Strange and Schafermeyer's Pediatric Emergency Medicine, Fourth Edition (Strange, Pediatric Emergency Medicine), 4th Ed.

CHAPTER 119. Psychotherapeutic Drugs

Timothy J. Meehan

Jared J. Marcucci

HIGH-YIELD FACTS

• The key targets of antidepressant and neuroleptic poisoning are the cardiovascular and central nervous systems.

• Tricyclic antidepressant poisoning is potentially life threatening due to ventricular dysrhythmias and hypotension. Treatment is supportive with consideration given to sodium bicarbonate for dysrhythmia prevention and treatment, and to pressors for hypotension.

• Children who are asymptomatic for 6 hours after the ingestion of antidepressants or neuroleptics may be discharged from the ED.

• The serotonin syndrome (SS) is a life-threatening condition manifested by mental status changes, autonomic instability, hyperthermia, and neuromuscular abnormalities such as hyperreflexia and tremors. Its treatment is supportive with consideration given to cyproheptadine.

• The neuroleptic malignant syndrome (NMS) is a life-threatening condition manifested by hyperthermia, skeletal muscle rigidity, and altered mental status. Its treatment is supportive with particular attention to cooling and consideration given to bromocriptine.

• Overdose of typical neuroleptics may produce an acute dystonic reaction, which can be reversed with diphenhydramine or benztropine mesylate.

INTRODUCTION

The symptoms and complications of antidepressant and neuroleptic poisoning can be difficult to distinguish. It is important to recognize the similarities and differences in patients with a potential toxic ingestion of these drugs because the initial approach has some overlap but ultimately requires different treatment. A focused approach to the specific toxic ingestion, including an accurate history and detailed physical examination, is essential to appropriately manage these patients.

image EPIDEMIOLOGY—ANTIDEPRESSANTS

Antidepressants are powerful modulators of the monoamine pathways of the CNS and are found in many households. According to the National Center for Health Statistics, antidepressants were the third most common prescription drug taken by Americans of all ages in 2005 to 2008 and the most frequently used by persons aged 18 to 44 years. From 1988–1994 to 2005–2008, the rate of antidepressant use in the United States among all ages increased nearly 400%.1 Because of their wide availability, both intentional and unintentional ingestions by children are not uncommon.

According to the 2011 report of the American Association of Poison Control Centers (AAPCC), Children younger than 6 years of age were involved in 21.7% of reported antidepressant exposures.2 There were a total of 9227 ingestions in patients younger than 6 years and 9425 in patients between 6 and 19 years of age. The vast majority of these ingestions were secondary to the 10,788 selective serotonin reuptake inhibitors (SSRIs) and 1645 due to cyclic antidepressants. However, the cyclic antidepressants resulted in more hospitalizations and serious outcomes.2 This is because of the narrow therapeutic index of TCAs compared to the SSRIs. Dosing as low as 10 to 20 mg/kg of a TCA can result in serious toxicity, whereas most adults can tolerate up to 1000 mg before encountering life-threatening consequences.

image EPIDEMIOLOGY—NEUROLEPTICS

The neuroleptics or antipsychotics are prescribed to treat schizophrenia and other psychiatric disorders. The 2011 AAPCC report shows that there were a total of 11,661 ingestions in patients younger than 6 years and 10,751 in patients between 6 and 19 years of age.2 Antipsychotics were noted to be among the categories of substance exposures increasing most rapidly compared to historical AAPCC data.

PHARMACOLOGY

image ANTIDEPRESSANTS

Tricyclic Antidepressants TCAs exert their therapeutic effects primarily through presynaptic reuptake inhibition of norepinephrine and serotonin. They also have anticholinergic, α1-blocking, and sodium channel blocking effects as well as GABA system interactions. Table 119-1 lists the commonly available TCAs typically seen in clinical practice.

TABLE 119-1

Antidepressant Class

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Selective Serotonin Reuptake Inhibitors SSRIs were developed in response to toxicity of TCAs.3 They act primarily on serotonin reuptake and, thereby, interact less with norepinephrine and dopamine metabolism. However, their mechanism of action is unclear. Unlike TCAs, they have minimal to no effect on the cholinergic, adrenergic, and GABA systems, and upon sodium channels.

Atypical Antidepressants Atypical antidepressants are derived from SSRIs. Consequently, most act on serotonin receptors and are considered serotoninergic. However, norepinephrine–dopamine reuptake inhibitors (NDRIs) such as bupropion are not considered serotoninergic.4 Table 119-1 lists the commonly available SSRIs and atypical antidepressants typically seen in clinical practice.

image NEUROLEPTICS (ANTIPSYCHOTICS)

Neuroleptics act by blocking dopaminergic, α-adrenergic, muscarinic, histaminic, and serotoninergic neuroreceptors. Blockade of the dopamine receptors results in the desired behavior modification but also produces extrapyramidal side effects such as dystonic reactions. α-adrenergic blockade produces peripheral vasodilation and orthostatic hypotension. Muscarinic blockade results in anticholinergic properties such as sedation, tachycardia, flushed or dry skin, urinary retention, and delayed GI motility. Neuroleptics also cause a membrane-depressant action or quinidine like effect that alters myocardial contractility and can result in conduction defects. There are several classes of neuroleptics all of which have the same basic three-ringed structure. Although all classes exhibit similar therapeutic and adverse effects, modification of the basic structure results in variable degrees of toxicity.5 Neuroleptics include broadly diverse chemical classes. These entities differ in the degree to which they cause anticholinergic, cardiovascular, or extrapyramidal system reactions.

Typical Antipsychotics All typical antipsychotic drugs tend to block D2 receptors in the dopamine pathway of the brain. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Typical antipsychotics such as haloperidol and chlorpromazine suppress dopaminergic signaling throughout its pathways, allowing dopamine receptors to function more normally. Typical antipsychotics are not selective, blocking dopamine receptors in many pathways in the brain other than the mesolimbic pathway. This is thought to produce the extrapyramidal reactions associated with these agents.6 Table 119-2 lists the available typical antipsychotics that may be seen in clinical practice.

TABLE 119-2

Common Typical Neuroleptics

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Atypical Antipsychotics Atypical antipsychotics primarily target serotoninergic neurons to overcome dopamine hyperactivity by restoring neurotransmitter balance in the central nervous system. They also have some D2 blocking activity but not as much as the typical antipsychotics. The affinity of atypical antipsychotics varies from drug to drug, and it has been hypothesized that it is varying in affinities that causes a change in effectiveness and side effects seen with individual drugs.6

CLINICAL PRESENTATION

image ANTIDEPRESSANTS

Tricyclic Antidepressants TCAs can have a direct or indirect effect at many sites. Cardiac effects are directly mediated by quinidine-like effects on sodium channels that slow phase 0 of depolarization and clinically manifest as widened QRS and QTc intervals; however, the most commonly encountered electrophysiological abnormality is sinus tachycardia. Norepinephrine reuptake inhibition leads to tachycardia and can cause hypertension, but upon depletion of norepinephrine stores, hypotension can occur. Blockade of the α1-receptor also contributes to hypotension by decreasing peripheral vasomotor tone. Also, antimuscarinic effects can cause an anticholinergic syndrome. This leads to decreased GI motility and may contribute to toxicity by prolonging absorption because of an increase in contact time with the intestinal mucosa.7

Selective Serotonin Reuptake Inhibitors Unlike TCAs, SSRIs have minimal activity in the cholinergic and sympathetic systems, and little effect on sodium channels. In overdose, SSRIs can present with a nebulous constellation of symptoms due to serotoninergic excess.8 These symptoms involve the GI (nausea, vomiting, and diarrhea), cardiovascular (sinus tachycardia), and CNS (dizziness, blurry vision, mental status changes) systems. In addition, both citalopram and escitalopram have been associated with prolongation of the QTc interval.911

Atypical Antidepressants Venlafaxine, desvenlafaxine, and duloxetine are classified as serotonin–norepinephrine reuptake inhibitors (SNRIs), and can present with nonspecific symptoms including tachycardia, vomiting, dizziness, stupor, or seizures. Quinidine-like effects with QRS widening, similar to TCA toxicity, have been reported.

Bupropion, a norepinephrine–dopamine reuptake inhibitor (NDRI), is a unicyclic compound. In overdose, symptoms include tachycardia, hypertension, vomiting/diarrhea, agitation, and CNS depression. It can lower the seizure threshold, and intractable seizures are the most concerning complication.12,13 In addition, widened-QRS tachycardia can occur.

Trazodone is a serotonin agonist as well as an α1-antagonist. Overdoses tend to result in CNS depression (serotonin) and orthostatic hypotension (α-antagonism). Priapism has been reported rarely as a side effect.

Mirtazapine acts as an SSRI as well as an α2-blocker, which increases norepinephrine and serotonin levels in the synaptic cleft. It interferes with negative feedback on presynaptic dopaminergic and adrenergic neurons, and overdoses manifest with tachycardia and mental status changes.

image NEUROLEPTICS

Typical Antipsychotics The primary toxicities of neuroleptics include sedation and hypotension. Serious cardiac dysrhythmias, respiratory depression, and seizures occur rarely.14

Acute dystonia is an unpredictable side effect of neuroleptics, which occurs in approximately 10% of overdoses. It can also occur as an idiosyncratic reaction following a single therapeutic dose of a neuroleptic. Dystonic reactions are characterized by slurred speech, dysarthria, confusion, dysphagia, hypertonicity, tremors, and muscle restlessness. Other reactions or dyskinesias include oculogyric crisis (upward gaze), torticollis (neck twisting), facial grimacing, opisthotonos, and tortipelvic gait disturbances. Symptoms usually begin within the first 5 to 30 hours after ingestion. Dystonic reactions are relatively common in infants and adolescents.

Of the neuroleptics, prochlorperazine most often causes acute dystonia. In recent years, several new neuroleptic agents have become very popular, including clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and paliperidone. This group of agents produces a lower incidence of extrapyramidal side effects than previous agents because they are primarily serotoninergic. Table 119-3 lists these agents, as well as their trade names, and examples of reported toxicity in children.

TABLE 119-3

Atypical Neuroleptic Agents

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Following an acute overdose, mild CNS depression is common, usually occurring within 1 to 2 hours of the ingestion. Children are more susceptible to sedative effects than adults. In the overdose setting, respiratory depression can occur but rarely requires aggressive airway management. Phenothiazines tend to lower a patient’s seizure threshold; however, the actual incidence of seizures in acute overdose is low.

Like tricyclic antidepressants, neuroleptic poisoning can result in orthostatic hypotension and cardiac dysrhythmias, particularly with the piperidine and aliphatic phenothiazines. Sinus tachycardia is the most common dysrhythmia, but QT interval prolongation can sometimes be noted on electrocardiogram. Other clinical effects in the acute overdose setting include pupillary miosis, which in one study was observed in 72% of children with high-grade coma following ingestion of a phenothiazine. Because of the anticholinergic properties of the neuroleptics, the patient may also exhibit decreased GI motility, urinary retention, hyperthermia, and dry or flushed skin. Mydriasis may occur; however, miosis is common because of α-adrenergic blockade.

Hypothermia can occur but is rarely clinically significant. Therapeutic phenothiazine use has been associated with sleep apnea and sudden death in infants.

Atypical Antipsychotics The existing pharmacovigilance data reports indicate these medications are relatively safe when taken in overdose, particularly when coingestants are not involved.15 They generally have a safer therapeutic and overdose profile than first-generation antipsychotic medications, but many adverse and toxic effects still need to be considered in therapeutic monitoring and overdose management.16,17 Toxicologic exposures and fatalities associated with atypical antipsychotics continue to increase in the United Sates and the toxicologic potential of these agents in children may be underestimated.18

Overdose of all atypical agents may cause sedation and sinus tachycardia. They may also cause miosis and hypotension. Through interference with the delayed-rectifier potassium channel in the cardiac conduction system, large ingestions may cause QTc prolongation that tends to be short-lived and resolves as toxicity improves.1821 Clozapine deserves special discussion because it has two clinically significant toxicities. It can cause significant hypersalivation due to muscarinic stimulation, and it can precipitate clinically significant agranulocytosis during chronic therapy.15,22

MANAGEMENT

image ANTIDEPRESSANTS

Tricyclic Antidepressants Seizures are often short-lived and often self-limited, but treatment with benzodiazepines may be necessary. Hypotension is frequently responsive to intravenous fluid resuscitation. Anticholinergic symptoms should not be treated with cholinesterase inhibitors as this can lead to cardiovascular collapse and sudden death.23

Patients with TCA overdose may present to the ED appearing clinically stable and may then suddenly deteriorate. The majority of patients who develop life-threatening problems do so within 2 hours of arrival in the ED. Drug screens do not correlate with clinical toxicity. If a possible TCA overdose is in the differential, then continuous cardiac monitoring and obtaining an EKG are essential first steps in the assessment. Sinus tachycardia may herald later clinical deterioration.

Several electrocardiographic parameters have been identified as markers of significant TCA toxicity. The QRS duration has received much attention as a marker for overdose. While not fully studied in children, a QRS duration between 100 and 160 ms is associated with seizures and dysrhythmias, and a QRS greater than 160 ms with a high risk of seizures and dysrhythmias.24 When confronted with a QRS of >120 ms, 1 to 2 mEq/kg boluses of sodium bicarbonate should be administered. If additional episodes of QRS widening occur, more bicarbonate boluses can be given. If the cardiac rhythm devolves into ventricular tachycardia despite aggressive treatment with bicarbonate, lidocaine can be given.

Selective Serotonin Reuptake Inhibitors Treatment is largely supportive. An EKG should be obtained to screen for coingestants such as TCAs but also because citalopram and escitalopram have been associated with QRS and QTc changes. The mechanism is similar to TCAs and atypical antipsychotics, respectively.11 They should be managed in the same way as those agents.

Atypical Antidepressants Venlafaxine and duloxetine: The rare quinidine-like effect can occur similar to that caused by TCAs; it is treated similarly with sodium bicarbonate.

Bupropion: Seizures should be treated initially with benzodiazepines; however, they can be very difficult to treat, and escalation to barbiturates and systemic sedation with propofol may be required. The use of intravenous fat emulsion to terminate intractable seizures has also been described in an adult.13 In addition, widened-QRS tachycardia can occur, and should be treated with sodium bicarbonate. In one case series involving children, most bupropion overdoses were noted to be accidental.25 Children should be observed for 24 hours for the development of seizures or other signs of toxicity, particularly after the ingestion of sustained-release preparations.

Trazodone: Treatment should focus on treatment of the presenting symptoms. Priapism should be managed in the usual manner and may require urology consultation. Hypotension should be treated with intravenous fluids and close monitoring. Respiratory support with mechanical ventilation or oxygen may be required.

Mirtazapine: Treatment should focus on the presenting symptoms and close monitoring of patient for any deterioration. An ECG is the only investigation required in clinically uncomplicated patients. Patients with possible serotonin toxicity should have electrolytes, creatine phosphokinase, and assessment of ventilation.

image NEUROLEPTICS

Typical and Atypical Antipsychotics Treatment is supportive with investigations tailored to the patient’s signs and symptoms. Serum concentrations correlate poorly with clinical effects, making their utility negligible.

Initial management of an acute neuroleptic overdose includes stabilizing the airway and circulation. If the patient remains hypotensive despite adequate amounts of IV fluid, a vasopressor with α-agonist activity, such as norepinephrine, may be considered. Vasopressors with both α- and β-agonist activity, such as dopamine, may actually exacerbate hypotension because of unopposed β-adrenergic stimulation, as the α1-receptors are being blocked by the neuroleptic. Because of the potential cardiotoxicity of phenothiazines, patients require close monitoring. α1-Receptor blockade, along with direct myocardial depression, may cause significant hypotension following overdose. Patients may also have orthostatic hypotension because of α-receptor antagonism while receiving therapy at standard doses. Sinus tachycardia is the most common dysrhythmia associated with neuroleptic toxicity; however, supraventricular and ventricular tachydysrhythmias can occur. Many agents, most notably the piperidine phenothiazines and the butyrophenones, have quinidine-like effects on the myocardium.17,28,29

Since phenothiazine toxicity classically demonstrates CNS depression and pupillary miosis, naloxone should be considered diagnostically to evaluate for potential coexistent opioid toxicity. Activated charcoal may be administered if a toxic dose has been ingested less than 1 hour prior to presentation. There is no antidote, and hemodialysis is not effective. Most children presenting after acute neuroleptic toxicity do well with supportive care alone.

Dystonia is treated with intravenous or intramuscular diphenhydramine. Alternatively, intramuscular benztropine can be used. Improvement usually occurs within 15 minutes.26,27 Doses exceeding 8 mg over a 24-hour period can result in severe anticholinergic symptoms.

SEROTONIN SYNDROME AND NEUROLEPTIC MALIGNANT SYNDROME

It can be difficult to distinguish the differences between a patient manifesting the serotonin syndrome (SS) or the neuroleptic malignant syndrome (NMS). These patients can have similar presentations; however, the underlying mechanisms are distinctly different and, thus, require different management strategies. The SS is caused by an excess of serotonin while the NMS results from dopamine depletion. Atypical antipsychotics can make differentiation between the two syndromes even more complicated because atypical antipsychotics have both serotoninergic and dopaminergic effects.

Serotonin syndrome: The most severe consequence of an overdose of a serotoninergic agent is a state of extreme serotonin excess, which has been termed as the SS. It has been reported following as little as a single dose of a serotoninergic agent and typically is seen early in therapeutic use or after a recent dose increase. It is manifested by hyperactivity of multiple physiologic systems and includes mental status changes, hyperreflexia, tremor, rigidity, and hyperthermia. In combination, these clinical problems can lead to profound multi-organ failure. This includes rhabdomyolysis, renal hepatic failure, and possibly hyperthermia-induced cellular dysfunction.30 The signs and symptoms of the SS are listed in Table 119-4.

TABLE 119-4

Serotonin Syndrome Signs and Symptoms

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image MANAGEMENT

Treatment of the SS focuses on reducing tremors and hyperthermia through the use of benzodiazepines and aggressive external cooling. There are data in adults that suggest a role for cyproheptadine, a serotonin antagonist, as targeted antidotal therapy. However, its benefit beyond supportive care is unproven. The adult dose is 4 to 8 mg orally.

image NEUROLEPTIC MALIGNANT SYNDROME

The NMS is the most severe consequence of neuroleptic overdose. Less than 1% of patients exhibit this life-threatening extrapyramidal dysfunction characterized by skeletal muscle rigidity, coma, and severe hyperthermia following the use of antipsychotics. This syndrome can occur following acute overdose or during chronic therapy; however, a single dose of a neuroleptic is not typically expected to manifest NMS, as depletion of dopamine stores is required. Patients with the NMS will present with a constellation of clinical manifestations (Table 119-5)31.

TABLE 119-5

Neuroleptic Malignant Syndrome Signs and Symptoms

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The presentation of the NMS is clinically similar to SS. When the etiologic agent or overdose history is not clear, a careful examination of the symptoms can help distinguish between the two. One noted difference between the two syndromes is hyperreflexia (SS) versus increased motor tone (NMS); however, this finding may not be sufficiently specific to decide on a clinical diagnosis.

image MANAGEMENT

NMS has a high mortality rate and is, therefore, treated aggressively with rapid cooling to control hyperthermia. Other supportive therapies include intubation accompanied by sedation and paralysis to maintain cardiorespiratory stability as well as the use of benzodiazepines to control agitation. Dantrolene, a skeletal muscle relaxant, and the treatment of choice for malignant hyperthermia (a genetic defect in intramyocyte ryanodine signaling) had been historically recommended for NMS. However, the pathophysiology of NMS is distinct from malignant hyperthermia and, thus, is not recommended for its treatment. Oral bromocriptine, a direct-dopamine agonist, has been used to treat adult patients with NMS.32,33

image DISPOSITION

Any symptomatic child presenting with acute antidepressant or neuroleptic poisoning should be admitted and observed for CNS and respiratory depression as well as cardiotoxicity and possible thermoregulatory problems. Patients with minor, asymptomatic ingestions should be observed for a minimum of 6 hours from the time of ingestion; they may be discharged home if they remain asymptomatic. If the patient is discharged, caretakers are advised to watch for signs of delayed dystonic reactions. If the child has been treated successfully for acute dystonia with either diphenhydramine or benztropine, a 2- to 3-day course of oral diphenhydramine is indicated since many of the neuroleptics have a long duration of action.

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