Antipsicoticos 2da Gen 3

10/10/2019 Second-generation (atypical) antipsychotic medication poisoning - UpToDate
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Second-generation (atypical) antipsychotic medication

poisoning
Authors: Raffi Kapitanyan, MD, Mark Su, MD, MPH
Section Editors: Stephen J Traub, MD, Michele M Burns, MD, MPH
Deputy Editor: Jonathan Grayzel, MD, FAAEM
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2019. | This topic last updated: Jan 03, 2018.
INTRODUCTION
A second generation of antipsychotic medications, commonly referred to as "atypical antipsychotics,"

was introduced in 1998. The term "atypical" refers to an antipsychotic medication that produces
minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses, has a low
propensity to cause tardive dyskinesia (TD) with long-term treatment, and treats both positive and
negative signs and symptoms of schizophrenia [1]. Atypical agents currently available include
clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone
(Geodon), aripiprazole (Abilify), and paliperidone (Invega), the active metabolite of risperidone. Some
newer atypical antipsychotics include asenapine (Saphris), iloperidone (Fanapt) and lurasidone
(Latuda).
Atypical antipsychotics have largely replaced traditional agents as first-line therapy in the treatment of
schizophrenia. Toxicologic exposures and fatalities associated with atypical agents pose a persistent
problem in the United States and elsewhere [2-4]. Consequently, it is important for the practicing
clinician to be familiar with the pharmacology and toxicology of these medications.
This topic review will discuss the basic pharmacology, presentation, and management of acute
intoxication with atypical antipsychotics. Discussions of the clinical use of these drugs, details
concerning potential side effects, and general management of drug overdose are found elsewhere.
(See "First-generation antipsychotic medications: Pharmacology, administration, and comparative
side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and
https://www.uptodate.com/contents/second-generation-atypical-antipsychotic-medication-poisoning/print?search=intoxicacion antipsicoticos&source=search_result… 1/21

side effects" and "Neuroleptic malignant syndrome" and "General approach to drug poisoning in
adults".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY
The pharmacology of atypical antipsychotic agents is complex. As a general rule, all exhibit dopamine
(D2) receptor blockade, similar to first-generation antipsychotics, but with a lower binding affinity [5].
In addition to lower D2 receptor potency and occupancy at therapeutic doses, atypical agents
selectively antagonize mesolimbic D2 receptors more so than those in the nigrostriatum and
prefrontal cortex. As a result, side effects attributable to nigrostriatal D2 blockade (eg, extrapyramidal
symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia) occur less
frequently, as do side effects attributable to mesocortical (ie, prefrontal) D2 blockade (eg,
neurocognitive impairment and negative symptoms).
Atypical antipsychotics are also serotonin (5-HT) antagonists at the 5-HT2A receptor subtype. This
pharmacologic effect mitigates the negative signs and symptoms of schizophrenia by disinhibiting the
dopamine system in the nigrostriatum and prefrontal cortex [5].
Serotonin-dopamine antagonism is the reason why atypical antipsychotics may be given at smaller
doses, producing fewer extrapyramidal side effects, while maintaining clinical efficacy [5].
In addition to the common mechanisms noted above, each atypical agent has a unique
pharmacodynamic profile that can be used to predict adverse effects in both therapeutic use and
overdose. Although each agent has different affinities for specific receptors, most drugs fall into one of
two groups. The first group consists of clozapine, olanzapine, and quetiapine, all of which
demonstrate multiple receptor antagonism (alpha-1, histamine-1, and muscarinic-1). The second
group consists of risperidone, paliperidone, and ziprasidone, which demonstrate alpha-1 adrenergic
and histamine-1 receptor antagonism [6,7].
The atypical antipsychotic aripiprazole possesses a unique receptor profile. Postsynaptic partial
dopamine agonism blunts positive symptoms, while basal D2 receptor activation produces fewer
movement disorders than nonspecific dopamine antagonists [8,9]. Aripiprazole also binds to
presynaptic dopamine autoreceptors, reducing dopamine release and synthesis [8,9]. These pre- and
postsynaptic actions result in a neurotransmitter-level stabilizing effect, blunting excess activity and
augmenting deficient activity. Aripiprazole also has a low affinity for serotonin, alpha-1 adrenergic, and
histamine-1 receptors. This novel receptor affinity pattern explains the efficacy and favorable side
effect profile of this agent [8,9].
The newer antipsychotics also have some unique features [10]:

● Iloperidone has low antimuscarinic receptor and antihistaminic receptor activity and should result
in less tachycardia sedation and agitation.
● Asenapine is taken via the sublingual route. If swallowed, its bioavailability significantly
decreases from 35 to 2 percent. It has high affinity and antagonism for serotonin, alpha
adrenergic, dopamine and histamine receptors but not muscarinic receptors. Consequently,
hypotension and sedation are more likely to occur without tachycardia or agitation.
● Lurasidone possesses potent alpha-2C adrenoreceptor antagonism and low alpha-1 adrenergic
antagonism. This may result in less hypotension. The alpha-2C adrenoreceptor is located
presynaptically and functions as an inhibitory autoreceptor similar to alpha-2A adrenoreceptors,
preventing norepinephrine release.
PHARMACOKINETICS
Atypical antipsychotics are completely and rapidly absorbed after oral administration, but undergo
significant first-pass hepatic metabolism (table 1). Time to peak plasma concentration ranges from 1
to 10 hours. Atypical antipsychotics have a large volume of distribution. They are highly lipophilic,
highly protein-bound, and accumulate in the brain, lung, and other tissues. Plasma concentrations
with therapeutic dosing are quite low (nanograms per milliliter). These agents enter breast milk and
fetal circulation.
The liver metabolizes atypical antipsychotics predominantly via cytochrome P450 enzymes
(isoenzymes 1A2, 2D6, and 3A4). Therefore, serum levels may be affected by other medications that
stimulate or inhibit the cytochrome P450 system.
Some atypical agents have active metabolites. Long elimination half-lives and active metabolites
allow for once or twice-daily therapeutic dosing. The correlation between doses, serum concentration,
and clinical effects is quite variable. Fetuses, infants, and the elderly have less ability to metabolize
these agents because of decreased cytochrome p450 activity, while children metabolize them more
rapidly [11,12]. While risperidone is subject to drug interactions affecting the CYP2D6 enzyme, in vivo
studies suggest this isozyme plays a limited role in the clearance of paliperidone, the major active
metabolite of risperidone. This property of paliperidone makes dose adjustment unnecessary in
patients with mild to moderate hepatic impairment.
CLINICAL FEATURES OF OVERDOSE

Overview — In acute overdose, atypical antipsychotics cause only mild to moderate toxicity in the
majority of patients, and may produce no symptoms (table 2) [5,13]. Although the number of reported
exposures has increased dramatically, mortality remains low [4,14]. Toxic effects that do occur
following overdose are largely an extension of a drug's physiologic effects (table 3). (See
'Pharmacology and cellular toxicology' above and 'History and physical examination' below.)
The toxic and lethal doses of atypical antipsychotics are highly variable and depend largely on the
specific drug, the presence of co-intoxicants, age, and whether the patient is taking the drug for the
first time. Children and unhabituated adults are more sensitive to the toxic effects of these agents.
(See 'Pediatric considerations' below.)
Toxicity from atypical antipsychotics usually begins within one to two hours and peaks by four to six
hours following ingestion, and the effects are similar for both adults and children. Resolution of toxicity
usually occurs by 12 to 48 hours following ingestion but has reportedly taken up to six days [5].
History and physical examination — The diagnosis of atypical antipsychotic overdose is primarily
based upon a history of ingestion and clinical findings. Central nervous system (CNS) effects occur
most frequently (table 3). Extrapyramidal side effects (EPS) and neuroleptic malignant syndrome
(NMS) are infrequent, but are more common in children [15]. (See "Neuroleptic malignant syndrome".)
The most common clinical presentation consists of:
● Lethargy and sedation (from histamine blockade)

● Miosis, tachycardia, and orthostatic hypotension (from alpha adrenergic blockade)
● Anticholinergic toxicity, including confusion (from muscarinic blockade) (see "Anticholinergic
poisoning")
Certain effects may be more common with specific agents. A large retrospective case series found
that quetiapine overdose appears more likely to cause respiratory depression, depressed mental
status, and hypotension compared to other antipsychotics [14]. Numerous case reports have
described rapid fluctuations between sedation and agitation in olanzapine overdose, deemed
"agitation despite sedation." The incidence of seizures is higher for clozapine (10 percent) than for
most atypical agents (less than 1 percent) [5].
The pharmacology of atypical antipsychotics is complex, and presentations of patients who have
overdosed on these drugs vary, especially if the patient has ingested a multiple receptor antagonist
(eg, clozapine or olanzapine). The development of pharmacobezoars following overdose of extended
release formulations of quetiapine has been reported [16]. (See 'Pharmacology and cellular
toxicology' above and "Gastric bezoars".)
Possible historical features

● CNS – Fatigue/lethargy/sedation/agitation, confusion, dizziness, slurred speech, seizure,

delirium, coma
● Cardiopulmonary – Dyspnea, chest pain, palpitations
● Anticholinergic manifestations – Blurry vision, dry mouth, constipation, urinary retention
● Gastrointestinal (rare) – Nausea, vomiting, abdominal pain
Possible examination findings
● CNS – Miosis (sometimes mydriasis), ataxia, dysarthria, dystonia, hypotonia, extrapyramidal side
effects (eg, acute dystonia, parkinsonism, akathisia, tardive dyskinesia), rapidly fluctuating mental
status (depression and agitation), hypersalivation, myoclonus, seizures, coma
● Cardiopulmonary – Tachycardia, orthostatic hypotension/mild hypertension, respiratory

depression
● Anticholinergic – Facial flushing, dry mucous membranes, decreased sweating, mild

hyperthermia
● Gastrointestinal – Abdominal tenderness, usually localized to the right upper quadrant,

decreased bowel sounds
LABORATORY EVALUATION
Routine laboratory evaluation of the poisoned patient includes the following:
● Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status
● Acetaminophen and salicylate levels, to rule out these common coingestions
● Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that affect the QRS
or QTc intervals
● Pregnancy test in women of childbearing age
No specific clinically useful test for atypical antipsychotic intoxication exists. Of note, atypical
antipsychotics, particularly quetiapine, may produce a false positive test for tricyclic antidepressants
[17].
Sinus tachycardia is the most common abnormal ECG finding, but other aberrations can occur. These
include dose-related repolarization abnormalities (QTc prolongation, ST depression, T wave

flattening) and supraventricular/ventricular dysrhythmias [5]. Such ECG findings are usually clinically
insignificant, and despite cases of QTc prolongation, Torsades de Pointes has not been reported
following overdose of atypical antipsychotics.
Ziprasidone has the greatest effect on the QTc interval compared with other atypical antipsychotics.
Aripiprazole did not cause QTc prolongation or cardiotoxicity in preclinical trials or in the few published
case reports of drug toxicity (table 4) [15,18-32].
Although unrelated to overdose, certain atypical agents have been shown to increase serum prolactin
levels (risperidone), cause hyperglycemia (clozapine and olanzapine), increase liver transaminases
(clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), and induce agranulocytosis or
leukopenia/neutropenia (clozapine and olanzapine) [33-36]. Most of these effects are idiosyncratic.
Additional testing may be needed depending upon the clinical situation, such as creatine
phosphokinase and urine myoglobin in a patient found down and at risk for rhabdomyolysis,
cerebrospinal fluid analysis in a patient with altered mental status of unclear etiology, or liver
transaminases in a patient with significant abdominal pain.
Qualitative screening by gas chromatography/mass spectrometry may be used to confirm the

presence of atypical agents, but this is almost never clinically indicated. Quantitative drug
concentrations are not generally used, since they are not readily available and do not predict toxicity
or guide treatment [5].
DIAGNOSIS
The diagnosis of second generation (atypical) antipsychotic poisoning is made clinically based upon a
history of ingestion and suggestive clinical findings. A definitive diagnosis may be established using
gas chromatography/mass spectrometry, but this is almost never clinically indicated and the results
typically cannot be obtained in time to affect management. The most common clinical findings
associated with atypical antipsychotic poisoning include lethargy and sedation; miosis, tachycardia,
and orthostatic hypotension; and, anticholinergic toxicity. Effects can vary by agent. (See
"Anticholinergic poisoning".)
DIFFERENTIAL DIAGNOSIS
Atypical antipsychotics interact with multiple receptors. Therefore, signs and symptoms of atypical
antipsychotic overdose are similar to those seen with many other agents, which can make
differentiation among potential poisons difficult. Below is a list of drugs commonly encountered in the

overdose patient and the potential manifestations of acute intoxication they share with atypical
antipsychotics:
● Traditional antipsychotics (table 2): extrapyramidal side effects (EPS), tardive dyskinesia (TD),
neuroleptic malignant syndrome (NMS), anticholinergic, alpha adrenergic-blockade, prolonged
QTc, CNS/respiratory depression (see "Neuroleptic malignant syndrome" and "Anticholinergic
poisoning")
● Cyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline, doxepin): sedation,

prolonged QRS/QT (see "Tricyclic antidepressant poisoning")
● Anticonvulsants (lorazepam, diazepam, phenytoin, phenobarbital): CNS/respiratory depression

(see "Phenytoin poisoning")
● Antihistamines (diphenhydramine): anticholinergic, sedation, prolonged QRS (see

"Anticholinergic poisoning")
● Opioids (morphine, hydromorphone, fentanyl): miosis, CNS/respiratory depression (see "Acute

opioid intoxication in adults")
● Muscle relaxants (cyclobenzaprine, metaxalone, methocarbamol): sedation
● Sedative/hypnotics (lorazepam, diazepam, phenobarbital): CNS/respiratory depression
● Ethanol/toxic alcohols (ethylene glycol, methanol): CNS/respiratory depression (see "Methanol

and ethylene glycol poisoning" and "Ethanol intoxication in adults")
● Antidysrhythmics (procainamide, quinidine, ibutilide, amiodarone, sotalol): dysrhythmia,

prolonged QRS/QT
MANAGEMENT
General management — The treatment for atypical antipsychotic overdose is primarily supportive.
The general approach to any poisoned patient begins with stabilization of the airway, breathing, and
circulation. General discussions of the management of poisoning are found elsewhere. Detailed
management of intoxication with second generation antipsychotics is discussed immediately below. A
summary table of signs and symptoms is provided (table 3). (See "General approach to drug
poisoning in adults" and "Gastrointestinal decontamination of the poisoned patient" and "Initial
management of the critically ill adult with an unknown overdose".)

Every patient requires continuous cardiac monitoring, intravenous access, an electrocardiogram

(ECG), and continual reevaluation for mental status changes. Altered mental status can range from
profound depression to signs of extrapyramidal side effects (EPS), tardive dyskinesia (TD),
neuroleptic malignant syndrome (NMS), or seizures (table 4) [36,37]. (See "Neuroleptic malignant
syndrome".)
Hypotension secondary to alpha adrenergic (alpha) blockade is treated initially with intravenous
boluses of isotonic crystalloid. Refractory hypotension, due to peripheral alpha blockade by atypical
antipsychotics, can usually be treated with vasoconstrictive alpha agonists such as norepinephrine or
phenylephrine. Drugs with beta 2 agonist effects (eg, epinephrine) should be avoided as they can
exacerbate the vasodilatory effects of alpha blockade [38].
Cardiac dysrhythmias (supraventricular and ventricular) are treated according to standard advanced
cardiac/pediatric life support guidelines, with a few exceptions. Antidysrhythmics that prolong the QTc
interval, such as type IA (quinidine, procainamide), IC (flecainide, propafenone), and III (amiodarone,
sotalol, ibutilide) medications should be avoided, as they may exacerbate conduction abnormalities. A
type IB antidysrhythmic agent (eg, lidocaine) may be used. QRS prolongation may be treated with
intravenous sodium bicarbonate, as with cyclic antidepressants and other Na+ channel blocking
agents [38]. (See "Advanced cardiac life support (ACLS) in adults" and "Tricyclic antidepressant
poisoning".)
Seizures secondary to atypical antipsychotic toxicity are usually isolated and self-limited, and
treatment with anticonvulsant agents is rarely needed. If treatment is necessary, benzodiazepines
(such as lorazepam) are first-line therapy [5].
Decontamination and enhanced elimination — Whenever feasible, we suggest a single dose of

activated charcoal (AC) with or without a cathartic (eg, sorbitol) be given as soon as the patient with
second generation antipsychotic poisoning has been stabilized [39]. Gastric lavage is not
recommended because these agents are associated with low mortality in overdose. AC should be
withheld in patients who are sedated and may not be able to protect their airway, unless tracheal
intubation is performed first. However, tracheal intubation should not be performed solely for the
purpose of giving AC. (See "Gastrointestinal decontamination of the poisoned patient".)
The high-protein binding, large volume of distribution, and low plasma levels of atypical antipsychotics
make extracorporeal removal, by either hemodialysis or hemoperfusion, unlikely to be of benefit [36].
We do not recommend its use.
Extrapyramidal and anticholinergic effects — Acute extrapyramidal side effects (eg, dystonia) due
to second generation antipsychotic poisoning may be treated with anticholinergic agents, such as
diphenhydramine or benztropine. Patients with neuroleptic malignant syndrome require supportive

treatment, which may include active cooling, benzodiazepines, bromocriptine, or neuromuscular

blockade, depending upon the degree of symptoms. Treatment for tardive dyskinesia includes
benzodiazepines and supportive care [40,41]. (See "Neuroleptic malignant syndrome" and "Tardive
dyskinesia: Etiology, risk factors, clinical features, and diagnosis" and "Tardive dyskinesia: Prevention,
prognosis, and treatment".)
Anticholinergic effects of atypical antipsychotics may contribute to the severe agitation and altered
level of consciousness seen in acute overdose. Benzodiazepines are usually adequate to control
these symptoms. Physostigmine, a short-acting acetylcholinesterase inhibitor, has been successfully
used to reverse the anticholinergic syndrome seen with clozapine and olanzapine [42-44]. (See
"Anticholinergic poisoning".)
Physostigmine has potential adverse effects (bradycardia, bronchospasm, bradypnea), and its use as
an antidote for atypical antipsychotic overdose is not clearly defined. We recommend that
physostigmine only be used in the treatment of atypical antipsychotic poisoning in consultation with a
medical toxicologist or poison control center. Patients with cyclic antidepressant toxicity should not
receive physostigmine [42,43,45]. Anticholinergic toxicity and physostigmine therapy are discussed in
detail elsewhere. (See "Anticholinergic poisoning", section on 'Antidotal therapy with physostigmine'.)
Refractory toxicity — In the rare case of severe poisoning from a second generation antipsychotic
that fails to improve with the standard treatments described above, lipid emulsion therapy may be
useful. However, support for this intervention consists solely of case reports and we cannot
recommend routine treatment with lipid emulsion [46,47].
Disposition — Second generation antipsychotic agents are associated with a rapid onset of
symptoms following overdose, so disposition is generally determined within four hours of ingestion.
Patients who remain asymptomatic after a four-hour observation period require no further medical
evaluation, assuming no other clinical issues exist. Psychiatry consultation is needed for suicidal
patients. Patients with moderate to severe toxicity (CNS/respiratory depression, hypotension,
agitation/delirium, dysrhythmias) should be admitted to a monitored bed or intensive care unit,
depending on symptom severity.
PEDIATRIC CONSIDERATIONS
Mental health clinicians are treating children and adolescents with atypical antipsychotics at
increasing rates for a range of psychiatric illnesses, despite limited data on their efficacy in this age
group [48]. The diversity of indications has contributed to the increased use of these agents, and
increased episodes of overdose. In the United States, approximately 6,000 annual exposures to
atypical antipsychotic agents occur in children 19 years of age and younger; international data is
limited. Significant adverse effects, including major outcomes and death, are uncommon in reported
single exposures [4].
Among the newer antipsychotics, asenapine is indicated in children 10 years and older for bipolar I
disorder. The other new agents, iloperidone and lurasidone, do not have this US Food and Drug
Administration (FDA)-approved pediatric indication.
Most published reports of overdose do not contain data on long-term consequences and are unable to
provide conclusions about the significance of blood levels, the differences in duration of symptoms by
age or size, or the relationship between the severity of symptoms and the dose ingested. Assessment
and management in children is similar to that of adults; history and clinical presentation remain
paramount. The most frequent clinical presentation of overdose in children includes nausea and
vomiting, lethargy, drowsiness, somnolence, tachycardia, and central nervous system (CNS)
depression [8,13,37,49].
Children may be at increased risk of toxicity with atypical antipsychotics. Children metabolize these
drugs more rapidly, and, because children generally have less adipose tissue and lower levels of
protein-binding, consequently there may be increased drug bioavailability [36]. Therefore, we suggest
that children who have ingested atypical antipsychotic medications and are asymptomatic be
observed for six hours. Clinicians should maintain a low threshold for admitting mildly symptomatic
children.
Supportive treatment and close observation are the mainstays of management. Sorbitol should not be
given to young children because of the risk of excessive fluid loss. As with adults, the majority of
toxicity in children due to atypical antipsychotics results in good outcomes [13,49]. Nevertheless, a
small number of case reports describe instances when endotracheal intubation and admission to an
intensive care unit were necessary [50,51]. (See "Gastrointestinal decontamination of the poisoned
patient".)
ADDITIONAL RESOURCES
Regional poison control centers in the United States are available at all times for consultation on
patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-
1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside
consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the
diagnosis and management of ingestions or overdoses. The World Health Organization provides a
listing of international poison centers at its website:
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html

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: General measures for acute
poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific
agents other than drugs of abuse".)
SUMMARY AND RECOMMENDATIONS
● Atypical (second generation) antipsychotic medications have largely replaced conventional first-
generation drugs for the treatment of schizophrenia because of their effectiveness and safer
therapeutic and overdose profile (table 2). As use of these drugs has increased, so has the
incidence of overdose.
● The pharmacology of atypical antipsychotic agents is complex, involving several types of

receptors. (See 'Pharmacology and cellular toxicology' above and 'Pharmacokinetics' above.)
● In acute overdose, atypical antipsychotics cause only mild to moderate toxicity in the majority of
patients, and may produce no symptoms. The toxic and lethal doses of atypical antipsychotics
are highly variable and depend largely on the specific drug, the presence of co-intoxicants,
patient age, and whether the patient is taking the drug for the first time (table 3). Children and
unhabituated adults are more sensitive to the toxic effects of these agents. (See 'Clinical features
of overdose' above and 'Pediatric considerations' above.)
● Because they work at multiple receptors, atypical antipsychotics can cause a range of signs and
symptoms, most often involving the central nervous system. The most common clinical
presentation consists of:
• Lethargy and sedation (from histamine blockade)
• Miosis, tachycardia, and orthostatic hypotension (from alpha adrenergic blockade)
• Anticholinergic toxicity, including confusion (from muscarinic blockade) (see 'Clinical features
of overdose' above)
● Rapid fluctuations between sedation and agitation can occur in olanzapine overdose. Clozapine
overdose is more often associated with seizures, although they are still uncommon. Ziprasidone
has the greatest effect on the QTc interval. A description of possible signs and symptoms is found
in the text. (See 'History and physical examination' above.)

● Signs and symptoms of atypical antipsychotic overdose are shared by many agents, which can
make differentiation among potential poisons difficult. Drugs commonly encountered in the
overdose patient that may share manifestations of acute intoxication with atypical antipsychotics
include: traditional antipsychotics, cyclic antidepressants, anticonvulsants, antihistamines,
opioids, muscle relaxants, sedative/hypnotics, ethanol/toxic alcohols, and antidysrhythmics. (See
'Differential diagnosis' above.)
● No specific, clinically useful test to identify atypical antipsychotic intoxication exists. Obtain an
electrocardiogram, salicylate and acetaminophen levels, a fingerstick glucose, and a qualitative
pregnancy test in women of childbearing age. We suggest obtaining liver transaminases and a
complete blood count in patients with altered mental status, abdominal pain, or other concerning
findings (eg, possible acetaminophen coingestion). (See 'Laboratory evaluation' above.)
● The treatment for atypical antipsychotic overdose is primarily supportive. Care includes
continuous cardiac monitoring, intravenous access, and continual reevaluation for mental status.
(See 'General management' above.)
● We suggest giving a single dose of activated charcoal (AC) with or without a cathartic (eg,
sorbitol) to the patient with an acute overdose of an atypical antipsychotic medication (Grade
2C). AC should be withheld in patients who are sedated and may not be able to protect their
airway, unless tracheal intubation is performed first. Tracheal intubation should not be performed
solely for the purpose of giving AC. (See 'Decontamination and enhanced elimination' above.)
● Severe effects from atypical antipsychotic poisoning are uncommon. Hypotension is treated
initially with intravenous crystalloid. Refractory hypotension, due to peripheral alpha adrenergic
blockade, can usually be treated with vasoconstrictive alpha agonists such as norepinephrine or
phenylephrine. Seizures are generally brief and self-limited, but may be treated with
benzodiazepines (eg, lorazepam), if necessary. Acute extrapyramidal side effects (eg, dystonia)
may be treated with anticholinergic agents, such as diphenhydramine or benztropine. (See
'General management' above.)
● Children may be at increased risk of toxicity following atypical antipsychotic ingestion. We

suggest that children who have ingested atypical antipsychotic medications and are
asymptomatic be observed for six hours. Clinicians should maintain a low threshold for admitting
mildly symptomatic children. Management is otherwise similar to adults. (See 'Pediatric
considerations' above.)
● Atypical antipsychotic agents are associated with a rapid onset of symptoms following overdose,
so disposition is generally determined within four hours of ingestion. (See 'Disposition' above.)

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antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2000; :CD002306.
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22. Bagnall A, Lewis RA, Leitner ML. Ziprasidone for schizophrenia and severe mental illness.
Cochrane Database Syst Rev 2000; :CD001945.
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:CD004578.
24. Pollak PT, Zbuk K. Quetiapine fumarate overdose: clinical and pharmacokinetic lessons from
extreme conditions. Clin Pharmacol Ther 2000; 68:92.
25. Palenzona S, Meier PJ, Kupferschmidt H, Rauber-Luethy C. The clinical picture of olanzapine
poisoning with special reference to fluctuating mental status. J Toxicol Clin Toxicol 2004; 42:27.
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drugs--data of the Acute Intoxication Unit in Wrocław]. Przegl Lek 2004; 61:392.
29. Chue P, Singer P. A review of olanzapine-associated toxicity and fatality in overdose. J

Psychiatry Neurosci 2003; 28:253.
30. Burton S, Heslop K, Harrison K, Barnes M. Ziprasidone overdose. Am J Psychiatry 2000;

157:835.
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Topic 304 Version 17.0

GRAPHICS
Pharmacokinetics of second generation antipsychotics
Therapeutic
Half-Life, Protein Vol. of
peak Route of Active
h, binding, distribuion,
plasma metabloism metabolite
therapeutic percent L/kg
level, h
Traditional 2-5 8-36 90-95 7-62 CYP2D6 Variable

agents CYP1A2
CYP3A4
Clozapine 1-4 7-13 92-95 2-5 CYP1A2 Norclozapine

CYP3A4
Olanzapine 5-6 20-30 93 10-20 CYP1A2 NO

CYP2D6
Quetiapine 1-2 4-10 83 10 CYP3A4 7-

hydroxyquetiapine
Risperadone 1-2 3-24 90 1-1.5 CYP2D6 9-

hydroxyrisperidone
Ziprasidone 4-5 4-10 >99 2 CYP3A4 NO
Aripiprazole 3-5 75-146 >99 4.9 CYP2D6 Dehydroaripiprazole

CYP3A4
Graphic 60825 Version 4.0

Common antipsychotic medications
Generic name Brand name* Generic name Brand name ¶
First generation agents Second generation agents
Chlorpromazine Thorazine Aripiprazole Abilify
Droperidol Inapsine Asenapine Saphris
Fluphenazine Prolixin Brexipiprazole Rexulti
Haloperidol Haldol Clozapine Clozaril, Fazaclo,

Versacloz
Loxapine Adasuve, Loxitane
Iloperidone Fanapt
Perphenazine Trilafon
Lurasidone Latuda
Thioridazine Mellaril
Olanzapine Zyprexa, Zyprexa
Thiothixene Navane
Relprevv, Zyprexa Zydis
Trifluoperazine Stelazine
Paliperidone Invega, Invega
Sustenna, Invega Trinza
Quetiapine Seroquel
Ziprasidone Geodon, Zeldox
* Most first generation antipsychotics are available only as generic versions in United States (US).
¶ Brand names of second generation agents available in US, Canada, and many other countries.

Atypical antipsychotic overdose: Signs and symptoms
Alpha-1:
Dizziness, orthostatic hypotension, reflex tachycardia, miosis, nasal congestion
Histamine-1:
CNS depression, appetite stimulation, hypotension
Muscarinic-1:
Central
Agitation, hallucinations, memory dysfunction
Peripheral
Dry skin and mucous membranes, hypertension, constipation, mydriasis, blurry vision, tachycardia, urinary retention

Selected adverse effects of atypical antipsychotic medications
Acute Chronic
Clozapine Seizures NMS, Agranulocytosis, Myocarditis
Risperidone Prolonged QT, dystonia EPS, TD, NMS
Olanzapine Seizures, dystonia EPS, TD, NMS, Agranulocytosis
Quetiapine Seizures, dystonia EPS, TD, NMS
Ziprasidone Prolonged QT, dystonia EPS
Aripiprazole Gastrointestinal (vomiting)
Asenapine Hypotension, sedation
NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia; EPS: extrapyramidal side effects.

Contributor Disclosures
Raffi Kapitanyan, MD Nothing to disclose Mark Su, MD, MPH Nothing to disclose Stephen J Traub,
MD Nothing to disclose Michele M Burns, MD, MPH Nothing to disclose Jonathan Grayzel, MD,
FAAEM Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

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10/10/2019 Second-generation (atypical) antipsychotic medication poisoning - UpToDate

Official reprint from UpToDate®

Second-generation (atypical) antipsychotic medication

A second generation of antipsychotic medications, commonly referred to as "atypical antipsychotics,"

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PHARMACOLOGY AND CELLULAR TOXICOLOGY

The newer antipsychotics also have some unique features [10]:

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CLINICAL FEATURES OF OVERDOSE

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The most common clinical presentation consists of:

● Lethargy and sedation (from histamine blockade)

Possible historical features

● CNS – Fatigue/lethargy/sedation/agitation, confusion, dizziness, slurred speech, seizure,

● Cardiopulmonary – Dyspnea, chest pain, palpitations

● Anticholinergic manifestations – Blurry vision, dry mouth, constipation, urinary retention

● Gastrointestinal (rare) – Nausea, vomiting, abdominal pain

Possible examination findings

● Cardiopulmonary – Tachycardia, orthostatic hypotension/mild hypertension, respiratory

● Anticholinergic – Facial flushing, dry mucous membranes, decreased sweating, mild

● Gastrointestinal – Abdominal tenderness, usually localized to the right upper quadrant,

Routine laboratory evaluation of the poisoned patient includes the following:

● Acetaminophen and salicylate levels, to rule out these common coingestions

● Pregnancy test in women of childbearing age

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Qualitative screening by gas chromatography/mass spectrometry may be used to confirm the

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● Cyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline, doxepin): sedation,

● Anticonvulsants (lorazepam, diazepam, phenytoin, phenobarbital): CNS/respiratory depression

● Antihistamines (diphenhydramine): anticholinergic, sedation, prolonged QRS (see

● Opioids (morphine, hydromorphone, fentanyl): miosis, CNS/respiratory depression (see "Acute

● Muscle relaxants (cyclobenzaprine, metaxalone, methocarbamol): sedation

● Sedative/hypnotics (lorazepam, diazepam, phenobarbital): CNS/respiratory depression

● Ethanol/toxic alcohols (ethylene glycol, methanol): CNS/respiratory depression (see "Methanol

● Antidysrhythmics (procainamide, quinidine, ibutilide, amiodarone, sotalol): dysrhythmia,

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Every patient requires continuous cardiac monitoring, intravenous access, an electrocardiogram

Decontamination and enhanced elimination — Whenever feasible, we suggest a single dose of

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treatment, which may include active cooling, benzodiazepines, bromocriptine, or neuromuscular

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SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● The pharmacology of atypical antipsychotic agents is complex, involving several types of

• Lethargy and sedation (from histamine blockade)

• Miosis, tachycardia, and orthostatic hypotension (from alpha adrenergic blockade)

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● Children may be at increased risk of toxicity following atypical antipsychotic ingestion. We

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Use of UpToDate is subject to the Subscription and License Agreement.

1. Freedman R. Schizophrenia. N Engl J Med 2003; 349:1738.

6. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin

8. Lofton AL, Klein-Schwartz W. Atypical experience: a case series of pediatric aripiprazole

13. Meli M, Rauber-Lüthy C, Hoffmann-Walbeck P, et al. Atypical antipsychotic poisoning in young

19. Srisurapanont M, Maneeton B, Maneeton N. Quetiapine for schizophrenia. Cochrane Database

https://www.uptodate.com/contents/second-generation-atypical-antipsychotic-medication-poisoning/print?search=intoxicacion antipsicoticos&source=search_result… 14/21

28. Magdalan J, Wasyko-Smolarek M, Antończyk A, et al. [Intoxications with atypical antipsychotic

29. Chue P, Singer P. A review of olanzapine-associated toxicity and fatality in overdose. J

30. Burton S, Heslop K, Harrison K, Barnes M. Ziprasidone overdose. Am J Psychiatry 2000;

31. House M. Overdose of ziprasidone. Am J Psychiatry 2002; 159:1061.

https://www.uptodate.com/contents/second-generation-atypical-antipsychotic-medication-poisoning/print?search=intoxicacion antipsicoticos&source=search_result… 15/21

48. Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation antipsychotic

Topic 304 Version 17.0

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