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Atypical antipsychotic drugs have been used off-label in clinical practice for treatment of serious dementia-associated agitation and aggression. Following reports of cerebrovascular adverse events associated with the use of atypical antipsychotic in elderly patients with dementia, the FDA issued black box warnings for several atypical antipsychotics, titled “Cerebrovascular Adverse Events, including Stroke, in Elderly Patients with Dementia.” Subsequently, the FDA initiated a meta-analysis of safety data from 17 registration trials across six antipsychotic drugs (five atypical antipsychotics and haloperidol). In 2005, the Agency issued a black box warning regarding increased risk of mortality associated with the use of atypical antipsychotic drugs in this patient population. Geriatric mental health experts participating in a 2006 consensus conference reviewed evidence on the safety and efficacy of antipsychotics, as well as nonpharmacologic approaches, in treating dementia-related symptoms of agitation and aggression. They concluded that, while problems in clinical trials design may have been one of the contributors to the failure to find a signal of drug efficacy, the findings related to drug safety should be taken seriously by clinicians in assessing the potential risks and benefits of treatment in a frail population, and in advising families about treatment. Information provided to patients and family members should be documented in the patient’s chart. Drugs should be used only when non-pharmacologic approaches have failed to adequately control behavioral disruption. Participants also agreed that that there is a need for an FDA-approved medication for the treatment of severe, persistent or recurrent dementia-related symptoms of agitation and aggression (even in the absence of psychosis), that are unresponsive to nonpharmacologic intervention. The authors have outlined methodological enhancements to better evaluate treatment approaches in future registration trials, and they provided an algorithm for improving the treatment of these patients in nursing home and non-nursing home settings.
The observation of behavioral disturbances in dementia began over a century ago with Alzheimer’s description of his first patient. Frequent and severe dementia-related behavioral symptoms can be extremely distressing to the individual, the family, and caregivers. Since there has been no FDA-approved treatment for these patients for more than 50 years, off-label prescribing of antipsychotic drugs has been commonly employed to treat symptoms of aggression and agitation in patients with dementia (1). Practitioners tend to use these medications for short periods and in low doses. Although believed to be modestly helpful, first-generation antipsychotic drugs sometimes produce substantial side effects, such as tardive dyskinesia, as well as extrapyramidal and anticholinergic symptoms (2). More recently, use of conventional neuroleptics has been associated with increased mortality in older patients with various diagnoses (3, 4). For the most part, these drugs have been replaced during the past decade by atypical antipsychotics for off-label treatment of patients with dementia-related behavioral symptoms. Industry-sponsored clinical (registration) trials have failed to establish the efficacy of antipsychotic drugs for treating dementia-related psychosis and behavioral disruption, a finding which has been confirmed by a Cochrane analysis (5) and by a multi-site National Institute of Mental Health sponsored study of the effectiveness of atypical antipsychotics for outpatients with dementia (published after this conference) (6). In the latter study, atypical antipsychotic drugs were not reliably more effective than placebo for psychotic symptoms of dementia.
Other studies have suggested that risperidone (7, 8), olanzapine (9), and quetiapine (10) may be more effective for treating the symptoms of agitation and aggression than for hallucinations and delusions in the psychosis of dementia. Small scale studies of treatment with drugs other than antipsychotics have produced equivocal results. Trazodone (11, 12, 13), anti-convulsant mood stabilizers (14), SSRIs (15, 16), benzodiazepines (17, 18), and cognitive enhancers (19, 20) may reduce symptoms of agitation and aggression in a proportion of patients with dementia, although the overall results are inconsistent. The available data are limited by small numbers of subjects or shortcomings in study design, and a number of these drugs have their own adverse effects. None of these drugs has been approved by the FDA for treatment of behavioral symptoms of dementia.
Given the frequency, severity, and distress caused by behavioral and psychotic symptoms in patients with dementia, there is a need for increased research and development of FDA-approved treatment approaches, including newer safe and effective drugs for these symptoms. In order to address an apparent discrepancy between the public health need for safe and effective treatment and the lack of FDA-approved treatments, the Department of Psychiatry at Harvard Medical School (Beth Israel Deaconess Medical Center) and Best Practice Project Management, Inc. convened a consensus development conference on June 28–29, 2006 in Bethesda, Maryland. Attendees included 40 participants from leading academic centers, the pharmaceutical industry, FDA, Centers for Medicare and Medicaid Services (CMS), National Institutes of Health (NIH), the medical leadership group in the nursing home industry, and advocates for patients and families with dementia. This paper represents a consensus of the participants. Three themes were addressed at the conference:
Despite extensive clinical experience with off-label prescribing, as well as published clinical trials (21) of conventional (typical) and atypical antipsychotic drug treatment of symptoms of agitation and aggression in dementia, the efficacy of these drugs for psychosis and these behavioral symptoms has not been established in FDA-required registration trials. In the past decade, in an effort to encourage research and improve clinical practice, geriatric psychiatrists (22) placed the behavioral and psychotic symptoms of Alzheimer disease (AD) into a new diagnostic category of “psychosis of Alzeheimer disease and related dementias”. By 2000, the FDA had accepted this new diagnosis, which made possible the diagnostic differentiation of dementia-associated psychosis from late-life schizophrenia and other late-life psychoses (23).
Data from functional imaging studies (24) and neuropathology (25) suggest that among the multiple causes of symptoms of agitation and aggression in AD, patients may have an identifiable pathophysiology. Since reliable and valid measurement instruments are now available to quantify dementia-associated symptoms of agitation and aggression, it may be possible to define a distinct syndrome that would represent an FDA-approvable target for appropriate use of antipsychotic and other medications to treat these symptoms of dementia even in the absence of psychosis, with the caveat that the symptoms should be severe, persistent or recurrent, and unresponsive to nonpharmacologic interventions. This diagnostic category would also promote further research into the treatment of these difficult behaviors.
Previous industry-sponsored registration trials involved persons with dementia (probable and possible AD) with psychosis and/or agitation. The studies were placebo-controlled and lasted for 6 to 12 weeks, typically 10 to 12 weeks. They were parallel-group, fixed-dose range or adjustable/titrated-dose trials, involving 200 to 650 patients. Most of these trials were nursing home studies, and included patients with a mean age over 80 years of age, 75% female. The clinical trials endpoints were based on behavior rating scales, including the BPRS, BEHAVE-AD, NPI, the PANSS and the PANSS-EC, CMAI * and subscales (proxy-based more common than direct observation), global assessments, and activities of daily living scales.
A number of methodological flaws limit the conclusions that can be drawn from these studies and indicate a need for better designed future research. Some studies required long periods of continuous symptomatology (as much as three weeks) to establish eligibility. This requirement disproportionately eliminated the most severe cases requiring immediate treatment, who may have been more likely to respond to drug than placebo. This could explain the failure to establish drug/placebo differences. Among subjects studied, there was a wide degree of variation in type and severity of symptomatology, which diminished the likelihood of coherent results. Additional design problems included the (non-random) statistical distribution of behavior test scores and lack of consideration of effect size.
The conference identified two additional aspects of clinical trial design that would improve the correct identification of improved and non-improved subjects.
In general, older persons are more sensitive to common and severe drug side effects, in part as a consequence of age-related pharmacokinetic changes that can result in higher and/or more variable drug concentrations (26, 27). In addition to adverse consequences of age-related changes in pharmacologic disposition and sensitivity to antipsychotic drugs, specific concern has emerged regarding apparent increases in mortality when antipsychotic drugs were given to patients with dementia. Following reports of cerebravascular adverse events associated with the use of atypical antipsychotics in elderly patients with dementia, the FDA issued black box warnings for several atypical antipsychotics, titled “Cerebrovascular Adverse Events, including Stroke, in Elderly Patients with Dementia.” Subsequently, on April 11, 2005, the FDA issued a public health advisory for atypical antipsychotic drugs prescribed for the treatment of behavioral disorders in elderly patients requesting that the manufacturers “include a Boxed Warning in their labeling describing mortality risk and noting that these drugs are not approved for the treatment of behavioral disturbances in elderly patients with dementia.” (28) The safety warning was based on an FDA analysis of 17 placebo-controlled trials, comparing six antipsychotic drugs to placebo. That analysis showed a statistically significant elevated risk of death -- a rate that was 71% greater than the death rate of placebo-treated patients. More than 5,000 individuals (average age 81) were included in the FDA analysis; and, two-thirds received an antipsychotic drug over a 6–12 week period. The increased mortality was seen with all atypical antipsychotic medications, in spite of differences in receptor-binding profiles; a finding consistent with later meta-analyses (4, 5) of placebo-controlled randomized clinical trials. This risk should be taken seriously by clinicians in assessing the potential risks and benefits of treatment in a generally frail population and in advising family members about treatment options.
Subsequently, in an observational study of patients in a pharmacy benefit program for the elderly, (3) reported that all-cause mortality associated with conventional antipsychotics was similar to that of patients on atypical antipsychotic drugs. In this study, frail elderly subjects and those with serious medical illness were not separated from other less susceptible nursing home residents. Additional studies are needed to verify this finding, preferably with greater control of severity of dementia, medical co-morbidities, and length of drug exposure
The conference raised questions regarding the possible causes of increased and diverse causes of mortality. While there may be an association between risperidone, olanzapine, and aripiprazole and risk of stroke (5) the reported causes of death in the 17 studies were mainly related to cardiovascular events and infection. It is possible that mortality by infection, specifically pneumonia, could be related to sedation and aspiration. Finally, in addition to the specific mortality risk associated with use of atypical antipsychotics in dementia, the FDA has also applied a class label to risk of weight gain, metabolic syndrome, hyperlipidemia and type 2 diabetes (29). Obviously, elderly subjects are also susceptible to these metabolic effects.
Since dementia-related agitation and aggression can occur from many causes, it is important to identify any contributing factors that can be modified without the use of medication. Nonpharmacologic interventions are based on the principle that a clinical care system serving patients with dementia must address issues in the physical environment and the care system (and its policies) that may contribute to the emergence of symptoms of agitation and aggression. Research has shown that verbal/vocal behaviors may be associated with pain, loneliness, or depression (30). Agitation may be associated with boredom and the need for activity and stimulation. Aggressive behaviors may be associated with avoiding discomfort, the communication of needs, or a demand for personal space (31). All treatment approaches should start with rigorous attempts to identify any reversible causes of these behaviors and eliminate or mitigate these factors. Typical precipitants of agitation and aggression include pain, medical illness, boredom, loneliness, depression, and social and environmental stressors. Identified causes should be addressed through individualized and/or systemic efforts to mitigate the triggers of agitation and/or aggression. Other individualized nonpharmacologic interventions for the person with dementia include tools to improve or stabilize cognitive function, behavior modification, self-affirming exercises such as reminiscence therapy, and structured socialization such as pet therapy and visualizing family videotapes. The efficacy of these interventions has been demonstrated in a series of small studies (32) and in some larger studies (33, 34, 35). Given the promising results reported, there is a need for additional scientifically sound, adequately powered studies designed to assess the effectiveness of nonpharmacologic interventions, which should be initiated with government and/or private-sector support. These studies are necessary in order to recommend any “evidenced-based” treatment for severe agitation or aggression associated with dementia.
Training programs for family caregivers of people with dementia, such as Savvy Caregiver, STAR-C1, REACH II2 have resulted in decreased agitation in people with dementia who live at home and reduced feelings of burden and depression for family caregivers (36, 37, 38, 39, 40, 41, 42). One study that compared the effectiveness of four interventions nonpharmacologic behavior management intervention, haloperidol, trazodone, and placebo and found no significant differences in outcomes, but fewer adverse events (e.g., bradykinesia and parkinsonian gait) in subjects who received the nonpharmacologic intervention (43). At this stage, nonpharmacologic treatments directed to the person with dementia (and/or the family caregiver[s]) can be incorporated into clinical practice and clinical trials as part of a treatment algorithm and/or decision tree in clinical practice in assessing the need for medication and, as adjuncts to medication treatment in clinical trials for people with dementia who are living at home or in nursing homes or assisted living facilities.
Given the identified risks observed in this population, it is incumbent on sponsors and investigators to ensure that only patients at lowest risk, who stand to benefit most, be entered into Phase 2 trials. If there is a good signal of efficacy in the treatment of dementia-related symptoms of agitation and aggression in these patients, later Phase 3 studies, as well as specific safety studies, should inform the FDA approval process and the use of pharmacotherapy in a broader group of patients with dementia and these behavioral symptoms. If the signal of efficacy is not statistically significant, there is no need to expose the test compound to a wider sample of patients. The black box warning for the atypical antipsychotic drugs highlights the potential for harm.
The methodological recommendations for clinical trials by the conference may strengthen study designs for any medication proposed for the treatment of dementia-related symptoms of agitation and aggression in patients with dementia. These recommendations are made with the following caveats:
Recommendations to improve drug safety monitoring need to be considered in the context of the unique characteristics of the patient population, including the fact that patients in nursing homes are on an average of 8–9 medications for the treatment of multiple chronic and acute medical problems. The interaction between drugs with different pharmacologic and metabolic characteristics and various diseases makes this population more vulnerable to adverse drug reactions. Moreover, the average age of these patients is over 80 years, with 25% of nursing home residents over age 90. Nursing home oversight varies considerably by state. In spite of the complexity of monitoring drug safety and effectiveness in these patients, it is critical that a better system of monitoring be established to supplement the limited data collected prior to drug approval. The following recommendations are meant to address this issue:
Atypical antipsychotic drugs have been commonly used off-label in clinical practice for treatment of serious dementia-associated agitation and aggression, although they have not been approved by the FDA for such use. Following reports of cerebrovascular adverse events associated with the use of atypical antipsychotics in elderly patients with dementia, the FDA issued black box warnings for several atypical antipsychotics, titled “Cerebrovascular Adverse Events, including Stroke, in Elderly Patients with Dementia.” Subsequently, the FDA initiated a meta-analysis of safety data from 17 registration trials across six antipsychotic drugs (five atypical antipsychotic drugs and haloperidol) and issued a black box warning regarding mortality with the use of these drugs in this patient population.*
Experts in the field of geriatric mental health who participated in this consensus conference reviewed the available evidence regarding the safety and efficacy of antipsychotic drugs, as well as nonpharmacologic approaches for the treatment of dementia-related symptoms of agitation and aggression. They concluded that problems in clinical trials design may have been a significant contributor to the negative results. Among many criticisms noted, participants emphasized the wide variation in type and severity of symptoms required for eligibility, inadequate statistical power and absence of clinically interpretable effect sizes to determine the true risk of these drugs, a prolonged drug-free baseline before randomization leading to potential bias that could favor placebo response, and the use of outcome measures and assessments that failed to differentiate agitation and aggressive behavior from psychosis. These issues could have influenced the negative trial results. Future studies should assess the balance of risk and benefit of treatment in this frail population, and they should be adequately powered to assess both benefit and risk.
Participants agreed that that there is a need for an FDA-approved indication for treating dementia-related symptoms of severe and persistent or recurrent agitation and aggression, even in the absence of psychosis. Participants further agreed that agitation and aggression associated with Alzheimer’s disease be considered an appropriate target for treatment development and ultimate registration. At present, many clinicians use atypical antipsychotic drugs as the off-label treatment for behavioral symptoms (21, 22) of dementia, despite the fact that the elderly are more sensitive to their side effects than young and middle-aged adults. The FDA analysis of the 17 registration trials across six antipsychotic drugs indicated a statistically significant elevated risk of death in drug-treated patients (either heart-related or from infections) that was 1.6 times greater than placebo-treated patients. These findings should be taken seriously by clinicians in assessing the potential risks and benefits of treatment in a generally frail population, and in advising family members about treatment options. In general, drugs may be used only when non-pharmacologic approaches have failed to adequately control serious behavioral disruption within 5–7 days.
Conference participants were unanimous in their call for additional research to further define pharmacologic as well as non-pharmacologic treatment approaches for individuals with dementia and behavioral disruption. Among the new methodologies that were recommended, the following received particular emphasis:
In their concluding discussions, participants developed recommendations for improving the treatment of patients with dementia in the nursing home as well as non-nursing home settings. Treatment algorithms were proposed, and non-pharmacologic interventions were encouraged as the initial treatment of choice. In view of the clinical need to treat very sick patients in the absence of perfectly safe and effective alternatives, treatment algorithms should support prescribing by physicians if a decision is made to initiate treatment with agents that have not been approved by the FDA for this indication and for which there is a “black box” warning. Clearly, patients and families must be adequately informed of risks and potential benefits in the context of the disease, the symptom picture, the adverse event profile, and the consequences of nontreatment of the symptoms. Treatment should only be initiated following preferably written consent by the responsible family member to such treatment, after being adequately informed of risks and potential benefits. The information provided by the physician should be documented in the patient’s chart.
The conference was funded by unrestricted educational grants from; *AstraZeneca, Bristol Myers Squibb/Otsuka America Pharmaceuticals, *Forest Laboratories, Johnson & Johnson (*Janssen Pharmaceuticals Inc.), *Eli Lilly and Company, *Pfizer, SanofiAventis, Solvay Pharmaceuticals/Wyeth, and Takeda. (*Indicates sent observers.)
*Brief Psychiatric Rating Scale; Behavioral Pathology in Alzheimer Disease Rating Scale; Neuropsychiatric Inventory; Positive and Negative Syndrome Scale; Positive and Negative Syndrome Scale Excited Component; Cohen-Mansfield Agitation Inventory
*“The CATIE-AD trial results were published after the consensus conference was held (Schneider LS, et al. N Engl J Med. 2006;355:1525-1538), so the data could not be discussed during the conference. The trial showed that there was no significant difference among the atypical antipsychotic medications studied on the primary outcome measure - i.e., time to discontinuation. There was no evidence of increased stroke or cardiac complications, although the CATIE study was not powered to examine this issue.”
Alphs L1, Baker A2, Buckholtz N3, Chow T4, Datto C5, Evans J6, Juncos J7, Laughren T8, McGann P9, Niederehe G10, Palmer B11, Pandina G12, Ryan L13, Schraa C14, Schneider L15, Silverberg N16, Smith G17, Stone M18, Sultzer D19, Trinh B20, Trzepacz P21
1 Pfizer; 2 The Copper Ridge Institute; 3 National Institute on Aging; 4 University of Toronto, Rotman Research Institute; 5 AstraZeneca; 6 National Institute of Mental Health; 7 Emory University School of Medicine, 8 U.S. Food and Drug Administration, 9 Centers for Medicare and Medicaid Services; 10 National Institute of Mental Health; 11 University of California, San Diego; 12 Janssen Pharmaceutica, Inc, 13 National Institute on Aging; 14 Forest Laboratories, Inc; 15 University of Southern California, Keck School of Medicine; 16 National Institute on Aging; 17 Albert Einstein College of Medicine; 18 U.S. Food and Drug Administration, 19 University of California, Los Angeles, 20 Ortho-McNeil Janssen Scientific Affairs, LLC; 21 Eli Lilly and Company
1STAR-C = Staff Training in Assisted-Living Residences Caregivers
2REACH II= Resources for Enhancing Alzheimer’s Caregiver Health