By: Ada Seldin, Staff Editor
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The overuse of antipsychotics in the nursing home population for off-label indications continues to impact patient safety. In 2005, the FDA issued a black box warning that stated, “The treatment of behavioral disorders in elderly patients with dementia with atypical antipsychotic medications is associated with increased mortality.” The evidence supporting this advisory was reported as a series of 17 placebo controlled trials performed with olanzapine, risperidone, aripiprazole, and quetiapine that yielded a 1.6-1.7 fold increase in mortality in the treatment arm. Most of the deaths were attributed to cardiac events or infectious pneumonias.1The warning was extended to all atypical antipsychotics, and in 2008, conventional antipsychotics were added to the fold.2 In the aftermath of the product labeling revisions, many studies demonstrated the lack of established efficacy and the potential for serious adverse events in elderly, demented patients treated with antipsychotics. The issue fell into the spotlight in 2011 when the Department of Health and Human Services released a report that emphasized the high use of atypical antipsychotic medications for off-label indications among nursing home residents, revealing that 83% of atypical antipsychotic drug claims were of this nature.3
Although unapproved by the FDA, antipsychotics are used to control neuropsychiatric symptoms, such as agitation and delusions, which afflict 97% of people with dementia over the course of their illness.4 There is currently no pharmacologic agent on the market that is approved for dementia-related psychosis, posing a serious dilemma when managing these patients. Because symptoms of dementia are particularly distressful and often manifest in danger for both the patient and those around him/her, and because there is no evidence that other psychotropic drug classes offer a safer or more effective alternattive, it is no surprise that nursing home staff turn to antipsychotics for symptom control.
The ability of antipsychotics to act as antagonists in four key dopaminergic pathways produces both their therapeutic and adverse effects. The target of therapeutic efficacy is the mesolimbic system in which excess dopamine signaling is responsible for the positive symptoms of schizophrenia. Therefore, reducing dopamine neurotransmission in this pathway may treat hallucinations, delusions, and thought disorders. Dopamine antagonism in the mesocortical pathway, on the other hand, may exacerbate cognitive and negative symptoms of schizophrenia. Disruption of dopamine signaling in the nigrostriatal pathway, involved in motor planning, leads to extrapyramidal symptoms. Finally, the tuberoinfundibular pathway plays an important role in the inhibition of prolactin release, the blockade of which causes hyperprolactinemia.5
Caution must be exercised as these medications are not benign. A meta-analysis of 15 randomized, placebo-controlled trials with a total cohort of 3353 patients receiving various atypical antipsychotics and 1757 patients randomized to placebo was performed. It included published and unpublished clinical trials on patients with Alzheimer’s disease, vascular dementia, mixed dementia, or primary dementia with cognitive impairment ranging from mild to severe. The mean age of study participants was 81.2, and 87% of patients had Alzheimer’s disease. Eleven of the trials were conducted in nursing homes and four occurred in an outpatient setting. The study durations ranged from 6 to 26 weeks. The results showed that more deaths occurred in the treatment group, 118 (3.5%) vs. 40 (2.3%). The odds ratio for death in patients treated with antipsychotics compared with placebo was 1.54 (95% CI, 1.06-2.23) and the absolute risk difference was 0.01 (95% CI, 0.004-0.02, p=.01).6
However, because the trials that comprised this analysis were generally 10 to 12 weeks in duration, it is unclear whether the risk of death would remain consistent over the length of treatment or would diminish over time. Furthermore, dose response was not assessed; eight trials allowed dosage adjustment, while the others had either one or several fixed doses of drug. There was no significant difference in dropouts between the drug-treated and placebo groups. Sensitivity analyses did not reveal heterogeneity between trials of patients of higher cognitive function (Mini-Mental State Examination score >10) compared with those that had participants of lower mental function, trials that selected only patients with psychosis of Alzheimer’s disease compared with those lacking such selection criteria, inpatient vs. outpatient trials, and among the four drugs included: aripiprazole, olanzapine, quetiapine, and risperidone.6
Although the individual causes of death were not examined in this analysis, other clinical trials have demonstrated that antipsychotics are associated with an increased risk of cerebrovascular events, including stroke, in elderly patients with dementia. Potential contributory mechanisms of these medications to cardiovascular injury include orthostatic hypotension, thromboembolic effects, dehydration caused by excessive sedation, impairment of endothelial function due to hyperprolactinemia, and venous stasis secondary to sedation or extrapyramidal symptoms. The cardiovascular effects of antipsychotics, namely syncope and QTc interval prolongation and torsades de pointes, also contribute to mortality risk. Whle atypical antipsychotics generally carry a decreased risk of fatal arrhythmias compared to conventional antipsychotics, ziprasidone has the highest incidence of QTc prolongation. Patients treated with antipsychotics are also at increased risk of death due to pneumonia, especially during the first week of treatment; Extrapyramidal symptoms, sedation, and dry mouth are all culprits in causing aspiration pneumonia.4
The Clinical Antipsychotic Trials of Intervention Effectiveness – Alzheimer’s Disease (CATIE-AD) study revealed the cognitive effects of atypical antipsychotics used to treat delusions, hallucination, agitation, and aggression in Alzheimer’s patients. The study analyzed a sample of 421 outpatients randomly assigned to receive masked, flexible-dose olanzapine, risperidone, quetiapine, or placebo. Patients were followed over a 36-week period and received cognitive assessments at baseline and at least one follow-up assessment at weeks 12, 24, and 36. Patients were excluded if they were taking antidepressants or anticonvulsants, but cholinesterase inhibitors were permitted. Participants who received any atypical antipsychotic for at least 2 weeks prior to assessment had significantly greater rates of decline in cognitive function than those who received placebo, measured by the category instances test, cognitive summary, MMSE, and BPRS. Overall, atypical antipsychotic use over 36 weeks was associated with cognitive decline comparable to one year’s deterioration in placebo.7
In an effort to ascertain whether the benefits outweigh the risks, a systematic review on the safety and efficacy of atypical antipsychotic use for off-label indications was performed. Study medications included aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Thirty eight clinical trials met inclusion criteria for efficacy evaluation and the outcomes examined were improvement in psychosis (delusions and hallucinations), improvement in agitation, and total global function measured by the Neuropsychiatric Inventory score (NPI). The resulting improvements were small but statistically significant. The NPI total score for atypical antipsychotics was a 35% improvement compared to baseline and the difference between treatment and placebo was 3.41 points. According to study authors, clinically observable changes are 30% improvement and 4-point advantage over placebo. For the outcome of psychosis, the pooled effect size was 0.20 (95% CI, 0.05 to 0.36) for risperidone, 0.20 (95% CI, 0.05 to 0.36) for risperidone, 0.20 (95% CI, −0.02 to 0.42) for aripiprazole, 0.05 (95% CI, −0.07 to 0.17) for olanzapine, and −0.03(95% CI, −0.24 to 0.18) for quetiapine. Thus, only risperidone showed statistically significant efficacy in psychosis. Aripiprazole, olanzapine, and risperidone (NNH = 10 and 20 respectively).8
In light of the aforementioned evidence, Centers for Medicare and Medicaid Services established the National Partnership to Improve Dementia Care in Nursing Homes and put forth an initial goal to reduce the national prevalence of antipsychotic use in long-term health facilities by at least 15% by the end of 2012. In the ensuing months, the prevalence of antipsychotic consumption among nursing home residents decreased from 23.8% to 20.2%, meeting the proposed objective. In the interest of transparency, CMS has made public the prevalence of antipsychotic medication use in each nursing home on a website called Nursing Home Compare. CMS and its associates track improvement and identify nursing homes in which rates remain high, and tackle deficiencies with direct outreach. State surveyors are sent to facilities to ensure that appropriate care of dementia patients is being upheld.3
Antipsychotic agents provide modest benefit in treating behavioral symptoms of dementia and Alzheimer’s disease. However, the high incidence and severity of adverse effects as well as the increased risk of death may not warrant the use of these medications in this patient population. Before prescribing potentially harmful medications to elderly patients with dementia, a thorough work-up should be conducted to rule out medical causes (e.g., pain and infection) that may be exacerbating the neuropsychiatric symptoms. If identified and treated appropriately, antipsychotic use can be avoided. In addition, factors in the environment or care giver interaction with the patient should be assessed and modified accordingly. Finally, non-pharmacological interventions, such as reassurance, redirection, increased structure and activities, should be implemented before turning to medications.
SOURCES:
- Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. U.S Food and Drug Administration Website. Published April 11, 2005. Last updated August 16, 2013. Accessed June 19, 2014. http://www.fda.gov/drugs/drugsafety postmarketdrugsafetyinformationforpatientsandproviders drugsafetyinformationforheathcareprofessionals/publichealthadvisories/ucm053171.htm
- FDA requests boxed warnings on older class of antipsychotic drugs. U.S Food and Drug Administration Website. Published June 16, 2008. Last updated April 15, 2013. Accessed June 19, 2014.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116912.htm
- Tritz K, Laughman M, Bonner A. Report on the CMS National Partnership to Improve Dementia Care in Nursing Homes: Q4 2011-Q1 2014. Published April 1, 2014. Accessed June 19, 2014. http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-14-19.pdf
- Steinberg M, Lyketsos C. Atypical antipsychotic use in patients with dementia: managing safety concerns.Am J Psychiatry. September 2012; 169(9): 900-906.http://journals.psychiatryonline.org/data/Journals/AJP/24848/900.pdf?resultClick=3
- Guzman F. The four dopamine pathways relevant to antipsychotics pharmacology. Psychopharmacology Institute Website. Accessed June 19, 2014. http://psychopharmacologyinstitute.com/antipsychotics-videos/dopamine-pathways-antipsychotics-pharmacology/
- Schneider L, Dagerman K, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia. JAMA. 2005;294(15):1934-1943.
- Vigen C, Mack W, Keefe R, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry 2011;168:831-839.
- Maher A, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adulsts. JAMA. 2011;306(12):1359-1369. doi:10.1001/jama.2011.1360.
[pubmed_related keyword1=”antipsychotic” keyword2=”dementia” keyword3=”elderly”]
