Antipsychotics for Patients with Dementia: Clinical Considerations and Risks

As psychiatrists treating an aging population, we frequently face the daunting challenges of managing medically complex and behaviorally unstable patients whose fragile condition tests the brightest among us. During the past decade, the number of people reaching age 65 has dramatically increased. As life expectancy improves, the “oldest old”—those age 85 and older—are the fastest-growing segment of the population. The prevalence of cognitive impairment, including mild cognitive impairment and dementia, in this cohort is >40%. According to the U.S. Department of Health and Human Services, in 2007, 88% of 1.4 million Medicare claims for second-generation antipsychotics (SGAs) in older adult nursing home residents were associated with a dementia diagnosis.

Behavioral and Psychological Symptoms of Dementia (BPSD)

Roughly 90% of patients with dementia will develop clinically significant behavioral problems at some point in the course of their illness. Behavioral and psychological symptoms of dementia (BPSD) include agitation, delusional beliefs, repetitive questioning, hallucinations, aggression, wandering, and various socially inappropriate behaviors. These occur almost universally in all types and stages of dementia and have a tremendous impact on the quality of life for both patients and their caregivers.

Although all expert organizations recommend nonpharmacologic strategies as first-line treatment for BPSD, for the most part, these recommendations have not been translated into standard clinical management or routine care. Because of a perceived lack of other options, the current mainstay of treatment is the off-label use of psychotropics such as antipsychotics. Of all the agents currently used for BPSD, SGAs have the strongest evidence base, although benefits are modest at best.

Weighing the Risks and Benefits of Antipsychotics

Antipsychotics have been one of the approaches used to address the challenges of behavioral disturbances and psychosis occurring in dementia. Unfortunately, there is conflicting evidence regarding the risks and benefits associated with the use of antipsychotics in this population. Several studies examining the efficacy of antipsychotics in the treatment of BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause. This evidence prompted the FDA to issue a “black-box” warning in 2005 to highlight the increased risk of mortality for patients with dementia who are treated with SGAs. Use of these medications is associated with a 1.6 to 1.7-fold increase in mortality.

Comparison of Mortality and Medication Risks

Both first-generation antipsychotics (FGAs) and SGAs have been associated with higher rates of mortality than most other psychotropic classes. FGAs appear to be associated with a greater mortality risk compared with SGAs. As a result, if antipsychotic treatment is necessary, the use of FGAs in this population is not recommended. The risk may also vary depending on the choice of SGA:

  • Quetiapine: Patients treated with quetiapine had a slightly lower risk of death than those who were treated with risperidone.
  • Risperidone: Has the best evidence for efficacy, with a meta-analysis of 5 published randomized controlled trials reporting that risperidone is superior to other SGAs for aggression in dementia.
  • Haloperidol: Patients who were treated with the FGA haloperidol were twice as likely to die during a subsequent 6-month observation period compared to those on risperidone.
  • Brexpiprazole: FDA-approved for Alzheimer’s agitation, but has modest benefits and significant mortality risks.
  • Pimavanserin: May benefit Parkinson’s patients with psychosis who develop EPS or sedation with quetiapine.

Adverse Effects and Clinical Data

The potential mechanisms leading to stroke and death remain unclear but could include orthostatic hypotension, anticholinergic adverse effects, QT prolongation, and venous thromboembolism. A meta-analysis of RCTs of SGAs found the following increased rates of adverse effects compared with placebo:

  • Somnolence: 17% drug vs 7% placebo
  • Extrapyramidal symptoms: 13% drug vs 8% placebo
  • Abnormal gait: 10% drug vs 2% placebo
  • Edema: 9% drug vs 4% placebo
  • Urinary tract infections/incontinence: 16% drug vs 12% placebo
  • Stroke: 1.9% drug vs 0.9% placebo

Clinical Considerations and Prescribing Guidelines

Because of the aging population and widespread prescription of antipsychotics to older patients, clinicians need information on the relative risks. As psychiatrists, we also face the challenges of the aging brain, severed neuronal networks, and neurotransmitter diminution. For antipsychotics in the elderly, consider “start low, go slow, and maybe stop” especially with dementia. The starting doses for these medications, we’re generally going to use about a quarter to half of the typical starting dose and titrate up. Although safety risks exist, they can be minimized through the careful selection of appropriate patients for treatment, close monitoring, and effective communication with patients and caregivers before and during treatment.