Antipsychotic (neuroleptic) medications are typically used in the treatment of schizophrenia and the other psychoses. The exact mechanism of action of the antipsychotics is not known. The majority of antipsychotics block the D2 dopamine receptors and 5-HT2A serotonin receptors in the brain to a varying degree. Antipsychotics are classified as either typical or atypical.
The typical antipsychotic medications are often categorized as being of low, medium, or high potency. The "potency" of these drugs does not refer to their effectiveness, but rather to the dosing of the drug for effective clinical response. In general, low-potency medications tend to be more sedating and are more often associated with hypotension, dizziness, and anticholinergic symptoms. High-potency medications are generally less sedating, but are more frequently associated with extrapyramidal effects such as tremors, rigidity, muscle spasms, and akathisia. Table 290-2 reviews the common typical antipsychotics.
TABLE 290-2Typical Antipsychotics
The U.S. Food and Drug Administration (FDA) has placed black box warnings on a number of the typical antipsychotics, due to concerns about possible cardiac dysrhythmias associated with their use. In particular, several of these medications have been associated with QTc prolongation and the FDA recommends evaluation of the QTc interval prior their use. In clinical situations in which rapid tranquilization is necessary, a priori determination of the QTc interval is impractical and usually impossible. If ECG data are available from the ED visit, these should be reviewed for evidence of QTc prolongation. Similarly, if prior ECG data are available, incorporate them into clinical decision making. Haloperidol remains a popular and effective agent for rapid tranquilization, and despite aggressive marketing claims to the contrary, its effectiveness is better supported by evidence than newer agents such as aripiprazole or ziprasidone.22 Unfortunately, QTc prolongation does not directly correlate with the clinical risk of dysrhythmias or the development of the malignant arrhythmia torsades de pointes. The black box warnings have led to apprehension in the use of highly effective medications.
The atypical antipsychotics (Table 290-3) are generally newer medications that more specifically target the dopamine receptors or inhibit the reuptake of serotonin. They also offer increased efficacy in the treatment of the negative symptoms of psychosis. Based on this improved receptor specificity, adverse effects such as sedation, extrapyramidal effects, QTc prolongation, and tardive dyskinesia are generally reduced but are not completely eliminated. The incidence of hypotension does not appear to have been significantly altered. The FDA has placed a black box warning on both typical and atypical psychotics for their off-label use in managing agitation and psychosis in elderly patients with dementia. Increased rates of cerebrovascular accidents, cardiovascular events, and mortality have been associated with chronic use.23,24
TABLE 290-3Atypical Antipsychotics ||Download (.pdf) TABLE 290-3 Atypical Antipsychotics
|Drug ||U.S. Food and Drug Administration–Approved Indications ||Warnings and Common Side Effects (BLACK BOX WARNINGS IN CAPS) |
|Clozapin (Clozaril) || |
Reduction in the risk of recurrent suicidal behavior in schizophrenic or schizoaffective disorders
|Sedation, dizziness, hypotension, tachycardia, salivation, weight gain, hyperthermia. |
|AGRANULOCYTOSIS, SEIZURES, MYOCARDITIS, OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS |
|Olanzapine (Zyprexa) || |
Agitation associated with schizophrenia and bipolar I mania
|CVAE, sedation, postural hypotension, hyperglycemia, weight gain, dizziness |
|Quetiapine (Seroquel) || |
|NMS, hyperglycemia, sedation, hypotension, headache, weight gain |
|CATARACT FORMATION |
|Risperidone (Risperdal) || |
|Extrapyramidal effects, hyperglycemia, hypotension, hyperprolactinemia, weight gain |
|Ziprasidone (Geodon) || |
Acute agitation in schizophrenic patients
|Sedation, rash, dizziness, hypotension, hyperglycemia, extrapyramidal effects |
|QT PROLONGATION AND RISK OF SUDDEN DEATH |
|Aripiprazole (Abilify) || |
|NMS, CVAE, hyperglycemia, seizure, hypotension, headache, akathisia |
|Asenapine (Saphris, Sycrest) || |
|Blood dyscrasias, cerebrovascular effects, dyslipidemia, extrapyramidal symptoms, NMS, hyperglycemia, QTc prolongation, orthostatic hypotension, increased mortality with chronic use in dementia patients |
|Iloperidone (Fanapt) ||Schizophrenia |
|Paliperidone (Invega, Sustenna) || |
The following side effects are more commonly associated with the typical antipsychotics but may also occur with medications in the atypical class: acute dystonia, akathisia or restlessness, parkinsonism, anticholinergic effects, cardiovascular effects, and neuroleptic malignant syndrome.
Acute dystonias are probably the most common side effect of antipsychotic medications seen in the ED. Muscle spasms of the neck, face, and back are the most common dystonias, but oculogyric crisis and even laryngospasm may also occur. Treatment with either benztropine, 1 to 2 milligrams IV, or diphenhydramine, 25 to 50 milligrams IV, rapidly corrects the dystonia. For persistent reactions, both medications may be used, and benzodiazepines may be added for treatment failures. Dystonias often recur despite dosage reduction or discontinuation of the offending antipsychotic.
Akathisia (Motor Restlessness)
Akathisia, a sensation of motor restlessness with a subjective desire to move, can begin several days to several weeks after initiation of antipsychotic treatment. Management can be difficult. If possible, decrease the dosage of the antipsychotic after psychiatric consultation. The best treatment is probably administration of β-blockers such as propranolol.
Antiparkinsonian or anticholinergic drugs such as benztropine, 1 milligram PO two to four times daily, may also afford some relief. In refractory cases, the antipsychotic may need to be changed to an atypical agent.
Antipsychotic-Induced Parkinson's Syndrome
A complete Parkinson's syndrome, including bradykinesia, resting tremor, cogwheel rigidity, shuffling gait, masked facies, and drooling, can occur, but often only one or two features of the syndrome are obvious. Antipsychotic dosage reduction and/or anticholinergic medication is usually effective.
Anticholinergic effects range from mild sedation to delirium. Peripheral manifestations may include dry mouth and skin, blurred vision, urinary retention, constipation, paralytic ileus, cardiac dysrhythmias, and exacerbation of angle-closure glaucoma. The central anticholinergic syndrome is characterized by dilated pupils, dysarthria, and an agitated delirium. Treatment is discontinuation of the antipsychotic and supportive measures.
Cardiovascular side effects, such as orthostatic hypotension and tachycardia, are commonly encountered with use of the antipsychotics. These effects are likely related to anticholinergic and adrenergic blockade and occur at therapeutic dosages. Typically, hypotension can be easily managed with IV fluids. In severe cases, vasopressor support may be required. Additional effects caused by blockade of sodium, calcium, and potassium channels in the central nervous and cardiac systems are less well delineated. However, effects on specific potassium channels in the myocardium have been linked to the drug-induced prolongation of the QTc interval associated with several of the antipsychotics.25,26 It is this mechanism of action by which the antipsychotics are believed to induce torsades de pointes.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome is an uncommon idiosyncratic reaction to neuroleptic drugs manifested by rigidity, fever, autonomic instability (tachycardia, diaphoresis, and blood pressure abnormalities), and a confusional state. Although high-potency antipsychotics may be more likely to cause the disorder, all antipsychotics are potential offenders. Neuroleptic malignant syndrome is a medical emergency and has a mortality rate as high as 20%. Management includes immediate discontinuation of the antipsychotic medication, hydration, and meticulous supportive treatment in an intensive care setting. Anticholinergic medications are not helpful and may worsen the condition by further impairing centrally mediated temperature regulation. Medications such as dantrolene sodium or bromocriptine are sometimes used to relieve the rigidity.