Carl Salzman, M.D.
Severe behavioral agitation and aggression—including restlessness, wandering, assaultiveness, or screaming—may accompany late-life psychosis, dementia, or mood disorders, with particularly high prevalence rates in nursing homes. Severely depressed or very anxious elderly individuals can also become behaviorally disruptive, endangering themselves and others as well as decreasing the quality of their lives (Banerjee et al. 2006). Behavioral and psychiatric symptoms develop in more than half of community-dwelling patients with dementia (Lyketsos et al. 2000), and virtually all individuals with dementia will display behavioral complications at some point. In nursing homes, rates of behavioral and psychiatric symptoms are estimated to be as high as 80% in patients with dementia (Testad et al. 2007; Zuidema et al. 2007); over the course of a lifetime, the risk of these symptoms is estimated at 100% (Lyketsos et al. 2000).
Serious behavioral symptoms, especially those associated with psychosis and dementia, may have devastating consequences for patients and their families. Such symptoms decrease the quality of life for the patient and family (Matsui et al. 2006) and may indicate a worse prognosis. Although various medications have been employed to treat disruptive behavior in elderly patients, no medications have been approved by the U.S. Food and Drug Administration (FDA) for this specific therapeutic indication. Antipsychotic drugs have been frequently used off-label for this purpose; however, these drugs can cause serious side effects in some patients. Other medications that have been tried, without reliable success, include antidepressants, mood stabilizers, cognitive enhancers, and even benzodiazepines.
Despite a growing awareness of the potential hazards of antipsychotic medications, these drugs are still the mainstay of pharmacological treatment given to elderly individuals with dementia who are agitated or psychotic (Ballard et al. 2014). In previous years, conventional antipsychotics (also known as first-generation antipsychotics [FGAs]) such as haloperidol were used to help control serious agitated behaviors. In recent years, the so-called atypical antipsychotics (also known as second-generation antipsychotics [SGAs]) have become the primary psychopharmacological approach to management of this difficult clinical state. Haloperidol and other FGAs have been shown to have higher rates of side effects and possible increased rates of mortality compared with the newer SGA drugs. Unfortunately, both FGA and SGA medications produce only modest benefits and carry a potential for serious adverse effects and inappropriate use (Jeste et al. 2005). As a general prescribing guideline, antipsychotic drug dosages used for elderly adults should be considerably lower than those used for younger and middle-aged adults.
SGAs are as effective as FGAs for late-life psychotic symptoms as well as for management of agitation and aggression with or without associated psychosis (Ballard and Waite 2006; Sink et al. 2005). Because of their more benign side-effect profile, the SGAs are now the preferred first-choice medications for management of behavioral symptoms in the elderly. Nonetheless, the overall efficacy of antipsychotic drugs in controlling serious behavioral and psychotic disturbance is modest; even with treatment, many older individuals with dementia continue to display behavioral and affective dyscontrol, especially when stressed, as well as in the evenings (i.e., sundowning). As a generalization, studies comparing SGAs with FGAs have reported greater efficacy for the SGAs (Lopez et al. 2013), and in all studies, the SGAs were associated with fewer extrapyramidal side effects (EPS) than the FGAs (Chan et al. 2001).
Pharmacological treatment of the aggression, agitation, and behavioral disruption commonly seen in moderate to severe dementia is difficult. Despite the obvious need for safe and effective pharmacological approaches, no drugs have been approved by the FDA for the management of persisting agitation or aggression associated with dementia. In one large study (the Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer’s Disease [CATIE-AD]), overall response rates ranged from 48% to 65% with olanzapine treatment versus 30%–48% with placebo, showing an incremental treatment benefit of about 18% for active drug over placebo (Schneider et al. 2006), although olanzapine was associated with worsening of cognition (Vigen et al. 2011). Other SGA medications also reported to be beneficial for disruptive behavior in the context of dementia include aripiprazole (Coley et al. 2009), ziprasidone (Greco et al. 2005), olanzapine (Street et al. 2000), risperidone (Brodaty et al. 2003; Devanand et al. 2012), and quetiapine (Tariot et al. 2006).
All antipsychotic medications produce side effects, and in general, elderly individuals are more susceptible and sensitive to these effects. For this reason, drugs with anticholinergic or orthostatic hypotensive properties (e.g., clozapine) should be avoided in the elderly whenever clinically possible. Because many antipsychotics are substrates of cytochrome P450–metabolizing enzymes, caution must also be exercised regarding the potential for adverse drug interactions.
In the early years of the twenty-first century, evidence pointing to increased rates of morbidity and early death in elderly individuals receiving antipsychotic drugs generated considerable concern. An initial report indicating a heightened risk of cerebrovascular adverse events (CVAEs; e.g., stroke, transient ischemic attack [TIA], death) in male nursing home residents older than 85 years who were treated with risperidone (Wooltorton 2002) prompted further investigation. Similar suggestive evidence was reported for olanzapine, and ultimately for other SGAs (Kryzhanovskaya et al. 2006). Taken together, these observations of increased CVAEs in elderly individuals receiving SGAs stimulated an examination of all studies. The findings supported the concerns regarding a possible increased risk of CVAEs associated with use of risperidone or olanzapine in elderly patients with dementia. Data from 11 olanzapine or risperidone studies collectively suggested that 2.2% of drug-treated subjects experienced CVAEs, compared with 0.8% of placebo-treated subjects. The combined relative risk was 2.7. Ballard and Waite (2006) concluded that despite the modest efficacy of these drugs, the significance of the adverse events dictated that “neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress.”
In 2003, the FDA issued a black box warning regarding a possible increased risk of CVAEs associated with use of atypical antipsychotics in older adults with dementia. The warning was eventually extended to include aripiprazole, olanzapine, and risperidone. The death rate in clinical trials was 3.5% with SGAs versus 2.3% with placebo, leading the FDA to impose a black box warning for all antipsychotics. Studies examining large public databases (Ballard and Waite 2006; Schneider et al. 2006) have found similar rates of death among elderly people receiving FGAs (Schneeweiss et al. 2007; Wang et al. 2005). Causes of death vary, but most of the deaths appear to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
The FDA warning has generated considerable controversy. Some observers concur with the FDA warning suggesting that mortality is increased (Kales et al. 2012) in a dose-dependent fashion (Ballard et al. 2014). Other researchers, examining the data on which the FDA’s warning was based, have become concerned that methodological faults in many of the studies may have compromised the meta-analyses and led to an overly harsh interpretation of the data and an unwarranted concern for safety. Some studies failed to find an increase in death rate or incidence of CVAEs. For example, Herrmann et al. (2004), as well as Haupt et al. (2006), Raivio et al. (2007), and Gill et al. (2005), found no significant increase in the risk of ischemic stroke with either FGAs or SGAs or among those receiving SGAs compared with FGAs. The American College of Neuropsychopharmacology issued a White Paper (Jeste et al. 2008) concluding that further research data are needed to clarify the ongoing significance, if any, of increased development of CVAEs with SGAs. An expert consensus conference held in 2006 (Salzman et al. 2008) essentially made the same point. It is clear that not all individuals with dementia who receive antipsychotic medication for disruptive symptoms have an increased risk of premature mortality (Devanand 2013).
When confronted with elderly patients with dementia who are possibly psychotic and who are manifesting extreme agitation and/or aggression, clinicians face a difficult treatment dilemma. The essential conclusion of the CATIE-AD study, and a sensible statement about the role of antipsychotics in management of behavioral symptoms in dementia (Jeste et al. 2008; Salzman et al. 2008; Sink et al. 2005), was that on average, patients receive modest benefit from these agents without being harmed: these are the patients for whom continued therapy is rational. The following clinical conclusions appear to be warranted at present:
Recognizing that the use of antipsychotic drugs to treat agitation or aggression is “off label,” clinicians must be certain that the behavior cannot be managed nonpharmacologically and that the severity of the disruptive behavior warrants the selection of antipsychotic medications.
SGAs are still preferred to FGAs because of the former’s lower likelihood of EPS and tardive dyskinesia.
Clinicians should confer with the patient’s family or significant others regarding the use of these drugs and should attempt to obtain some type of informed consent, balancing the possible risks of using these medications against the likelihood of worsening behavior and clinical status without such treatment.
Clinicians should closely follow patients receiving antipsychotics for early warning signs of a CVAE.
Antipsychotic medications are often prescribed at dosages that are too high for elderly individuals, especially those with dementia. Clinicians should strive to use the lowest therapeutic doses. If necessary, liquid preparations can facilitate very-low-dose administration.
Clinicians should be mindful of an elderly individual’s medical status and medication treatment to avoid unwanted side effects of drug interactions due to polypharmacy.
The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients with Dementia (Reus et al. 2016) notes that antipsychotic medication may be modestly helpful, but emphasizes that medication must be part of a comprehensive program of medical care that includes careful medication monitoring.
An increasing number of other medication classes are being used as second-line choices for management of agitation and aggression, but with less reliable effectiveness (Salzman et al. 2008). These include trazodone, benzodiazepines, anticonvulsants (mood stabilizers), serotonergic antidepressants, and cognitive enhancers.
The antidepressant drug trazodone was reported to be effective in treating agitation and severely disruptive behavior (Pinner and Rich 1988; Seitz et al. 2011; Tariot 1996), although these studies did not distinguish between psychotic and nonpsychotic patients. Extensive clinical experience suggests that trazodone is effective at dosages of 50–200 mg/day, with few side effects other than sedation. The mechanism of trazodone’s effect is unknown. Current clinical experience continues to suggest that trazodone is often extremely helpful as an add-on medication when antipsychotics or other drugs alone cannot control disruptive behavior. Priapism is a rare side effect of trazodone in elderly men.
Although benzodiazepines are quite widely used in the elderly agitated population, there have been no studies of benzodiazepine treatment of agitation or aggression in nearly a decade. Most of the older studies were not placebo controlled, but they nonetheless suggested that on average, agitation could be reduced with short-term benzodiazepine therapy (Loy et al. 1999). For example, Coccaro et al. (1990) compared oxazepam (10–60 mg/day) with low-dose haloperidol in patients with dementia diagnoses. Five percent of patients in the benzodiazepine group improved, compared with 24% of those in the haloperidol group, a difference that was not statistically significant, perhaps because of the small sample size. Christensen and Benfield (1998) compared alprazolam (0.5 mg twice daily) with haloperidol (0.6 mg/day) in a crossover study. Adverse events were not significantly different between groups. The dosages of both agents used in this study were probably too low to expect an effect, and none was seen. Meehan et al. (2002) noted that intramuscular lorazepam 1.0 mg or 0.5 mg was superior to placebo at 2 hours but not at 24 hours.
Possible side effects of benzodiazepines in elderly individuals include ataxia, falls, confusion, anterograde amnesia, sedation, light-headedness, and tolerance and withdrawal syndromes. There is evidence that mild anterograde amnesia may occur in elderly patients who are taking therapeutic doses of a benzodiazepine, although this side effect is often reversible (Salzman et al. 1992). A recent review suggests that benzodiazepines may increase the risk of developing Alzheimer’s disease (Billioti de Gage et al. 2014), although this finding is controversial (Salzman and Shader 2015). Nevertheless, the potential side effects of benzodiazepines in the context of scant evidence of efficacy suggest that their use for agitation should be time limited or on a low-dose, as-needed basis, with chronic use reserved for those patients in whom other agents have proved ineffective. Benzodiazepines with simpler metabolisms and relatively short half-lives, such as lorazepam and oxazepam, are always preferred.
Although early studies reported benefit for carbamazepine in elderly patients with agitation (Tariot et al. 1994), most subsequent studies suggested that anticonvulsants are not reliably helpful for controlling agitation and aggression in elderly individuals, especially those with dementia. Small clinical observation studies have reported a modest benefit for divalproex, as well as for lamotrigine, but subsequent experience has not borne out the clinical usefulness of these agents.
Although disappointing experience has been reported for serotonergic antidepressants, the combination of a selective serotonin reuptake inhibitor (SSRI) antidepressant and a cognitive-enhancing cholinesterase inhibitor is commonly used in an effort to control agitation without resorting to use of antipsychotics. However, clinical experience suggests that this combination has inconsistent, modest efficacy (Holmes et al. 2004).
A new approach to the treatment of dementia-related agitation has recently been published. In a preliminary 10-week Phase II randomized clinical trial of patients with probable Alzheimer’s disease, combination dextromethorphan–quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated (Ballard et al. 2015; Cummings et al. 2015).
Another recent study suggested that some patients with Alzheimer’s disease accompanied by aggression or agitation may respond to citalopram 20–30 mg/day (Peters et al. 2016; Schneider et al. 2016). The authors noted a significant clinical heterogeneity of agitation and aggression in this disorder that made specific symptoms or identifying patient data predict response or nonresponse. Residence in long-term care, however, was associated with a negative outcome with citalopram. Patients for whom citalopram was more effective were more likely to be outpatients, to have the least cognitive impairment, to have moderate agitation, and to be in the age range of 76–82 years.
Dementia-associated agitation is common and can be difficult to treat. The usual first-choice medications are the antipsychotics, but they have only modest efficacy and may cause significant side effects. New treatment guidelines do not favor these drugs, although clinicians may find that the other choices are less effective. Trazodone is a useful second choice or an addition to the antipsychotics. Anticonvulsants have an uncertain therapeutic effect; initial data were promising, but subsequent experience and further research has not supported their routine use. Benzodiazepines and other sedative-hypnotics are generally not recommended for the behavioral treatment of individuals with dementia or agitation. Cognitive enhancers, alone or in combination with SSRI antidepressants, are commonly used, but their therapeutic effect is unreliable and usually inadequate when behavioral disruption is severe or frequent. Most recently, the report of treatment success with a dextromethorphan–quinidine combination has raised hopes that treatment of this difficult behavioral problem associated with dementia may be making progress.
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