147 Antidepressants and Antipsychotics
Key Points• Central nervous system depression is the most common sign of antidepressant or antipsychotic overdose.
• Tachycardia, hypotension, seizures, and ventricular dysrhythmias can also occur, especially after tricyclic antidepressant (TCA) overdose.
• Airway intervention, benzodiazepines, intravenous fluids, and cooling measures (especially for serotonin syndrome and/or neuroleptic malignant syndrome) are the mainstays of supportive care and treatment.
• Specific treatment options include sodium bicarbonate for TCA toxicity and crystalloid fluids or hemodialysis for lithium poisoning.
• Controversial treatment modalities include dantrolene for toxin-induced hyperthermia, cyproheptadine for serotonin syndrome, bromocriptine for neuroleptic malignant syndrome, and prophylactic magnesium for long QTc intervals without evidence of hypomagnesemia or torsades de pointes.
Epidemiology
Data reported from United States poison control centers reveal that toxic exposures from antidepressants and antipsychotic agents continue to remain significant (Figs. 147.1 and 147.2). Tricyclic antidepressant (TCA) and monoamine oxidase inhibitor (MAOI) overdoses have historically resulted in the most significant morbidity and mortality. Currently, however, these agents are prescribed much less frequently than serotonin reuptake inhibitors (SRIs), atypical antipsychotics, and lithium. Atypical antipsychotic agents have largely replaced the older typical agents because these newer agents effectively reduce hallucinations, restructure thinking, and control agitation while assisting with the negative effects of psychotic disorders (flattened affect, avolition, social withdrawal). In addition, movement disorders such as dystonia, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome occur less often with atypical antipsychotics than with the typical agents.
Pathophysiology
Tricyclic Antidepressants
TCAs have similar ring structures and, with only a few exceptions, result in a related toxicity. Examples are amitriptyline (Elavil), imipramine (Tofranil), and doxepin (Sinequan). The five major pharmacologic effects of TCAs are listed in Table 147.1.
Table 147.1 Five Major Pharmacologic Effects of Tricyclic Antidepressants
| PHARMACOLOGIC EFFECT | SYMPTOMS |
|---|---|
| Blockade of sodium conductance through fast channels in the myocardium | Prolonged phase 0 of the cardiac action potential that results in a widened QRS complex on an electrocardiogram |
| Blockade of potassium efflux | Prolonged phase 3 of the cardiac action potential resulting in an increased QTc interval that lends itself to the development of torsades de pointes |
| Peripheral α1-receptor blockade | Vasodilation, decreased perfusion, and hypotension |
| Serotonin and norepinephrine reuptake inhibition | Agitation, delirium, or seizure activity |
| Anticholinergic activity | Range of physical findings (coma, delirium, urinary retention, mydriasis, seizures, tachycardia, flushing hyperthermia, dry skin) |
| “Hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter, fast as a cat, full as a tick” |
Monoamine Oxidase Inhibitors
Phenelzine (Nardil) and tranylcypromine (Parnate) are the two most commonly prescribed MAOIs in the United States, and they account for the majority of toxicity seen with this class of agents. The pharmacologic effects of MAOIs are listed in Box 147.1. These effects in overdose may result in a sympathomimetic toxidrome followed by profound hypotension. A therapeutic dose of an MAOI can interact with certain foods, drinks, and other pharmacologic agents and cause serious toxicity.
selective Serotonin Reuptake Inhibitors
Selective SRI antidepressants commonly prescribed are sertraline (Zoloft), paroxetine (Paxil), fluoxetine (Prozac), citalopram (Celexa), and escitalopram (Lexapro). The clinically beneficial central nervous system (CNS) effects of SRIs are thought to result from blockade of presynaptic reuptake of serotonin at 5-hydroxytryptamine type 1 (5-HT1) receptors. This blockade leads to higher synaptic serotonin levels and hence has positive effects on mood. Overdoses of these agents are much safer than overdoses of TCAs or MAOIs, although significant morbidity and mortality may occur with significant overdose or, more commonly, with ingestion of an SRI in combination with ingestion of agents possessing proserotonergic activity.1
Atypical Antipsychotics
The pharmacologic mechanism of action of atypical agents includes blockade at dopamine (D2) receptors and serotonin (5-HT2A) receptors.2 These agents can also cause repolarization abnormalities by blocking potassium efflux in the myocardium and thereby increasing the risk of torsades de pointes (Box 147.2).
Presenting Signs and Symptoms
Tricyclic Antidepressants
Serious toxicity is usually seen within 6 hours of ingestion. Signs and symptoms include obtundation, seizures, hypertension (early), hypotension (late), tachycardia (supraventricular or ventricular), and respiratory depression. Patients can deteriorate rapidly and usually do so within an hour of ingestion of the drug.3 Seizures and cardiovascular collapse can occur.4–6 In addition, profound hemodynamic instability follows seizure activity in some patients who have been poisoned with TCAs. Seizures result in further acidemia, which contributes to cardiovascular poisoning.
Monoamine Oxidase Inhibitors
Overdose of an MAOI results in sympathomimetic overdrive. Several phases have been described,7,8 and they can be classified as follows:
MAOI interactions with foods or beverages (aged cheeses, fava beans, ales, wines) produce early onset of signs and symptoms within minutes to hours.8 Because of tyramine’s short-lived action on the adrenal medulla (to increase endogenous amines), these interactions last only several hours. Interactions of MAOIs with other drugs (sympathomimetics, methylxanthines, SRIs, meperidine) also lead to elevated sympathetic tone. This effect manifests within minutes to hours and can last several hours to days.
Serotonin Reuptake Inhibitors
Overdose of SRIs causes CNS abnormalities (sedation, agitation, delirium), peripheral alterations (tremor, hyperreflexia, rigidity), cardiovascular changes (tachycardia, bradycardia), nausea or vomiting, and lightheadedness.9–11 The patient with citalopram or escitalopram overdose should be observed for seizures and QTc and/or QRS interval lengthening. Although isolated SRI ingestions frequently result in only mild toxicity, severe overdose or concomitant ingestion of proserotonergic medications can lead to serotonin excess and serotonin syndrome (Fig. 147.3). A history of ingestion of serotonergic agents, altered mental status, autonomic instability, and peripheral signs of rigidity or hyperreflexia are usually present.
Atypical Antipsychotics
The most significant extrapyramidal effect is neuroleptic malignant syndrome (NMS).12 NMS results when dopamine-blocking agents yield “dopamine-depleted” activity at D2 receptors in the CNS. Although NMS can occur after an intentional overdose, it usually arises after an increase in dose or after the addition of agents with similar activity (e.g., lithium inhibition of dopamine secretion). Manifestations of NMS include CNS abnormalities (sedation, agitation, delirium), peripheral alterations (tremor, hyperreflexia, rigidity), and cardiovascular changes with autonomic instability (tachycardia, bradycardia, hyperthermia) much like those seen in serotonin syndrome. Unlike serotonin syndrome, in which onset of symptoms is normally rather quick, NMS occurs insidiously. Historical information and medication lists are often required to differentiate between the two conditions (Table 147.2).
Table 147.2 Comparison of the Manifestations of Serotonin Syndrome and Neuroleptic Malignant Syndrome
| FEATURE | SEROTONIN SYNDROME | NEUROLEPTIC MALIGNANT SYNDROME |
|---|---|---|
| History | Drug(s) with serotonergic activity | Dopamine-blocking agents |
| Time of onset | Hours | Days |
