Agitation is a complex condition that affects many people, particularly those with mental health disorders, dementia, or serious medical illnesses. Understanding how to manage it effectively can make a significant difference in quality of life for both patients and their caregivers.

Understanding Treatment Goals for Agitation

Treating agitation focuses on several important goals that go beyond simply calming someone down. The primary aim is to help the person feel more comfortable and reduce their inner restlessness and distress. Healthcare providers work to identify what is causing the agitation so they can address the root problem rather than just the symptoms. This might mean treating pain, adjusting medications that may be contributing to the problem, or managing an underlying illness^[1].

Another crucial goal is ensuring safety. When agitation becomes severe, it can escalate to aggression or self-harm, putting the person and those around them at risk. Treatment approaches aim to prevent this escalation while respecting the person’s dignity and autonomy as much as possible^[2].

The treatment approach varies greatly depending on the person’s specific situation. Factors like age, the underlying cause of agitation, whether it’s a short-term crisis or ongoing problem, and the setting where treatment occurs all influence how healthcare providers manage the condition. For someone with dementia, the approach differs from treating agitation in a person experiencing acute psychiatric crisis or drug withdrawal^[4].

Medical societies and expert groups have developed guidelines for treating agitation, though researchers acknowledge that more high-quality studies are needed. These guidelines help doctors choose the most appropriate treatments while new therapies continue to be tested in clinical trials. The goal is always to find the least restrictive, most effective approach that helps the person while minimizing side effects^[7].

Standard Treatment Approaches

The first step in treating agitation doesn’t always involve medication. Healthcare providers often begin with de-escalation techniques, which are methods to help calm someone without using drugs or physical restraints. These approaches include speaking in a calm, reassuring voice, reducing environmental stimulation like loud noises or bright lights, and addressing basic needs such as pain relief, proper positioning, or bathroom assistance^[6].

For people with dementia, simplifying routines and creating a peaceful environment can significantly reduce agitation. This might include playing soothing music, ensuring someone familiar stays with the person, and maintaining a consistent daily schedule. Sometimes just changing a person’s view or helping them move to a different position can ease their restlessness^[12].

When medication becomes necessary, several types of drugs have been used as standard treatments for agitation. Antipsychotic medications are among the most commonly prescribed. Haloperidol is a typical antipsychotic that has been used for decades to treat acute agitation, particularly in emergency settings. It works by affecting dopamine, a chemical messenger in the brain. Haloperidol can control agitation without necessarily causing heavy sedation, though it carries a risk of extrapyramidal symptoms (involuntary muscle movements) as a side effect^[7].

To reduce these movement-related side effects, doctors often combine haloperidol with promethazine, an antihistamine medication with anticholinergic properties (meaning it blocks certain nerve signals). This combination not only helps prevent the muscle stiffness and restlessness that haloperidol alone might cause, but promethazine’s sedating properties can also enhance the calming effect^[7].

Benzodiazepines represent another major class of medications used for agitation. These drugs, including lorazepam and diazepam, work by enhancing the calming effects of a brain chemical called GABA. They are particularly effective at inducing sedation and reducing anxiety. Lorazepam has shown effectiveness with relatively fewer side effects compared to some antipsychotics, and it can be given by mouth or by injection^[9].

Midazolam, another benzodiazepine, acts very quickly to provide rapid sedation. However, it poses greater risks, especially in older adults, and requires careful monitoring. Its fast action makes it useful in emergency situations, but the potential for severe side effects means it must be used judiciously^[9].

Treatment duration varies based on the underlying cause of agitation. For acute episodes related to psychiatric emergencies or substance intoxication, medication might be needed for just hours or days. For chronic conditions like dementia, where agitation is an ongoing problem, treatment may continue long-term with regular reassessments to ensure medications remain necessary and effective^[1].

Side effects are an important consideration with all agitation medications. Antipsychotics can cause drowsiness, low blood pressure when standing up, movement disorders, and in rare cases, serious heart rhythm problems. Benzodiazepines may cause excessive sedation, confusion (particularly in older people), difficulty breathing, and can lead to dependence if used long-term. The risk of falls increases with both medication types, which is especially concerning for elderly patients^[7].

Innovative Treatments Being Tested in Clinical Trials

Researchers are actively investigating new ways to treat acute agitation that may offer advantages over traditional approaches. These clinical trials are exploring different routes of medication delivery, new drug formulations, and novel therapeutic approaches that could transform how agitation is managed.

One significant advancement is inhaled loxapine powder, an antipsychotic medication that patients breathe in through an inhaler device. Studies have shown that the 10 mg dose is more effective than the 5 mg dose in reducing agitation within 120 minutes in patients with acute psychosis. The inhaled route allows the medication to be absorbed quickly through the lungs, providing rapid relief. This approach is particularly beneficial because it doesn’t require an injection, which can be distressing for agitated patients^[9].

Sublingual dexmedetomidine represents another innovative approach. This medication comes in a film that dissolves under the tongue, allowing the drug to be absorbed directly into the bloodstream. Dexmedetomidine works differently from typical antipsychotics—it affects receptors that normally respond to norepinephrine, producing a calming effect without heavy sedation. This formulation has been approved by the United States Food and Drug Administration for treating acute agitation^[10].

Researchers are also developing intranasal formulations of olanzapine, meaning medication delivered as a spray into the nose. Two different formulations are currently in development. Intranasal delivery offers several potential advantages: it provides rapid onset of action because the medication is absorbed quickly through the nasal membranes, it’s easy to administer without needing injections, and patients can potentially self-administer it. These features make it particularly attractive for managing agitation while respecting patient preferences and comfort^[10].

Aripiprazole, an atypical antipsychotic, has been studied extensively in clinical trials for acute agitation. Research shows it effectively reduces agitation while causing less sedation compared to olanzapine. This is significant because excessive sedation can interfere with a person’s ability to communicate, participate in their care, or engage with family members. Aripiprazole works by partially activating dopamine receptors rather than blocking them completely, which may explain its more balanced effect profile^[9].

Studies have compared ziprasidone, another atypical antipsychotic, to traditional treatments. When given intramuscularly (injected into muscle), ziprasidone demonstrated faster onset of action and was better tolerated than haloperidol. Patients experienced fewer movement-related side effects, making it a promising alternative for acute agitation management^[9].

Droperidol, a medication that has been available for years but saw reduced use due to safety concerns, is being reevaluated in clinical trials. Studies show it’s as effective as olanzapine for controlling agitation but works faster to achieve sedation. Researchers are carefully examining its safety profile to determine how it can be used most safely^[9].

Clinical trials are organized into phases to systematically evaluate new treatments. Phase I trials focus primarily on safety, testing the drug in a small number of people to understand how the body processes it and what side effects occur. Phase II trials expand to more participants and begin assessing whether the treatment actually works—in this case, whether it effectively reduces agitation. These trials also continue monitoring safety. Phase III trials involve large numbers of patients and compare the new treatment directly against standard treatments to determine if the new approach is better, equivalent, or inferior to existing options^[2].

Many of these clinical trials are being conducted in multiple locations, including emergency departments, psychiatric facilities, and general hospital settings across Europe, the United States, and other regions. Patient eligibility for trials typically includes adults experiencing acute agitation related to conditions like schizophrenia, bipolar disorder, or dementia. Trials usually exclude people with certain medical conditions that might make the treatment unsafe or confound the results^[10].

Preliminary results from various trials have been encouraging. Studies show improvements in clinical parameters measured by standardized agitation scales, with some treatments achieving significant symptom reduction within as little as 20 minutes to 2 hours. Safety profiles have generally been favorable, though researchers continue monitoring for side effects. The positive results are guiding the development of treatment guidelines and informing clinical practice^[9].

Most common treatment methods

• Non-pharmacological interventions
  • De-escalation techniques using calm voice and reassurance
  • Environmental modifications like reducing noise and adjusting lighting
  • Addressing basic needs such as pain relief and proper positioning
  • Simplifying routines and creating peaceful surroundings
  • Playing soothing music and maintaining familiar company
• Typical antipsychotics
  • Haloperidol administered orally or by injection for acute agitation control
  • Combination of haloperidol with promethazine to reduce side effects and enhance calming
  • Droperidol for rapid sedation in emergency settings
• Atypical antipsychotics
  • Aripiprazole offering effective agitation control with less sedation
  • Olanzapine providing powerful sedative effects
  • Ziprasidone administered intramuscularly for faster onset and better tolerability
  • Inhaled loxapine powder for rapid relief without injections
• Benzodiazepines
  • Lorazepam given orally or by injection with fewer side effects
  • Diazepam for anxiety reduction and sedation
  • Midazolam for rapid sedation in emergency situations
  • Combination therapy with antipsychotics for enhanced effectiveness
• Alternative delivery methods
  • Sublingual dexmedetomidine film that dissolves under the tongue
  • Intranasal olanzapine formulations currently in development
  • Inhaled medications avoiding the need for injections