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CHAPTER 178: Atypical and Serotonergic Antidepressants 1199 >100 milliseconds. Hyperventilation represents a reasonable alter native to sodium bicarbonate therapy in the setting of renal failure, pulmonary edema, or cerebral edema, although hyperventilation is less effective in reversing toxicity. Ventricular dysrhythmias should be treated with sodium bicarbonate. Consider 3% hypertonic saline, 1 to 3 mL/kg IV over 10 minutes, to decrease ventricular ectopy or dysrhythmia in a patient with cardiotox icity refractory to sodium bicarbonate therapy. Torsades de pointes should be treated initially with 2 grams of IV magnesium sulfate. Identify and treat electrolyte disorders that are associated with torsades de pointes. Overdrive pacing may be considered for refractory tachydysrhythmias. Older case reports indicate that IV isoproterenol may be of some benefit when overdrive pacing is not available. The following medications are contraindicated in the treatment of cyclic antidepressant–induced dysrhythmias: all class I antiar rhythmic agents, β-blockers, calcium channel blockers, and all class III antiarrhythmic agents. Lidocaine, a sodium channel blocker, has unclear benefits in cyclic antidepressant–induced dysrhythmias, and there are no convincing data to support its effectiveness.  LIPID EMULSION Cyclic antidepressants are highly lipid soluble, and it has been postu lated that IV lipid emulsion creates a “lipid sink” that sequesters the drug and prevents toxicity. 32 Case descriptions of lipid emulsion ther apy for cyclic antidepressant overdoses report benefit, 33-39 no benefit, 40 and complications.32,41 Currently, there is no consensus or convincing evidence for the use of lipid emulsion in cyclic antidepressant toxicity.20,42-44 In patients with cardiotoxicity refractory to other measures, it seems reasonable to infuse a 20% lipid emulsion in an amount based on that recommended for local anesthetic systemic toxicity: 100 mL IV bolus (1.5 mL/kg) over 2 to 3 minutes, followed by an infusion of 18 mL (0.25 mL/kg) per minute to a total dose of 10 mL/kg. DISPOSITION AND FOLLOW-UP Patients who remain asymptomatic after 6 hours of observation do not require hospital admission for toxicologic reasons. 10 All symptomatic patients require hospital admission to a monitored bed. Patients demonstrating signs of moderate to severe toxicity should be admitted to an intensive care unit. Hospitalized patients can be cleared medically after they are asymptomatic, with a normal or baseline ECG, normal mental status, and resolution of all antimuscarinic symptoms. Patients with an intentional overdose require mental health evaluation. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Atypical and Serotonergic Antidepressants Frank LoVecchio Erik G. Mattison  INTRODUCTION 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 antidepres sants. 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. CHAPTER These antidepressants produce less severe toxicity in overdose and are associated with fewer fatalities than either cyclic antidepressants or monoamine oxidase inhibitors. 2-4 This favorable overdose profile is tempered by the U.S.

epression, obsessive-compulsive disorder, panic disorders, and eating disorders. CHAPTER These antidepressants produce less severe toxicity in overdose and are associated with fewer fatalities than either cyclic antidepressants or monoamine oxidase inhibitors. 2-4 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 Nonethe less, 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. These agents have negligible affinity for acetylcholine, dopamine, γ-aminobutyric acid, glutamate, and β-adrenergic receptors. These agents do not inhibit monoamine oxidase activity and are not associated with tyramine-like reactions. Most of these antidepressants do not significantly inhibit cardiac sodium, calcium, or potassium ion channels. 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 P450 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 and does not affect patient management.  SPECIFIC AGENTS ATYPICAL ANTIDEPRESSANTS The atypical antidepressants have 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. 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. The most com monly 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. 6 Bupropion infrequently produces catatonia, hallucinations, psychosis, and paranoia, which are likely related to its dopaminergic activity.

therapeutic dosages are mild and include dry mouth, dizziness, agitation, nausea, headache, constipation, tremor, anxiety, confusion, blurred vision, and increased motor activity. 6 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 antidepres sants in that it has a narrow therapeutic index and possesses high morbidity and mortality indices after exposure. 4,7 Toxicity can occur Tintinalli_Sec15_p1187-1332.indd 1199 8/2/19 8:39 PM

pitating neuroleptic malignant syndrome after discontinuation. Clinical Features Bupropion differs from other atypical antidepres sants in that it has a narrow therapeutic index and possesses high morbidity and mortality indices after exposure. 4,7 Toxicity can occur Tintinalli_Sec15_p1187-1332.indd 1199 8/2/19 8:39 PM 1200 SECTION 15: Toxicology at dosages equal to or just slightly greater than the maximum thera peutic 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. 8,9 Mild hyperthermia is reported occasionally. Sinus tachycardia is the most common ECG abnormality seen following overdose, but QRS widening and QT interval prolon gation have been reported. 10,11 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 sever ity. Coma and cardiac arrest have been reported in severe bupropion overdoses. Seizures are more common with bupropion toxicity than with other atypical antidepressants 9,12 and usually are accompanied by other signs such as sinus tachycardia or altered mental status. 8,9,13 Seizures can develop suddenly in otherwise asymptomatic patients. Seizures usually occur within the first 1 to 4 hours after ingestion of immediaterelease bupropion, but their appearance may be delayed for up to 8 hours. Ingestions of extended-release preparations may predispose patients to seizures up to 24 hours after exposure. 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. 9 There is no evidence to support multidose activated charcoal or whole-bowel irrigation, even in overdoses of sustainedrelease 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 extendedrelease bupropion require monitoring for approximately 24 hours.  MIRTAZAPINE Mirtazapine is a tetracyclic compound that, in contrast to other atypi cal antidepressants, does not inhibit neuronal amine uptake.1 Instead, it TABLE 178-1 Atypical Antidepressants Agent Recommended Maximum Daily Adult Dose (milligrams) Elimination Half-Life Parent Compound (h) Major Active Metabolite Bupropion 450 10–21 Hydroxybupropion Mirtazapine 45 20–40 Desmethylmirtazapine Nefazodone 600 2–4 Hydroxy-nefazodone Trazodone 400 3–6 (first phase) 5–9 (second phase) Meta-chlorophenylpiperazine Vilazodone 40 25 None Vortioxetine 20 66 None TABLE 178-2 Treatment of Bupropion Overdose •   IV access, cardiac rhythm monitor, and ECG •   Anticipate seizures; be prepared to treat with benzodiazepines •   Single-dose activated charcoal if ingestion within 1 h, especially if extended-release formulation •   Sodium bicarbonate for QRS complex prolongation >110 ms •   Magnesium sulfate for QTc interval prolongation >500 ms •   Consider IV lipid emulsion therapy for refractory  cardiovascular  instability (case reports only) blocks central presynaptic α2-adrenergic receptors and the postsynaptic serotonin 5-HT2 and 5-HT 3 receptors.

icarbonate for QRS complex prolongation >110 ms •   Magnesium sulfate for QTc interval prolongation >500 ms •   Consider IV lipid emulsion therapy for refractory  cardiovascular  instability (case reports only) blocks central presynaptic α2-adrenergic receptors and the postsynaptic serotonin 5-HT2 and 5-HT 3 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 P450 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. 14-16 The risk of coma and respiratory depression is greatest at larger doses or when mirtazapine is combined with other sedative drugs. 16 Cardiac abnormalities such as sinus tachycardia or QT interval prolongation are rarely of clinical significance.14-16 Treatment Isolated mirtazapine overdose is managed with supportive care alone in the majority of ingestions.14-16 Administer single-dose activated charcoal if the ingestion has occurred within the past hour. Ipecac syrup is contraindicated, and multidose activated charcoal or wholebowel 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.  NEFAZODONE Nefazodone overdose is relatively benign; the most common symptom is drowsiness. 17 Hypotension, mild bradycardia, and prolonged QT interval can be seen in rare cases. 17,18 In general, symptoms occurred within 2 hours of ingestion and resolved with time and minimal sup portive care.17,18  TRAZODONE Trazodone is a triazolopyridine derivative with an antidepressant action believed to be due to a combination of serotonin reuptake inhibition and antagonism of postsynaptic serotonin 5-HT 2 receptors.1 Trazodone is a moderately potent nonselective α-adrenergic receptor blocker with at least five times greater affinity for α 1-adrenergic than α 2-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 oxida tion by the cytochrome P450 isoenzyme system producing one active metabolite, meta-chlorophenylpiperazine, which has a complex phar macologic profile, including inhibition of serotonin uptake, stimulation and inhibition of multiple postsynaptic serotonin receptors, and interactions with other neurotransmitter systems.

tion by the cytochrome P450 isoenzyme system producing one active metabolite, meta-chlorophenylpiperazine, which has a complex phar macologic 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 dura tion of, or inappropriate penile or clitoral engorgement. 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 Tintinalli_Sec15_p1187-1332.indd 1200 8/2/19 8:39 PM

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 Tintinalli_Sec15_p1187-1332.indd 1200 8/2/19 8:39 PM CHAPTER 178: Atypical and Serotonergic Antidepressants 1201 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 hypoten sion 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. 17 Polymorphic ventricular tachycardia (torsades de pointes) has been reported in rare cases. 19 Commonly reported GI complaints include nausea, vomiting, and nonspecific abdominal pain. Treatment Establish IV access, initiate cardiac rhythm monitoring, and obtain an ECG ( Table 178-3). GI decontamination with singledose 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 trazodoneinduced α-adrenergic receptor antagonism. Treat QT interval prolongation and/or torsades de pointes arrhythmia with IV magnesium sulfate, followed by cardiac pacing as needed. 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.  VILAZODONE Vilazodone is an antidepressant with selective serotonin reuptake inhibition and partial serotonin 5-HT1A agonism. Following overdose, the most common clinical features are drowsiness, vomiting, tachycardia, and agitation. 20 Most patients have symptoms for between 2 and 24 hours, although some remain symptomatic for more than 24 hours. Serotonin syndrome rarely occurs in isolated vilazodone overdoses.  VORTIOXETINE Vortioxetine selectively inhibits serotonin reuptake; antagonizes serotonin 5-HT 3, 5-HT 1D, and 5-HT 7 receptors; stimulates the serotonin 5-HT 1A receptor; and is a partial agonist at the serotonin 5-HT 1B receptor.17 Common side effects with therapeutic use include nausea, constipation, and vomiting. Clinical features in overdose are limited but appear to be minimal. 21 Serotonin syndrome would be a risk based on the mechanism of action.17 SELECTIVE SEROTONIN REUPTAKE INHIBITORS Selective serotonin reuptake inhibitors (SSRIs) are a structurally heterogeneous group of drugs that share selective affinity for inhibiting presynaptic serotonin reuptake without significantly affecting norepinephrine or dopamine reuptake ( Table 178-4). 1 SSRIs are essentially devoid of direct presynaptic or postsynaptic receptor interactions. Thus, they are associated with fewer unwanted pharmacologic actions, in contrast with cyclic antidepressants. SSRIs are the most common form of pharmacotherapy for depression in the United States.

pamine reuptake ( Table 178-4). 1 SSRIs are essentially devoid of direct presynaptic or postsynaptic receptor interactions. Thus, they are associated with fewer unwanted pharmacologic actions, in contrast with cyclic antidepressants. SSRIs are the most common form of pharmacotherapy for depression in the United States. 1 This class of antidepressants is the most frequently reported to be involved in drug overdoses, but fatalities are uncommon due to the high therapeutic index of these drugs. 2-4 The SSRIs have similar pharmacokinetic profiles, including rapid and complete oral absorption, peak plasma levels occurring 4 to 8 hours after ingestion (except citalopram and escitalopram, which achieve peak plasma levels at 2 to 4 hours), significant first-pass hepatic metabolism, a high degree of protein binding (except citalopram and escitalopram), and a large volume of distribution. Fluoxetine is unique in that the active metabolite, norfluoxetine, is as potent as the parent compound. The half-life of norfluoxetine is 7 to 14 days, so the clinical effects of fluox etine may last for up to 5 weeks after the last fluoxetine dose. The SSRIs are metabolized almost entirely by the hepatic cytochrome P450 isoenzyme system, and these agents can inhibit the metabolism of other drugs dependent on that system. The most serious drug-related adverse effect of SSRI psychopharmacotherapy is serotonin syn drome (see later section, “Serotonin Syndrome”). Adverse effects with therapeutic doses include hyponatremia, which is believed to be secondary to inappropriate secretion of antidiuretic hormone. 1 Priapism has been reported but is extremely rare. A with drawal syndrome consisting of nonspecific neurologic, psychiatric, and GI symptoms has been described in conjunction with abrupt discon tinuation. It is less likely to occur with fluoxetine due to its long-acting metabolite. Other neurologic adverse effects associated with SSRIs include headache, sedation, insomnia, dizziness, weakness or fatigue, tremor, and nervousness. 1 Seizures are uncommon but have been reported with all of these agents, with citalopram associated with the highest incidence of seizures among the SSRIs. 1 Serotonin has varying effects on the dopaminergic system. In many cases, extrapyramidal symptoms such as dystonic reactions, akathisia, dyskinesia, hypokinesia, and parkinso nian symptoms have been reported in association with SSRI therapy. Consequently, SSRIs should be used cautiously with antipsychotic agents because they can potentiate antidopaminergic activity. Patients taking SSRIs commonly report GI complaints, such as nausea, diarrhea, con stipation, vomiting, and anorexia. Other adverse effects less commonly reported include dry mouth, increased sweating, and blurred vision.  CLINICAL FEATURES The greatest amount of human SSRI overdose experience has been with fluoxetine.22 Information from case series involving the other SSRIs is consistent with the information accumulated on fluoxetine. 23,24 Fortunately, all of the SSRIs are characterized by a high therapeutic index, and fatalities are uncommon with pure overdoses. 2-4 Most adult and pediatric patients remain asymptomatic following SSRI overdose. The most common clinical features in symptomatic patients from overdose include nausea, vomiting, sedation, tremor, and sinus tachycardia. Less frequently observed are mydriasis, seizures, diarrhea, agitation, halluci nations, hypertension, and hypotension. Sinus bradycardia is observed more frequently in fluvoxamine overdoses than in overdoses of other SSRIs.

omatic patients from overdose include nausea, vomiting, sedation, tremor, and sinus tachycardia. Less frequently observed are mydriasis, seizures, diarrhea, agitation, halluci nations, hypertension, and hypotension. Sinus bradycardia is observed more frequently in fluvoxamine overdoses than in overdoses of other SSRIs. Prolongation of the QRS complex and QT interval occurs in association with significant TABLE 178-3 Treatment of Trazodone Overdose •   IV access, cardiac rhythm monitor, and ECG •   Single-dose activated charcoal if ingestion within 1 h •   Treat seizures with IV benzodiazepines •   IV fluids for hypotension •   Direct-acting vasopressor (norepinephrine) for persistent hypotension and circulatory shock •   Magnesium sulfate for QTc interval prolongation and/or torsades de pointes TABLE 178-4 Selective Serotonin Reuptake Inhibitors Agent Recommended Maximum Daily Adult Dose (milligrams) Elimination Half-Life Parent Compound (h) Active Metabolite Citalopram 40 35 Monodesmethylcitalopram Didesmethylocitalopram Escitalopram 20 27–32 Desmethylcitalopram Fluoxetine 80 96–144 Norfluoxetine Fluvoxamine 300 16 None Paroxetine 50 21 None Sertraline 200 26 Desmethylsertraline Tintinalli_Sec15_p1187-1332.indd 1201 8/2/19 8:39 PM

Life Parent Compound (h) Active Metabolite Citalopram 40 35 Monodesmethylcitalopram Didesmethylocitalopram Escitalopram 20 27–32 Desmethylcitalopram Fluoxetine 80 96–144 Norfluoxetine Fluvoxamine 300 16 None Paroxetine 50 21 None Sertraline 200 26 Desmethylsertraline Tintinalli_Sec15_p1187-1332.indd 1201 8/2/19 8:39 PM 1202 SECTION 15: Toxicology TABLE 178-5 Treatment of Selective Serotonin Reuptake Inhibitor Overdose •   IV access, cardiac rhythm monitor, and ECG •   Single-dose activated charcoal if ingestion within 1 h •   Treat seizures with IV benzodiazepines •   Sodium bicarbonate for prolonged QRS complex •   Magnesium sulfate for QTc interval prolongation and/or torsades de pointes citalopram and escitalopram ingestions. 25-30 In most cases, the ECG abnormalities gradually resolve over 24 hours. Tachycardia, mild hypotension, and lethargy are seen more commonly when SSRIs are com bined with ethanol. Mixed-drug ingestions can produce a wide variety of additional symptoms depending on the toxicity of the co-ingestant. About 10% of reported instances of serotonin syndrome occur as a consequence of acute overdose.  TREATMENT In patients who intentionally overdose, establish a peripheral IV line, initiate cardiac rhythm monitoring, and obtain an ECG ( Table 178-5). Pure SSRI overdoses are associated with limited toxicity except for the infrequent development of life-threatening complications such as generalized seizures and serotonin syndrome. Based on the high therapeutic index and unlikelihood of serious toxicity, treatment with single-dose activated charcoal is logical for patients presenting within 1 hour of ingestion. Gastric lavage, ipecac syrup, multidose activated charcoal, and whole-bowel irrigation are not recommended. Benzodiazepines are recommended as initial anticonvulsant therapy, followed by phenobarbital if seizures persist. Prolonged QRS or QT intervals are usually seen with citalopram or escitalopram but have been reported with other SSRIs in polydrug ingestions. 31 Delayed-onset serotonin syndrome, extrapyramidal reactions, and torsades de pointes are possibilities, especially with sustained-release compounds. 31,32 Patients should be observed for 6 hours, during which time sup portive care is generally adequate. Hospital admission with continuous cardiac rhythm monitoring is recommended for all patients who remain tachycardic, have altered mental status, ingested citalopram or escitalo pram, demonstrate cardiac conduction abnormalities, or have features of the serotonin syndrome. SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS The serotonin/norepinephrine reuptake inhibitors (SNRIs) are pri marily nonselective inhibitors of serotonin and norepineph rine reuptake with a very small amount of dopamine reuptake inhibition (Table 178-6).1 These drugs have no significant direct effect on presynaptic or postsynaptic neurotransmitter receptors. The SNRIs differ in their degree of protein binding and apparent volume of dis tribution, from venlafaxine with 27% protein binding and 6 to 7 L/kg volume of distribution, to duloxetine with 95% protein binding and a 1640 L/kg volume of distribution. Venlafaxine is absorbed the fastest after ingestion, achieving peak levels at 2 hours, whereas duloxetine reaches peak blood levels 6 to 10 hours after ingestion. The adverse effect profile during therapeutic use for these medications is similar to that for SSRIs. 33 Venlafaxine is a notable exception and is able to produce mild to moderate hypertension when dosages exceed 225 milligrams/d, probably secondary to inhibition of norepinephrine reuptake. Duloxetine appears to have more GI side effects, such as nausea, dizziness, and vomiting, but causes less hypertension than venlafaxine.

lafaxine is a notable exception and is able to produce mild to moderate hypertension when dosages exceed 225 milligrams/d, probably secondary to inhibition of norepinephrine reuptake. Duloxetine appears to have more GI side effects, such as nausea, dizziness, and vomiting, but causes less hypertension than venlafaxine.  CLINICAL FEATURES All SNRIs cause sympathetic nervous system stimulation via inhibition of norepinephrine reuptake, which predisposes patients to tachycardia, hypertension, diaphoresis, tremor, and mydriasis. Most of these effects are of moderate severity and can usually be managed with supportive care alone. 35 Patients may display alterations in level of consciousness, with mild to moderate sedation being fairly common and progressing to coma on rare occasions. Generalized seizures tend to occur early after ingestion and are more common after overdose with venlafaxine than after most SSRI exposures. 12 Subclinical rhabdomyolysis has been observed in about 25% of patients without seizures and 60% of patients with seizures following a venlafaxine overdose. 36 Large overdoses of venlafaxine can produce severe global impairment of left ventricular systolic contraction with a markedly reduced ejection fracture. ECG abnormalities are common following intentional SNRI over doses. Sinus tachycardia is the most common ECG abnormality observed, but QRS widening and QT interval prolongation have also been reported. 10 Mortality is low in isolated overdose.4,38  TREATMENT Establish a peripheral IV line, initiate cardiac rhythm monitoring, and obtain an ECG ( Table 178-7). Single-dose activated charcoal is logical therapy for most SNRI overdoses if seen within an hour after ingestion. 39 Gastric lavage and ipecac syrup are contraindicated due to the potential for seizures and aspiration. Consider whole-bowel irriga tion with a large venlafaxine ingestion. 39 Benzodiazepines are the anti convulsants of choice. Hypertension and sinus tachycardia rarely require specific pharmacologic therapy, and β-blockers have the theoretical disadvantage of allowing unopposed α-adrenergic receptor stimulation. Treat hypotension with fluids and direct-acting α-agonists. Asymptomatic patients should be observed for 6 hours. Symptom atic patients should be admitted to a monitored bed. Patients ingesting extended-release preparations require additional observation for at least 24 hours due to the possibility of delayed onset of toxicity.  SEROTONIN SYNDROME Serotonin syndrome is a potentially life-threatening adverse drug reaction to serotonergic medications. It can be produced by any drug or, more commonly, by a combination of drugs that increase central serotonin neurotransmission ( Table 178-8). 40-44 Antidepressants are the drug class most commonly associated with serotonin syndrome. Serotonin syndrome is characterized by a combination of alterations in cognition and behavior, autonomic nervous system function, and TABLE 178-6 Serotonin/Norepinephrine Reuptake Inhibitors Agent Recommended Maximum Daily Adult Dose (milligrams) Elimination Half-Life (h) Major Active Metabolites Desvenlafaxine 100 11 None Duloxetine 120 12 None Levomilnacipran 120 12 None Venlafaxine 375 5 Desmethylverlafaxine TABLE 178-7 Treatment of Serotonin/Norepinephrine Reuptake Inhibitor Overdose •   IV access, cardiac rhythm monitor, and ECG •   Single-dose activated charcoal if ingestion within 1 h •   Consider whole-bowel irrigation with large (>4000 milligrams) venlafaxine overdoses •   Treat seizures with IV benzodiazepines •   IV fluids for rhabdomyolysis •   Sodium bicarbonate for prolonged QRS complex •   Magnesium sulfate for QTc interval prolongation •   IV fluids and direct-acting vasopressors for hypotension Tintinalli_Sec15_p1187-1332.indd 1202 8/2/19 8:39 PM

igrams) venlafaxine overdoses •   Treat seizures with IV benzodiazepines •   IV fluids for rhabdomyolysis •   Sodium bicarbonate for prolonged QRS complex •   Magnesium sulfate for QTc interval prolongation •   IV fluids and direct-acting vasopressors for hypotension Tintinalli_Sec15_p1187-1332.indd 1202 8/2/19 8:39 PM CHAPTER 178: Atypical and Serotonergic Antidepressants 1203 neuromuscular activity. 40-44 The degree of abnormality in any one area is highly variable. The stimulation of specific postsynaptic serotonin receptors is required for full expression of this syndrome, primarily the serotonin 5-HT 1A and 5-HT 2A receptors, but other receptor subtypes may contribute. Drugs that block postsynaptic serotonin receptors are incapable of inducing this syndrome and are often used as a form of treatment. CLINICAL FEATURES The triad of cognitive, autonomic, and neuromuscular effects is a classic feature of the serotonin syndrome ( Table 178-9). The vast majority of serotonin syndrome cases occur in patients taking serotonergic drugs at therapeutic dosages, but approximately 10% of cases develop after an overdose of serotonergic medication. Serotonin syndrome usually occurs within 2 to 24 hours after the dosage of a serotonin agonist (e.g., a monoamine oxidase inhibitor or an SSRI) has been increased or after a second serotonergic agent (e.g., dextromethorphan) has been added. The importance of serotonin syndrome in emergency practice is twofold. First, the diagnosis of serotonin syndrome is very challenging because of its nonspecific symptomatology. 45,46 Mild cases of serotonin syndrome frequently are misinterpreted as other psychiatric and medi cal disorders, and severe cases are often misdiagnosed as neuroleptic malignant syndrome because the two disorders share some features such as hypertension, tachycardia, tachypnea, fever, hypersalivation, and diaphoresis (Table 178-10). 47,48 Without proper recognition of patients at risk for serotonin syndrome, one may inadvertently precipitate sero tonin syndrome by administering serotonergic agents (e.g., meperidine, tramadol, dextromethorphan). To prevent iatrogenic precipitation of the serotonin syndrome, use drug databases and other resources to evaluate for potential drug interactions. The severity of serotonin syndrome varies ( Table 178-11). The most commonly reported signs and symptoms associated with serotonin syndrome are altered mental status, hyperthermia, and increased mus cle tone. 40-44 Myoclonus is a common finding in serotonin syndrome and is an important distinguishing feature, because myoclonus is rarely seen in other conditions that mimic serotonin syndrome (see Chapter 179, “Monoamine Oxidase Inhibitors, ” Chapter 180, “ Antipsychotics, ” and Chapter 202, “ Anticholinergics”). 47-50 Muscle rigidity, when present, is especially prominent in the lower extremities, which serves as another valuable clinical marker for sero tonin syndrome. Patients with ataxia should be examined carefully for lower extremity hypertonia. Unilateral muscle rigidity and focal neu rologic findings are not expected. Seizures are always generalized and usually short lived. Hyperthermia is usually of moderate severity, but temperatures >41°C (106°F) have been reported and are a marker of a poor prognosis. Hypertension is twice as common as hypotension and is associated with a more favorable prognosis. There are no confirmatory laboratory tests for serotonin syndrome. Therefore, the diagnosis of serotonin syndrome is based entirely on clinical assessment and exclusion of other psychiatric and medical conditions.

ognosis. Hypertension is twice as common as hypotension and is associated with a more favorable prognosis. There are no confirmatory laboratory tests for serotonin syndrome. Therefore, the diagnosis of serotonin syndrome is based entirely on clinical assessment and exclusion of other psychiatric and medical conditions. Published diagnostic criteria for serotonin syndrome emphasize exposure to a known serotonergic drug and the presence TABLE 178-8 Serotonergic Drugs Antidepressants •   Monoamine oxidase inhibitors: phenelzine, tranylcypromine, isocarboxazid, pargyline, rasagiline, and selegiline •   Selective serotonin reuptake inhibitors: fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram •   Serotonin/norepinephrine reuptake inhibitors: venlafaxine, desvenlafaxine, levomilnacipran, and duloxetine •   Cyclic antidepressants: amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine •   Atypical antidepressants: trazodone (moderate potency), bupropion (low potency), and vilazodone (moderate potency) Other Agents (potency to cause serotonin syndrome) Amantadine (low potency) Amphetamines (moderate potency) Bromocriptine (low potency) Buspirone (moderate potency) Carbamazepine (low potency) Cocaine (moderate potency) Codeine (low potency) Dextromethorphan (high potency) Fentanyl (moderate potency) Levodopa (moderate potency) Linezolid (high potency) Lithium (high potency) l-Tryptophan and 5-hydroxytryptophan (high potency) Lysergic acid diethylamide (moderate potency) Meperidine (high potency) Mescaline (moderate potency) Metoclopramide (low potency) Pentazocine (low potency) Pergolide (low potency) Reserpine (low potency) St. John’s wort (moderate potency) Sumatriptan and related triptans (high potency) Tramadol (high potency) TABLE 178-9 Clinical Features of Serotonin Syndrome Major Minor Cognitive Altered level of consciousness Agitation Insomnia Restlessness Anxiety Autonomic Hyperthermia Diaphoresis Tachycardia Hypertension or hypotension Tachypnea Mydriasis Neuromuscular Muscle rigidity Hyperreflexia Myoclonus Tremor Akathisia Incoordination TABLE 178-10 Comparison of Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Anticholinergic Toxicity

n Insomnia Restlessness Anxiety Autonomic Hyperthermia Diaphoresis Tachycardia Hypertension or hypotension Tachypnea Mydriasis Neuromuscular Muscle rigidity Hyperreflexia Myoclonus Tremor Akathisia Incoordination TABLE 178-10 Comparison of Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Anticholinergic Toxicity Serotonin Syndrome Neuroleptic Malignant Syndrome Anticholinergic Toxicity Precipitating event Addition of serotonergic agent Addition of dopamine antagonist or withdrawal from dopamine agonist Addition of anticholinergic agent Onset Usually within 24 h Usually within days to weeks Usually within 1–2 h Distinguishing features Myoclonus, tremor Bradyreflexia (sluggish reflex response) and bradykinesia (motor slowing or psychomotor retardation) Dry skin and mucous membranes Hyperreflexia Lead pipe rigidity Normal muscle tone and reflexes TABLE 178-11 Severity Pattern of Serotonin Syndrome Category Clinical Features Mild Mild agitation, mild fever (<40°C), tremor, myoclonus, hyperreflexia, diaphoresis, mydriasis, elevated blood pressure and heart rate Moderate Marked agitation, hyperthermia (>40°C), myoclonus, hyperreflexia, ocular clonus, increased bowel sounds Severe Hyperthermia (>41.1°C), delirium, marked muscle rigidity, marked swings in blood pressure and heart rate Tintinalli_Sec15_p1187-1332.indd 1203 8/2/19 8:39 PM