73: Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) have a unique history, pharmacology, and toxic syndromes associated with their use. This drug class has fallen in and out of favor with scientists and clinicians over the last several decades. While toxicity from MAOI ingestion is becoming less common due to more limited clinical usage of the traditional nonselective MAOIs, an understanding of MAOI toxicity is fundamental to any clinician who takes care of patients with acute poisoning.

Monoamine oxidase (MAO) was discovered in 1928 and named by Zeller when the enzyme was recognized to be capable of metabolizing primary, secondary, and tertiary amines such as tyramine and norepinephrine.¹³¹ Subsequently, the “monoamine hypothesis” postulated depression as a monoamine deficiency state and MAOIs targeted monoamine metabolism for therapeutic benefit. In the early 1950s, iproniazid, a drug previously used to treat tuberculosis, was found to produce favorable behavioral adverse events. By the mid 1950s, it was demonstrated that iproniazid inhibited MAO, and it then became the first antidepressant used clinically.⁴⁶

In the late 1960s, two MAO isoforms were identified each with substrate and inhibitor specificity. This determination led to the development of selective MAOIs in attempts to minimize the many food and drug interactions that occur with the traditional nonselective MAOIs. Nonselective MAOIs proved to be potent and efficient antidepressants and became first-line therapy for depression. In the 1970s, alternative therapies for depression, such as tricyclic antidepressants, were developed and achieved clinical success without as many food interactions.

Intentional MAOI overdose is relatively uncommon and accounts for a dwindling number of annual exposures reported to the American Association of Poison Control Centers. From 2000 to 2010 there was a decreasing trend in the number of exposures with only 228 exposures reported in 2010,¹⁶ representing less than 1% of all antidepressant exposures. Of the reported exposures in 2010, there were only five cases of “major toxic effect” (defined as life-threatening signs or symptoms) and no deaths were reported. Over the past two decades, annual reported MAOI exposures have decreased 34% since 1985 (Chap. 136). Global MAOI exposure rates declined in proportion with the United States, with the possible exception of exposures to moclobemide, a drug not approved by the US Food and Drug Administration (FDA).³³

Chemistry

Monoamines, also known as biogenic amines, include the neurotransmitters norepinephrine, dopamine, and serotonin, which share the presence of a single amine group and the ability to be metabolized by MAO. Monoamine oxidase is a flavin-containing enzyme present on the outer mitochondrial membrane of central nervous system (CNS) neurons, hepatocytes, and platelets. In a two-step reaction, MAO catalyzes the oxidative deamination of its various substrates. The reaction liberates H₂O₂, a reactive oxygen species. Deamination by MAO is one of two major routes of elimination of monoamines, the other being extracellular degradation by catechol-O-methyltransferase (COMT). Serotonin, which is not metabolized by COMT, is the exception to this rule.

Monoamine Neurotransmitter Stores

Monoamine neurotransmitter synthesis, vesicle transport, vesicle storage, uptake, and degradation are described in detail in Chap. 14. In the neuron, MAO functions as a “safety valve” to metabolize and inactivate any excess monoamine neurotransmitter molecules. Once monoamines reenter the cytoplasm from the synaptic cleft, they can either reenter vesicles for further storage and release, or can be rapidly enzymatically degraded by MAO.

MAO Isoforms

There are two MAO isoforms, each with their own substrate and inhibitor specificity (Table 73–1). MAO-A preferentially metabolizes norepinephrine and serotonin, and MAO-B preferentially metabolizes benzylamine in vitro. Both isoforms metabolize tyramine and dopamine with comparable efficiency, but they are localized to differing anatomic regions, with MAO-A concentrated in the intestine and liver, whereas MAO-B is concentrated in the basal ganglia of the brain.²²

Mechanism of Action

MAOIs are transported into the neuron by the Na⁺-dependent membrane norepinephrine-reuptake transporter.⁷³ Inhibition of MAO prevents presynaptic degradation of monoamines, thus increasing the concentration of monoamine neurotransmitters available for synaptic storage and subsequent release (Fig. 73–1). Inhibition of MAO also results in indirect release of norepinephrine into the synapse, via displacement from presynaptic vesicles in a manner similar to amphetamines.¹¹⁶

Elevated synaptic concentrations of serotonin are most closely correlated with the antidepressant therapeutic effects of MAOIs. The enzymatic inhibition produced by MAOIs precedes the clinical effects by as long as 2 weeks. This finding, which is similar to other antidepressants, may relate to the relatively slow downregulation of postsynaptic CNS serotonin receptors.⁹⁴

MAOIs impair norepinephrine synthesis due to dopamine-β-hydroxylase inhibition. Impaired norepinephrine synthesis leads to eventual depletion of norepinephrine stores. Additionally, indirect dopamine agonism occurs via elevated synaptic concentrations of dopamine. Dopamine agonism results in β-adrenergic stimulation, peripheral vasodilation, and direct α-adrenergic stimulation at high doses.

The hydrazide MAOIs (eg, phenelzine, isocarboxazid) are thought to be cleaved to liberate pharmacologically active products (eg, hydrazides), which are cleared by acetylation in the liver.

First-Generation MAOIs: Nonselective and Irreversible

Monoamine oxidase inhibitors are a chemically heterogeneous group of xenobiotics (Fig. 73–2). First-generation MAOIs (ie, irreversible and nonselective) in clinical use include the reactive hydrazide derivatives (phenelzine, isocarboxazid) and an amphetamine derivative (tranylcypromine).⁴⁵ First-generation MAOIs bind covalently to MAO and irreversibly inhibit the function of the enzyme. Thus, patients taking these MAOIs are depleted of the enzyme until new MAO is synthesized, a process that typically takes up to 3 weeks. Patients taking first-generation MAOIs remain at risk for food and xenobiotic interactions during much of this period. Because nonselective MAOIs inhibit both isoforms of MAO (ie, MAO-A and MAO-B), inhibition of intestinal and hepatic degradation of biogenic amines occurs. As a result, patients who receive these xenobiotics must be placed on a restrictive diet to prevent adverse events resulting from the absorption of undigested tyramine from the gut.

Phenelzine, isocarboxazid, and tranylcypromine are currently FDA approved for treatment of refractory depression.^58,77 Pargyline, previously approved for use as an antihypertensive due to decreased peripheral vascular resistance, is no longer routinely used.¹²⁶ Phentermine is a nonselective MAOI, which is prescribed for the short term treatment of obesity.¹²²

Other enzyme systems inhibited by first-generation MAOIs include amine oxidases such as diamine oxidase and semicarbazide-sensitive oxidases, arylamine N-acetyltransferase (by tranylcypromine), ceruloplasmin, alcohol dehydrogenase (by tranylcypromine), dopa decarboxylase, l-glutamic acid decarboxylase, γ-aminobutyric acid (GABA) decarboxylase and GABA transaminase (by hydrazide MAOIs), alanine aminotransferase (by phenelzine), and other pyridoxine (B₆)-containing enzyme systems.⁴⁹ The clinical implications of inhibiting these diverse enzyme systems, other than alcohol dehydrogenase and cytochrome P450,¹⁰³ are poorly understood.

Second-Generation MAOIs: Selective and Irreversible

Selective MAOIs preferentially inhibit one of the two MAO isoforms, although isoform selectivity is lost as the dose is increased.

MAO-A Inhibitors.

Clorgyline is an MAO-A inhibitor structurally related to pargyline. Once thought to be useful for treatment of depression, it has not found widespread use in psychiatry due to disappointing results from clinical trials. However, clorgyline is now being investigated in congestive heart failure and may see a future role in the treatment for those patients.

MAO-B Inhibitors.

Selegiline is a selective MAO-B inhibitor that is FDA approved for the treatment of Parkinson disease,⁵⁸ although it does exhibit weak MAO-A inhibition at therapeutic doses.⁶⁸ Selegiline transdermal system is FDA approved for treatment of major depressive disorder in adults as an alternative to the traditional oral delivery system.^6,58,98 Rasagiline is another MAO-B selective MAOI that is FDA approved to treat Parkinson disease.¹⁹

Third-Generation MAOIs: Selective and Reversible

Reversible inhibitors of monoamine oxidase-A (RIMAs) are a class of drugs that selectively and reversibly inhibit MAO-A.⁵⁸ These xenobiotics were developed in an effort to compensate for the limitations of first- and second-generation MAOIs (see Clinical Manifestations). RIMAs can be displaced by tyramine from the active site of the enzyme MAO-B, thereby enabling peripheral metabolism of the amine. Because tyramine is not present in high concentrations in the brain, MAO-A continues to be inhibited and the antidepressant effects are achieved.⁵⁸ Moclobemide is the most widely studied RIMA and is approved as an antidepressant in Europe and other parts of the world.³³ However, due to lack of financial incentives to gain approval, the drug is not currently available in the United States. Brofaromine and toloxatone are other RIMAs that were recently introduced but are less well studied.

Naturally Occurring MAOIs

The extract of the plant St. John wort (Hypericum perforatum) is licensed in Germany for use as an antidepressant. Although the major constituents, hypericin or hyperforin have weak MAOI activity, it is uncertain whether this activity is responsible for its antidepressant effect. However, MAOI activity explains sporadic reports of hypertensive crises, cardiovascular collapse during anesthesia, and serotonin toxicity associated with use of this herbal product.^52,85

Ayahuasca, a hallucinogenic beverage used by South American natives, is an ethnobotanical mixture of dimethyltryptamine and harmala alkaloids that circumvents gastrointestinal (GI) MAO. Dimethyltryptamine, which is a potent visual hallucinogen, is derived from several local plant species,²⁶ but is not orally bioavailable because of its first-pass metabolism by MAO.⁷⁴ When Banisteriopsis caapi, a plant containing the MAO-inhibiting harmala alkaloids, is mixed with dimethyltryptamine-containing plants, the bioavailability of this hallucinogenic amine is improved.^74,75

MAO-B activity in tobacco plants has prompted studies to find a link between the lower platelet MAO-B activity of smokers and their lower rate of Parkinson disease.¹⁸ This finding has led to interest in studying other MAO-B inhibitors for potential applications as neuroprotective xenobiotics.¹³⁰

Miscellaneous and Experimental MAOIs

Other xenobiotics with nonselective MAO inhibitory properties are used for purposes unrelated to MAO inhibition. Furazolidone is an antimicrobial used to treat protozoan-related diarrhea and bacterial enteritis. Procarbazine is a hydrazide derivative indicated as a chemotherapeutic for Hodgkin lymphoma and some brain tumors. Linezolid is an antibiotic that produces weak, nonselective MAO inhibition.^29,112,120 Azure B, a metabolite of methylene blue, is a high-potency reversible inhibitor of monoamine oxidase.⁸⁶

Research is active for novel MAO combination xenobiotics that target multiple mechanistic approaches for the treatment of dementia and parkinsonism.²⁷ Ladostigil combines the cholinergic effects of a carbamate with the aminergic effects of MAO-B inhibition.¹⁰⁴ M30 is an actively researched xenobiotic that combines iron chelation and radical scavenger effects with irreversible, nonselective MAO inhibition.³⁵ Neither xenobiotic has been approved by the FDA.

Monoamine oxidase inhibitors are absorbed readily when given by mouth, and peak plasma concentrations are reached within 2 to 3 hours. Like other antidepressants, these xenobiotics are lipophilic and readily cross the blood–brain barrier. MAOIs are hepatically metabolized by both oxidation (various CYP450 isoenzymes, including CYP2D6 and CYP2C19) and acetylation (N-acetyltransferase), to metabolites that are excreted in the urine.⁸

Like the original MAOI, iproniazid, phenelzine and isocarboxazid are metabolized to hydrazides. The rate of metabolism of the hydrazide MAOIs is dependent on the N-acetyltransferase phenotype (ie, “acetylator status”) of the patient (ie, fast or slow). About one-half of the US population, but as low as 10% of Native Americans, have a recessive single gene trait that effects the N-acetylate transferase enzyme in the liver and contributes to exaggerated clinical effects despite standard therapeutic dosing or even mild overdose.

The clinical effects of MAOI inhibition occur rapidly and are usually maximal within a few days. First-generation (ie, irreversible) MAOIs have durations of effect that far surpass their pharmacologic half-lives, and recovery from their effects requires the synthesis of new enzyme over a period of up to 3 weeks (the “washout period” is a misnomer as the effective period is dependent on enzyme regeneration).¹¹⁷ Thus, when switching from one serotonergic (ie, MAOI, SSRI, cyclic antidepressant) to another, a sufficient time period of 2 to 3 weeks must be allowed to prevent an adverse drug interaction. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, a time period of 5 weeks is recommended when switching from fluoxetine to an MAOI.

As discussed above (see Mechanism of Action), MAOIs contribute to adrenergic stimulation via release of norepinephrine from sympathetic nerve terminals.⁶⁴ This phenomenon may lead to hyperadrenergic crises particularly in the presence of foods or xenobiotics that serve as substrates for, or enhancers of, monoamine formation, such as tyramine.⁶³ In addition, norepinephrine release combined with MAO inhibition may result in so-called “autopotentiation,” or synergistic sympathomimetic effects. Autopotentiation may be responsible for paradoxical or hypertensive reactions sometimes observed following therapeutic doses of MAOIs.^5,23

Hydrazide MAOIs (eg, phenelzine) inactivate pyridoxal 5′ phosphate, the cofactor necessary for neuronal decarboxylation of glutamic acid to the inhibitory neurotransmitter GABA. In addition, hydrazides may complex with pyridoxine, the precursor of pyridoxal 5′ phosphate, thus enhancing its urinary elimination and further inhibiting the formation of neuronal GABA.⁸⁴ Decreased availability of neuronal GABA leads to CNS excitation following overdose of hydrazide MAOIs (Chaps. 58 and 120).⁶¹

Impaired GABA_A activity may contribute to symptoms of CNS excitation such as seizures, which occur in MAOI overdose. In animal models, isocarboxazid and tranylcypromine directly inhibit GABA-mediated Cl^– influx at GABA_A receptors.¹¹³ The exact binding site of MAOIs on the GABA_A receptor complex is unknown. GABA effects appear to be most localized in the caudate-putamen and nucleus accumbens areas in one animal model.⁸⁴ Elevated neuronal glutamate concentrations due to MAOI effects may also synergistically enhance CNS excitation.¹⁰⁶

Many authors recommend the prescription of nonselective MAOIs only for resistant or atypical depression with prominent neurovegetative symptoms.³⁰ However, selective and reversible MAOIs are the subject of renewed clinical applicability and basic science research interest. MAO-B selective xenobiotics, such as selegiline, are widely used for the treatment of Parkinson disease. Reversible inhibitors of MAO, such as moclobemide, are used in Europe for depression, phobias, anxiety, and other select indications.¹²⁹ Current applicability of a new generation of experimental MAOIs is being investigated as neuroprotective xenobiotics for a variety of neurodegenerative diseases.¹³⁰

Hyperadrenergic crises may occur in patients with MAO-A inhibition when tyramine-containing foods such as aged cheeses and fermented drinks are eaten (Table 73–2).¹³⁰ Tyramine is an indirect-acting sympathomimetic amine with an amphetaminelike mechanism of action.¹³² The MAO-A present in the intestinal wall and liver extensively metabolizes dietary amines preventing them from entering the circulation, but in the presence of irreversible MAO-A inhibition this protective mechanism is lost, allowing tyramine and other dietary monoamines to enter the circulation.¹² This enzymatic failure results in an amphetaminelike induction of norepinephrine from peripheral adrenergic neurons and provocation of hyperadrenergic crisis. A meal that contains 6 to 8 mg of tyramine per serving can potentially precipitate this reaction, and ingestion of a total of 25 to 50 mg can produce a severe and possibly life-threatening reaction.^28,118,124 A recent European study of biogenic amines contained in retail meat products (eg, sausage, cold cuts) found that such products contained up to 50 mg/kg tyramine which would pose a high risk for individuals receiving first-generation MAOI therapy.⁸² Additionally, despite compliance with diet, chronically elevated cytoplasmic and synaptic concentrations of norepinephrine due to therapeutic MAOI administration can lead to adrenergic crises in some patients. Dietary restrictions and recommendations for patients prescribed first-generation MAOIs are summarized in Table 73–2.^28,118,124 As detailed above, a time period of 3 weeks is sufficient to allow a normal diet to be resumed.¹¹⁹

The clinical syndrome of tyramine-related hyperadrenergic crisis is characterized by hypertension, headache, flushing, diaphoresis, mydriasis, neuromuscular excitation, and potential cardiac dysrhythmias.¹²¹ This reaction is subjectively reported in up to 10% of patients taking MAOIs chronically,⁹² and can occur up to 3 weeks following discontinuation of the drug.¹²⁷ Monoamine oxidase inhibitors specific for the MAO-B isoform are less likely to predispose to food or drug interactions by maintaining significant hepatic MAO-A activity; however, isoform specificity is lost as dose is increased.

Any xenobiotic with serotonin-potentiating activity can interact with the MAOIs to produce serotonin toxicity. Combinations of xenobiotics commonly implicated in this reaction are involved with serotonin synthesis (eg, l-tryptophan), release (eg, amphetamines), agonism (eg, triptans metabolized by MAO), neuromodulation (eg, lithium), or reuptake inhibition (eg, selective serotonin reuptake inhibitors, meperidine, dextromethorphan). Animal studies have demonstrated that both meperidine¹⁰⁸ and dextromethorphan¹⁰⁹ administration can lead to fatal serotonin toxicity. Serotonin toxicity most commonly occurs in patients receiving combination therapy with two or more serotonergic agents; however, it may rarely occur with just one serotonergic agent.⁸³

Clinically, serotonin toxicity runs a spectrum of severity,¹³ and is des­cribed in detail in Chap. 75. Minor findings can include akathisia, myoclonus, hyperreflexia, diaphoresis, penile erection, shivering, hyperactive bowel sounds, and tremor. Tremor and hyperreflexia are typically greater in the lower extremities. Shivering is classically described as similar to “wet dog shakes,”⁴³ and can occur at a range of body temperatures.⁸⁰ Severe signs and symptoms can include life-threatening autonomic instability, muscular rigidity, and hyperthermia.

Several diagnostic schemes for serotonin toxicity exist.^{13,24,47,93,114} However, the key diagnostic criterion is exposure to a serotonergic. Because no diagnostic test is yet available, the diagnosis of serotonin toxicity must be established on clinical grounds. The onset of clinical symptoms may occur within minutes after a change in medication or self-poisoning.⁶⁹ Most patients with serotonin toxicity develop symptoms within 6 hours. Key clinical features of MAOI-induced serotonin toxicity are summarized in Table 73–3.

Monoamine oxidase inhibitor overdose may result in severe and life-threatening clinical manifestations, especially if the MAOI is a first-generation drug such as phenelzine. Classically, the clinical course involves a biphasic response characterized by initial CNS excitation and peripheral sympathetic stimulation that terminates in coma and cardiovascular collapse.⁶⁶ This biphasic model is hypothesized to result from an initial adrenergic crisis followed by inhibition of norepinephrine release,¹³² and is supported by animal studies.^37,41 Additionally, depletion of norepinephrine stores may be partially or fully responsible for late hypotension observed in MAOI overdose. Toxic dose-response relationships in man are unclear, but overdose of 5 mg/kg of a first-generation MAOI is potentially life threatening.^11,66 Clinical manifestations of MAOI overdose are summarized in Table 73–3.

Patients with MAOI overdose are initially asymptomatic for several hours. Delays in clinical toxicity are well described.^70,72,96 Unstudied hypotheses that might explain this phenomenon include all of the following: initial reversible binding to MAO, cumulative effects, time-dependent alterations to MAO substrate stores, individual acetylator status, and hydrolysis of the hydrazide MAOIs. While clinical toxicity should generally be apparent within the first several hours (initially with neuromuscular and sympathetic effects),⁶⁶ maximal toxicity may be delayed up to 24 hours after overdose.^66,72,96

Neurologic effects can be considered neuropsychiatric, neuromuscular, mental status alteration, seizures, and chronic effects. Neuropsychiatric effects include agitation, akathisia, and hallucinations. Neuromuscular effects include flailing and tremor of the extremities, nystagmus, opsoclonus, fasciculation, myoclonus, hypertonia, hyperreflexia, muscular irritability, and muscular rigidity, the latter of which may lead to secondary effects such as hyperthermia and rhabdomyolysis. Effects on mental status alteration include a variable spectrum from confusion to coma, the latter of which is a typically end-stage finding. Seizures may be either partial or generalized, and decorticate or decerebrate rigidity may alternate with periods of flaccid paralysis.

Severe hyperthermia (> 106°F) due to MAOI toxicity may have a multifactorial etiology and is an ominous sign.¹⁰⁷ Temperature dysregulation may be due to adrenergic crisis, muscular hypertonia, or CNS effects. Secondary effects from severe hyperthermia include disseminated intravascular coagulation and metabolic acidosis.⁷²

Cardiovascular effects follow the previously described initial hyperadrenergic crisis followed by cardiovascular collapse. Thus, initially, hypertension, tachycardia, palpitations, and tachydysrhythmias are to be expected.⁵⁵ In severe poisoning, late toxicity can include development of hypotension, reflex tachycardia or bradycardia, bradydysrhythmias, and sudden death.^70,97 Alterations in myocardial supply/demand dynamics may lead to myocardial injury with elevations of serum cardiac biomarkers (eg, troponin I). Myonecrosis⁸⁸ and myocarditis¹²⁵ are also attributed to MAOI overdose.

Abnormalities on electrocardiography (ECG) may include ischemic changes on ECG (contiguous lead findings of T-wave inversion or ST-segment depression/elevation). Peaked T waves, in the presence⁶⁶ or absence⁹¹ of hyperkalemia, are also noted. Myocardial manifestations associated with catastrophic CNS processes (eg, intracranial hemorrhage) can also lead to T-wave inversions.

In addition to the effects mentioned above and listed in Table 73–3, reported complications of MAOI overdose include acute kidney failure,^66,70,88,97 fetal demise,⁹⁷ and hemolysis.^66,72

Selegiline Overdose

Selegiline is metabolized to l-methamphetamine, which may result in hypertension and tachycardia, even at therapeutic doses.^1,7,101 Postmarketing surveillance safety data on the selegiline transdermal system demonstrated that only 13 (< 1%) out of 1516 patients studied reported a hypertensive event, none of which were objectively confirmed.⁸¹ Selegiline overdose produces hallucinations and convulsions and is associated with elevated urinary concentrations of l-methamphetamine and l-amphetamine.^32,57

Moclobemide Overdose

Moclobemide overdose typically produces mild to moderate CNS depression (drowsiness, disorientation), GI effects (nausea), and cardiovascular effects (tachycardia and mild hypertension).^33,76 Serotonin toxicity due to the ingestion of moclobemide, alone⁵⁰ and in combination with other serotonergics^{78,87,123,128} is well described. In massive overdose, fatalities attributed solely to the toxic effects of moclobemide are reported.^17,34,40

Clinically significant drug interactions with MAOIs can be due to serotonergic effects (see Serotonin Toxicity) and alterations to drug metabolism. Chronic use of phenelzine is also associated with an isoniazidlike peripheral neuropathy,⁴² possibly explained by pyridoxine deficiency.¹¹⁵ Administration of opioids with serotonergic properties (eg, meperidine, dextromethorphan) is absolutely contraindicated due to risk of precipitating the serotonin ­toxicity.^{13,39,100,108,109} Adverse drug reactions with other coadministered drugs that are metabolized by cytochrome P450 may be problematic, as first-generation MAOIs have an extensive inhibitory effect on CYP2C9, CYP2C19, and CYP2D6.^8,103 Thus, barbiturates (eg, phenobarbital) and benzodiazepines (eg, diazepam, lorazepam) that are metabolized by hepatic cytochrome P450 may produce prolonged sedation and respiratory depression. Table 73–4 summarizes analgesic safety in combination with MAOI drugs.³⁹

Monoamine oxidase inhibitor withdrawal may be severe, beginning 24 to 72 hours after discontinuation. Classically, MAOI withdrawal symptoms are the worst following discontinuation of high therapeutic doses of tranylcypromine and isocarboxazid.⁹ Symptoms range from nausea, vomiting, and malaise, to CNS symptoms such as agitation, psychosis, and convulsions. Treatment is generally supportive and typically involves a benzodiazepine such as diazepam and restarting the medication if clinically indicated.

The clinical utility of therapeutic drug monitoring in the routine use of MAOIs is limited. Evaluation of MAO activity is not routinely available, requires a fresh specimen (preferably jejunal biopsy),⁶⁵ and is therefore not recommended. Experimental evidence suggests that inhibition of human platelet MAO-B activity by at least 85% may be associated with a favorable clinical antidepressant response to phenelzine.^31,36

Evaluation of MAOI toxicity remains a clinical diagnosis. Serum concentrations of MAOIs that correlate meaningfully with clinical effects are not well established. In addition, serum concentrations of any antidepressant, in general, can be misleading when obtained postmortem for forensic purposes.^90,99 Hyperglycemia and leukocytosis may be present. Elevations in serum lactate concentrations and metabolic acidosis may be present from seizures, muscular hypertonia, or hyperthermia.

Measurement of blood and urinary concentrations of MAO substrates may provide indirect evidence of MAOI effects. MAOIs may cause increase serum serotonin, increase or decrease serum norepinephrine, increase urinary epinephrine and norepinephrine, and decrease urinary serotonin metabolites. Due to the indirect nature of this testing and the fact that its interpretation is fraught with confounding factors (eg, if the patient is receiving vasopressors), the routine measurement of serum and urinary MAO substrates is not recommended in the assessment of MAOI toxicity. Of note, patients taking selegiline¹⁰⁵ and tranylcypromine¹³³ may test positive for amphetamines on drug screens due to their metabolites.

Out of Hospital

Decisions regarding referral to the emergency department (ED) must take into account factors such as patient age, intent of exposure, symptoms, as well as timing of exposure. All patients with MAOI exposures who display suicidal intent should be referred to an ED for evaluation. Children with exposure to even one adult formulation MAOI tablet or selegiline patch should be referred to the ED due to the potential for late-onset significant toxicity.³ Patients who exhibit more than mild headache or minimal diaphore­sis following an acute MAOI ingestion should be referred to an ED. Observation at home is warranted in patients who are asymptomatic and more than 24 hours have elapsed since the time of ingestion. Due to paucity of data at this time, patients with selegiline patch ingestion should be referred to the ED for observation, even if suicidal intent is absent.

Prehospital

Induction of emesis is not recommended.³ Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of MAOI if no contraindications are present.² Transportation to the hospital should not be delayed in order to administer activated charcoal. Use of intravenous benzodiazepines for seizures and external cooling measures for severe hyperthermia (> 106°F {> 41.1°C})¹⁰⁷ should be performed in consultation or authorization with medical direction from emergency medical services, by a written treatment protocol or policy, or with direct medical oversight.

Initial Approach in the Emergency Department

As with any serious ingestion, initial stabilization must include rapid assessment of the airway, breathing, and circulation as well as establishment of intravenous access, supplemental oxygen, and cardiac monitoring. Evidence of hyperthermia or hemodynamic instability following MAOI ingestion may be a manifestation of significant toxicity. Intravenous volume repletion should begin while gastrointestinal decontamination is considered. In any patient with altered mental status who will likely deteriorate progressively, early orotracheal intubation may facilitate safe gastric decontamination measures. Subsequent management should focus on stabilization of hyperthermia, seizures, and muscular rigidity.

Gastrointestinal Decontamination

Patients who overdose with MAOIs are more likely to benefit from gastrointestinal decontamination than most other overdose patients because of their high potential for morbidity and mortality.^59,89 Orogastric lavage with a large bore orogastric tube (36–40 French) should be considered if a life-threatening ingestion is suspected to have occurred within several hours prior to presentation.^39,59,89 Single-dose activated charcoal should be orally administered for ingestions presenting within several hours, unless contraindications are present. Whole bowel irrigation with oral polyethylene glycol electrolyte solution likely has limited utility unless there are coingestions with other sustained-release preparation medications. The lack of early clinical findings of poisoning should not dissuade the use of gastrointestinal decontamination given the potential for delayed clinical deterioration.

Cooling Measures

Severe hyperthermia must be treated with aggressive cooling. Use of ice baths (first choice for life-threatening hyperthermia),¹¹⁰ cold water, and fans are the mainstay of treatment (Chap. 30). There is no available evidence to support use of invasive cooling devices (ie, catheter based) or noninvasive devices such as cooling blankets. Indications for ice bath immersion to treat MAOI toxicity include rectal temperature greater than 106°F (41.1°C),¹⁰⁷ rigidity, and altered mental status. Benzodiazepines help control muscular rigidity, seizures, and agitation that may contribute to amelioration of hyperthermia and tachycardia. Patients with refractory hyperthermia despite the above measures may require neuromuscular blockade, using nondepolarizing paralytics, in conjunction with tracheal intubation and ventilation. The depolarizing paralytic succinylcholine should be avoided in severe MAOI toxicity due to the risk of precipitating lethal dysrhythmia due to hyperkalemia in the setting of rhabdomyolysis. Neuromuscular blockade eliminates hyperthermia that results from muscular rigidity, and can be employed if first-line treatments are unsuccessful. Antipyretics such as acetaminophen are unlikely to be efficacious because the hyperthermia is not due to alterations in the hypothalamic temperature set point.¹⁰⁷

Blood Pressure Control

Because there is characteristic fluctuation in vital signs associated with MAOI overdose, hemodynamic monitoring should be instituted even for patients who initially are stable. When supporting the patient’s blood pressure, preference should be given to titratable drugs with a rapid onset and termination of action because of the potential for rapid hemodynamic changes. Use of β-adrenergic antagonists is contraindicated for control of hypertension in MAOI-related toxicity because the action of monoamines (eg, norepinephrine) at the neuronal synapse in the autonomic nervous system could result in refractory hypertension due to unopposed α-adrenergic agonism.⁹⁵

Patients who are normotensive at baseline and who experience MAOI-related severe hypertension can be treated with a short-acting α-adrenergic antagonist such as phentolamine (intravenous 2–5 mg) for effective control.¹² Other therapies such as nitroprusside and nitroglycerin may be preferred because they allow for titratable blood pressure control.²¹ Tyramine-related hypertensive crises can successfully be controlled with the dihydropyridine calcium channel blockers such as nifedipine and possibly the oral α-adrenergic antagonists such as terazosin but should be used with caution.^20,48 Particular caution must be exercised in patients with baseline hypertension because overly aggressive blood pressure lowering may reduce cerebral perfusion pressure sufficiently to cause cerebral ischemia.

Patients who are hypotensive may require aggressive support with intravenous fluid resuscitation and vasopressors. Direct-acting sympathetic agents (eg, epinephrine, norepinephrine) can be used safely in patients taking MAOIs.¹⁴ Rather than causing release of a stored pool of norepinephrine, these xenobiotics bind directly with postsynaptic α- and β-adrenergic receptors.

Dopamine is contraindicated in hypotensive patients who have overdosed on MAOIs for several reasons. The indirect action of dopamine administration may produce a synergistic effect with MAOI, resulting in excessive adrenergic activity and exaggerated rises in blood pressure. In addition, most of the α-adrenoceptor mediated vasoconstriction of dopamine is secondary to norepinephrine release; in the presence of MAOIs, norepinephrine synthesis may be impaired from concomitant dopamine-β-hydroxylase inhibition, and dopamine may not reliably raise blood pressure if cytoplasmic and vesicular neuronal stores have been depleted. Finally, in the presence of impaired norepinephrine release or α-adrenergic blockade by any cause, unopposed dopamine-induced vasodilation from action on peripheral dopamine and β adrenoceptors may paradoxically lower blood pressure further.

Dysrhythmias

Due to the unique pharmacologic and toxicokinetic considerations of MAOI toxicity, adherence to advance cardiac life support protocols may not provide optimal results.⁴ In any stable patient, removal of the offending xenobiotic as well as correction of hypoxia, hypokalemia, and hypomagnesemia, if present, is a rational initial step.

Patients with immediately life-threatening dysrhythmias require rapid cardioversion. In the presence of the nonperfusing dysrhythmias such as ventricular fibrillation, pulseless ventricular tachycardia, and torsade de pointes unsynchronized electrical defibrillation is the treatment of choice.

Stable patients with ventricular tachycardia may benefit from a trial of antidysrhythmic drugs such as amiodarone or lidocaine. High-quality studies evaluating the use of these xenobiotics in the setting of MAOI overdose are not available.

Hemodynamically significant supraventricular tachycardia from MAOI toxicity should be corrected to prevent myocardial ischemia or infarction, ventricular dysrhythmia, and high-output heart failure. Benzodiazepines are safe and effective to treat sinus tachycardia, as long as respiratory status remains monitored. Adenosine and synchronized cardioversion are unlikely to be useful in the setting of ongoing presence of the MAOI, but may be considered in rare cases that are unresponsive to benzodiazepines. In patients with borderline hypotension, nondihydropyridine calcium-channel antagonists such as diltiazem and verapamil are relatively contraindicated because they may further lower blood pressure.

Hemodynamically significant bradycardia from MAOI toxicity may be refractory to standard advance cardiac life support protocols. An initial approach with intravenous fluid and atropine is a rational first-line therapy to temporize the patient with bradycardia and hypotension. Epinephrine and isoproterenol may also be administered while a pacemaker (transcutaneous or transvenous) is considered.

Management of CNS Manifestations

In acute altered mental status, hypoglycemia should be rapidly excluded.^15,102 Mild to moderate CNS excitation may be treated with small incremental doses of parenteral diazepam. Seizures should be treated with benzodiazepines such as lorazepam in standard incremental doses. Empiric administration of pyridoxine (vitamin B₆), intravenously at 70 mg/kg, up to 5 g in adults should be considered in patients with status epilepticus, particularly following massive ingestions of hydrazide-derived MAOIs such as phenelzine which may deplete endogenous pyridoxine stores (Antidotes in Depth: A14).¹¹⁵ Theoretically, phenytoin is not likely to be useful for treatment of MAOI-induced seizures because there is no distinct seizure focus, but rather generalized neuronal dysfunction in the presence of MAOI (and metabolites) in the CNS.

Cyproheptadine

Cyproheptadine is a nonselective serotonin antagonist that is recommended as third-line therapy (after benzodiazepine administration and cooling measures) for MAOI-induced serotonin toxicity.¹³ Cyproheptadine prevents lethality in animal models of serotonin toxicity⁷⁹ and reportedly is beneficial in humans although its efficacy has not been rigorously established.^38,44 It should be strongly considered when the diagnosis of serotonin toxicity is likely, especially if incomplete response has been achieved with aggressive cooling and benzodiazepine therapy.⁶² In addition, its use to treat neuromuscular rigidity and hyperthermia associated with MAOI overdose has been reported.^10,25

The recommended initial dose in adults is 12 mg orally, to be followed by 2 mg every 2 hours while symptoms continue.¹³ A dose of 12 to 32 mg will bind 85% to 95% of serotonin receptors.⁵⁴ The dose of cyproheptadine used to treat the serotonin toxicity may cause sedation, but this effect is a goal of therapy and should not deter clinicians from using the drug. Relative contraindications to its use include acute asthma exacerbation, GI obstruction, and age less than 2 years (due to lack of safety information for this age group).

Dantrolene

Use of dantrolene in patients with serotonin toxicity is not recommended (Antidotes in Depth: A21). Case reports citing its utility with off-label usage probably involved misdiagnosis.^13,53 Malignant hyperthermia, for which dantrolene is actually indicated, is a disease that is completely unrelated to serotonin toxicity. In animal models of serotonin toxicity, dantrolene administration has no effect on survival.^51,79 In addition, dantrolene has been implicated in the fatality of one case of serotonin toxicity.⁵⁶

Extracorporeal Elimination

The utility of extracorporeal measures, such as hemodialysis, to treat MAOI toxicity remains to be demonstrated. The ability to dialyze a xenobiotic depends largely on its protein binding the volume of distribution. Unfortunately, data regarding protein binding and volumes of distribution of the first-generation MAOI drugs such as isocarboxazid are not well characterized. Use of peritoneal dialysis⁶⁷ and hemodialysis⁷¹ to treat MAOI overdose has been reported in the literature. However, time to resolution of symptoms for all cases did not differ (~ 24 hours) from those in which hemodialysis was not employed. Therefore, extracorporeal elimination is not recommended in the management of MAOI overdose unless other indications are present such as severe acidemia or life-threatening hyperkalemia, or the need to eliminate dialyzable toxic coingestions.

Disposition

Recommendations for the ideal time frame for observation of patients with suspected MAOI overdose are limited by a paucity of relevant studies in the clinical toxicology literature. Patients with presumed MAOI (selective or nonselective) overdose should be observed with telemetry monitoring, preferably in an intensive care unit, for at least 24 hours regardless of the initial clinical findings. This recommendation takes into account the potential for delayed-onset of clinical toxicity as well as the potential for severe morbidity and mortality.^70,72,96 However, patients with MAOI–food or MAOI–xenobiotic interactions may not require hospital admission if the interaction is mild, resolution of symptoms is complete, and the patient has been observed for 4 to 8 hours.

• Toxicity from MAOI exposures is becoming less common due to more limited clinical usage of the traditional nonselective MAOIs; however, clinical and research use of selective MAOIs and RIMAs is increasing.

• Inhibition of MAO has effects on myriad neuronal neurotransmitters, which are responsible for the majority of the therapeutic and toxic effects of MAOIs.

• The clinical effects of MAOI overdose may be life threatening and should be managed aggressively.

• Aside from overdose, other consequential manifestations of MAOI toxicity may include hyperadrenergic crisis and the serotonin toxicity.

References