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Selection of Appropriate Pharmacotherapy

As previously stated, an important factor in selecting pharmacotherapy is knowing the underlying cause. For example, a patient with stimulant-induced psychosis may need to use antipsychotics only for a few days, while a patient with schizophrenia requires chronic antipsychotic treatment. Agitated dementia patients are often managed with nondrug means. If medication is warranted, they can be managed with high-potency typical anti-psychotic agents such as haloperidol rather than lower potency typical agents such as chlorpromazine, which could complicate matters by inducing an anticholinergic-induced delirium or dementia. Agitation associated with alcohol intoxication and withdrawal is managed by benzodiazepines due to their cross-tolerance with alcohol. Individuals with bipolar disorder are managed chronically with mood stabilizers such as lithium, divalproex sodium, carbamazepine or atypical antipsychotics such as olanzapine, but may require acute doses of benzodiazepines or antipsychotics to control behavior until the maintenance medications begin to produce their effect.

The pharmacist could also present a review of other considerations, which include the relative risk of adverse events in the patient, available dosage forms, comorbid physical conditions, concurrent medications, and drug cost.

Benzodiazepines and high-potency conventional antipsychotic agents such as haloperidol are currently the mainstays in treating acute agitation and aggression; however, atypical antipsychotics (such as olanzapine, clozapine, risperidone, ziprasidone, and quetiapine) are playing an increasingly important role as they are commonly used as maintenance medications and new dosage forms are becoming available making them easier to administer in acute situations.

Benzodiazepines: Benzodiazepines are useful for treating acute agitation and aggression as they are effective and generally safe in a wide range of causes. They usually are not, however, primary agents in treating the underlying disorder. Benzodiazepines have a rapid onset of action. Following administration, response should be assessed approximately 30 minutes after intramuscular and 30 to 60 minutes after oral administration of medications. All benzodiazepines are equally efficacious when dosed equipotent, with the primary clinically significant differences being lipophilicity, half-life, and metabolic pathways. Lorazepam is the most commonly used and extensively studied benzodiazepine in agitation because of its short half-life and availability of oral and easy to use parenteral dosage forms. Lorazepam offers the advantage of decreased risk of accumulation and toxicity because its metabolites are inactive. If a longer half-life agent is desired, oral diazepam is the most commonly used agent because of its rapid onset of action. A single dose has about the same duration of action as short-acting agents, but after repeated doses the active metabolite desmethyldiazepam accumulates, reducing major fluctuations in blood concentrations, thereby allowing fewer repeat doses. The primary disadvantage of repeated doses of a longer acting agent is excessive sedation, which interferes with the patient’s cognition, potentially decreasing participation in their treatment planning.

All benzodiazepines have the potential for abuse, dependence, withdrawal, tolerance and overdose. During the treatment of an acute episode of agitation, the risks of abuse, dependence, withdrawal and tolerance are low due to the short duration of benzodiazepine administration. Assessment of these risks should be carefully considered during the treatment planning process in patients requiring benzodiazepines for more than a few days to weeks. Overdose is a risk if inadequate time is given for a single dose to work leading to excess dosing, or if other causes of the aggression that are nonresponsive to benzodiazepines are unaddressed. Symptoms of excessive dosing include confusion, drowsiness, lethargy, slurred speech, and ataxia. Respiratory depression and hypotension are rare complications usually seen with very high doses or IV use. Pharmacists should be reassured that benzodiazepines are remarkably safe in most patients and the risk of complications in acute use is low.

A relatively rare (<1%) idiosyncratic reaction to benzodiazepines is disinhibition. Patients who are elderly, mentally retarded, have brain damage, or are already intoxicated with other sedative agents appear to have the greatest risk.Disinhibition presents with irritability, verbal aggression, physical violence, increased suicidal/homicidal thoughts, or hostility and can be confused with an incomplete response or return of symptoms after the dose wears off. The primary difference between disinhibition and inadequately treated agitation is the timeframe. Disinhibition is the likely case when symptoms worsen soon after the benzodiazepine is given and not hours later when the drug may have worn off. Also, these symptoms worsen with increased concentration of the drug. If disinhibition occurs, the benzodiazepine should be discontinued.