INTRODUCTION — The dual-action serotonin-norepinephrine reuptake inhibitors (SNRIs) and other atypical antidepressants were introduced over the last two decades and are used to treat of a variety of conditions, such as depression, anxiety, and smoking cessation. Atypical antidepressants are those that do not clearly fit the standard classifications for antidepressants (discussed below). Most are derivatives of selective serotonin reuptake inhibitors (SSRIs).
While generally safer in overdose than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), SNRIs may exhibit greater toxicity than SSRIs [1]. Commonly used atypical antidepressants include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), milnacipran (Savella), mirtazapine (Remeron), and bupropion (Wellbutrin, Zyban), and vilazodone (Viibryd).
The clinical manifestations, diagnosis, and management of acute poisoning from SNRIs and other common atypical antidepressants are reviewed here. The therapeutic use of these medications, management of poisoning from SSRIs, the diagnosis and management of serotonin syndrome, and other related issues are discussed separately. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects" and "Selective serotonin reuptake inhibitor poisoning" and "Serotonin syndrome (serotonin toxicity)" and "General approach to drug poisoning in adults" and "Approach to the child with occult toxic exposure".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY — Atypical antidepressants are those that do not clearly fit the standard classifications for antidepressants. They are not monoamine oxidase inhibitors (MAOI), cyclic antidepressants (CA), or selective serotonin reuptake inhibitors (SSRIs). However, most share structural similarities with SSRIs. Although atypical antidepressants manifest fewer side effects than MAOIs and CAs, a few drugs in this class are more toxic than SSRIs in overdose.
Serotonin is produced by the metabolism of L-tryptophan. It exerts its action by binding to 5-hydroxytryptophan (5-HT) receptors, of which there are seven types that are further divided into multiple subtypes. In the central nervous system (CNS), serotonergic neurons are primarily located in the brainstem and assist in the regulation of sleep, affective behavior, food intake, temperature regulation, migraines, emesis, sexual behavior, nociception, and motor tone. In the peripheral nervous system, serotonin plays a role in the regulation of vascular tone and gastrointestinal motility. Although most adverse effects of SNRIs are a direct extension of the pharmacologic effects of serotonin, certain agents have unique toxicities, as outlined below [2].
All atypical antidepressants inhibit the reuptake of biogenic amines as part of their mechanism of action. In addition to inhibiting serotonin reuptake, venlafaxine, desvenlafaxine, duloxetine, and milnacipran all inhibit norepinephrine reuptake. Bupropion is chemically characterized as a monocyclic-aminoketone and is unlike any other antidepressant on the market. The parent drug and its metabolites have a weak inhibitory effect on the reuptake of norepinephrine and dopamine, with no effect on the reuptake of serotonin. Mirtazapine is a potent presynaptic antagonist of central alpha-adrenoreceptors (alpha-2>alpha-1), promoting monoamine release. Mirtazapine also acts as an antagonist at both 5-HT2 and 5-HT3 receptors. Therefore, the released 5-HT is believed to exert its effects primarily on 5-HT1 receptors.
Many of the atypical antidepressants are substrates for, and some inhibit, cytochrome P450 2D6 (CYP2D6), CYP3A4, and other CYP isoenzymes. As examples, venlafaxine and mirtazapine are substrates for CYP2D6, trazodone and vilazodone are substrates for CYP3A4, while bupropion inhibits CYP2D6. Drug-drug interactions (see Lexicomp drug interactions program) may occur when other medications are taken that inhibit drug metabolism or (less frequently) act as substrates for the same isoenzymes. Metabolism of the individual atypical antidepressants and their effects on metabolism of other drugs are listed separately (table 1 and table 2 and table 3).
KINETICS — Atypical antidepressants are rapidly absorbed, and all are metabolized by hepatic enzymes, with the exception of milnacipran (table 1 and table 2 and table 3). This raises concern for drug-drug interactions (see Lexicomp drug interactions program) in patients who take other medications that inhibit or induce hepatic cytochrome P450 (CYP) enzymes. All drugs in this class have a large volume of distribution, which affects treatment, as discussed below. (See 'Management' below.)
Several specific kinetic issues warrant mention. Both bupropion and venlafaxine have active metabolites, which extends the duration of their effects. Venlafaxine is metabolized to desvenlafaxine via the hepatic enzyme cytochrome 2D6 (CYP2D6); as a result, patients with defective CYP2D6 metabolism (known as poor metabolizers) are more likely to develop elevated drug levels and are at increased risk of potential adverse effects. The use of desvenlafaxine in such patients reduces such risk [3]. Bupropion has several metabolites with significant pharmacologic activity (eg, hydroxybupropion and threohydrobupropion). These have plasma concentrations and elimination half-lives that are approximately double that of the parent compound [1].
Although the kinetics of therapeutic dosing are well described, data pertaining to the kinetics of overdose are limited. It is reasonable to assume that in overdose most atypical antidepressants have increased bioavailability and a prolonged half-life, both presumably due to saturation of metabolic pathways [1].
CLINICAL FEATURES OF OVERDOSE
Overview of toxicity — The large majority of atypical antidepressant poisonings cause immediate central nervous system (CNS) toxicity that is only mild to moderate in severity. Important exceptions include bupropion (which may cause agitation or seizure), and venlafaxine (which may be associated with adverse cardiac effects). With both of these agents, toxicity is often delayed. The adverse effects of select atypical antidepressants is summarized in the following table (table 4).
While generally safer in overdose than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), SNRIs may exhibit greater toxicity than selective serotonin reuptake inhibitors (SSRIs) [1]. In 2015, atypical antidepressants were implicated in 111 deaths reported to US poison control centers; SNRIs were implicated in 57 deaths [4]. (See "Tricyclic antidepressant poisoning" and "Selective serotonin reuptake inhibitor poisoning".)
History — The diagnosis of atypical antidepressant overdose is primarily based upon a history of ingestion and corresponding physical examination findings. When taking a history, it is important to learn the following:
●What specific atypical antidepressant was ingested, and in what formulation (eg, extended release [XR])?
●How much was ingested, and when?
●Were any other drugs – licit or illicit – or alcohol ingested?
In the event of mental status changes, information can be obtained from emergency medical personnel, police, family, friends, pharmacists, psychiatrists, and primary care clinicians. A detailed discussion of the history in the poisoned patient is provided separately. (See "General approach to drug poisoning in adults", section on 'History'.)
Physical examination — The examination of the poisoned patient is discussed in detail separately; findings of note in patients with atypical antidepressant poisoning are reviewed here. (See "General approach to drug poisoning in adults", section on 'Diagnosis of poisoning'.)
In the patient with an acute overdose from an atypical antidepressant, the most common finding is CNS depression, with the important exception of bupropion, which can cause agitation. Severe serotonergic effects, such as hyperthermia, autonomic instability, and altered mental status, are not common, but milder symptoms and signs, such as anxiety, tremor, clonus, nausea, and tachycardia, may be observed.
Notable potential findings in the patient with atypical antidepressant poisoning include the following:
●CNS – Sedation, coma, tremor, seizures; agitation
●Cardiopulmonary – Tachycardia, hypertension
●Gastrointestinal – Abdominal tenderness, vomiting, diarrhea
●Neuromuscular – Clonus (ankle more specifically), hyperreflexia
Important potential features of SNRI poisoning
Serotonin toxicity — Serotonin toxicity, or serotonin syndrome, is a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism at central and peripheral nervous system receptors, predominantly at postsynaptic 5-hydroxytryptamine1A and 5- hydroxytryptamine2A. The spectrum of possible symptoms and signs associated with serotonin toxicity is broad, and presentations range from benign to lethal. Serotonin syndrome is reviewed in detail separately. (See "Serotonin syndrome (serotonin toxicity)".)
Serotonin syndrome is characterized by a triad of CNS symptoms, autonomic hyperactivity, and neuromuscular abnormalities. In severe cases, patients manifest altered mental status, confusion, agitation, or coma. Autonomic findings may include tachycardia, mydriasis, labile blood pressure, and hyperthermia. Neuromuscular signs include tremor, clonus, nystagmus, and hyperreflexia. Sustained ankle clonus is more often seen with serotonin toxicity than in other conditions that share clinical features, such as neuroleptic malignant syndrome (NMS) or malignant hyperthermia. (See "Serotonin syndrome (serotonin toxicity)", section on 'Differential diagnosis'.)
The usual clinical picture is one of rapid onset (within 24 hours), shortly after the initiation of a serotonergic medication. Diagnosis is based upon the presence of characteristic clinical findings in a patient with a history of exposure to serotonergic agents and the exclusion of other conditions. No radiologic or laboratory test is available to confirm the diagnosis.
Seizures — Bupropion and venlafaxine are known to cause seizures [3,5-10]. In particular, given the high incidence of seizures after bupropion overdose, and because these seizures can be multiple or delayed, clinicians should consider such patients to be at high risk and close monitoring is indicated [3,5,6,8,11]. (See 'Bupropion' below and 'Management' below.)
According to data drawn from several studies, seizure activity occurs in 21 percent of patients with a bupropion overdose involving the immediate release (IR) formulation, 11 percent involving mostly sustained release (SR) formulations, and 32 percent involving the extended release (XR) formulation [6-8]. Multiple seizures may occur, but status epilepticus is rare. In an observational study of bupropion XR overdoses, almost one-half of patients experienced more than one seizure [8].
Bupropion–induced seizures may be delayed in onset. Seizure activity has been reported to occur up to 8 hours (mean 3.7 hours), 14 hours (mean, 4.3 hours), and 24 hours (mean 7.3 hours) after overdose of IR, SR, and XR formulations, respectively [6-8,11]. Patients who develop seizures typically manifest other physical findings suggesting toxicity, such as agitation, tremor, or tachycardia. However, seizures have occurred in patients lacking any signs or symptoms of CNS toxicity [6-8].
In overdose, venlafaxine is associated with a higher incidence of seizures compared with most other antidepressants. In a 2003 prospective cohort study, seizures occurred in approximately 14 percent of venlafaxine overdoses, and occurred more often than in patients who had overdosed on SSRI or tricyclic antidepressants (TCAs). All patients who experienced a venlafaxine overdose–induced seizure had ingested 900 mg or more [9]. In a retrospective poison center study of venlafaxine ingestions, the majority of patients who developed seizures ingested the sustained-release formulation and sustained a single seizure [12]. Although the majority of seizures appear to occur soon after ingestion, a substantial period of observation is recommended. (See 'Disposition' below.).
Vilazodone has also been associated with seizures, especially in children. In a systemic review of all peer-reviewed, published literature about vilazodone poisoning, six of the eight children (ranging from 19 months to 3 years) presenting with exploratory ingestions experienced seizures [13]. Of these, two had status epilepticus and one was reported to have had "multiple seizures." (See 'Pediatric considerations' below.)
The mechanisms responsible for seizures in patients with an atypical antidepressant overdose remain poorly understood [3]. Some researchers think the mechanisms may involve an increase in nitric oxide synthase (NOS) activity or partial agonism at the 5-HT1A receptor [14].
QTc interval prolongation — A prolonged QTc interval (>500 to 550 msec) predisposes the patient to torsade de pointes (TdP), a life-threatening arrhythmia. Drug-induced QTc interval prolongation may occur in the setting of atypical antidepressant overdose. QTc prolongation is not unique to atypical antidepressants and has been reported for a variety of psychotropic drugs including first-generation antipsychotics, newer antipsychotics, TCAs, and some SSRIs [15,16]. (See "First-generation (typical) antipsychotic medication poisoning" and "Second-generation (atypical) antipsychotic medication poisoning" and "Tricyclic antidepressant poisoning" and "Selective serotonin reuptake inhibitor poisoning".)
It is difficult to draw conclusions regarding QTc prolongation risk from newer non-SSRI antidepressants, as QTc prolongation is multifactorial: The QTc interval can be affected by a variety of factors including genetics, cardiovascular disease, age, female gender, electrolyte abnormalities, concomitant medications, and heart rate. Previous episodes of TdP, bradycardia, or frequent premature ventricular contractions may also increase the risk for TdP if the QTc interval is prolonged.
Although the SNRI duloxetine is safe for most patients, QTc prolongation may occur in cases of duloxetine overdose and in patients susceptible to developing acquired long QT syndrome [16]. At therapeutic doses, bupropion does not prolong the QTc interval and in some studies was found to decrease it. However, in overdose, particularly when taken with other QT-prolonging medications, bupropion may prolong the QTc interval [17,18]. (See 'Duloxetine' below and 'Bupropion' below and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
TOXICOLOGY OF SPECIFIC AGENTS
Bupropion — Bupropion is a monocyclic antidepressant that is structurally similar to amphetamine and inhibits the reuptake of dopamine and norepinephrine. Bupropion was approved for use as an antidepressant in the United States in 1986, but was withdrawn from the market because of a high incidence of seizures occurring at therapeutic doses. It was reintroduced in 1989 with a lower recommended maximum dose of 450 mg/day [1]. Bupropion has a narrow therapeutic margin, and several case series report that seizures may occur with doses as low as 600 mg [6-8,11]. Although seizures are typically self-limited, in one case series, approximately one-half of the patients who had a seizure after bupropion extended release (XR) overdose experienced more than one seizure [8]. Recreational misuse of bupropion by nasal insufflation has been reported, and it can produce adverse effects similar to oral overdose, including sinus tachycardia, seizures, tremors, and agitation [19].
Bupropion commonly causes cardiovascular side effects such as tachycardia and hypertension in overdose [6,10,20]. At therapeutic doses, malignant dysrhythmias are rare [17], as are other manifestations of cardiac toxicity, such as QRS or QTc interval prolongation and hypotension that have been reported in massive overdoses [18]. However, in overdose, particularly when taken with other QT-prolonging medications, bupropion may prolong QTc intervals, although this effect seems to be less significant compared with other antidepressants.
There is some in vitro evidence that bupropion is a weak blocker of rapid delayed rectifier (IKr) channels, which may lead to QTc prolongation. A review of bupropion overdoses found that the mean QTc value for patients who experienced a seizure (mean 482 milliseconds [ms]; range 389 to 681 ms) was longer than those who did not (mean 454 ms; range 252 to 624 ms) [21]. However, it was not possible to identify a QTc threshold above which seizures occur.
In a retrospective review of cases from the United States National Poison Data System involving overdose by adolescents with depression, bupropion was implicated in all eight deaths reported during the study period [20]. In addition, according to this review, bupropion overdose was more likely than SSRI overdose to cause tachycardia (83.7 versus 59.9 percent), vomiting (24.8 versus 20.6 percent), cardiac conduction disturbances (20.0 versus 17.1 percent), agitation (20.2 versus 11.7 percent), seizures (27.0 versus 8.5 percent), and hallucinations (28.6 versus 4.3 percent). In one case report, status epilepticus and cardiogenic shock were observed after an ingestion of 12 g [22].
Of note, the chemical structures of bupropion, erythrohydrobupropion, and threohydrobupropion are similar to amphetamine, which may result in cross-reactivity with antibodies used in urine drug screen immunoassays [23]. (See "Testing for drugs of abuse (DOAs)".)
Venlafaxine — Venlafaxine was introduced in 1994 and use has increased, especially in patients who do not respond adequately to selective serotonin reuptake inhibitors (SSRIs). When used therapeutically it is associated with several adverse effects including tachycardia, increased blood pressure, headache, dizziness, and dry mouth. In overdose, the most common adverse effects are tachycardia, lethargy, hypotension, agitation, cardiac conduction abnormalities, and respiratory depression [12]. Dose-dependent QT prolongation, QRS prolongation, seizures, and serotonin toxicity have been described. There is a higher prevalence of seizures and dysrhythmias in patients who overdose on venlafaxine compared with most other antidepressants [24]. Venlafaxine overdose was complicated by seizures frequently (14 percent in one series) [9], more often than with SSRI or tricyclic antidepressant (TCA) overdose [1]. Seizures may be due to blockade of dopamine reuptake, although the mechanism is poorly understood [12].
In fatal cases of venlafaxine overdose, ventricular arrhythmia and cardiac arrest are the most common causes. Deaths due to left ventricular dysfunction and cardiogenic shock have been reported, presumably due to catecholamine-induced myocardial damage [25,26]. Studies using animal models report venlafaxine to be a potent cardiac sodium channel blocker, thereby causing prolonged QRS intervals [27]. Altered kinetics and severe clinical manifestations may be linked to cytochrome 2D6 (CYP2D6) polymorphism [28].
In rare instances, hypoglycemia has been reported in venlafaxine overdose. Although the mechanism is unclear, reduced hepatic gluconeogenesis and increased peripheral glucose uptake and insulin sensitivity have been suggested [29,30].
Duloxetine — Duloxetine is a dual SNRI first discovered in 1986. It was subsequently approved by the US Food and Drug Administration (FDA) in 2004 under the brand name Cymbalta for use in adults with major depressive disorder, diabetic peripheral neuropathy, and several other disorders.
Clinically significant or persistent symptoms following duloxetine overdose have been reported infrequently. Symptoms are predominantly gastrointestinal or neurologic, including central nervous system (CNS) depression [31,32]. QTc prolongation may be seen.
Desvenlafaxine — Desvenlafaxine is a potent SNRI that was approved in the United States and Australia for the treatment of major depressive disorder in 2008 [15,33]. Desvenlafaxine is available commercially as an XR formulation of the synthetic succinate salt [34]. Desvenlafaxine is the major active metabolite of the parent drug, venlafaxine [35].
The effects of desvenlafaxine overdose are typically mild. In a series of 182 acute desvenlafaxine overdoses, tachycardia was common (39 percent) but seizures and QTc prolongation were not observed and only one patient met criteria for serotonin toxicity [35]. When it occurred, CNS depression was mild. Overall, the risk of significant effects in overdose appears to be lower compared with venlafaxine [35].
Although desvenlafaxine does not appear to be associated with QTc prolongation, the scarcity of case reports may be due to the brief time it has been available [34]. In premarketing studies, four patients reported QT prolongation and one patient experienced an arrhythmia (n = 4158); however, no difference in QTc interval duration was noted among the 1492 patients treated with desvenlafaxine and the 984 patients given placebo.
Mirtazapine — Mirtazapine is an atypical antidepressant that promotes release of norepinephrine and serotonin. It is unlike other commonly prescribed antidepressants and structurally is related to mianserin, a tetracyclic antidepressant. Mirtazapine antagonizes 5-HT2 and 5-HT3 receptors, thereby resulting in greater stimulation of the 5-HT1 receptor by serotonin. In addition, mirtazapine is a potent presynaptic antagonist of central alpha-adrenoreceptors (alpha2>alpha1) [1,36].
CNS depression is the primary adverse effect of mirtazapine in overdose. Other than sedation, no major sequelae have been reported and the relative safety of the drug in overdose appears similar to SSRIs. In a study of single-agent mirtazapine ingestions, 41 of 89 patients (46 percent) had a Glasgow Coma Scale (GCS) between 9 and 14, and none had a GCS below 9 [36,37]. The median time to reach the minimum GCS for these 41 patients was 3 hours. Patients who ingested doses over 1000 mg were more likely to experience a decline in their GCS. In the same series, 33 percent of patients had sinus tachycardia, and mild hypertension was observed in some. Adverse cardiac effects, including prolongation of the QRS or QTc intervals, were not observed.
Milnacipran — Milnacipran is a relatively new SNRI used to treat fibromyalgia [38]. The mechanism by which milnacipran blocks pain is unclear. Serotonin toxicity has been reported but only in patients taking milnacipran with other serotonergic agents or following an overdose. Rare dermatologic reactions have been described, including morbilliform rash and Steven-Johnson syndrome [39,40]. Although data are limited, QTc prolongation has not been reported in safety studies.
Vilazodone — Vilazodone is a potent inhibitor of serotonin reuptake and a partial agonist at 5HT-1A receptors [41]. Vilazodone has a 30-fold greater potency for serotonin reuptake inhibition than the SSRI fluoxetine, and selectivity for the inhibition of norepinephrine and dopamine reuptake comparable to that of fluoxetine. This unique, dual mechanism of vilazodone has been shown, in nonclinical studies, to increase serotonin levels [42].
In overdose, vilazodone can cause a range of adverse effects. According to a retrospective review of vilazodone exposures, including 1734 cases of isolated ingestion reported to the National Poison Data System of the United States, the most common signs of toxicity were drowsiness (20 percent), vomiting (14 percent), tachycardia (11 percent), and agitation (10 percent) [43]. Based on the data reviewed, the authors concluded that serotonin syndrome is common following vilazodone overdose. (See "Serotonin syndrome (serotonin toxicity)".)
Reports of pediatric ingestions describe somnolence, sinus tachycardia, seizures, and serotonergic symptoms [13,43-47]. In one retrospective study, the proportion of children admitted to a health care facility following single-substance exposure to vilazodone was significantly higher than other SSRIs. In addition, single substance exposures to vilazodone led to a significantly higher proportion of major (4.9 percent) and moderate (20.3 percent) outcomes compared with ingestions involving other SSRIs [46]. Among children with a vilazodone overdose, the most common effects were drowsiness/lethargy (33.9 percent), vomiting (29.2 percent), tachycardia (11.9 percent), and agitation (10.9 percent), all of which developed in a larger proportion than among children who ingested other SSRIs [46].
A systemic review of the peer-reviewed literature about vilazodone poisoning highlighted the potential serious adverse effects [13]. Young children are at particularly high risk and may develop life-threatening toxicity after small ingestions. In this review, all children (age 19 months to 3 years) were symptomatic upon presentation, with mental status changes, vomiting, tachycardia, and seizures being the most common signs. Four of eight children underwent endotracheal intubation in the emergency department, and six developed seizures. A retrospective analysis of data reported to United States poison control centers found that serious effects, such as coma, hallucinations, and seizures, were observed in young children (age <6 years old) who ingested doses as low as 10 mg [48]. As the starting dose of vilazodone is typically 10 mg, serious clinical effects may be observed in children following an ingestion of just one pill.
Although cardiac effects are not commonly described following vilazodone ingestions, there is a case report of a 15-year-old patient who ingested 780 mg and manifested QRS prolongation, which corrected with sodium bicarbonate administration [49]. It may be prudent to monitor patients for cardiac effects, especially those who are critically ill, following large ingestions.
DIAGNOSIS — The diagnosis of SNRI or atypical antidepressant poisoning is made based on a history of ingestion and consistent examination findings. Serum drug concentrations are not readily available and therefore not helpful in the acute management of the poisoned patient. Isolated SNRI poisoning generally causes mild symptoms. However, large ingestions may lead to central nervous system (CNS) depression, seizures, and cardiac conduction abnormalities.
DIFFERENTIAL DIAGNOSIS — With the exceptions of venlafaxine and bupropion, significant toxicity from isolated ingestions of an atypical antidepressant appears to be uncommon. If a patient with suspected atypical antidepressant poisoning is comatose or critically ill, the presence of coingestants or alternative causes should be investigated. The approach to such patients is reviewed separately. (See "Initial management of the critically ill adult with an unknown overdose" and "Approach to the child with occult toxic exposure" and "Stupor and coma in adults".)
Of note, many atypical antidepressants are relatively new, and additional medications in this class may follow. Published studies describing the effects of acute overdose from these newer medications are sparse, and manifestations and associated risks remain unclear. We suggest consultation with a medical toxicologist or poison control center when managing such patients. (See 'Additional resources' below.)
LABORATORY EVALUATION — Specific serum concentrations of atypical antidepressants are not readily available and not helpful in the acute management of a poisoned patient. In the setting of an SNRI or atypical antidepressant overdose, the following diagnostic studies are typically obtained:
●Fingerstick glucose to rule out hypoglycemia as the cause of any alteration in mental status
●Electrocardiogram (ECG) to evaluate for QRS prolongation, QTc prolongation, and other conduction abnormalities
●Acetaminophen and salicylate concentrations to rule out these common coingestants
●Pregnancy test in women of childbearing age
●Basic serum electrolytes to evaluate for acidosis and electrolyte abnormalities that could potentiate cardiac conduction abnormalities
In patients who have hyperthermia, muscle rigidity, or any other symptoms concerning for serotonin toxicity, a broader laboratory evaluation may be needed, as these patients may develop acute kidney injury, acute liver injury, rhabdomyolysis, and disseminated intravascular coagulation. (See "Serotonin syndrome (serotonin toxicity)", section on 'Laboratory evaluation'.)
MANAGEMENT — A summary table to facilitate emergency management of atypical antidepressant poisoning is provided (table 5). As most ingestions of atypical antidepressants, including SNRIs, produce minimal toxicity, management should focus on supportive care and avoiding harmful interventions. Treatment with a medication whose mechanism includes serotonin agonism (table 6) should be avoided to minimize the risk of serotonin toxicity. Likewise, medications that may prolong the QTc interval (table 7) should be avoided.
Hypotension and seizures were common after venlafaxine and bupropion overdose and both have led to arrhythmias and several deaths. Risk factors for seizures should be identified and include history of seizures, head trauma, polypharmacy, central nervous system (CNS) lesions, and concomitant substance abuse or withdrawal. (See "Evaluation and management of the first seizure in adults", section on 'Causes of seizures'.)
Serotonin toxicity — Patients who develop signs and symptoms concerning for serotonin toxicity warrant careful evaluation and treatment, which begins by withholding any serotonergic medication. The clinical findings, diagnosis, and management of serotonin toxicity are reviewed in detail separately, while emergency diagnosis and treatment is summarized in the accompanying table (table 8). (See "Serotonin syndrome (serotonin toxicity)".)
Patients who develop severe serotonin toxicity should be treated aggressively, including sedation with benzodiazepines and supportive care. Hyperthermia is treated with external cooling initially, but such patients often require neuromuscular paralysis and mechanical ventilation. Patients with mild to moderate symptoms typically improve after 24 to 48 hours of withholding the offending agent.
Seizure — For the patient who is actively seizing from atypical antidepressant poisoning, treatment with benzodiazepines (eg, diazepam, lorazepam) is first-line therapy. Second-line therapy may include barbiturates, such as phenobarbital and pentobarbital. However, in patients with refractory seizures, tracheal intubation may be necessary for airway protection and ventilation. Propofol has been used successfully to treat seizures due to antidepressant overdose that are refractory to benzodiazepine and barbiturate therapy, and can be used as an induction medication for rapid sequence intubation (RSI) [3]. (See "Initial management of the critically ill adult with an unknown overdose", section on '"D": Disability and neurological stabilization' and "Convulsive status epilepticus in adults: Management".)
To treat patients who are actively seizing, the initial diazepam dose is 5 to 10 mg intravenous (IV), given every 5 to 10 minutes (children older than 5 years: 1 to 2 mg; children younger than 5 years: 0.2 to 0.5 mg). The initial lorazepam dose is 1 to 2 mg IV/IM, given every 5 to 10 minutes (children 0.04 mg/kg).
If RSI is necessary for a seizing patient, a nondepolarizing neuromuscular blocking agent with a short duration of action, such as rocuronium, is preferred. Bedside electroencephalogram (EEG) monitoring may be needed to determine the presence of further seizure activity in a sedated and paralyzed patient who was previously seizing. (See "Rapid sequence intubation for adults outside the operating room".)
Cardiac toxicity — All patients with an atypical antidepressant poisoning should have an electrocardiogram (ECG) performed as part of their initial evaluation and should remain on cardiac monitoring while under observation for treatment of their acute overdose in the emergency department or the hospital. While uncommon with atypical antidepressant overdose, cardiac toxicity manifesting as ventricular dysrhythmia can occur as a result of sodium channel blockade or QTc interval prolongation.
Signs of sodium channel blockade — Patients with an overdose of an atypical antidepressant that causes cardiac sodium channel blockade (primarily venlafaxine) should be assessed with serial ECGs. Patients who are seizing following such an overdose should be treated with standard antiepileptic therapy as above.
Reliable signs of sodium channel blockade include the following:
●Prolongation of the QRS complex ≥120 msec
●Terminal R wave of 3 mm or more in lead aVR
●Ratio of terminal R wave to S wave of 0.7 or more in lead aVR
In patients with signs suggesting sodium channel blockade, ECGs should be monitored at least every hour and the patient should be treated with IV boluses of sodium bicarbonate. The dose of sodium bicarbonate is 1 to 2 mEq/kg (typically, 50 to 100 mEq for an adult). Doses may be repeated as needed until the QRS interval narrows, or the blood pH reaches 7.55. Additional details of how to give sodium bicarbonate for this indication are provided separately. (See "Tricyclic antidepressant poisoning", section on 'Sodium bicarbonate for cardiac toxicity'.)
In animal studies, hypertonic saline has produced therapeutic effects similar to sodium bicarbonate. If the blood pH reaches 7.55 but the patient continues to manifest signs of cardiovascular toxicity, such as QRS prolongation or ventricular dysrhythmia, hypertonic saline (3 percent sodium chloride) 100 to 200 mL IV bolus may be administered.
If cardiac toxicity persists despite treatment with sodium bicarbonate, lidocaine may be beneficial. Lidocaine is a Type 1b antiarrhythmic that inhibits fast sodium channels. Although it may be counterintuitive to use lidocaine for the treatment of sodium channel blockade, lidocaine dissociates relatively quickly from cardiac sodium channels and is thought to displace agents with less favorable binding characteristics. Lidocaine has been shown to be helpful in tricyclic antidepressant (TCA) poisoning [50]. In bupropion toxicity, cardiac conduction delay is due to inhibition of intercellular coupling rather than sodium channel blockade and may not respond to treatment with sodium bicarbonate [51].
QTc interval prolongation — A prolonged QTc interval (>500 to 550 msec) predisposes the patient to torsade de pointes (TdP), a life-threatening arrhythmia. QTc prolongation may occur in cases of duloxetine or bupropion overdose, and in other poisoned patients susceptible to developing acquired long QT syndrome. (See 'QTc interval prolongation' above and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
If the initial ECG from a patient with an atypical antidepressant overdose reveals a prolonged QTc interval, serial ECGs should be performed. The frequency of serial ECGs depends on the severity of poisoning. If a patient presents with a minor ingestion and mild symptoms, a single additional ECG may suffice if normal. It is reasonable to repeat the ECG every two to four hours in patients with QTc intervals >500 msec, until clinical improvement is seen.
Immediate nonsynchronized electric defibrillation is indicated in patients with hemodynamically unstable TdP. In the conscious patient, a brief trial of medical therapy may be attempted prior to cardioversion. Magnesium sulfate is first line medical therapy for treatment and prevention of TdP, and it should be given to any patient with acute poisoning from an atypical antidepressant that is associated with a QTc interval of 550 msec or longer. Magnesium sulfate 2 g should be administered intravenously (IV) over two minutes in patients with life-threatening dysrhythmias. In patients with a QTc of >550 msec who are otherwise hemodynamically stable, magnesium sulfate 2 g IV may be administered over 20 minutes, while close monitoring is performed. In addition, any hypokalemia or hypocalcemia should be corrected. The management of prolonged QTc is reviewed in detail separately. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
Gastrointestinal decontamination — The primary forms of gastrointestinal decontamination used to treat patients with atypical antidepressant poisoning are activated charcoal (AC) and whole bowel irrigation (WBI). A single dose of AC, 1 g/kg (typical adult dose is 50 g), may be given to a patient who presents within one to two hours of ingestion. AC should not be given to patients at risk for aspiration, such as those with vomiting or altered mental status. Tracheal intubation should not be performed for the sole purpose of administering AC. WBI refers to the administration of osmotically balanced polyethylene glycol electrolyte solution to induce liquid stool and mechanically flush pills or tablets from the gastrointestinal tract. The general use of AC and WBI in poisoning is reviewed separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal' and "Gastrointestinal decontamination of the poisoned patient", section on 'Whole bowel irrigation'.)
As the most commonly prescribed formulations of venlafaxine and bupropion are extended-release (XR) preparations, gastrointestinal decontamination is likely to be effective even if presentation is delayed several hours after ingestion. A single dose of AC, followed by WBI, may be considered for a significant overdose of a sustained or XR preparation of a toxic drug, mainly bupropion or venlafaxine. However, with both venlafaxine and bupropion overdose, patients are at risk for seizures, and the risk of aspiration must be considered when deciding whether to pursue gastrointestinal decontamination. In addition, although WBI may enhance clearance, there are few data demonstrating that it improves morbidity or mortality. WBI may be given if a patient presents early after a potentially life-threatening ingestion, as long as the patient'-s mental status is normal at that time.
Cardiovascular collapse — Cardiovascular collapse in patients with atypical antidepressant poisoning is rare. In addition to standard resuscitative efforts, lipid emulsion, a novel therapy believed to work by pulling lipid-soluble drugs from tissues, has been used successfully to restore circulation in a patient who experienced seizure activity and cardiovascular collapse from an overdose of bupropion and lamotrigine [52]. Whenever possible, we recommend consultation with a medical toxicologist or poison control center before initiating treatment with lipid emulsion therapy. Lipid emulsion treatment for poisoning, including dosing information, is discussed separately. (See "Calcium channel blocker poisoning", section on 'Lipid emulsion therapy'.)
Extracorporeal membrane oxygenation (ECMO) has been used successfully in several cases of cardiovascular failure from bupropion [53,54] and venlafaxine overdose [55,56]. If available, ECMO may be an important treatment option for patients with refractory cardiac shock, as drug toxicity is likely to resolve after several days.
Extracorporeal removal — There is no role for extracorporeal removal techniques such as hemodialysis in the treatment of atypical antidepressant poisoning due to the large volume of distribution of these drugs.
DISPOSITION — Following an intentional overdose with atypical antidepressants, patients who manifest significant complications (eg, severe serotonin syndrome, ventricular dysrhythmia, seizure) are admitted to an intensive care setting. Patients without significant clinical complications but whose electrocardiogram (ECG) manifests concerning abnormalities such as QT interval prolongation are admitted to a setting with cardiac monitoring.
Most patients with an atypical antidepressant ingestion may be medically cleared for a psychiatric evaluation if they are asymptomatic after six hours of observation and have no ECG changes attributable to the overdose. Closer observation is needed for patients whose ingestion involves any of the following:
●Sustained-release or extended-release (XR) formulations
●Drugs associated with delayed-onset seizures, such as bupropion or venlafaxine [12]
●Drugs associated with cardiotoxicity, such as bupropion or venlafaxine
Delayed-onset cardiac and neurologic toxicities following overdose of bupropion and venlafaxine are well described. Such toxicity appears to be due to slow gut absorption from sustained release (SR) or extended release (XR) formulations. For this reason, it is advisable to admit patients with such ingestions for a longer observation period (24 hours is generally sufficient) with cardiac monitoring, especially if the formulation of the ingested drug is unknown.
PEDIATRIC CONSIDERATIONS — Children may be at increased risk of toxicity following ingestion of atypical antidepressants. According to multiple cases reports of pediatric exposures, the symptoms observed are similar to those seen in adults. As an example, in a retrospective case series of unintentional bupropion ingestions in children ≤6 years, the most common clinical effects reported to the National Poison Data System included nausea/vomiting (4.3 percent), tachycardia (3.9 percent), agitation/irritability (3.1 percent), drowsiness/lethargy (2.4 percent), and seizures (1.4 percent) [57]. The average time to the development of seizures was 4.2 +/- 3.2 hours, and the longest delay was 14 hours.
Given the paucity of literature about the newer atypical antidepressants, we suggest admitting even mildly symptomatic children for monitoring, especially with cases involving medications associated with an increased risk of toxicity (eg, vilazodone). If a patient is asymptomatic after 6 to 8 hours of observation, they may be medically cleared. However, any patient who ingested a sustained-release or extended-release (XR) product, or bupropion or venlafaxine, should be admitted for at least 24 hours of observation of cardiac monitoring.
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse" and "Society guideline links: General measures for acute poisoning treatment".)
SUMMARY AND RECOMMENDATIONS
●Definition – Atypical antidepressants are those that do not clearly fit standard classifications for antidepressants. Most share structural similarities with selective serotonin reuptake inhibitors (SSRIs). (See 'Pharmacology and cellular toxicology' above and 'Kinetics' above.)
●Emergency management table and summary of toxicities – A summary table to facilitate the emergency management of atypical antidepressant poisoning is provided (table 5).
The large majority of poisonings are well tolerated and cause immediate central nervous system (CNS) toxicity of only mild to moderate severity (sedation is most common effect). Important exceptions include bupropion (may cause agitation or seizures), and venlafaxine (may cause adverse cardiac effects or seizures). Toxicity is often delayed with either drug. Status epilepticus and life-threatening cardiac dysrhythmia may be seen with a massive overdose of either drug. Major potential complications from atypical antidepressant overdose include serotonin toxicity, seizures, and QTc interval prolongation. (See 'Overview of toxicity' above and 'Important potential features of SNRI poisoning' above and 'Bupropion' above and 'Venlafaxine' above.)
●History and physical examination – Clinicians should attempt to obtain information about what medications were taken and their formulation (eg, extended release [XR]), the timing of ingestion and amount ingested, and whether any coingestants were involved. A detailed neuromuscular examination should be performed to identify signs of serotonin toxicity, such as clonus and hyperreflexia. Notable potential findings with atypical antidepressant overdose include:
•CNS – Sedation, coma, tremor, seizures; agitation
•Cardiopulmonary – Tachycardia, hypertension
•Gastrointestinal – Abdominal tenderness, vomiting, diarrhea
•Neuromuscular – Clonus (ankle more specifically), hyperreflexia
(See 'History' above and 'Physical examination' above and 'Toxicology of specific agents' above.)
●Diagnostic testing – Diagnostic studies should include an electrocardiogram (ECG) for all patients. Serial ECGs should be performed in patients at risk for significant cardiac effects (eg, venlafaxine overdose), with concerning findings on the initial ECG (eg, QRS or QT interval prolongation), or with a significant poisoning. (See 'Laboratory evaluation' above.)
●Management – In most cases, management consists of supportive care and avoiding harmful interventions. A summary table to facilitate the emergency management is provided (table 5). Treatment with a medication whose mechanism includes serotonin agonism (table 6) should be avoided to minimize the risk of serotonin toxicity. Medications that may prolong the QTc interval (table 7) should be avoided. (See 'Management' above.)
•Serotonin syndrome – Patients who develop signs and symptoms concerning for serotonin toxicity warrant careful evaluation and treatment, which begins by withholding any serotonergic medication. Serotonin toxicity is reviewed in detail separately, while emergency diagnosis and treatment are summarized in the accompanying table (table 8). (See "Serotonin syndrome (serotonin toxicity)".)
•Seizures – For the patient who is actively seizing, treatment with benzodiazepines (eg, diazepam, initial dose 5 to 10 mg IV; lorazepam, initial dose 1 to 2 mg IV) is first-line therapy. If seizures are not well controlled by benzodiazepines, barbiturates or propofol may be given. (See 'Seizure' above.)
•Sodium channel blockade (including QRS prolongation) – Patients whose ECG shows evidence of sodium-channel blockage (eg, QRS prolongation) should be treated with sodium bicarbonate 1 to 2 mEq/kg IV boluses as needed until the ECG changes resolve. Hypertonic saline and lidocaine may be used if cardiotoxicity persists. (See 'Cardiac toxicity' above.)
•Gastrointestinal decontamination – A single dose of activated charcoal (AC) may be administered for gastrointestinal decontamination. The typical dose is 50 g in adults and 1 g/kg in children. AC should not be administered in any patient with altered mental status, seizures, or vomiting, due to the risk of aspiration. (See 'Gastrointestinal decontamination' above.)
●Increased risk for children and patient disposition – Children may be at increased risk of toxicity following ingestion of atypical antidepressants. We suggest admitting even mildly symptomatic children for monitoring, especially with cases involving medications associated with an increased risk of toxicity (eg, vilazodone). Disposition of the adult patient varies with the severity of the poisoning and is discussed in the text. (See 'Pediatric considerations' above and 'Disposition' above.)
