitters norepinephrine, dopamine, and serotonin, resulting in hypertension, tachycardia, tremors, seizures, and hyperthermia.

Remembering that symptomatology of intentional overdose may be delayed for 6-12 hours post ingestion is extremely important. These patients require prolonged close monitoring to prevent morbidity.

Frequency

United States

In 2003, the American Association of Poison Control Centers' Toxic Exposure Surveillance System (AAPCC-TESS) reported 285 MAOI exposures in the United States.⁴ This is compared with 463 MAOI exposures in 1997, which was an increase from the 451 exposures reported in 1996 but a significant drop compared with the 618 cases reported in 1990.^{5, 6, 7}

Of the toxic exposures reported in 2003, 32 occurred in children younger than 6 years and 244 occurred in those older than 19 years. The data from 2003 also showed that 157 of the toxic exposures were unintentional and 74 were intentional. In 2003, of those who ingested MAOIs, 2 died and 20 had severe clinical manifestations.⁴

In 2005, the same database reported 275 exposures with 2 deaths. Thus, the rate of exposures seems to be steady.⁸

Mortality/Morbidity

Severe toxicity is manifested by hyperthermia, seizures, respiratory depression, and CNS depression. Hypotension, cardiovascular collapse, and death may ensue.

Race

No scientific data have found that outcomes of toxic MAOI exposure are dependent on race.

Sex

No scientific data have found that outcomes of toxic MAOI exposure are dependent on sex.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The MAOI agents currently available in the United States include phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate), isocarboxazid (Marplan), and selegiline (specific for the MAO-B enzyme), all of which irreversibly bind to MAO. Reversible inhibitors of MAO are available in Europe (eg, brofaromine, cimoxatone, clorgyline, lazabemide, moclobemide). Substances, such as St. John's wort, that may have MAOI-like activity are frequently used for self-treatment of depression.

According to recent reviews of the experience with one of the newer selective MAOIs, moclobemide, little is expected in the way of symptoms and signs from a simple overdose, except in the circumstance of the co-ingestion of another serotonin-active substance.

For food and drug interactions, the history must include a careful search for potential offending agents, including over-the-counter preparations.

• Ingestion of an MAOI can induce a complex array of hypermetabolic signs that include the following:
• • Fever
  • Tachycardia
  • Generalized muscle rigidity
  • Tachypnea
  • Metabolic acidosis
  • Hypoxemia
  • Hypercapnia
• Acute overdose usually does not produce a hypertensive crisis unless the patient provokes the interaction.
• Early mild symptoms
• • Irritability
  • Anxiety
  • Flushing
  • Sweating
• Moderate symptoms
• • Anxiousness
  • Restlessness
  • Fever
• Severe symptoms
• • Severe fever
  • Seizures
  • Sleepiness

Physical

MAOI overdoses or interactions present with excessive catecholamine stimulation toxidromes. Late in the course, the patient may become hypotensive and comatose. Symptoms can be classified into mild, moderate, and severe.

• Mild symptoms
• • Agitation
  • Confusion
  • Flushing
  • Diaphoresis
• Moderate symptoms
• • Altered mental status
  • Fever
  • Diplopia
  • Hypertension
  • Tachycardia
  • Tachypnea
• Severe symptoms
• • Severe hyperpyrexia
  • Seizures
  • CNS depression
  • Coma
  • Cardiorespiratory depression
  • Malignant hyperthermia
  • Muscle rigidity

Causes

MAOIs may have drug interactions with serotonin reuptake inhibitors, several analgesics (particularly meperidine), and tyramine-containing foods. Any drug that releases catecholamines may precipitate life-threatening events in individuals also using MAOIs.

• Tyramine-containing foods
• • Aged cheeses
  • Aged, pickled, or smoked meats (eg, salami)
  • Yeast extracts
  • Beer (dark more than light, on tap more than in bottles because tyramine is adsorbed to glass)
  • Red wine more than white wine
  • Avocado
  • Sauerkraut
• Potential drug interactions
• • Meperidine
  • Dextromethorphan
  • Selective serotonin reuptake inhibitors (SSRIs) – Fluoxetine, paroxetine
  • Sertraline
  • Sumatriptan
  • All serotonergic agents
  • Linezolid, an antibiotic used to treat certain drug-resistant organisms such as MRSA, has been determined to be a reversible, nonselective MAOI and has been implicated in acute serotonin syndrome, so it may be a risk.⁹

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Standard laboratory tests for poisoned patients are indicated if the patient has significant symptoms.
• Quantitative levels of MAOIs are not clinically useful.
• Toxicology screens are primarily useful in ruling out other toxins.
• Obtain pregnancy tests in women of childbearing age.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Stabilization of vital signs
• Treatment of seizure activity
• Attention to airway maintenance
• Attention to temperature control

Emergency Department Care

• If the patient is hyperthermic, rapidly decreasing the temperature is imperative.
• • Antipyretics and use of a cooling blanket are generally inadequate.
  • The best methods for cooling patients include increasing evaporative losses by wetting their skin with warm water and maintaining airflow over them with fans.
  • Removing the patient's clothing and exposing the patient to room air may help. In extreme cases, packing the individual in ice or in a bath of ice water may prove life saving.
• Fluid therapy is of paramount importance. Patients may be significantly dehydrated from hyperthermia.
• Treating the associated hypertension is usually not necessary.
• • It may actually be dangerous because of the eventual hypotensive phase (avoid beta-blockers because they leave unopposed alpha-stimulation), which may exacerbate the clinical picture.
  • If antihypertensive therapy is deemed necessary, use of a short-acting antihypertensive agent, such as nitroprusside, is advisable.
• Intravenous benzodiazepines are useful for agitation and seizure control; they also may help control the hypertension.

Consultations

• 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 toxic exposure to the MAOIs, or from a drug-drug, or drug-food interaction.

Drug Category: GI decontaminants

Useful for limiting systemic burden of the ingested substance, especially if administered within 1-4 h of ingestion.

Drug Category: Cardiovascular agents

Used to lower blood pressure during hypertensive crisis.

Drug Name	Nitroglycerin (Deponit, Nitrostat)
Description	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, q5-10min until desired clinical or hemodynamic response is achieved. Infusion rates of 500 mcg/min have occasionally been required.
Adult Dose	400 mcg SL or 5 mcg/min IV; titrate to effect
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe anemia, hypovolemia, constrictive pericarditis or pericardial effusion, hypertrophic cardiomyopathy, shock, postural hypotension, head trauma, closed-angle glaucoma, cerebral hemorrhage, and sildenafil (Viagra) use in previous 24 h
Interactions	Aspirin and indomethacin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary); concurrent use with DHE may increase toxicity of both agents
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in coronary artery disease, low systolic blood pressure, glaucoma, hepatic disease, and hyperthyroidism

Drug Category: Benzodiazepines

Useful to control agitation and for treatment of drug-induced seizures.

Drug Name	Lorazepam (Ativan)
Description	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.
Adult Dose	0.044 mg/kg (2-4 mg) IV; titrate to effect Status epilepticus: 4 mg IV over 2-5 min; may repeat second dose in 10-15 min if needed; not to exceed 8 mg
Pediatric Dose	Infants and children: 0.02-0.1 mg/kg IV slowly over 2-5 min; repeat in 10-15 min at 0.05 mg/kg prn; not to exceed 4 mg/dose Adolescents: 0.7 mg/kg IV slowly over 2-5 min; repeat in 10-15 min at 0.05 mg/kg prn; not to exceed 4 mg/dose
Contraindications	Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma
Interactions	Toxicity of benzodiazepines in CNS increases when used concurrently with ethanol, phenothiazines, barbiturates, and MAOIs
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses

Drug Name	Midazolam (Versed)
Description	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.
Adult Dose	0.01-0.05 mg/kg (usually 0.5-4 mg, up to 10 mg) IV slowly over several min; may repeat q10-15min until adequate response achieved
Pediatric Dose	<32 weeks: 0.5 mcg/kg/min IV infusion >32 weeks: 1 mcg/kg/min IV infusion Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion Status epilepticus (refractory to standard therapy), >2 months and children: 0.15 mg/kg followed by continuous infusion of 1 mcg/kg/min, titrating dose upward q5min until seizures controlled
Contraindications	Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)
Interactions	Sedative effects may be antagonized by theophyllines; narcotics, cimetidine, ethanol, and erythromycin may accentuate sedative effects because of decreased clearance; reduce dose of thiopental by 15% when using together
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Maintain vigilance regarding recrudescence of fever and fluid requirements.
• Because toxicity may be delayed in onset of overdose, admit the patient and observe in a monitored setting.

Prognosis

• Patients should recover without sequelae if no adverse reactions occur, such as renal failure, stroke, or refractory hypotension.

Patient Education

• All patients medicated with MAOIs should receive extensive education regarding drug and food interaction problems. Encourage them to have all of their prescriptive and nonprescriptive drugs dispensed from one pharmacy so that an accurate medication profile can be maintained.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize toxicity, particularly the potential for drug/drug interaction
• Failure to admit and observe patients with MAOI overdose
• Administering contraindicated drugs, especially meperidine, to patients taking MAOIs

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Brunton LL, Lazo JS, Parker KL. Drug therapy of depression and anxiety disorders. In: Goodman and Gillman: The Pharmacological Basis of Therapeutics. 11^th ed. New York: McGraw-Hill; 2006:429-459/chap17.
2. Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. Feb 2003;64(2):208-14. [Medline].
3. Preskorn SH. Why the transdermal delivery of selegiline (6 mg/24 hr) obviates the need for a dietary restriction on tyramine. J Psychiatr Pract. May 2006;12(3):168-72. [Medline].
4. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2004;22(5):335-404. [Medline]. [Full Text].
5. Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1998;16(5):443-97. [Medline]. [Full Text].
6. Litovitz TL, Smilkstein M, Felberg L, et al. 1996 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1997;15(5):447-500. [Medline]. [Full Text].
7. Litovitz TL, Bailey KM, Schmitz BF, et al. 1990 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1991;9(5):461-509. [Medline]. [Full Text].
8. Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932. [Medline].
9. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. Jul 15 2006;43(2):180-7. [Medline].
10. Dawson JK, Earnshaw SM, Graham CS. Dangerous monoamine oxidase inhibitor interactions are still occurring in the 1990s. J Accid Emerg Med. Mar 1995;12(1):49-51. [Medline].
11. Erich JL, Shih RD, O''Connor RE. "Ping-pong" gaze in severe monoamine oxidase inhibitor toxicity. J Emerg Med. Sep-Oct 1995;13(5):653-5. [Medline].
12. Francois B, Marquet P, Desachy A, et al. Serotonin syndrome due to an overdose of moclobemide and clomipramine. A potentially life-threatening association. Intensive Care Med. Jan 1997;23(1):122-4. [Medline].
13. Henry JA. Epidemiology and relative toxicity of antidepressant drugs in overdose. Drug Saf. Jun 1997;16(6):374-90. [Medline].
14. Hernandez AF, Montero MN, Pla A, Villanueva E. Fatal moclobemide overdose or death caused by serotonin syndrome?. J Forensic Sci. Jan 1995;40(1):128-30. [Medline].
15. Isbister GK, Hackett LP, Dawson AH, et al. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol. Oct 2003;56(4):441-50. [Medline].
16. Kokan L. Monoamine oxidase inhibitors. In: Goldfrank, Flomenbaum, Howland, Hoffman, Nelson. Goldfrank's Toxicological Emergencies. 7^th ed. New York: McGraw-Hill; 2002:885-900/chap60.

Article Last Updated: Jan 8, 2008