In ideal cases of dementia and Alzheimer’s disease, agitation is mild, time-limited, and responds to behavioral interventions. In reality, however, agitation can be severe and persistent, responding partially or not at all to initial approaches. Medications become a necessary addition to treatment when agitation is causing ongoing and significant distress to the affected person, is posing a risk of harm to self or others, is resistant to behavioral interventions, or is caused by underlying psychiatric symptoms, such as psychosis, panic disorder, major depression, or bipolar disorder.
Medications for Agitation
Although there has been extensive research looking at both efficacy and safety of many medications, there is great variability in terms of subject profiles, methodology, and outcomes (with high placebo responses) and, until recently, there was no FDA-designated indication for agitation associated with neurocognitive disorders.1 In addition, safety issues loom large as aging individuals are more sensitive to medications and more vulnerable to side effects, especially given significant comorbidities and potential drug-drug interactions.2
Initial Considerations
When a decision has been made to add a medication to the treatment of agitation, there are several rules of thumb.2 First, make certain you know what you are treating with the particular agent so you can track the response. It’s best to focus on the most salient behaviors and not expect to always reduce all forms of agitation.
Make certain you are targeting comorbid psychiatric conditions appropriately, such as using a mood stabilizer for someone with underlying bipolar disorder versus an antidepressant alone. Be aware of how different medications can impact comorbid medical conditions or lead to drug-drug interactions.
Watch for side effects that can be particularly problematic in aging individuals, such as sedation, dizziness, and orthostasis. When initiating a medication, start low (eg, 50% of the adult dose), go slow, but go, meaning that you continue titration until you have an effect, or need to alter course for side effects or lack of effect.
If you are working in long-term facilities, keep in mind important guidelines such as the Beers Criteria3 and regulations such as those aimed at proper management of medication dosage, gradual dose reductions, and percentage of residents receiving antipsychotics.4
Medication Selection
Selecting a medication will depend upon several factors, including:
How quickly is an effect needed? Urgently, or over days to weeks?
comorbid symptoms or conditions to be targeted
potential side effects and drug-drug interactions
management issues (eg, are blood levels needed? ECG monitoring?)
pharmacogenomic considerations (see also, Cacabelos R on pharmacogenomics of cognitive dysfunction in dementia)
For example, consider someone with severe aggression who is very unsteady on their feet. A quicky acting medication is needed but one in which sedation, orthostasis, or dizziness is not likely to increase the risk of falling. Selecting a medication requires a lot of thought with a focus on balancing effect versus side effect, and there are numerous options. Table I lists the major medication types and commonly used agents, along with pros and cons of each type.
| Medication Type (commonly used agents) |
Pros | Cons |
|---|---|---|
Antipsychotics5-10
|
|
|
Benzodiazepines11,12
|
|
|
Antidepressants13-15
|
|
|
Mood Stabilizers16
|
Best for underlying mania, bipolar disorder, or recurrent depression |
|
Other Agents17-20
|
Different pharmacological approaches when other methods fail | Limited efficacy studies |
Table I certainly does not list all potential medications, but the ones that tend to be used mostly, sometimes alone but often in combination. Although acetylcholinesterase inhibitors including donepezil, rivastigmine, and galantamine have been associated with lower rates of behavioral disturbances, they have not been shown to be effective for agitation.22
The following algorithm can help to further shape the selection of medications:23
Step 1 – Make certain the underlying diagnoses and comorbidities are established and that everything has been done in terms of treating underlying causes and engaging nonpharmacological approaches.
Step 2 - Determine the urgency of starting a medication. For severe and/or dangerous behaviors, an effect is needed urgently. Less severe and more intermittent behaviors can be addressed over time. Some intermittent behaviors may respond to as-needed dosing only, while others clearly need daily dosing. Trazodone and low-dose benzodiazepines may be used for use on an as-needed or PRN basis.15
Step 3 – Match the medication to the symptoms. More depressive symptoms might be best addressed by antidepressants; disinhibited and/or manic behaviors might be best addressed by mood stabilizers or antipsychotics; agitation associated with psychosis or panic will shape the best medication for each situation.24
Step 4 – Be definitive with treatment. As noted, start low, go slow but go until the medication has either worked or not. If not, taper the medication and try something else.
Step 5 – For partial response, optimize the dose and then consider augmentation with something for breakthrough symptoms. For example, someone whose agitation is responding to an SSRI but still having outbursts might do better when a shorter-acting agent such as trazodone is added either routinely or as a PRN.
Step 6 – Consider gradual dose reductions of all agents on a regular basis as long as they are not needed for chronic, recurrent, or severe symptoms or disorders.25
For treatment-resistant agitation, it is sometimes best to taper and stop all medications not working, revisit the work-up and attend to comorbid medical and psychiatric disorders, revise or boost nonpharmacological approaches, and consider alternative or novel agents and combinations, such as dronabinol, prazosin, dextromethorphan-quinidine, buspirone, or a novel and more potent antipsychotic such as clozapine. In severe situations when medications do not work, electroconvulsive therapy (ECT) can be considered. Several reviews of multiple studies using ECT for agitation and aggression in dementia and found significant clinical responses with good tolerability as side effects were mild and transitory.26,27
Clinical Considerations for Antipsychotic Use in Agitation
Antipsychotic medications are widely used to treat agitation and have perhaps the largest body of efficacy data compared to all other medications, but there are some concerns to consider.
A seminal meta-analysis by Tampi and colleagues points out that antipsychotics are frequently used, especially in long-term care, but with limited monitoring, variable efficacy, and moderate to high risk of side effects.28 The Tampi et al review of efficacy studies found that risperidone, olanzapine, and aripiprazole have modest benefits for aggression and psychosis in dementia, but there is less robust evidence for quetiapine – despite its popularity. Adverse events are increased on antipsychotics, including sedation, abnormal gait, metabolic disturbances, extrapyramidal symptoms, cerebrovascular events, and death.29-31 Most people tolerate discontinuation, although those with higher baseline behavioral problems often have worsening symptoms.32
When using an antipsychotic, it is important to be aware of the black-box warnings concerning the potential increased mortality in elderly patients with dementia-related psychosis treated with antipsychotic agents, and notify patients and caregivers of these risks. Documentation must justify the clinical rationale for their use with recognition that the benefits outweigh the risks. Documentation must also note discussions with the patient and legally authorized representatives.2
Always follow appropriate dosing and management, including frequent re-assessment, and avoid inappropriate uses such as for insomnia, mild anxiety, or depression. Due to regulations, antipsychotics should not be used on a PRN basis in long-term care facilities.4
Case Example: A Final Visit
As a reminder, the case presented in Chapters 1 through 3 of this Clinician Guide involved an 81-year-old male with a diagnosis of Alzheimer’s disease associated with moderate cognitive impairment, who lives at home with his 80-year-old wife. Due to his increasing care needs and agitated behaviors, she had to quit her volunteer work and serve as his 24/7 aide.
Table II outlines the disruptive behaviors in the ABC model. Note that chapter 3 of this guide provides more details with suggested behavioral approaches, and then pairs them with suggested medications for symptoms that are severe and/or not responsive.
| Causes / Antecedents |
Behaviors | Consequences | Motivation | Function and Behavioral Plan |
Medication Treatment |
|---|---|---|---|---|---|
| Back pain | Angry outbursts / screaming | Wife gives pain medication | History of med-seeking for pain | Get a tangible (pain medication) Try to reduce antecedent with scheduled pain medication |
Medications such as SSRIs, duloxetine, or gabapentin might reduce pain which is triggering agitation |
| Wife starts to leave house on errand | Belligerence and threats directed at wife | Wife feels isolated and depressed | Patient is socially isolated | Get and maintain attention from wife. Suggest alternative approach to get attention and reduce isolation by attending a day program | SSRIs could be used to reduce belligerence and threats. For more severe symptoms, antipsychotics would be an option |
| Fear of getting sick from some foods | Accusations that wife is poisoning him | Wife prepares specific foods for him to decrease his worries | Underlying OCD with obsessive worries about food safety | He gets attention for his obsessive worries. One approach is to ignore his food worries and give attention to positive behaviors | An antipsychotic could reduce these thoughts if they represent paranoid delusions |
| Wife tries to bathe or shower him after he is incontinent | Attempts to elope from the house; refuses to change clothes | He is unkempt and has itchy rash and feels embarrassed and overpowered | Embarrassed by soiling and smell when being changed and washed | Escape from an unpleasant situation. Try to change the consequence by increasing privacy and engaging his active help during hygiene | A low dose of trazodone or a benzodiazepine could be used prior to bathing to calm him |
| Fearful of people he doesn’t know or recognize | Resists help from anyone other than his wife | Both the patient and caregiver are increasingly isolated | Underlying social anxieties | Escape from being with someone strange. Spend more time with aide and others to reduce social anxiety |
An SSRI or other antidepressant / anti-anxiety medication such as mirtazapine could be used to reduce anxiety. Buspirone is also an option |
It is clear that the severity and risks of agitation require a creative and comprehensive approach to treatment, and medications are typically a major component. To this end, the bottom line is to involve a trained expert to find the best match between symptoms and response, mindful of potential side effects and drug-drug interactions in individuals with significant comorbid conditions and polypharmacy. Medications are best as adjuncts to and not substitutes for behavioral approaches. With these considerations in mind, most agitation can be ameliorated safely and successfully over time.