Beyond the Black Box: What is The Role for Antipsychotics in Dementia?

Alzheimer disease (AD) likely affects over 5 million Americans, with this number expected to grow nearly exponentially over the upcoming decades (1). Additionally, millions of Americans are afflicted with other types of dementia. Regardless of the etiology, dementias share certain diagnostic features regarding cognitive and functional decline. Yet, for many patients and their families, the nearly ubiquitous neuropsychiatric symptoms of dementias (e.g. depression, psychosis, aggression, sleep disturbance) are the most problematic aspects of these illnesses, leading to caregiver morbidity, poor patient quality of life, and early patient institutionalization (2). Psychosis, for instance, affects approximately 40% of persons with AD, while agitation occurs in 80% or more of persons with dementia at some point in the illness (3). Although empirical research regarding the treatment of neuropsychiatric manifestations of dementia has been sparse relative to the growing public health significance of this problem, no medication has been FDA-approved for the treatment of these symptoms. Psychotropic medications, especially antipsychotics, have often been used off-label in attempts to ameliorate these symptoms. Yet, this has not been without controversy, as some public perception (at times validated by unfortunate institutional practices) has viewed the use of antipsychotics in dementia as a means of creating “zombies” in order to lighten the work burden of healthcare workers. Nonetheless, psychosis and severe agitation/aggression in dementia can pose significant risks to patients and those around them, such that efforts to treat these symptoms are indeed warranted. While possibly underutilized because of time constraints, reimbursement issues, and lack of training, non-pharmacological strategies to treat aggression and psychosis are appealing alternatives to “knee-jerk” antipsychotic prescriptions; nonetheless, the empirical evidence base for non-pharmacological strategies to control psychosis and/or agitation in dementia remains generally inadequate as well (4). Adding another layer of complexity onto the use of antipsychotics in treating dementia-related psychosis and/or agitation are the recent FDA black-box warnings regarding atypical agents in this patient population. Beginning with a warning regarding increased risk of “cerebrovascular adverse events including stroke” in dementia patients treated with risperidone versus placebo in 2003, a cascade of warnings for this class of agents has ensued. Similar cerebrovascular black-box warnings have been issued for olanzapine and aripiprazole. While the absolute risk difference was generally 1–2 % between antipsychotic- and placebo-treated patients, the relative risk was approximately two times higher (due to the overall low prevalence of these events in both groups) (5). Perhaps even more daunting, after a meta-analysis of 17 placebo-controlled trials using atypical antipsychotics in dementia, the FDA issued a black-box warning (Table 1) citing an increased risk of mortality for patients receiving atypical antipsychotics (relative risk 1.6–1.7) versus placebo. This warning was applied to atypical antipsychotics as a class, and as with the cerebrovascular risks, the absolute risk difference was between 1–2% (6). Indeed, the public is well-served by evidence-based pharamaco-vigilance that identifies previously unrecognized risks associated with prescription medications, but the FDA data does little to answer the question, “And so, what now? ” for the millions of families grappling with these symptoms. Recognizing the limits of answering this question without solid empirical evidence, we attempt to address this question that lingers for clinicians, patients, and caregivers, who must deal with these symptoms while science tries to provide a more definitive answer to this question. TABLE 1 The FDA Black Box Warnings Regarding Atypical Antipsychotics in Dementia TEXT HYPOTHETICAL CASE EXAMPLE: Mrs. B is an 82-year old Caucasian woman diagnosed 7 years ago with Alzheimer disease who resides in an assisted living facility with a “dementia waiver,” indicating that their staff has some training in dealing with issues unique to providing care to older persons with dementia. Despite attempts to provide more one-to-one attention and verbal reassurance, Mrs. B has demonstrated an escalating pattern of psychosis and aggression over the past two months. At first the psychosis was restricted to occasional accusations of rape during assisted bathing, and the aggression was primarily manifested by Mrs. B banging her hand repetitively on furniture (occasionally causing skin tears). However, over the prior week, Mrs. B has spent much of the day accusing staff and other patients of having stolen her personal belongings and even assaulted both a staff member (causing minor bruises to the staff member’s forearm) and another resident (pushing another female over, prompting an emergency room evaluation for this resident’s fall). This latter incident finally prompted supervisors at the assisted living to advise Mrs. B’s family that she could no longer stay there and suggested that they take her to a local emergency room. From the emergency room, the patient is admitted involuntarily to the nearest geriatric psychiatry inpatient unit. “And so, what now? ” Table 2 summarizes an approach to the initial evaluation of persons with dementia presenting with psychosis and/or agitation/aggression (7). For this patient (and most older adults), a list of current medications (including “as needed” medications from records at a facility or from family report) will be important to review. A review of the medication administration record from the assisted living reveals potentially relevant information: atenolol 25 mg daily, aspirin 81 mg daily, oxybutynin extended release 10 mg at bedtime, psyllium one packet daily, hydrocodone/acetaminophen 5/500 mg every 4 hours as needed for pain, lorazepam 1 mg every 6 hours as needed for agitation, diphenhydramine 25 mg at bedtime, in and out catheter every 8 hours as needed for urinary retention, paroxetine 20 mg daily, haloperidol 5 mg at bedtime, and memantine 10 mg twice daily. This medication list is revealing for many reasons that are unfortunately not rare. There are several anticholinergic medications (oxybutynin, diphenhydramine, and paroxetine) that may be worsening mental status and behavior directly through central nervous system effects, possibly in combination with frequent benzodiazepine use. Anticholinergics can also lead to behavioral changes via peripheral side effects—constipation and urinary retention may cause significant discomfort that is “acted out” rather than verbalized in the aphasic patient. The patient may be having pain related to these side effects and receiving opioid analgesics for pain, which ironically worsen constipation and urinary retention. However, uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment and reduce behavioral disturbances. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior directly and risks causing one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection. TABLE 2 Suggested Approach to the Evaluation of Patients with Dementia Presenting with Psychosis and or Agitation*/Agression After admission, and having recognized all these factors, the patient’s polypharmacy is reduced by limiting medications to atenolol, aspirin, psyllium, memantine, and a taper of lorazepam and paroxetine. Complete laboratory, radiological, and physical examinations reveal a urinary tract infection, fecal impaction, bladder distension, and mild hyponatremia. The patient is given an enema, antibiotic therapy, and integrated into the milieu of the unit. Despite one-to-one nursing care, frequent re-orientation, and attempts to interest the patient in art therapy, the patient remains agitated and postures to strike staff and other patients. The patient denies pain or discomfort. The nurse pages the psychiatrist on duty because she fears for the safety of the Mrs. B, staff, and other patients.