Antidepressants

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Chapter 151

Antidepressants

Depression is one of the most common medical conditions in the United States, with a lifetime prevalence of 16.2%.1 Whereas many treatment strategies are used in the management of depressed patients, pharmacotherapy remains a cornerstone of modern practice. Modern antidepressant therapy hinges on the 50-year-old monoamine hypothesis, which suggests that depressive symptoms are mediated through an imbalance of the dopaminergic, noradrenergic, and serotonergic systems.1,2 As a result, numerous antidepressant classes have emerged in an attempt to increase synaptic monoamine concentrations.

In the early 1950s, isoniazid and iproniazid were introduced for the treatment of tuberculosis. Shortly after, it was noted that these patients had improved mood, which was attributed to the ability of iproniazid to inhibit monoamine oxidase. Iproniazid, a derivative of isoniazid, subsequently became the first drug marketed specifically as an antidepressant.3 This led to the advent of other monoamine oxidase inhibitors (MAOIs). In 1956, the antidepressant effect of imipramine, a tricyclic agent, was recognized, and it was marketed the following year.4 The MAOIs and tricyclic antidepressants (TCAs) became the mainstay for treatment of depression for several decades until the advent of the safer selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Antidepressant overdose is highly lethal. It accounts for only 3.7% of human exposures reported to U.S. Poison Control Centers but is involved in 10.5% of all poisoning fatalities.5

Monoamine Oxidase Inhibitors

Principles of Disease

Monoamine oxidase (MAO) is located on the outer mitochondrial membrane and is responsible for breakdown of cytoplasmic catecholamines. Type A (MAO-A) primarily deaminates serotonin and norepinephrine; type B (MAO-B) primarily deaminates phenylethylamine.6 Tyramine and dopamine are metabolized equally by both isoenzymes.3 Whereas most tissues contain both isozymes, MAO-A is primarily found in the placenta, sympathetic nerve terminals, and intestinal mucosa; MAO-B is found primarily in platelets and the basal ganglia.3

Drugs targeting the monoamine oxidase system can act as specific or nonspecific inhibitors. The first-generation MAOIs are nonselective and irreversible. Drugs belonging to this class include phenelzine, isocarboxazid, and tranylcypromine. The second-generation MAOIs can preferentially inhibit either MAO-A or MAO-B.

Although MAOIs have fallen out of favor for treatment of depression, their use in treatment of Parkinson’s disease is increasing. Drugs that selectively inhibit MAO-B disproportionately increase dopamine concentrations in the striatum.7 Selegiline is an irreversible MAO-B inhibitor used in the treatment of Parkinson’s disease. Although it is marketed as a selective inhibitor of MAO-B, at high doses its receptor specificity is lost, and it can cause inhibition of MAO-A as well.8 Rasagiline is also an irreversible inhibitor of MAO-B but appears to be more potent than selegiline.6 Furthermore, unlike selegiline, which is metabolized to L-methamphetamine, rasagiline is not metabolized to an amphetamine derivative.6

In addition to its antibiotic properties, linezolid, an oxazolidinone class antibiotic, is a reversible inhibitor of monoamine oxidase. Specifically, linezolid can produce significant inhibition of MAO-A.

As a class, MAOIs are rapidly absorbed from the gastrointestinal tract and are bound extensively to plasma proteins. With overdose, the MAOIs initially stimulate release of neurotransmitters from the presynaptic neuron but later inhibit their release.

Clinical Features

Patients have MAOI toxicity as a result of an acute overdose or as a consequence of a food or drug interaction. Depending on the scenarios that lead to toxicity, the clinical presentations may be very different.

After an overdose, patients may have symptoms within several hours or may be asymptomatic for up to 24 hours before significant, possibly 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. Laboratory abnormalities are nonspecific but can include hyperglycemia, leukocytosis, and elevated creatine kinase.

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 aged cheeses, red wine, smoked or pickled and aged meats, and other foods. Usually, tyramine is metabolized in the gut and liver by monoamine oxidase, 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.9 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.10

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, so use of medications with serotonin-potentiating activity should be avoided in patients taking MAOIs.

Management

Even if they are initially asymptomatic, all patients presenting after an MAOI overdose should be admitted or observed in a monitored setting until 24 hours after the ingestion because of the risk of delayed, rapid deterioration. As with most intoxications, supportive care is paramount. Central nervous system (CNS) excitation should be treated with intravenous administration of benzodiazepines, such as lorazepam and diazepam, in usual titrated doses. Hyperthermia should be treated with external cooling. Mild hypertension should not be treated, but severe hypertension is best managed with a rapid, short-acting agent, such as phentolamine or nitroprusside. Hypotension should first be managed by aggressive volume resuscitation. 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, is not likely to be beneficial. Extracorporeal elimination is also unlikely to be beneficial because of extensive protein binding and large volume of distribution of MAOIs. Because of the potential for intracranial hemorrhage in the setting of severe MAOI-induced hypertension, patients with a seizure or significant neurotoxicity should undergo a non–contrast-enhanced head computed tomography (CT) scan.

Patients presenting with a tyramine reaction may have spontaneous resolution of symptoms during 6 hours. Severe hypertension higher than 200 mm Hg systolic with symptoms may be treated with phentolamine or nitroprusside. Patients with persistent severe headache and hypertension should have a head CT scan to look for intracranial hemorrhage. Patients with chest pain should be evaluated for myocardial infarction (see Chapter 26).

Treatment of suspected serotonin syndrome is supportive (see later section).

Tricyclic Antidepressants

Principles of Disease

In the 1950s, imipramine became the first tricyclic antidepressant (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.11 Whereas use of TCAs for treatment of depression has waned, use for other conditions, including nocturnal enuresis, attention-deficit/hyperactivity syndrome, trigeminal neuralgia, and migraines, has increased.

Clinical Features

Cyclic antidepressant toxicity can result from overdose of a TCA or drug-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 can decrease metabolism of these drugs, resulting in unexpectedly high serum concentrations and clinical toxicity.12 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-drug interactions. Another drug interaction that occurs with TCAs is the serotonin syndrome, which occasionally results when a TCA is combined with another serotonergic drug, such as MAOI or SSRI.

After an overdose of a TCA, symptoms typically begin within 1 to 2 hours. With smaller ingested amounts, symptoms may be minimal and resolve quickly; patients who take large amounts may deteriorate rapidly soon after ingestion. All seriously poisoned patients have symptoms within 6 hours of an overdose. Early TCA poisoning is characterized primarily by anticholinergic effects. Patients typically present with tachycardia, flushed and dry skin, mydriasis, and altered level of consciousness. They may be alert and confused, severely agitated, mute, hallucinating, or even deeply comatose. Speech is often rapid and mumbling in character. Urinary retention is common. Seizures may occur and are likely to be multifactorial, resulting from increased synaptic monoamines, sodium channel inhibition, and possibly γ-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 myocardial depression resulting from severe sodium channel antagonism may also lead to hypotension and bradycardia.13,14 Significant sodium channel blockade is associated with widening of the QRS interval. TCAs also block potassium efflux, which leads to a prolonged QT interval.15 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-drug interactions or decreased ability to metabolize the drug because of genetic polymorphism may be manifested in a more subtle fashion. Confusion, urinary retention, and prolonged QTc interval are common. Chronic toxicity presents more gradually and should be considered in any confused patient taking therapeutic doses of a TCA.

Diagnostic Strategies

After overdose, the electrocardiogram can yield prognostic information. Early anticholinergic effects cause sinus tachycardia, which occurs virtually uniformly before other effects. Whereas the serum tricyclic concentrations are not particularly beneficial in predicting adverse events, the electrocardiogram is prognostic. A QRS duration longer than 100 milliseconds is predictive of seizures, whereas a QRS duration longer than 160 milliseconds is predictive of ventricular dysrhythmias.16 Additional findings on the electrocardiogram include a rightward shift of the terminal 40 milliseconds of the QRS complex seen as an R wave in aVR longer than 3 milliseconds.17 QT prolongation is less important clinically 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. Serum tricyclic levels do not correlate with severity of illness.16 General management (see Chapter 147) suggests other supportive care measures.

Differential Considerations

Other agents with anticholinergic properties produce a similar early clinical presentation. In addition, sympathomimetic toxicity, serotonin syndrome, and hypoglycemia should be included in the differential diagnosis. Other toxins causing sodium channel blockade, a wide QRS, and subsequently intraventricular conduction delay include Vaughn-Williams class IA antidysrhythmics (e.g., procainamide, disopyramide, quinidine) and class IC antidysrhythmics (e.g., flecainide, encainide, and propafenone), amantadine, carbamazepine, cocaine, diphenhydramine, mesoridazine, and thioridazine. In addition, 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.

Management

Ensuring stability of the airway, breathing, and circulation is of primary importance. There are no randomized controlled trials demonstrating improved patient-oriented outcomes (e.g., improved mortality) with activated charcoal in patients with cyclic antidepressant overdose. Nonetheless, because of the high lethality of the acute overdose, a patient who presents within 1 hour after ingestion and who is awake and alert can be given activated charcoal, if it is recommended by the regional poison center consultant and if the patient will readily drink it. It should not be administered to patients who are unwilling or unable to voluntarily consume it and is contraindicated if the patient has any decreased level of consciousness because charcoal aspiration may pose a greater risk to the patient than the benefit, if any, of charcoal administration. 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. Early hypertension should not be treated. Hypotensive patients should first receive fluid resuscitation with an isotonic crystalloid.13 Patients who remain hypotensive should be treated with direct-acting vasopressors, such as norepinephrine and epinephrine.13,14 There are some data that epinephrine may be superior to norepinephrine in this setting.

Hypertonic sodium bicarbonate should not be given prophylactically and should be given only to treat specific evidence of sodium channel blockade, such as a wide QRS and ventricular dysrhythmias. Recommendations vary about how to administer this therapy. A conservative approach is to administer a bolus of 1 to 2 mEq/kg hypertonic sodium bicarbonate if the QRS interval exceeds 100 milliseconds. This dose may be repeated in a few minutes if the QRS does not narrow. A sodium bicarbonate infusion can be used to maintain a pH between 7.50 and 7.55.13

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