UNDERSTANDING THE RISKS
To improve individual patient outcomes, clinicians must identify modifiable factors that facilitate or amplify antipsychotic-related adverse effects and understand what (if any) patient-specific characteristics decrease the risk of serious events.
CVAE. Kryzhanovskaya and colleagues11 analyzed possible associations between CVAE and patient demographics, dementia diagnosis, and treatment-emergent adverse effects. A diagnosis of mixed or vascular dementia was significantly associated with CVAE in patients 80 years or older who were receiving either olanzapine(Drug information on olanzapine) or placebo. Orthostatic hypotension and gender were not significant risk factors in this analysis.
Antipsychotic agents and mortality risk. The impact of select characteristics (baseline sedation, malnutrition, dehydration, change in weight, BMI, extrapyramidal adverse effects, number of concurrent medications, and dysphagia) on risk of dying during olanzapine dementia trials also was investigated.11 Conditions identified as additive risk factors for death in olanzapine-treated patients included age 80 years or older, treatment-emergent sedation, benzodiazepine use, and treatment- emergent pulmonary conditions. Presence of multiple risk factors, in addition to treatment assignment to olanzapine, significantly amplified the risk of dying during the studies (0.7% if no risk factors; 1.5% with 1 risk factor; 3.8% with 2 risk factors; 18.7% with 3 risk factors; and 30% with 4 risk factors).
Atypical antipsychotic agents will continue to be prescribed for the behavioral symptoms of dementia in the absence of more effective, better-tolerated, and safer alternatives. The current evidence, although incomplete, suggests that modest treatment effect sizes are offset by the risk of considerable adverse effects.
In CATIE-AD, it was reported that the sum total of the risk/benefit equation of atypical antipsychotic therapy was no greater than that achieved by placebo. However, CATIE-AD was designed to study the efficacy of atypical antipsychotic treatment in community-dwelling patients with AD. It is uncertain whether the results can be generalized to the populations of dementia patients residing in nursing homes who have more severe cognitive impairment and significant behavioral symptoms.
Nursing home patients with dementia complicated by severe behavioral symptoms—particularly agitation and aggression without accompanying psychosis—may achieve more symptomatic benefit from atypical antipsychot-ic treatment than patients with milder behavioral symptoms. Subgroup analyses across atypical antipsychotic trials showed that larger effect sizes were associated with greater cognitive impairment, residence in nursing home versus community settings, and the presence of severe agitation without psychosis.19
Nevertheless, patients who reside in extended-care settings, are 80 years or older, have pulmonary conditions such as chronic obstructive pulmonary disease or asthma, and are receiving benzodiazepines probably represent a highly vulnerable subgroup.11 Indeed, benzodiazepine-associated sedation exacerbates preexisting cognitive impairment and increases the risk of complications such as aspiration pneumonia. The report by Kryzhanovskaya and colleagues11 suggests the need for caution in antipsychotic dose titration and in the monitoring of patients who have multiple risk factors.
Aggressive monitoring of signs of adverse effects in the first 1 to 2 months of antipsychotic therapy may be especially important. In 2 studies, the risk of death was greatest up to 40 days after an antipsychotic agent was initiated.17,19 Factors such as titration-related sedation, gait instability, and increased risk of injury when symptoms are not initially responsive to treatment may be contributive.
PRESCRIBING ATYPICAL AGENTS AND RISK MANAGEMENT
According to Recupero and Rainey,20 who recently developed a framework for managing medicolegal risks when prescribing atypical antipsychotics for dementia-related psychiatric and behavioral problems, symptom severity and frequency, as well as assessment of the risk of self-harm or endangerment of others, should be carefully considered in assessing whether a patient requires antipsychotic therapy.
If nonpharmacological methods fail, the risk of adverse effects must be weighed against the potential benefit of antipsychotic treatment,20 particularly in the patient with comorbidities such as cardiac disease, diabetes, obesity, and movement disorders.
The treatment plan should include ongoing assessment and documentation of potential adverse effects of antipsychotic therapy, such as weight gain, hyperlipidemia, and hyperglycemia, which may exacerbate comorbidities.
When unsatisfactory outcomes occur, malpractice lawsuits are more likely to be initiated if patients and caregivers feel excluded from the treatment planning process. If the patient's decision-making ability is impaired, it is recommended that consent for treatment with antipsychotic therapy is obtained from the patient's designated proxy.20
Education on the adverse effects associated with the atypical antipsychotics and other pharmacological interventions allows the caregiver to share in the decision-making process. Use of written materials such as Treatment of Dementia and Agitation: A Guide for Families and Caregivers can inform and facilitate discussions with caregivers.24
Current evidence suggests that the potential cost of adverse effects associated with antipsychotic treatment of behavioral and psychiatric symptoms may offset marginal therapeutic benefits for many patients with dementia. In the absence of better alternatives, off- label prescribing of antipsychotic agents for dementia-related neuropsychiatric symptoms will continue. Documentation of the risk-benefit assessment and a monitoring plan are important risk management strategies.