Atypical and serotonergic antidepressants are commonly referred to as newer or second-generation antidepressants, to distinguish them from the first-generation monoamine oxidase inhibitors and cyclic antidepressants. As a group, these antidepressants are the most popular form of psychopharmacologic therapy for the treatment of major depression, obsessive-compulsive disorder, panic disorders, and eating disorders.¹ These antidepressants produce less severe toxicity in overdose and are associated with fewer fatalities than either cyclic antidepressants or monoamine oxidase inhibitors.^2,3 This favorable overdose profile is tempered by the U.S. Food and Drug Administration black box warning regarding the use of some agents by patients <24 years old due to increased suicidal ideation and behavior.

This group of antidepressants is a heterogeneous collection of drugs that differ significantly in chemical structure, mechanism of action, pharmacokinetic characteristics, and adverse effect profile.¹ Nonetheless, they also share many important similarities.

Most possess serotonergic activity and, especially in combination with other serotonergic agents, have the potential to produce serotonin syndrome. Thus, they all carry specific warnings about this syndrome, particularly against their combination with monoamine oxidase inhibitors and other high-potency agents.

Most of these antidepressants do not significantly inhibit cardiac sodium, calcium, or potassium ion channels, with a lower risk for cardiac toxicity, which in large part explains their greater safety in overdose compared with cyclic antidepressants. These agents do not inhibit monoamine oxidase activity and are not associated with tyramine-like reactions. Unlike monoamine oxidase inhibitor toxicity, indirect sympathomimetics can be used for hypotension induced by these atypical antidepressants.

These agents have negligible affinity for acetylcholine, dopamine, γ-aminobutyric acid, glutamate, and β-adrenergic receptors. Although their exact mechanism of action remains poorly understood, it is traditionally attributed to inhibition of neurotransmitter reuptake or interruption of negative feedback loops.

These antidepressants are metabolized primarily by hepatic enzyme systems (cytochrome P-450 pathways). If two drugs are given that interact with a common metabolic pathway, drug levels can increase or decrease depending on the interaction. In addition, hepatic dysfunction can lead to elevated drug levels and subsequent drug toxicity. These antidepressants are not detected by routine hospital serum and urine drug screens. Specialty laboratories can measure parent drug and metabolite plasma levels, but this information is useful only for the confirmation of suspected drug overdose. Specific levels are not immediately available, nor do they affect patient management. Postmortem drug redistribution is likely to occur with these agents, which affects forensic investigation.

The atypical antidepressants have unique chemical structures different from each other and from the other antidepressant classes (Table 178-1). They possess some unique clinical features at therapeutic doses and with overdoses.

BUPROPION

Bupropion has a monocyclic phenylaminoketone chemical structure that resembles the phenylethylamines (e.g., amphetamine), but does not produce stimulant effects or drug-addictive behavior at therapeutic dosages. The therapeutic mechanism of action of bupropion is primarily inhibition of neuronal reuptake of norepinephrine and dopamine with very minimal serotonergic activity.⁴

Bupropion is absorbed rapidly after oral administration, with peak plasma levels within 2 hours for regular-release tablets and within 3 hours for sustained-release preparations. Bupropion undergoes extensive first-pass hepatic metabolism, is highly protein bound, has an extremely large volume of distribution, and readily crosses the blood–brain barrier. The active metabolite, hydroxybupropion, although less potent than bupropion, preferentially inhibits norepinephrine reuptake and may contribute to seizure development.

Bupropion antidepressant therapy is well tolerated. It does not produce mental status depression, orthostatic hypotension, or cardiovascular changes, or impair sexual function at therapeutic dosages. The most commonly reported adverse effects at therapeutic dosages are mild and include dry mouth, dizziness, agitation, nausea, headache, constipation, tremor, anxiety, confusion, blurred vision, and increased motor activity.⁵ Seizures with therapeutic dosages are rare, but the incidence increases drastically at dosages of >450 milligrams/d. Bupropion infrequently produces catatonia, hallucinations, psychosis, and paranoia, which are likely related to its dopaminergic activity. Abrupt discontinuation of bupropion has not been associated with withdrawal symptoms, but as a dopamine agonist, it may pose a slight theoretical risk of precipitating neuroleptic malignant syndrome after discontinuation.

Clinical Features

Bupropion differs from other atypical antidepressants in that it has a narrow therapeutic index. Toxicity can occur at dosages equal to or just slightly greater than the maximum therapeutic dose of 450 milligrams/d. Conversely, significant toxicity is not expected in pure bupropion overdose with adult ingestions of <450 milligrams. The most commonly reported symptoms in pure bupropion overdose include agitation, dizziness, tremor, nausea and vomiting, drowsiness, and tachycardia.^6,7 Mild hyperthermia is reported occasionally. Sinus tachycardia is the most common ECG abnormality seen following overdose, but QRS widening and QT interval prolongation have been reported.⁸ Hypotension is unexpected in pure bupropion overdoses but has been reported in mixed-drug overdoses. Hypertension may occur but is usually of only mild to moderate severity. Coma and cardiac arrest have been reported in severe bupropion overdoses.

Seizures are more common with bupropion toxicity than with other atypical antidepressants^7,9 and usually are accompanied by other signs such as sinus tachycardia or altered mental status.^6,7,10 Unfortunately, seizures can develop suddenly in otherwise asymptomatic patients. Seizures usually occur within the first 1 to 4 hours after ingestion of immediate-release bupropion, but their appearance may be delayed for up to 8 hours.⁶ Ingestions of extended-release preparations may predispose patients to seizures up to 24 hours after exposure.¹⁰

Treatment

Establish a peripheral IV line, initiate cardiac rhythm monitoring, and obtain an ECG (Table 178-2). GI decontamination with activated charcoal is recommended provided it can be done within 1 hour of ingestion.⁷ There is no evidence to support multidose activated charcoal or whole-bowel irrigation, even in overdoses of sustained-release products. Ipecac syrup is contraindicated due to the risk of seizures. Early onset of generalized seizures should be anticipated in all cases of bupropion ingestion and treated with benzodiazepines followed by phenobarbital, if necessary.

Hospital admission is recommended for all patients with seizures, persistent sinus tachycardia, or lethargy. Asymptomatic patients who have ingested only regular-release bupropion should be observed for 8 hours before discharge. Adult patients ingesting >450 milligrams of extended-release bupropion require monitoring for at least 24 hours.¹⁰

MIRTAZAPINE

Mirtazapine is a tetracyclic compound structurally unrelated to other currently available antidepressants. In contrast to other atypical antidepressants, mirtazapine does not inhibit neuronal amine uptake.¹ Instead, it blocks central presynaptic α₂-adrenergic receptors and postsynaptic 5-HT₂ and 5-HT₃ receptors. This has the therapeutic effect of increasing central norepinephrine and serotonin neurotransmission. Mirtazapine has a high affinity for blocking histamine-1 receptors and a moderate affinity for blocking muscarinic receptors. These effects commonly produce somnolence, especially in overdose.

Mirtazapine has a pharmacokinetic profile similar to other atypical antidepressants. It is absorbed rapidly with peak plasma levels within 2 hours after ingestion. Bioavailability is approximately 50% due to significant first-pass hepatic metabolism. The elimination half-life for mirtazapine is shorter in males than females, attributed to decreased cytochrome P-450 metabolism in females. Mirtazapine is highly protein bound (85%) and has a large volume of distribution (5 L/kg). Agranulocytosis is a rare but potentially serious complication of chronic mirtazapine use.

Clinical Features

Mirtazapine produces limited toxicity in overdose; the most common features are sedation, confusion, sinus tachycardia, and mild hypertension.^11,12,13 The risk of coma and respiratory depression is greatest at larger doses or when mirtazapine is combined with other sedative drugs.¹³ Cardiac abnormalities such as sinus tachycardia or QT interval prolongation are rarely of clinical significance.^11,12,13

Treatment

Isolated mirtazapine overdose is managed with supportive care alone in the majority of ingestions.^11,12,13 Administer single-dose activated charcoal if the ingestion has occurred within the past hour. Ipecac syrup is contraindicated, and multidose activated charcoal or whole-bowel lavage is unnecessary. Symptomatic patients should be admitted to a monitored bed, but significant cardiac toxicity is very unlikely. Asymptomatic patients can be discharged after 6 hours of observation.

TRAZODONE

Trazodone is a triazolopyridine derivative that is structurally unrelated to other antidepressants. The antidepressant action is believed to be due to a combination of serotonin reuptake inhibition and antagonism of postsynaptic serotonin type 2 (5-HT₂) receptors.¹ Trazodone is a moderately potent nonselective α-adrenergic receptor blocker with at least five times greater affinity for α₁-adrenergic than α₂-adrenergic receptors. Consequently, trazodone is frequently associated with orthostatic hypotension, which is maximal within the first 6 hours after ingestion, so the harmful consequences can be minimized by taking the medication at bedtime. Sedation, which is a common side effect of trazodone therapy, is believed to be secondary to inhibition of central α-adrenergic and histamine receptors.

Trazodone is absorbed rapidly and completely, with peak plasma levels occurring between 1 and 2 hours following oral administration. It is highly protein bound (89% to 95%) and has a moderate volume of distribution (1.2 L/kg). Trazodone primarily undergoes hepatic oxidation by the cytochrome P-450 isoenzyme system producing one active metabolite, meta-chlorophenylpiperazine, which has a complex pharmacologic profile, including inhibition of serotonin uptake, stimulation and inhibition of multiple postsynaptic serotonin receptors, and interactions with other neurotransmitter systems.

The adverse effect profile for trazodone during therapeutic use is very favorable except that trazodone is one of the most common causes of drug-induced priapism, with an estimated incidence ranging from 1 to 10 per 10,000 patients. Trazodone should be discontinued immediately in any patient with a history of increased frequency of, increased duration of, or inappropriate penile or clitoral engorgement. Rare case reports describe reversible elevation of liver enzyme levels, jaundice, and abnormal liver histologic findings in association with trazodone therapy. Trazodone has been reported occasionally to be arrhythmogenic during therapeutic use, especially in patients with underlying cardiac risk factors such as conduction abnormalities or ischemic heart disease.

Clinical Features

The most common symptom of acute trazodone poisoning is CNS depression. Other neurologic symptoms include ataxia and dizziness, and rarely, coma and seizures. Coma and seizures are more common when another epileptogenic drug is co-ingested. Pupils are usually of normal size and remain reactive. Trazodone-induced neurologic symptoms show marked improvement within 6 to 12 hours after ingestion and almost always resolve by 24 hours. Orthostatic hypotension is the most frequently reported cardiovascular abnormality noted in trazodone overdose and usually responds to fluid administration. The most common ECG abnormality is moderate prolongation of the QT interval.¹⁴ Polymorphic ventricular tachycardia (torsades de pointes) has been reported in rare cases.¹⁵ Commonly reported GI complaints include nausea, vomiting, and nonspecific abdominal pain. Respiratory depression is unlikely with pure trazodone overdoses.

Treatment

Establish IV access, initiate cardiac rhythm monitoring, and obtain an ECG (Table 178-3). GI decontamination with single-dose activated charcoal can be used in appropriate patients who present within 1 hour. Patients who ingest >2 grams of trazodone or co-ingest other substances are at increased risk for serious toxicity with coma, seizures, respiratory arrest, cardiac dysrhythmias, and cardiac arrest.

Hypotension is treated initially with isotonic IV fluid administration. For persistent hypotension, use a direct-acting vasopressor (e.g., norepinephrine). Drugs with β-adrenergic receptor activity (e.g., dopamine) theoretically can worsen the hypotension in the presence of trazodone-induced α-adrenergic receptor antagonism. Treat QT interval prolongation and/or torsades de pointes dysrhythmia with IV magnesium sulfate, followed by cardiac pacing as needed.¹⁵

Patients who have remained asymptomatic for at least 4 to 6 hours can be discharged safely from the ED, provided that necessary psychiatric evaluation has been completed or arranged. Patients with neurologic and/or cardiac symptoms require hospital admission to a monitored bed.