SECOND GENERATION ANTIPSYCHOTIC OVERDOSE

Julie Weber Poison Alerts

Second-generation antipsychotics (SGA) include aripiprazole (Abilify®), quetiapine (Seroquel®), risperidone (Risperdal®), olanzapine (Zyprexa®) and ziprasidone (Geodon®).  They were originally called “atypical neuroleptics” when introduced in the 1990s because they had an “atypical” side effect profile compared to the long-used, first-generation antipsychotics (FGA) such as haloperidol and the phenothiazines.  SGA have similar efficacy with fewer extrapyramidal side effects and have largely supplanted the FGA.  These medications are among the most commonly prescribed drugs to treat mental health disorders including schizophrenia, bipolar disorder, depression, and irritability secondary to autism.  They are very commonly involved in adult overdoses reported to US poison centers.

MECHANISM OF ACTION

Second-generation antipsychotics are antagonists at the D2 and 5-HT2 receptors.  The unique feature that sets them apart from FGA is binding to 5-HT2 receptors at a higher affinity than at D2 receptors.  Strong serotonin antagonism serves to normalize dopamine levels in the synapses. This happens because there are serotonin receptors on nerve axons that encourage release of dopamine into the synaptic cleft at the nerve terminus. When these receptors are antagonized, less dopamine is released.  The agents also bind loosely to the D2 receptor (i.e., higher dissociation constant). Because of lower synaptic dopamine levels due to serotonergic binding, and higher dissociation of dopamine from its receptor, SGAs have a lower incidence of extrapyramidal symptoms (EPS) compared to FGAs. SGAs also are able to better treat the so-called “negative” symptoms of schizophrenia, such as apathy, withdrawal, and blunt affect.  There are also actions at other dopamine and serotonin receptors, along with anti-α1-adrenergic, anti-histamine, and anti-muscarinic effects. This provides some variation in mechanism and therapeutic uses among the agents.

NOTE: A newer SGA, pimavanserin (Nuplazid®) does not block dopamine receptors. This makes it useful in Parkinson patients who are already short on dopamine and cannot be given a regular antipsychotic medicine if they develop hallucinations, paranoia, and thought abnormalities.

MECHANISM OF TOXICITY

Toxicity of large doses is related to the antagonistic effects at multiple neuroreceptor sites (e.g., dopamine, serotonin, α1-adrenergic, histamine). Symptoms vary somewhat depending on the particular agent.

SYMPTOMS OF TOXICITY

Overall, SGA overdoses can cause CNS depression, orthostatic hypotension, and sinus tachycardia. Some agents may cause QTc prolongation, which is usually clinically insignificant in individuals with healthy hearts because tachycardia is protective against this arrhythmia.  Risk of Torsades can be evaluated by plotting heart rate and QT interval from the same EKG on the QT nomogram.  The CNS effects may include: drowsiness, somnolence, dizziness, headache, agitation, insomnia, slurred speech, ataxia, and tremors.   Sedation can be prolonged; serious cases may exhibit coma.  In rare cases, seizures may also occur.

Although EPS is less common with atypical antipsychotics when taken as prescribed, abnormal drug-induced movements may occur in overdose.  Extrapyramidal symptoms include acute dystonic reaction, akathisia, increased muscle tone, tremor and impaired swallowing.  Of note, neuroleptic malignant syndrome (NMS) is very rare and generally less severe if it does occur.

The table below shows the kinetics and relative adverse effect profile of the various SGA agents.

CLINICAL EFFECTS (Dose-dependent)

DRUG

PEAK

HALF-LIFE

Anti-cholinergic

EPS

Sedation

Sinus tachy-cardia

Seizure

QT Prolong

Orthostatic hypoTN

Aripiprazole
Abilify

3-5 hr

Extensive: 3 days

Poor: 6 days

0

0

+++

++

0

0

++

Asenapine
Saphris

0.5-1 hr

24 hr

0

++

++

0

0

0

+

Brexpiprazole
Rexulti

4 hr

91 hr

Range 3.5-4 days

+

++

+

0

0

0

0

Cariprazine
Vraylar

3-6 hr

24-48 hr

Active metab: 1-3 wk

+

+++

0

+

0

0

0

Clozapine
Clozaril, Fazaclo

2.5 hr

(1-6 hr)

Single dose: 4-12 hr

Multi Dose: 12 hr

+++

+

+++

+++

+++

++

+++

Iloperidone
Fanapt

2-4 hr

Extensive: 18-23 hr

Poor: 31-37 hr

+

++

++

+++

+

+

+++

Lurasidone
Latuda

1-3 hr

18 hr

0

+++

+++

0

0

0

+

Olanzapine
Zyprexa, Zydis

6 hr

30 hr

Range 21-54 hr

++

++

++

+++

++

+

+++

Pimavanserin
Nuplazid

6 hr

(4-24 hr)

57 hr

Active metab: 200 hr

0

0

0

0

0

+

0

Paliperidone
Invega

24 hr

23 hr

0

++

++

++

0

+

+

Quetiapine
Seroquel

IR 1.5 hr

ER 6 hr

IR 6 hr

ER 7-12 hr

++

0

+++

++

+

+

++

Risperidone
Risperdal

1 hr

Active metab: 3-17 hr

20 hr

0

++

++

++

0

+

++

Ziprasidone
Geodon

6-8 hr

7 hr

0

++

++

++

0

+

++

TREATMENT OF OVERDOSE

Monitoring patients with SGA overdose includes routine labs, 12-lead EKG and continuous cardiac monitoring.  Note: Quetiapine may cause a false positive for tricyclic antidepressants or methadone on a urine drug screen.

There is no specific antidote; treatment is symptomatic and supportive:

  • HYPOTENSION:  IV boluses of normal saline should be given as needed. Vasopressors such as dopamine and norepinephrine may also be given if significant hypotension develops. The use of adrenergic agents with pure beta-agonist activity is NOT recommended due to beta stimulation leading to vascular dilation, which may worsen hypotension in the presence of alpha-blockade.
  • QT PROLONGATION: QT prolongation is often clinically insignificant in healthy individuals. Monitor QT with serial 12-lead EKG and keep the patient under continuous cardiac monitoring. Use the QT nomogram to plot their risk for Torsades. Maintain magnesium and potassium in the high normal range.
  • SEIZURES: IV benzodiazepines are first-line, escalating to levetiracetam, then propofol when needed. If there is no IV access, midazolam IM is also appropriate as initial therapy.
  • DRUG-INDUCED MOVEMENT DISORDERS:  Treat classic acute dystonic with diphenhydramine (all ages) OR benztropine (adults only). Upon resolution of dystonia, patients should be started on an oral maintenance dose of either diphenhydramine or benztropine for 1 to 2 days. If the pharmacology of a drug-induced movement disorder is mixed or unknown, benzodiazepines are to be used first-line.
  • NEUROLEPTIC MALIGNANT SYNDROME (NMS): If a patient is suspected of having NMS, provide good supportive care to reduce body temperature and maintain respiratory, cardiovascular, and renal function. All dopamine-blocking and anticholinergic agents should be discontinued. The resolution of NMS may take up to a week after discontinuation. Unfortunately, there is no evidence that any pharmacologic therapy is effective to quicken the resolution of NMS. Dantrolene is not effective in NMS.

Second generation antipsychotic overdoses can be challenging to manage with the combination of cardiac and central nervous system effects. Our advice is to call the Missouri Poison Center at 1-800-222-1222 where specially trained nurses, pharmacists, and medical toxicologist can provide you with the most up-to-date management advice on common and uncommon exposures.

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