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.

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 Between 2005 and 2010 more than 6% of adolescents reported psychotropic medication use in the last month (3.2% antidepressants, 1% antipsychotics).² Because of their wide availability, both intentional and unintentional ingestions by children are not uncommon.

According to the 2015 report of the American Association of Poison Control Centers (AAPCC), antidepressants accounted for 4.6% of all exposures, and children younger than 6 years of age were involved in 9.3% of reported antidepressant exposures. Antidepressant ingestion displayed the third most rapid increase in serious outcomes compared to historical data.³ There were a total of 7899 ingestions in patients younger than 6 years and 10,075 in patients between 6 and 19 years of age. The vast majority of antidepressant ingestions were due to selective serotonin reuptake inhibitors (SSRIs), with far fewer coming from serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, and tricyclic antidepressants. However, bupropion and the TCAs resulted in a higher likelihood of hospitalization and serious outcomes.³ This is due to the narrow therapeutic index of bupropion and the TCAs compared to the SSRIs. Doses as low as 10 mg/kg of a TCA or bupropion can result in toxicity, whereas most adults can tolerate up to 1000 mg before encountering life-threatening consequences.

EPIDEMIOLOGY—NEUROLEPTICS

The neuroleptics or antipsychotics are prescribed to treat schizophrenia and other psychiatric disorders. The 2015 AAPCC report shows that there were a total of 6306 pediatric single-substance antipsychotic ingestions. Sedative/hypnotic/antipsychotics were also noted to be among the categories of substance exposures increasing most rapidly compared to historical AAPCC data.³ Although atypical antipsychotics have been regarded as safer than older agents, this has not been clearly demonstrated in overdose.⁴

ANTIDEPRESSANTS

Tricyclic Antidepressants

TCAs exert their therapeutic effects primarily through presynaptic reuptake inhibition of norepinephrine and serotonin. They also have anticholinergic, α₁-blocking, sodium channel blocking, and GABA modulating effects. Table 120-1 lists the commonly available TCAs typically seen in clinical practice.

Selective Serotonin Reuptake Inhibitors

SSRIs were developed because of the toxicity of TCAs.⁵ 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 sodium channels or the cholinergic, adrenergic, or GABA systems.

Atypical Antidepressants

Atypical antidepressants such as the SNRIs are derived from SSRIs and typically display activity at the serotonin receptor. However, norepinephrine–dopamine reuptake inhibitors (NDRIs) such as bupropion are not considered serotoninergic.⁶ Table 120-1 lists the commonly available SSRIs and atypical antidepressants typically seen in clinical practice.

NEUROLEPTICS (ANTIPSYCHOTICS)

Neuroleptics act by blocking dopaminergic, α-adrenergic, muscarinic, histaminic, and serotonergic 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.⁷ Neuroleptics include broadly diverse chemical classes. These entities differ in the degree to which they cause anticholinergic, cardiovascular, or extrapyramidal system reactions.

Typical Antipsychotics

Typical antipsychotic drugs block both D1 and D2 receptors in the dopamine pathways of the brain. Excess release of dopamine in the mesolimbic and mesocortical pathways have 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 throughout the brain. This is thought to produce the extrapyramidal reactions associated with these agents.⁸ Table 120-2 lists the available typical antipsychotics that may be seen in clinical practice.

Atypical Antipsychotics

Atypical antipsychotics target serotonergic neurons and D1 receptors 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.⁹ 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.⁸

ANTIDEPRESSANTS

Tricyclic Antidepressants

TCAs can have direct or indirect effects 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 brief 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.¹⁰

Selective Serotonin Reuptake Inhibitors

Unlike TCAs, SSRIs have minimal activity in the cholinergic and sympathetic systems, and little effect on sodium channels. QTc prolongation can occur due to the effects of SSRIs on the hERG potassium channel.¹¹

In overdose, SSRIs can present with a constellation of symptoms due to serotonergic excess. These symptoms involve the gastrointestinal (GI) (nausea, vomiting, and diarrhea), cardiovascular (sinus tachycardia), and CNS (dizziness, blurry vision, mental status changes) systems.¹² In addition, both citalopram and escitalopram have been associated with prolongation of the QTc interval and risk for torsades de pointes, though toxicity with escitalopram is typically less than that with citalopram.^13,14

Atypical Antidepressants

Venlafaxine, desvenlafaxine, and duloxetine are classified as SNRIs and can present with nonspecific symptoms including tachycardia, vomiting, dizziness, stupor, or seizures.¹⁵