Agitation and Aggression in the Elderly

US Pharm. 2006;11:20-28.

Agitation (increased verbal and/or motor activity as well as restlessness, anxiety, tension, and fear) and aggression (self-assertive verbal or physical behavior arising from innate drives and/or a response to frustration that may manifest by cursing/threats and/or destructive and attacking behavior toward objects or people) are symptoms commonly present in patients with central nervous system (CNS) disorders.

For example, patients with dementia present with cognitive impairment as well as behavioral and psychological symptoms, including agitation, aggression, irritability, delusions, sleep disorders, anxiety, and phobias.¹ The most common form of dementia, Alzheimer's disease, is characterized by a gradual decline in cognitive performance, an increasingly impaired ability to perform activities of daily living, and neuropsychiatric and behavioral disturbances.² Neuropsychiatric symptoms of dementia are associated with poor outcomes for both patients and caregivers.³ Aggression, agitation, or psychosis occurs at some point in the majority of people with this illness.⁴

Agitation and aggression (i.e., in the form of impulsivity and self-injurious behavior) are also seen in patients with other conditions such as traumatic brain injury, mental retardation, and developmental disabilities and in patients with psychiatric illnesses (e.g., depression, schizophrenia).

Qualifying and quantifying reports of agitation and aggression can assist the clinician in the assessment, treatment, and monitoring of neuropsychiatric disorders. This article will discuss the importance of individualizing therapy and present an outline of various agents as well as data regarding their use, specifically in the elderly. Please note: This article discusses off-label or investigational uses of psychotropic and other medications that may not be approved by the FDA.

Special Patient Populations
The Older Adult: Psychological signs and symptoms, like physical signs and symptoms, may be nonspecific in geriatric patients. For example, paranoid psychosis may be the manifestation of an underlying depression.⁵ In this case, treating the underlying depression may attenuate agitation and aggression secondary to the mood disorder. In addition, unrecognized or undertreated pain, as well as delirium secondary to anticholinergic toxicity and anxiety secondary to medical conditions (e.g., hyperthyroidism, cardiac arrhythmias, hypoglycemia, shortness of breath/pulmonary edema) may present as agitation. Appropriate treatment of these underlying conditions may result in resolution of agitation.

It is also possible that agitation or disruptive behaviors in geriatric patients are reasonable responses to inappropriate situations or personal interaction with a caregiver, nursing facility staff person, spouse, etc.⁵ Therefore, it is important to introduce psychotropic medications only after a physician has identified the patients' symptoms and what might have caused them. ⁵

In elderly patients with traumatic brain injury, agitation may be indicative of an exacerbation of a preexisting dementia-related behavioral disorder, or it may be related to frontal disinhibition or dysphoric mania.⁶

Mental Retardation/Developmental Disabilities: Presently, the life expectancy of a person with mental retardation is 66 years, as compared to 19 years in the 1930s. Behavioral disorders are the most common reason why people with mental retardation are placed in out-of-home facilities or referred for psychiatric care.⁷ It is important to bear in mind that behavioral problems are frequently situational, and factors precipitating a behavioral episode can usually be identified. Therefore, environmental changes and behavior modification (table 1) are important components in the development of a comprehensive treatment plan.

Self-injurious behavior is one of the most common and challenging behavior problems encountered in patients with autism or severe mental retardation. When self-injurious behavior is resistant to environmental changes and behavior modification, the most effective intervention is the treatment of the underlying psychiatric disorder with an appropriate psychotropic agent.⁸ Careful assessment and diagnosis are key to selecting appropriate treatment.⁸

Treatment for Agitation and Aggression
Choosing a first-line therapy for aggression is dependent on the underlying disorder. While environmental and behavioral interventions (table 1) should always be attempted, current and evidence-based recommendations are needed to guide the use of a wide variety of pharmacologic agents in the management of neuropsychiatric symptoms. ³ For patients with aggression, pharmacotherapy is considered primary treatment, since agitation and aggression can escalate to violence that may result in emergency hospitalization.⁹

Individualized therapy is a key component in the appropriate selection of a pharmacologic therapy. Careful assessment and treatment of an underlying psychiatric illness and tailoring medication regimens are essential. Assessing for drug efficacy and periodic medication tapers and/or drug-free periods in clinical trials have also been suggested.

Acute Pharmacologic Intervention: When an acute threat includes aggression or violence, a short-acting benzodiazepine (e.g., lorazepam; t _1/2 = 10 to 16 hours and no active metabolites) and an antipsychotic agent (i.e., conventional [e.g., haloperidol] or second generation [e.g., ziprasidone]) are effective and recommended for short-term intervention.^7,9-11

Long-Term Pharmacologic Approaches: While more well-controlled studies in aggression research are needed, many of data from clinical trials, case reports, letters, and review articles have been reported on the etiology and pharmacotherapy of aggression.⁹ Agents such as clozapine, beta-blockers, carbamazepine, valproic acid, buspirone, trazodone, and serotonin reuptake inhibitors have been used for the treatment of aggression.⁹

It is important to note that sedation as a long-term measure will not improve an individual's level of functioning and may adversely affect adherence to medication.¹⁰ Because paradoxical reactions--including hyperactive and aggressive behavior, particularly in psychiatric patients--have been reported with benzodiazepines, these agents should be avoided in seniors when possible.¹¹ Also, while continued use of lorazepam is recommended in patients with schizophrenia who exhibit symptoms of agitation, missed doses may result in withdrawal symptoms that can lead to increased agitation, irritability, and excitability. ¹⁰ Other treatments involve agents used adjunctively or for individuals without comorbid psychiatric disorders.  

Second-Generation Antipsychotics: A double-blind placebo-controlled trial by Brodaty et al. revealed that treatment with low-dose risperidone (mean dose, 0.95 mg/day) resulted in significant improvement of aggression, agitation, and psychosis in elderly nursing home patients with dementia.¹² Ninety-four percent of the risperidone group and 92% of the placebo group reported at least one adverse event, with somnolence and urinary tract infection reported more commonly in patients taking risperidone and agitation reported more commonly in those taking placebo. The percentage of patients who reported extrapyramidal symptoms did not differ significantly between the risperidone (23%) and placebo (16%) groups.¹²

Additionally, a recent study by Onor et al. looked at the efficacy and tolerability of risperidone for the treatment of dementia-associated psychological and behavioral disturbances in 135 patients with Alzheimer's disease ages 60 to 85.¹ Participants were treated with risperidone at an initial dose of 0.5 mg once daily at bedtime. The dosage was increased to 1 mg in two doses (morning and evening) after the first three days of therapy and further to 1.5 mg every three days (alternatively in the morning and in the evening) until psychiatric symptoms attenuated.¹ Results indicated that there was a statistically significant improvement at four and 12 weeks (P <.0001; results better at 12 than at four weeks). The researchers noted that intervention with low-dose risperidone was well tolerated in patients with dementia and was clearly associated with reductions in agitation and aggression, as well as in irritability, delusions, sleep disorders, anxiety, and phobias.¹

On the other hand, Sink et al. found that pharmacologic therapies are not particularly effective for the management of neuropsychiatric symptoms of dementia.³ Of the agents they reviewed, the atypical antipsychotics risperidone and olanzapine had the best evidence for efficacy, although the effects were modest and further complicated by an increased risk of stroke.³ They proposed that additional trials exploring the use of cholinesterase inhibitors in patients with high levels of neuropsychiatric symptoms may be warranted.³

In addition, following a systematic review of trials of atypical antipsychotics for the treatment of aggression and psychosis, Ballard and Waite concluded that risperidone and olanzapine are useful in reducing aggression and that risperidone reduces psychosis; however, both are associated with serious adverse cerebrovascular events and extra-pyramidal symptoms.⁴ Therefore, despite their modest efficacy, neither risperidone nor olanzapine should be routinely used to treat patients with dementia who exhibit aggression or psychosis, unless there is marked risk or severe distress.⁴ Furthermore, the authors noted that although insufficient data were available from the considered trials, a meta-analysis of 17 placebo controlled trials of atypical neuroleptics for the treatment of behavioral symptoms in individuals with dementia suggested a significant increase in mortality.⁴

Hence, the black box warnings: Increased mortality risk in elderly dementia patients receiving second-generation (atypical) antipsychotic agents; these agents are not FDA-approved for dementia-related psychosis (most deaths due to cardiovascular or infectious events). Important to bear in mind is the increased risk of fatal arrhythmias associated with several conventional and second-generation antipsychotic agents (e.g., haloperidol, thioridazine, olanzapine, risperidone, ziprasidone) secondary to prolongation of the QT interval.⁷

Beta-Blockers: Enhanced behavioral responsiveness to CNS norepinephrine in Alzheimer's disease may contribute to the pathophysiology of disruptive behaviors such as aggression, uncooperativeness with necessary care, irritability, and pressured pacing.¹³ This theory is further substantiated by evidence indicating that beta-blockers are effective in decreasing the frequency and intensity of aggressive outbursts associated with a wide variety of conditions such as dementia, profound mental retardation, brain injury, posttraumatic stress disorder, and schizophrenia. Beta-blockers (e.g., propranolol, metoprolol, pindolol) have been used to treat aggressive, impulsive, self-injurious, and violent behavior in some patients with mental retardation and psychiatric illness.^14,15 Propranolol has also been used to target rage outbursts in patients with attention-deficit disorder and intermittent explosive disorder.¹⁶

Although several reports suggest that intermediate to high doses of propranolol (80 to 160 mg/day and 200 to 600 mg/day, respectively) can effectively treat aggressive behavior in patients with dementia, significant side effects can occur at this dose.¹⁷ To minimize these side effects, Shankle et al. treated a small group of patients with dementia and disruptive, aggressive behavior with low-dose propranolol monotherapy (10 to 80 mg/day).¹⁷ Low-dose propranolol effectively reduced aggression in 67% of patients within two weeks of treatment and remained effective for the duration of follow-up (one to 14 months). Those who responded to treatment had significant reductions in physical and verbal aggression/agitation and in pacing/wandering. The researchers suggested that low-dose propranolol should be studied further as a treatment for aggression or agitation in patients with dementia.

Another small randomized double-blind study by Peskind et al. evaluated the efficacy of propranolol for the management of treatment-resistant disruptive behaviors and overall behavioral status in nursing home residents with probable or possible Alzheimer's disease.¹³ Individuals (age 85 ± 8) with probable or possible Alzheimer's disease and persistent disruptive behaviors that interfered with necessary care were given either propranolol or placebo. All patients were continued on stable doses of their previously prescribed psychotropics, which were maintained at prestudy doses throughout the study. Following a propranolol or placebo dose titration period of up to nine days (as per dosing algorithm), individuals were maintained on maximum achieved dose for six weeks.

Propranolol (mean dose, 106 ± 38 mg/day) was significantly more effective than placebo in improving overall behavioral status.¹³ Among patients taking propranolol, improvement in individual Neuropsychiatric Inventory items was significant only for "agitation/aggression" and "anxiety" and reached borderline statistical significance favoring propranolol over placebo only for "agitation/aggression"; pressured pacing and irritability did not appear to respond to propranolol.¹³ In patients who took propranolol who were rated as "moderately improved" or "markedly improved" at the end of the double-blind study phase, improvement of overall behavioral status diminished after six months of open-label propranolol treatment.¹³ Researchers concluded that short-term propranolol augmentation treatment appeared to be modestly effective and well tolerated for overall behavioral status in nursing home residents with probable or possible Alzheimer's disease complicated by disruptive behaviors. While the researchers suggested propranolol might be helpful for treating aggression and uncooperativeness in this patient population, they noted that its usefulness was limited by the high frequency of relative contraindications to beta-adrenergic antagonist treatment and by the decrease of initial behavioral improvements over time.¹³

In another study, Herrmann et al. randomized patients to seven weeks of treatment with the norepinephrine agent pindolol (maximum dose 20 mg bid) or placebo in a crossover design. They noted that changes in norepinephrine responsivity (as reflected by a blunted growth hormone response to clonidine challenge) and more severe aggression were associated with better response to pindolol.¹⁸ They concluded that individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.¹⁸

It is important to note that beta-blockers are contraindicated for patients with cardiac conduction defects, overt heart failure, brady­ arrhythmia, reactive airways disease, peripheral vascular disease, and insulin-treated diabetes.⁵ Further, propranolol may cause fatigue, somnolence, or depression.⁵ If cardiac output is decreased, the use of a beta-blocker may cause renal blood flow and glomerular filtration rate to fall.⁵ These agents must be withdrawn slowly in patients with coronary artery disease. ⁵   

Mood Stabilizers: Empirically, a trial of adjunctive divalproex sodium, lithium, or carbamazepine may be considered for patients with schizophrenia accompanied by persistent aggressive behavior.¹⁰ For patients with schizophrenia who exhibit agitation, excitement, aggression, or violence, expert consensus guidelines suggest the use of mood stabilizers as an adjunct to antipsychotic therapy.¹⁹ Mood stabilizers regulate mood and possibly reduce impulsivity and thus have been increasingly used in patients with schizophrenia or other disorders (e.g., mental retardation accompanied by impulse control disorder).¹⁰ Parameters that should be monitored during the first six months of therapy include liver function and complete blood count (CBC), though serum concentrations are not correlated with behavioral response.¹¹

A number of studies have demonstrated benefit of divalproex sodium in the treatment of agitation and dementia.¹¹ In a recent randomized, double-blind, placebo-controlled trial by Tariot et al., nursing home residents with probable or possible Alzheimer's disease complicated by agitation were given divalproex sodium (target dose, 750 mg/day) or placebo for six weeks. Contrary to findings from previous studies, divalproex sodium (mean dose, 800 mg/day) was not found to be beneficial for the treatment of agitation in dementia. ²⁰

Data for the use of lithium in schizophrenic patients are mixed.¹⁰ Lithium has been used adjunctively for aggressive behavior and has even been recommended as a first-line antiaggression agent for patients without comorbid psychiatric disorders.⁹ However, extreme sensitivity to the effects of lithium may be seen in some older adults.¹¹ While initial doses need to be adjusted for renal function, doses thereafter should be adjusted based on serum concentrations and response. Seniors can usually be maintained at the lower end of the therapeutic range (0.6 to 0.8 mEq/L); lithium serum concentrations are drawn 12 hours postdose.¹¹ Monitoring parameters include renal, thyroid, and cardiovascular function; fluid status, serum electrolytes, CBC with differential, and urinalysis; and signs of toxicity (e.g., sedation, confusion, tremors, joint pain, visual changes, seizures, coma).¹¹ The use of lithium in the elderly is limited by numerous drug interactions, renal dosage adjustments, sensitivity to effects, and difficulties in monitoring for signs of toxicity.

Antidepressants: Impulsive aggression and violence may be related to effects on serotonin receptors.^10,21,22 Additionally, a disturbance of the serotonergic system has been implicated from low levels of the 5-hydroxyindoleacetic acid in the cerebrospinal fluid or from a blunted response to neuroendocrine challenges.^23-27 These inferences have been drawn from studies assessing aggressive patients with personality disorders and substance use disorders.¹⁰

Data indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) is beneficial in patients with aggression; fluoxetine has been shown to decrease violent incidents in patients with chronic schizophrenia; fluvoxamine (discontinued in the United States) added to risperidone has demonstrated efficacy in managing aggression in patients with schizophrenia; and adjunctive citalopram has been effective in decreasing aggressive incidents in patients with violent schizophrenia. ¹⁰ 

One study assessing the efficacy of sertraline augmentation (50 to 200 mg) in outpatients with Alz­ heimer's disease who were treated with donepezil found a modest but statistically significant advantage of sertraline over placebo augmentation and a clinically and statistically significant advantage in a subgroup of patients with moderate to severe behavioral and psychological symptoms of dementia.²⁸

Recent studies assessing acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine) suggest that donepezil reduces behavioral symptoms, particularly mood disturbances and delusions, in patients with Alzheimer's disease with relatively severe psychopathology.²⁹ In addition, among nursing home residents with moderate to severe probable Alzheimer's disease, 26 weeks of treatment with rivastigmine was associated with decreased assessment scores for a wide range of behavioral disturbances in the subgroup of patients with behavioral symptoms at baseline.²

It is important to note that SSRIs should be used with caution in patients with a history of mania (e.g., bipolar disorder), as they may activate hypomania/mania or lead to rapid cycling.^10,11

Nonpharmacologic Intervention: Adjunctive electroconvulsive therapy (ECT) has been used in aggressive schizophrenic patients who are unresponsive to pharmacologic therapy.¹⁰ In fact, ECT is an effective treatment for severe mental disorders (e.g., major depression, delusional depression, malignant catatonia, bipolar disorder, manic delirium, schizophrenia, and neuroleptic malignant syndrome) and has been shown to be effective in patients who are deemed refractory to other treatments.³⁰ ECTreduces aggression, excitement, suicidality, melancholia, and catatonia.³⁰ Successful treatment in children, adolescents, and the elderly has indicated that age is not a barrier to ECT.

While beyond the scope of this article, information about the use of, contraindications to, and advantages of physical restraints in aggressive, violent patients, as well as information about the Joint Commission on Accreditation of Healthcare Organizations guidelines, can be found in the Merck Manual of Diagnosis and Therapy, 18th edition. 

Conclusion

While environmental and behavioral interventions should be initially attempted for neuropsychiatric symptoms such as agitation and aggression in patients with dementia, current and evidence-based recommendations should guide the use of a wide variety of pharmacologic agents. Treating the underlying comorbid psychiatric disorder is recommended, and individualized, tailored therapy is suggested based on the overall clinical scenario. When considering long-term treatment of persistent symptoms, periodic reassessment and reevaluation of the treatment plan is advised. 

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