Antidepressants

Clinical Features

Patients may develop toxicity from an MAOI either as a result of an interaction with a medication or food, or because of an overdose. Depending on the scenario that leads to toxicity, the clinical presentation may vary. Obtaining a thorough medication history is critical to establishing the diagnosis of MAOI toxicity. After acute overdose, a patient may remain asymptomatic for up to 24 hours before life-threatening toxicity develops. After this asymptomatic period, hyperadrenergic symptoms, including tachycardia, hypertension, and hyperthermia, can develop. Seizures, rhabdomyolysis, coma, and ultimately cardiovascular collapse can occur once presynaptic catecholamines are depleted.

Patients who take nonselective MAOIs in therapeutic doses are at risk for food-drug interactions. Tyramine is an indirectly acting sympathomimetic amine that is present in foods including aged cheeses, red wine, smoked or pickled and aged meats. Usually, tyramine is metabolized in the gut and liver by MAO, rarely causing systemic effects. When MAO-A is inhibited, tyramine is absorbed systemically and enters presynaptic vesicles, ultimately causing release of norepinephrine and serotonin into the synapse, leading to a hypertensive crisis. This tyramine syndrome, which can occur within minutes to hours of ingestion of foods with high tyramine content, is characterized by headache, hypertension, flushing, and diaphoresis. This syndrome can occur up to 3 weeks after discontinuation of a nonselective MAOI. Although it is theoretically possible, this syndrome is rare with therapeutic use of MAO-B inhibitors. A drug-drug interaction may result when MAOIs are combined with other agents that have serotonergic effects. A variety of prescription and over-the-counter medications may interact with MAOIs to produce a constellation of symptoms referred to as serotonin syndrome (see later section). This syndrome may be life-threatening, therefore the use of medications with serotonin-potentiating activity should be avoided in patients taking MAOIs.

Differential Diagnoses

The differential diagnosis for MAOI toxicity includes sympathomimetic drugs of abuse such as cocaine and amphetamine derivatives, anticholinergic (or antimuscarinic) toxicity (e.g., diphenhydramine, cyclic antidepressants, anti-Parkinson drugs, and jimson weed), and methylxanthine toxicity (e.g., theophylline and caffeine). Other toxicologic considerations include acute withdrawal states (e.g., ethanol and benzodiazepines), neuroleptic malignant syndrome (NMS), and the serotonin syndrome from other serotonergic drug combinations. Nontoxicologic causes to consider include environmental hyperthermia or heatstroke, febrile illness from infectious causes (e.g., meningitis and encephalitis), pheochromocytoma, carcinoid syndrome, thyroid storm, and hypertensive emergency.

Diagnostic Testing

Laboratory abnormalities are nonspecific but can include hyperglycemia and leukocytosis, secondary to a hyperadrenergic state, and elevated creatine kinase due to rhabdomyolysis. Immunoassay urine drug screens that are commonly used in the emergency department do not detect MAOIs, and even gas chromatography–mass spectroscopy of urine may fail to detect the presence of an MAOI. Patients taking selegiline will test positive for methamphetamine because methamphetamine is a metabolite. Spectral analysis is needed to differentiate illicit methamphetamine from selegiline.

Symptomatic patients presenting after an MAOI overdose should have an electrocardiogram (ECG) to assess the QT and QRS intervals and for evidence of cardiac ischemia. Patients with chest pain should be evaluated for myocardial infarction. Measurement of serum glucose and electrolytes are indicated if the patient is obtunded. Because of the potential for intracranial hemorrhage in the setting of severe MAOI-induced hypertension, patients with a seizure or focal neurologic deficit should undergo a non–contrast-enhanced head computed tomography (CT) scan.

Management

As with most intoxications, supportive care is paramount. Central nervous system (CNS) excitation should be treated with intravenous (IV) administration of benzodiazepines such as lorazepam and diazepam in titrated doses. Lorazepam may be given IV in a dose of 1 to 4 mg, depending on the severity of symptoms. Dosing can be repeated at 5- to 15-minute intervals for patients with severe toxicity. Alternatively, diazepam, 5 mg IV every 5 to 10 minutes, can be given until the patient is stabilized. Hyperthermia should be treated with external cooling using evaporative techniques and strategic ice packing. Antipyretics such as acetaminophen or nonsteroidal antiinflammatory medications have no role in the management. Hyperthermia that persists, despite administration of benzodiazepines and external cooling measures, may need intubation, ventilation, and chemical paralysis with a nondepolarizing neuromuscular blocker, such as rocuronium (0.6 to 1.2 mg/kg IV). The use of succinylcholine is discouraged as this may cause hyperkalemia if rhabdomyolysis has occurred, and fasciculation from succinylcholine may further increase metabolic heat production. Furthermore, many of these patients are already acutely hyperkalemic, which is a relative contraindication to succinylcholine. Mild hypertension should not be treated, but sustained severe hypertension (e.g., systolic blood pressure exceeding 200 mm Hg or a diastolic exceeding 100 mm Hg) is best managed with a rapid onset, short-acting agent such as phentolamine (titrated slowly by repeated IV doses of 1 mg every 3 minutes) or nitroprusside (0.25 to 0.5 mcg/kg/min by IV infusion). Treatment should target a 25% reduction in the mean arterial pressure. Hypotension should first be managed by volume resuscitation with normal saline. Persistent or severe hypotension requires treatment with infusion of a direct-acting catecholamine such as norepinephrine or epinephrine. Because hypotension and cardiovascular collapse after MAOI overdose are due to catecholamine depletion, the use of indirect-acting agents such as dopamine are not likely to be beneficial. Extracorporeal elimination methods such as hemodialysis are also unlikely to be beneficial because of extensive protein binding and large volume of distribution of MAOIs.

Patients presenting with a tyramine reaction may have spontaneous resolution of symptoms within 6 hours. Severe hypertension higher than 200 mm Hg systolic with symptoms such as headache, flushing, or chest pain should be treated with phentolamine or nitroprusside. Patients with persistent severe headache and hypertension should have a head CT scan to assess for intracranial hemorrhage. Patients with chest pain should be evaluated for myocardial infarction (see Chapter 64 ).

Treatment of suspected serotonin syndrome is supportive (see later section) and consists primarily of benzodiazepine administration and active cooling measures.

Disposition

Patients presenting with an MAOI overdose should be admitted to a monitored setting for 24 hours due to the risk of delayed, rapid deterioration and development of hyperadrenergic symptoms. Asymptomatic patients chronically taking an MAOI who present out of concern for a possible drug-food interaction can be discharged after 6 hours if no signs of toxicity develop over that period. The care of any patient with suspected toxicity from an MAO inhibitor should be discussed with a medical toxicologist or poison control center (800-222-1222).

Principles of Toxicity

In the 1950s, imipramine became the first TCA used for the treatment of depression. Until the introduction of the SSRIs, TCAs remained the primary agents for treatment of depression. The therapeutic benefit of TCAs results from monoamine reuptake inhibition. Whereas use of TCAs for treatment of depression has waned, use for other conditions, including treatment of migraines, various neuropathies, trigeminal neuralgia, and nocturnal enuresis has increased.

Clinical Features

Cyclic antidepressant toxicity can result from overdose of a TCA or drug interactions. Overdose is more commonly associated with life-threatening toxicity, but toxic effects can also occur when a TCA is combined with drugs that impair its metabolism through cytochrome P450. Tertiary amine TCAs such as amitriptyline, imipramine, and clomipramine are substrates of CYP2C19 and CYP1A2. Doxepin is also a substrate for CYP2D6. Drug-induced inhibition of these enzymes as well as genetic polymorphisms of these isoenzymes can decrease metabolism of these drugs, resulting in unexpectedly high serum concentrations and clinical toxicity. Conversely, inhibition of CYP2D6 and other P450 enzymes by these TCAs can also lead to increased serum concentrations of other drugs metabolized by the same enzymes. Because desipramine and nortriptyline are only weak CYP2D6 inhibitors, they cause fewer drug interactions. Another toxicity that can occur with TCAs is serotonin syndrome, which can result when a TCA is combined with another serotonergic drug such as an MAOI or SSRI.

Following a TCA overdose, clinical toxicity typically begins within 1 to 2 hours. When smaller quantities are ingested, symptoms may be minimal and resolve quickly; patients who take large amounts may deteriorate rapidly soon after ingestion. Severely poisoned patients typically have symptoms within 1 to 2 hours after ingestion, but nearly always by 6 hours after ingestion. Early cyclic antidepressant toxicity (within the first 2 hours) is primarily characterized by anticholinergic effects. These findings include dry mucosal membranes, urinary retention, and hot dry skin. Despite having potent antimuscarinic properties, the pupils are often small due to competing alpha effects. Patients may be alert and confused, severely agitated, hallucinating, or even deeply comatose. Speech is often rapid and mumbling in character. Seizures may occur and are likely to be multifactorial, resulting from increased synaptic monoamines, sodium channel inhibition, and gamma-aminobutyric acid (GABA) receptor antagonism. Early hypertension is common from the anticholinergic effects of the TCA and excess norepinephrine in the synapse from blockade of norepinephrine reuptake, but hypotension may also be due to alpha-receptor antagonism and also norepinephrine depletion.

Later (2 to 6 hours post ingestion), myocardial depression resulting from severe sodium channel antagonism may also lead to hypotension and bradycardia. Significant sodium channel blockade is associated with widening of the QRS interval. The degree of widening is prognostic for both arrhythmias and seizures. Tricyclic antidepressants also block potassium efflux, which leads to a prolonged QT interval. Clomipramine and amitriptyline are especially associated with QT prolongation. Furthermore, clomipramine is associated with significant QT dispersion, which has been shown to be a risk for ventricular arrhythmias and mortality. With severe poisoning, the combined effects of the TCA on various receptors and ion channels lead to depressed level of consciousness, seizures, hypotension, and wide-complex cardiac arrhythmias.

Chronic toxicity from drug interactions or decreased ability to metabolize the drug because of genetic polymorphism may be manifested in a less evident fashion. Confusion, urinary retention, and prolonged corrected QT (QTc) interval are common. Chronic toxicity presents more gradually and should be considered in any confused patient taking therapeutic doses of a cyclic antidepressant.

Differential Diagnoses

Many agents with anticholinergic properties produce similar clinical features as TCAs. Diphenhydramine and carbamazepine, in particular, can also produce seizure and sodium-channel blockade. Agents that produce sympathomimetic toxicity (e.g., cocaine, amphetamines) or serotonin syndrome (e.g., SSRIs, MAOIs) should be included in the differential diagnosis. Other drugs with sodium channel blockade, and hence a wide QRS complex, include the Vaughn-Williams class IA antidysrhythmics (e.g., procainamide, disopyramide, quinidine) and class IC antidysrhythmics (e.g., flecainide, encainide, and propafenone), along with amantadine, carbamazepine, cocaine, diphenhydramine, mesoridazine, and thioridazine. Propoxyphene and propranolol can also cause an intraventricular conduction delay by sodium channel blockade but typically cause a bradycardic rhythm rather than a tachycardic rhythm. The constellation of early anticholinergic symptoms, decreased level of consciousness followed by seizures, wide QRS and cardiovascular collapse, is highly suggestive of acute TCA overdose.

Diagnostic Testing

After overdose, the ECG can yield prognostic information. Early anticholinergic effects cause sinus tachycardia, which occurs uniformly before other effects. Whereas the serum tricyclic concentrations are not particularly beneficial in predicting adverse events, the ECG is prognostic. Historically, it is felt that QRS duration longer than 100 milliseconds is predictive of seizures, whereas QRS duration longer than 160 milliseconds is predictive of ventricular dysrhythmias, but hard evidence does not exist for either of these assertions. Additional findings on the ECG include a rightward shift of the terminal 40 milliseconds of the QRS complex seen as an R wave in augmented vector right (aVR) longer than 3 milliseconds. Figure 141.1 demonstrates lead aVR following a tricyclic ingestion. QT prolongation has less prognostic value than the QRS duration.

Urine drug of abuse screens commonly test for the presence of TCAs, but a positive test result suggests only use of a TCA or another xenobiotic that cross-reacts with the screen (e.g., antipsychotic medications, antimuscarinic agents, carbamazepine, or the muscle relaxant cyclobenzaprine). Quantitative serum tricyclic levels do not correlate well with severity of illness.

Management

Ensuring stability of the airway, with adequate ventilation, and volume repletion are of primary importance. There are no randomized controlled trials demonstrating improved patient-oriented outcomes and decreased mortality with activated charcoal administration in patients with cyclic antidepressant overdose. Nonetheless, because of the high lethality of the acute overdose, a patient who presents within 1 hour after an overdose and who is awake, alert, and cooperative and is not exhibiting any signs of toxicity (e.g., no tachycardia or intraventricular conduction delay) can be given oral activated charcoal. Patients who are not cooperative or who are not willing to drink charcoal should not have a nasogastric tube inserted for the sole purpose of administering charcoal. Due to risk of seizures with subsequent aspiration, activated charcoal is not routinely recommended in patients with an unprotected airway who are already exhibiting toxicity. There is no role for gastric lavage.

Patients with sinus tachycardia alone do not need specific treatment but should be monitored to detect QRS widening early in the clinical course. Early hypertension should not be treated. Hypotensive patients should first receive fluid resuscitation with an isotonic crystalloid. Patients who remain hypotensive should be treated with direct-acting vasopressors such as norepinephrine and epinephrine.

Hypertonic sodium bicarbonate is given only to treat specific evidence of sodium channel blockade such as a wide QRS and ventricular dysrhythmias. Sodium bicarbonate should not be given strictly to treat tachycardia. Recommendations regarding the specific administration of sodium bicarbonate vary. We recommend a conservative approach by administering a bolus of 1 to 2 mEq/kg hypertonic sodium bicarbonate intravenous push (IVP) if the QRS interval exceeds 100 milliseconds. This dose may be repeated in 5 to 10 minutes if the QRS does not narrow. After IV bolus, a sodium bicarbonate infusion can be used to maintain a serum pH between 7.50 and 7.55. Such an infusion can be created by the addition of 150 mEq sodium bicarbonate and 850 mL of dextrose 5% in water (D5W). The infusion should be created with a 5% dextrose solution, and not normal saline, due to the risk of hypernatremia with the latter. The infusion should be administered at twice the normal maintenance rate, titrating to QRS width and serum pH. Alternatively, infusions of 1 mEq sodium bicarbonate per milliliter of fluid may be used if volume overload is a concern. Additional IV boluses of sodium bicarbonate may be necessary if the QRS widens. The use of a bicarbonate-containing infusion should not be a substitute for IV sodium bicarbonate boluses for the initial treatment of intraventricular conduction delay. Figure 141.2 demonstrates a 12-lead ECG from a patient poisoned with a TCA before and after sodium bicarbonate therapy. If ventricular dysrhythmias persist despite maximal alkalinization (pH > 7.55), 3% hypertonic saline (in an adult) can be used. Class Ia or Ic antidysrhythmics should be avoided. Seizures are best treated with an IV benzodiazepine (lorazepam 1 to 4 mg IVP; diazepam 5 to 10 mg IVP) along with sodium bicarbonate. Refractory seizures can be treated with phenobarbital (15 to 20 mg/kg IV loading dose). Because seizure leads to acidosis and worsens the cardiac status, patients with intractable seizures who do not respond to benzodiazepines or phenobarbital should be rapidly paralyzed, intubated, and mechanically ventilated to prevent increasing metabolic acidosis.

Physostigmine, the antidote of choice for pure anticholinergic toxicity (see Chapter 140 ), is considered by many experts to be relatively contraindicated in the management of TCA overdose. Asystole has been reported after physostigmine use in TCA toxicity, particularly in patients with bradycardia and AV block. It is not advised to administer this agent to patients with QRS or QTc prolongation following TCA overdose. However, we recommend it be considered in patients with delirium of unclear etiology who are therapeutically taking anticholinergic agents and in whom toxicity is suspected, but only if there is no bradycardia, no history of seizures, and the PR, QRS, and QTc intervals are normal. Physostigmine (1 to 2 mg slow IV infusion over 5 minutes in adults) should be given with caution in a monitored setting, because it may exacerbate bradycardia, AV block, and seizures related to the overdose (see Chapter 140 ).

Intravenous lipid emulsion (ILE) therapy has gained interest recently for reversal of toxicity caused by lipophilic drugs, including TCAs. Although the exact mechanism of ILE is not clearly defined, it likely involves redistribution of a lipophilic drug from the tissue receptors back into the vascular compartment in the context of a large bolus of concentrated lipid solution, the so-called lipid sink phenomenon. Other mechanisms such as enhanced cardiac metabolism are also possible explanations. Because not all studies reveal beneficial effects from ILE in the treatment of TCA toxicity and due to the potential for iatrogenic harm, its use is currently reserved for life-threatening toxicity that remains refractory to sodium bicarbonate administration. ILE should be administered only on advice of a medical toxicologist or regional poison center. If ILE is to be administered, there are several different dosing strategies. We recommend 1.5 mL/kg of a 20% lipid solution over 2 to 3 minutes. This bolus can be repeated once in 5 minutes if there is no clinical improvement. If clinical improvement does occur, the bolus may be followed by an infusion of 0.25 mL/kg/min.

Complications of ILE include extreme lipemia resulting in interference with laboratory blood tests (complete blood counts, chemistries, and coagulation studies), as well as acute pancreatitis, and acute respiratory distress syndrome.

Disposition

If the heart rate has not exceeded 100/minute for a sustained period of time (at least 10 to 15 minutes), ECG intervals are normal, level of consciousness is normal, and no seizures have developed within 6 hours of a TCA overdose, it is unlikely that toxicity will occur. The patient can be medically cleared from the ED for psychiatric evaluation and disposition if needed. Patients with signs of cyclic antidepressant cardiotoxicity, seizures, or coma should be admitted to an intensive care unit.