Cardiovascular

Hypertensive crisis

Blood pressure exceeding 180/110; may include headache, dyspnea, mental status changes.

MAOIs, SNRIs

Discontinue causal agent.

Cutaneous

Purpura

Nonblanching hemorrhagic eruptions beneath the skin.

Carbamazepine

Indicative of thrombocytopenia; discontinue likely causal agent and refer for medical management.

Stevens-Johnson syndrome or toxic epidermal necrolysis

Blistering, burnlike lesions on mucocutaneous tissues; facial edema, lymphadenopathy.

Bupropion, carbamazepine, lamotrigine

Discontinue likely causal agent. Steroids may be indicated early in the course of disease but are contraindicated later in course. Do not rechallenge after a serious rash.

Gastrointestinal

Acute pancreatitis

Acute abdominal presentation; diagnose by clinical examination and elevated serum lipase and amylase. A history of pancreatitis unrelated to divalproex is not a known contraindication or predisposing risk factor for developing pancreatitis from divalproex.

Divalproex

Discontinue divalproex and do not reintroduce. Medical management mainly involves taking no food by mouth accompanied by intravenous hydration and rest.

Hematological

Aplastic anemia

—

Carbamazepine, clozapine

Discontinue offending agent. Monitor for the development of and treat infections (e.g., pharyngitis) that arise in the setting of an immunocompromised state. Bone marrow typically replenishes within 21 days without the need for further intervention.

Neurological

Acute dystonia

Markedly increased muscle tone and rigidity in extremities; difficulty swallowing or clearing salivary secretions may indicate laryngospasm.

All FGAs, particularly higher-potency agents that lack anticholinergic effects (e.g., haloperidol, fluphenazine)

Administer oral or intramuscular anticholinergic agents (e.g., diphenhydramine or benztropine).

Seizure

—

All FGAs, SGAs, bupropion

Maintain airway and safety; avoid aspiration or head injury.

Systemic

Aseptic meningitis

Systemic illness involving high fever, nuchal rigidity, nausea, vomiting, photophobia, confusion, depressed sensorium.

Lamotrigine

Discontinue lamotrigine.

Neuroleptic malignant syndrome

Fever, abdominal cramping, muscle rigidity; elevated CK (typically >1,000 IU/L).

All antipsychotics

Discontinue the antipsychotic; hydrate; administer dantrolene for marked autonomic instability that does not respond adequately to supportive treatment.

Serotonin syndrome

Clonus

SSRIs, SNRIs, tramadol

Discontinue serotonergic drugs; hydrate, maintain airway, consider cooling blankets.

Atomoxetine

1,400 mg

Gastrointestinal symptoms, somnolence, dizziness, tremor, abnormal behavior; reports of seizures, hyperactivity, agitation; rare QTc prolongation, disorientation, hallucinations.

Gastric lavage with administration of activated charcoal if recent ingestion. Monitor cardiac and vital signs.

Buspirone

375 mg

Nausea, vomiting, dizziness, miosis, gastric distress.

Gastric lavage if recent ingestion. Monitor vital signs. No specific management strategies apart from general supportive measures.

Anticonvulsants and lithium

Carbamazepine

>6,000 mg

Neuromuscular disturbances, irregular breathing, respiratory depression, tachycardia, hyper- or hypotension, shock, QRS prolongation and ventricular arrhythmias, impaired level of consciousness (including drowsiness or coma), nystagmus, mydriasis, seizures, nausea, vomiting, anticholinergic effects.

Maintain adequate airway; gastric lavage with activated charcoal may be considered; monitor cardiac rhythm and vital signs.

Divalproex

Maximum dose not reported; maximum recommended dose in epilepsy=60 mg/kg; maximum reported serum valproate level= 2,120 μg/mL

Fever, hallucinations, somnolence (CNS depression at doses > 200 mg/kg [valproate > 180 μg/mL]), hyperammonemia, tachycardia, heart block, coma; fatalities reported.

Supportive measures, gastric lavage with emesis. Naloxone (0.8–2.0 mg) may reverse the CNS depressant effects of divalproex.

Gabapentin

49,000 mg

Ataxia, labored breathing, ptosis, sedation, hypoactivity, excitation, double vision, slurred speech, drowsiness, lethargy, diarrhea; no fatalities reported.

Supportive care, cardiovascular monitoring, gastric lavage. Gabapentin is dialyzable.

Lamotrigine

15,000 mg (oral LD₅₀=250 mg/kg in rats)

Dizziness, diplopia or blurry vision, rotatory or downbeat nystagmus, truncal ataxia, cognitive disorganization; fatalities reported.

Supportive care, cardiovascular monitoring, induction of emesis, gastric lavage.

Lithium

Not reported; serum levels>3 mEq/L may produce seizures, coma, and death; maximum recommended dose=2,400 mg/day

Neurotoxicity (ataxia, nystagmus, tremor, slow shuffling gait, myoclonic jerks, confusion and disorientation), GI symptoms (nausea, vomiting, abdominal cramps, diarrhea), and cardiac toxicity (including sinus bradycardia and sinoatrial- or atrioventricular block that can produce complete heart block [Serinken et al. 2009]); reports of pulmonary edema; mortality results from CNS toxicity and subsequent cardiovascular collapse.

Consequences of lithium toxicity may persist for weeks or even months after serum lithium levels become undetectable. Following acute overdose, measurement of plasma lithium–erythrocyte lithium ratios may reveal higher lithium in plasma than erythrocytes. Management involves hydration, gastric lavage (although activated charcoal does not bind lithium well and tends not to be recommended), and cardiac monitoring; hemodialysis is rarely necessary for serum lithium levels <2.5 mEq/L but is usually required for levels >6 mEq/L, or for lower levels in medically debilitated patients or patients with coma, convulsions, cardiovascular symptoms, or respiratory failure.

Oxcarbazepine

24,000 mg

Somnolence, hypotension, tremor, seizures, diplopia, dyspnea, miosis, nystagmus, decreased urine output; no fatalities reported.

Supportive care, gastric lavage with activated charcoal is recommended.

Topiramate

110,000 mg

Stupor or coma, severe metabolic acidosis, convulsions, drowsiness, speech disturbances, blurred vision, diplopia, cognitive impairment, lethargy, abnormal coordination, hypotension, abdominal pain, agitation, dizziness, depression; no reported fatalities.

Gastric lavage or induction of emesis if recent ingestion. Activated charcoal is not thought to absorb topiramate.

Antidepressants

Bupropion

17,500 mg

Seizure (~1/3 of cases), hallucinations, loss of consciousness, tachycardia.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion (but not induction of emesis), with administration of activated charcoal. EEG monitoring is advised for first 48 hours.

Citalopram

6,000 mg

Dizziness, sweating, nausea, vomiting, tremor, somnolence, tachycardia; QTc prolongation, nodal rhythms, ventricular arrhythmias, and torsades de pointes reported.

Maintain adequate airway; gastric lavage with activated charcoal may be considered; monitor cardiac rhythm and vital signs.

Desvenlafaxine

>600 mg

Tachycardia, somnolence, mydriasis, seizures, vomiting, hypotension, liver necrosis, rhabdomyolysis, serotonin syndrome; QTc or QRS prolongation and bundle branch block on ECG.

Maintain adequate airway; monitor cardiac rhythm and vital signs; gastric lavage if soon after ingestion.

Escitalopram

>1,000 mg

Seizures, coma, dizziness, hypotension, insomnia, acute renal failure, tachycardia; QTc prolongation and rare torsades de pointes on ECG.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion.

Fluoxetine

8,000 mg

Variable outcomes (e.g., full recovery) after 8,000-mg ingestion, although 34 fatalities reported by manufacturer following 633 monotherapy overdoses; signs of overdose include seizures, nausea, vomiting, tachycardia, somnolence; more severe overdoses may lead to visual and gait disturbances, confusion, unresponsiveness, nervousness, respiratory distress, tremor, hypertension, impotence, movement disorders, hypomania.

Maintain adequate airway; cardiac rhythm and vital sign monitoring; gastric lavage if soon after ingestion. Do not induce emesis. Beware of coingestion of TCAs and the pharmacokinetic potential for their increased accumulation.

Fluvoxamine

12,000 mg

Variable outcomes (e.g., full recovery after 12,000-mg ingestion but lethality after 1,400-mg ingestion); signs of overdose include GI upset, coma, hypokalemia, hypotension, respiratory difficulties, somnolence, tachycardia, bradycardia, QTc prolongation, first-degree AV block and other arrhythmias, seizures, tremor, hyperreflexia.

Maintain adequate airway; cardiac rhythm and vital sign monitoring; gastric lavage if soon after ingestion. Beware of coingestion of TCAs and the pharmacokinetic potential for their increased accumulation.

Levomilnacipran

360 mg

Not described; no fatalities reported.

Supportive care; no specific interventions recommended.

Mirtazapine

975 mg (Fawcett and Barkin 1998)

Disorientation, somnolence, impaired memory, tachycardia; no known potential for seizures or ECG abnormalities; unlikely fatality.

Maintain adequate airway; monitor cardiac rhythm and vital signs. Gastric lavage with activated charcoal if soon after ingestion. Induction of emesis is not recommended.

Nefazodone

11,200 mg

Nausea, vomiting, somnolence; fatalities reported when overdoses occurred in combination with other substances.

Maintain adequate airway; monitor cardiac rhythm and vital signs. Gastric lavage if soon after ingestion. Induction of emesis is not recommended.

Paroxetine

2,000 mg

Somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, dizziness.

Maintain adequate airway; gastric lavage if soon after ingestion (but not induction of emesis), with administration of activated charcoal.

TCAs

Not reported

Drowsiness, lethargy, confusion, tachycardia, hyper- or hypotension, urinary retention with desipramine (highest risk for fatality due to potent sodium channel blockade), nortriptyline, imipramine, amitriptyline, clomipramine, protriptyline, doxepin.

Cardiac monitoring; intravenous hydration (observe for hypotension due to sodium channel blockade); gastric lavage with activated charcoal if within first few hours after ingestion; intravenous administration of sodium bicarbonate (alkalinize urine) if QRS > 100 msec, ventricular arrhythmias; observe for seizure risk (highest in first several hours after ingestion; may require anticonvulsant benzodiazepines, phenobarbital, or other antiseizure therapy). Avoid β-blockers, calcium channel blockers, ipecac syrup.

Vilazodone

280 mg

Serotonin syndrome, lethargy, restlessness, hallucinations, disorientation.

Maintain adequate airway; monitor cardiac rhythm and vital signs. Gastric lavage with activated charcoal if soon after ingestion. Induction of emesis is not recommended.

Vortioxetine

75 mg

Nausea, dizziness, diarrhea, abdominal discomfort, pruritis, somnolence, flushing.

Supportive care.

Anxiolytics/Sedative-hypnotics

Benzodiazepines

Not reported

Somnolence, confusion, coma, hyporeflexia, hypotension, miosis or sluggish/delayed pupillary responses, nystagmus.

Supportive care including cardiovascular monitoring, gastric lavage, and intravenous hydration. Flumazenil may be administered to reverse sedative effects of benzodiazepines.

Buspirone

375 mg

Nausea, vomiting, dizziness, drowsiness, miosis, gastric distress; no fatalities reported.

Supportive care, cardiovascular monitoring.

Eszopiclone

270 mg

Somnolence, coma, rare fatalities when combined with other CNS drugs or alcohol.

Immediate gastric lavage where appropriate; IV fluids; flumazenil may be useful; monitor vital signs; general supportive care.

Ramelteon

Not reported

Somnolence.

General supportive care; gastric lavage where appropriate; IV fluids as needed.

Suvorexant

240 mg

Somnolence.

General supportive care; gastric lavage where appropriate; IV fluids as needed.

Tasimelteon

Not available

Somnolence.

General supportive care; gastric lavage where appropriate; IV fluids as needed.

Zaleplon

200 mg

CNS depression, drowsiness, coma, ataxia, hypotonia, hypotension, respiratory depression, rare fatalities.

General supportive care; gastric lavage where appropriate; IV fluids as needed; flumazenil may be appropriate; monitor vital signs.

Zolpidem

Not available

Somnolence, coma, cardiovascular and respiratory compromise, possible fatality.

General supportive care; gastric lavage where appropriate; IV fluids as needed; flumazenil may be useful (but may lead to convulsions); monitor vital signs.

Psychostimulants

Amphetamine

Deaths reported at dosages > 1.3 mg/kg

Restlessness, tremor, hyperreflexia, tachypnea, confusion, assaultiveness, hallucinations, panic, hyperpyrexia, rhabdomyolysis, convulsions, coma, arrhythmias, hypo- or hypertension, circulatory collapse, nausea, vomiting, diarrhea, abdominal cramps, death.

General supportive care; gastric lavage where appropriate; administration of activated charcoal; IV phentolamine may counteract hypertension, if necessary; chlorpromazine antagonizes the central stimulant effects of amphetamine and may be useful.

Methylphenidate

1,134 mg (Klampfl et al. 2010)

Vomiting, agitation, muscle twitching, seizures, confusion, psychosis, hyperhidrosis, headache, fever, tachycardia, palpitations, rhabdomyolysis, mydriasis, dry mouth, death.

General supportive care; gastric lavage where appropriate; administration of activated charcoal.

Modafinil

12,000 mg

Excitation, agitation, restlessness, insomnia, disorientation, confusion, hallucinations, nausea, diarrhea, tremor, tachycardia, bradycardia, hypertension, chest pain; no fatalities reported.

Supportive care, cardiovascular monitoring, induction of emesis or gastric lavage if not contraindicated.

SGAs

Aripiprazole

1,260 mg

Vomiting, somnolence, tremor, confusion, bradycardia, tachycardia, QTc prolongation, coma, respiratory failure, seizures.

Supportive care, cardiac monitoring; activated charcoal if given soon after ingestion may reduce serum levels.

Asenapine

400 mg

Agitation, confusion.

Maintain adequate airway; cardiac monitoring. Monitor for possible hypotension and circulatory collapse. Anticholinergic medication should be used if severe EPS occur.

Brexpiprazole

Not available

Not described.

Supportive monitoring, maintenance of airway; administration of activated charcoal if within 4 hours of overdose.

Cariprazine

48 mg

Orthostatic hypotension, sedation.

Supportive monitoring, maintenance of airway; no other specific intervention recommended.

Iloperidone

576 mg

Drowsiness, sedation, tachycardia, hypotension, EPS, QTc prolongation; no fatalities reported.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion with activated charcoal plus a laxative should be considered. Cardiac monitoring should include continuous electrocardiography due to the risk for arrhythmias. Monitor for seizure risk and dystonic reactions.

Lurasidone

560 mg

Recovery without medical sequelae.

Avoid α-adrenergic blocking agents or sympathomimetic drugs with β-agonist activity (e.g., epinephrine, dobutamine) to minimize risk for hypotension; avoid disopyramide, procainamide, or quinidine if arrhythmias occur, to minimize additive risk for QTc prolongation. No sequelae following single overdose case of 560 mg/day.

Olanzapine

1,500 mg

Agitation, dysarthria, tachycardia, EPS, reduced level of consciousness or coma; fatality from overdoses of olanzapine alone reported from doses as low as 450 mg.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion with activated charcoal plus a laxative should be considered. Cardiac monitoring should include continuous electrocardiography due to the risk for arrhythmias.

Paliperidone

405 mg

Gait unsteadiness, drowsiness, EPS, seizures, QTc prolongation, tachycardia, hypotension.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion. Anticholinergic agents should be used for severe EPS. Intravenous hydration may be necessary to counteract hypotension. Avoid parenteral epinephrine or dopamine because beta stimulation may exacerbate hypotension from paliperidone-induced alpha blockade.

Pimavanserin

Unavailable

Nausea, vomiting, possible QTc prolongation.

Immediate cardiovascular/continuous ECG monitoring; if antiarrhythmics are needed, avoid agents that may further prolong QTc (e.g., procainamide, quinidine, disopyramide).

Quetiapine

9,600 mg

Drowsiness, sedation, tachycardia, hypotension, hypokalemia, first-degree heart block; prolonged delirium described in adolescents.

Maintain adequate airway; cardiac monitoring; gastric lavage with activated charcoal and a laxative if soon after ingestion; continuous ECG monitoring.

Risperidone

360 mg

Drowsiness, sedation, tachycardia, hypotension, EPS, electrolyte abnormalities, seizures, QTc prolongation with QRS widening on ECG.

Maintain adequate airway; cardiac monitoring; gastric lavage with activated charcoal and a laxative if soon after ingestion; continuous ECG monitoring.

Ziprasidone

3,240 mg

Sedation, slurred speech, transient hypertension, EPS, somnolence, tremor, anxiety.

Maintain adequate airway; cardiac monitoring; gastric lavage if soon after ingestion.