The Importance of Diagnosis Before Prescribing
Agitation is a symptom, not a diagnosis, and it can be caused by a wide range of medical, psychiatric, or substance-related issues. Therefore, the most critical step before administering any medication is to identify and address the underlying cause. Medications are typically used to calm a patient and facilitate further diagnostic evaluation and treatment, not as a permanent solution on their own. For example, a patient with delirium caused by an infection requires antibiotics, and the agitation is a secondary symptom.
Whenever possible, non-pharmacological interventions like verbal de-escalation, creating a calm environment, or addressing basic comfort needs should be attempted first. In emergency situations, however, medication may be necessary for patient and staff safety.
Benzodiazepines: The Calming Agents
Benzodiazepines are a class of anxiolytic medications that act by enhancing the effect of the neurotransmitter GABA in the brain, which leads to a sedative effect. They are particularly effective for agitation associated with:
- Alcohol withdrawal: Benzodiazepines are the treatment of choice for managing alcohol withdrawal syndrome and preventing related seizures.
- Anxiety and panic: For agitation driven primarily by anxiety or panic, a benzodiazepine may be appropriate.
- Undifferentiated agitation: In cases where the cause of agitation is unknown but does not involve prominent psychosis, a benzodiazepine might be considered, sometimes in combination with an antipsychotic.
Common benzodiazepines used for agitation include lorazepam (Ativan) and midazolam. Lorazepam is often favored due to its reliable absorption and minimal drug accumulation. However, benzodiazepines carry a risk of oversedation and respiratory depression, particularly when combined with other CNS depressants like alcohol. They can also paradoxically worsen confusion, especially in elderly patients with delirium.
Antipsychotics: For Psychosis and Beyond
Antipsychotics are a cornerstone of pharmacological treatment for agitation related to psychiatric conditions like schizophrenia, bipolar disorder, and dementia.
First-Generation Antipsychotics (FGAs):
- Haloperidol (Haldol): A potent D2 receptor blocker, it has a long history of use for psychosis-induced agitation and is considered a first-line agent in many emergency settings. A major drawback is a high risk of extrapyramidal symptoms (EPS), such as dystonia and parkinsonism. To mitigate this, it is often administered with a benzodiazepine or an anticholinergic agent.
Second-Generation Antipsychotics (SGAs):
- Olanzapine (Zyprexa): Available in oral and intramuscular (IM) forms, it is effective for acute agitation and has a lower EPS risk than haloperidol. However, IM olanzapine should not be given with IM lorazepam due to respiratory suppression risks.
- Risperidone (Risperdal): Effective for agitation, including in children with autism spectrum disorders and in some cases of psychosis. It also has a lower EPS risk than haloperidol but can cause weight gain.
- Brexpiprazole (Rexulti): As of 2023, this is the only antipsychotic with specific FDA approval for treating agitation associated with Alzheimer's dementia.
Black Box Warning: It's crucial to note that both FGAs and SGAs carry a black box warning regarding increased risk of death in elderly patients with dementia-related psychosis. Their use in this population should be approached with extreme caution, prioritizing non-pharmacological methods.
Special Populations and Considerations
Agitation in Dementia:
- Non-drug strategies first: The National Institute on Aging and Alzheimer's Association emphasize non-pharmacological strategies as the first-line approach.
- Medication as a last resort: When medication is necessary, it is used for severe, persistent symptoms that pose a safety risk. Brexpiprazole has an FDA indication for Alzheimer's-related agitation. Off-label use of other antipsychotics or certain antidepressants like citalopram may occur, but requires careful monitoring due to significant side effects.
Agitation in Delirium:
- Treat the cause: The primary focus is always on resolving the underlying medical condition (e.g., infection, metabolic derangement).
- Antipsychotics over benzodiazepines: Antipsychotics are preferred for managing symptoms of delirium, as benzodiazepines can worsen confusion. Low-dose olanzapine or risperidone are often used.
Agitation in Children and Adolescents:
- Extreme caution: Medication for agitation in pediatric patients is used with extreme caution and often as a last resort in emergencies.
- FDA-approved for ASD irritability: Risperidone and aripiprazole are FDA-approved for managing irritability associated with autism spectrum disorder.
- Specialized protocols: Pediatric-specific guidelines exist for emergency departments, but medication is only part of a larger treatment plan.
Comparison of Common Agitation Medication Classes
| Medication Class | Example Drugs | Best for (Indications) | Key Considerations/Risks |
|---|---|---|---|
| Benzodiazepines | Lorazepam, Midazolam | Alcohol/substance withdrawal, acute anxiety, undifferentiated agitation | Respiratory depression, worsening delirium/confusion, potential for abuse, dependence |
| FGAs (Typical Antipsychotics) | Haloperidol | Psychosis-induced agitation (often in emergency settings) | Higher risk of extrapyramidal symptoms (EPS), QTc prolongation |
| SGAs (Atypical Antipsychotics) | Olanzapine, Risperidone, Brexpiprazole | Agitation due to psychiatric conditions, dementia (Brexpiprazole) | Metabolic side effects (weight gain, diabetes), orthostatic hypotension, sedation, black box warning for dementia patients |
| Antidepressants | Citalopram, Sertraline | Co-occurring depression or anxiety in dementia; off-label use | Mixed efficacy for agitation; monitor for side effects like QT prolongation |
Routes of Administration
Medications can be administered in several ways, and the route often depends on the severity of the agitation and patient cooperation.
- Oral (PO): The preferred route when a patient is cooperative, offering a less invasive option. Orally disintegrating tablets (ODTs) like Zyprexa Zydis may offer faster absorption.
- Intramuscular (IM): Used for more severe, uncooperative agitation requiring rapid control. IM formulations of drugs like olanzapine, haloperidol, and midazolam are common choices.
- Inhaled: Inhaled loxapine is a fast-acting option for cooperative patients with schizophrenia or bipolar I disorder, but requires a bronchodilator nearby.
Conclusion
In summary, there is no single best medicine for agitation. The appropriate treatment is a nuanced decision based on a thorough assessment of the underlying cause, the patient's medical history, and the severity of the symptoms. For all patients, non-pharmacological strategies should be the first line of defense. When medication is necessary, the choice between benzodiazepines, first- or second-generation antipsychotics, or other agents must be made in consultation with a healthcare professional, carefully weighing the potential risks and benefits. Given the seriousness of many underlying conditions and the risks associated with some of these powerful medications, professional medical guidance is essential for ensuring patient safety and optimal outcomes. For more information, the National Institutes of Health provides numerous resources on evidence-based treatment guidelines.
