Antipsychotic Drug Interactions and Mortality Among Nursing Home Residents With Cognitive Impairment

Antipsychotic Drug Interactions and Mortality Among Nursing Home Residents With Cognitive Impairment

Rosa Liperoti, MD, PhD, MPHa,*; Federica Sganga, MDa; Francesco Landi, MD, PhDa; Eva Topinkova, MD, PhDb; Michael D. Denkinger, MDc; Henriëtte G. van der Roest, PhDd; Andrea D. Foebel, PhDe; Harriet Finne-Soveri, MD, PhDf; Roberto Bernabei, MDa; and Graziano Onder, MD, PhDa

Antipsychotic medications are approved for the treatment of schizophrenia and psychotic disorders. Although regulatory agencies worldwide have issued recommendations not to use antipsychotics in the elderly population without these two indications, these drugs are frequently prescribed off-label for the treatment of behavioral and psychological symptoms of dementia.1-3

Numerous side effects ranging from cardiovascular events, extrapyramidal symptoms, falls, sedation, and metabolic and hematologic disturbances are known to occur during antipsychotic treatment.4,5 In particular, among older adults with dementia, antipsychotics have been shown to be potentially associated with serious adverse events including ischemic stroke, fractures, arrhythmias, venous thromboembolism, and pneumonia, leading ultimately to increased mortality rate.6-11

Elderly patients, including those with dementia, are a heterogeneous group of subjects with very different individual clinical profiles. In such populations, genetic, clinical, and environmental factors may interact with each other and modify the effect of antipsychotics, thus influencing response to treatment and onset of adverse events.12 In this context, multiple medications used to treat comorbidities in residents with dementia can interact with antipsychotics and increase the risk of adverse drug reactions.

Nursing home residents represent a category of frail, elderly individuals who often present with some degree of cognitive impairment and are usually given 7 to 8 different medications during the day.13,14 Polypharmacy coupled with the age-related changes in pharmacodynamics and pharmacokinetics makes this population particularly susceptible to developing adverse events related to drug interactions.

A review15 of observational studies conducted between 2000 and 2010 has identified 16 studies reporting an increased risk of hospitalization for elderly patients due to drug interactions. The drugs commonly involved in the interactions included cardiovascular agents (angiotensin-converting enzyme inhibitors, diuretics, angiotensin receptor blockers, calcium channel blockers, digoxin), antibiotics (sulfamethoxazole/trimethoprim, macrolide antibiotics, ciprofloxacin), psychotropics (benzodiazepines, zolpidem, phenytoin, lithium), sulfonylureas, theophylline, warfarin, and nonsteroidal antiinflammatory drugs. In addition, a single study16 reported increased mortality for breast cancer in women treated with paroxetine and tamoxifen.

Numerous possible pharmacodynamic and pharmacokinetic interactions have been described for antipsychotic medications17; nonetheless, data on the negative outcomes possibly associated with such interactions are lacking.

The purpose of this study is to estimate the prevalence of potential drug interactions involving antipsychotic medications and their effect on increasing the risk of death in a population of elderly nursing home residents treated with antipsychotics in 7 European Union (EU) countries and Israel.

METHODS

Data Source

We conducted a retrospective, longitudinal cohort study among elderly nursing home residents with cognitive impairment. The participants were a selected subset of the SHELTER—Services and Health for Elderly in Long TERm care—study population. The SHELTER study was funded by the 7th Framework Programme of the EU.18 The study population consisted of 4,156 nursing home residents in 59 facilities of 7 EU countries (Czech Republic, England, Finland, France, Germany, Italy, The Netherlands) and 1 non-EU country (Israel) participating in the SHELTER study. The SHELTER study was primarily aimed at validating the inter-Resident Assessment Instrument for Long Term Care Facilities (interRAI LTCF), a comprehensive standardized instrument, as a tool to assess the care needs and provision of care to residents of nursing homes in Europe.

• Antipsychotic medications have been associated with an increased risk of death in elderly individuals with dementia. Mechanisms underlying such adverse effects are still unclear.
• Part of the excess risk of death associated with the use of antipsychotic medications may be attributable to antipsychotic drug interactions.
• Antipsychotics should be used with extreme caution especially among elderly individuals receiving cardiovascular or psychotropic medications.

Methodology of the SHELTER study is described in detail elsewhere.18,19 The study was conducted during the years 2009 to 2011. Briefly, older adults residing in participating nursing homes at the beginning of the study and those admitted in the 3-month enrolment period following the initiation of the study were assessed using the interRAI LTCF (baseline assessment) and reassessed at 6 and 12 months (follow-up assessments) if still residing in the facility. If no longer in the facility, reason (death, hospitalization, discharged to home or to another institution) and date of death or discharge were recorded. The only exclusion criteria were age less than 65 years and unwillingness to participate to the study.

Study researchers responsible for data collection were trained following a previously validated procedure.18 Study researchers were ordinary clinical staff, external research staff, or a mixture of both. All data were processed anonymously.

Ethical approval for the study was obtained in all countries according to local regulations. Residents were invited to take part in the study and were free to decline participation. Informed consent was obtained with assurance of data confidentiality.

Antipsychotic Drug Interactions

Data about any drugs residents received in the 3 days prior to the assessment were collected from physician order sheets and drug administration records. Drug information included nonproprietary and proprietary name, Anatomic Therapeutic and Chemical code of the WHO Collaborating Centre for Drug Statistics Methodology,20 formulation, dosage, frequency (number of times per day, week, or month the drug was taken), and route of administration.

For the purpose of the present study, we considered all drug interactions involving antipsychotics that have been described in previous literature. According to the classification proposed by Bleakley,21 interactions were classified based on potential adverse effects into the following categories: pharmacodynamic interactions causing QT prolongation, increased risk of neutropenia or agranulocytosis, increased sedation, increased risk of anticholinergic side effects, decreased blood pressure or falls, increased risk of seizures, increased weight gain or metabolic changes, and pharmacokinetic interactions involving the induction or inhibition of cytochrome P450 1A2, 2D6, and 3A4.17,21-23 Participants were defined as potentially exposed to antipsychotic drug interactions if at least 1 of the described interactions was documented for that person at the baseline assessment.

Mortality

Residents were followed during their stay in nursing homes and all deaths were recorded. Time-to-death was calculated from the date of the baseline assessment to the date of death. The maximum length of follow-up was 12 months. Participants were censored at the time of their death, at discharge from nursing home, or at the end of the follow-up period (12 months).

Potential Confounders

Residents’ sociodemographic characteristics, indicators of functional and cognitive status, comorbid conditions, and concurrent drug use were assessed. The demographic variables included age and sex. The Cognitive Performance Scale24 (CPS) was used to assess cognitive status. The CPS combines information on memory impairment, level of consciousness, and executive function, with scores ranging from 0 (intact) to 6 (very severe impairment). To evaluate functional status, the 7-point Minimum Data Set (MDS) Activities of Daily Living (ADL) Hierarchy scale25 was used. The ADL Hierarchy scale groups ADLs according to the stage of the disablement process in which they occur. The ADL Hierarchy scale ranges from 0 (no impairment) to 6 (total dependence). ADL disability was categorized as follows: assistance required (ADL Hierarchy scale score 2 to 4) and dependence (ADL Hierarchy scale score ≥ 5). The MDS Depression Rating Scale26 was used to assess the presence of depressive symptoms, and a score ≥ 3 indicates a probable diagnosis of depression. Presence of pain in the 3 days prior to assessment was also assessed based on nurse reports and review of medical records. Clinical diagnoses were recorded by study physicians gathering information from the patient, the general practitioner, physical examination, careful review of clinical documentation, and previous medical history.

Study Sample

From the initial sample of 4,156 residents participating in the SHELTER study, those receiving antipsychotic drugs were selected (n = 1,064). To improve homogeneity of the sample with respect to level of cognition and cardiovascular risk profile, residents with schizophrenia (n = 88), those cognitively intact (defined as CPS score of 0 or 1, n = 149), and those with very severe cognitive impairment or in comatose state (defined as CPS score of 6, n = 141) were excluded. Finally, those residents with missing data at follow-up (n = 82) were also excluded. The final analytic sample consisted of 604 residents.

Analytic Approach

Baseline characteristics of participants according to presence of potential antipsychotic drug interactions were compared using analysis-of-variance analyses for normally distributed variables, nonparametric Mann-Whitney U test for skewed variables, and χ2 analyses for dichotomous variables.

Cox proportional hazards regression models were fit to evaluate the effect of antipsychotic drug interactions on time-to-death, adjusting for potential confounders. To exclude departure from proportionality assumption, the log-log survival function was examined. Analyses were adjusted for age, sex, country, severity of cognitive impairment, and variables associated with potential antipsychotic drug interactions at the univariate analysis with P ≤ .10 (number of drugs, ischemic heart disease, heart failure, and total number of diseases). The impact of antipsychotic drug interactions on survival was also tested comparing the survival curves obtained with the Kaplan-Meier method. All analyses were conducted using PASW Statistics for Windows, Version 18.0 (SPSS Inc, Chicago, Illinois, released 2009).

RESULTS

Mean ± SD age of the 604 residents was 82.9 ± 8.8 years, and 433 (71.7%) were women. Of the total sample, antipsychotic drug interactions were observed in 278 residents (46.0%). Among these, 248 residents (89%) presented 1 interaction and 30 residents (11%) presented 2 or more interactions.

Characteristics of the study sample according to presence of potential antipsychotic drug interactions are summarized in Table 1. Compared to the remaining sample, residents in the antipsychotic drug-interaction group were more frequently women, received a higher number of drugs, and presented a higher number of coexisting diseases. In particular, prevalence of ischemic heart disease and heart failure was highest in the antipsychotic drug-interaction group.

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Table 2 presents most common interactions and their potential adverse effects. Interactions causing decreased blood pressure and falls were the most common (n = 210; 34.8% of study sample), followed by those causing QT prolongation (n = 44; 7.3%), sedation (n = 43; 7.1%), and inhibition of cytochrome P450 (n = 9; 1.5%). Most patients with a potential antipsychotic drug interaction at the baseline assessment were still taking interacting drugs at the 6-month assessment (64.5%) and at the 12-month assessment (61.1%).

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Overall, 108 residents (17.9%) died during the 12-month follow-up period. The median follow-up time was 11.4 months in both groups. As shown in Table 3, antipsychotic drug interactions were associated with higher mortality: 59/278 (incidence rate [IR] = 0.26 per person-year) in the antipsychotic drug-interaction group and 49/326 residents in the no antipsychotic drug-interaction group (IR = 0.17 per person year) died during follow-up. After adjusting for potential confounders (including age, sex, country, severity of cognitive impairment, number of drugs, number of diseases, ischemic heart disease, and heart failure), risk of death was higher in the group of residents with potential antipsychotic drug interactions relative to those unexposed to such interactions (hazard ratio [HR] = 1.71; 95% CI, 1.15-2.54). The observed excess risk of death was found to increase with the number of interactions (1 interaction: HR = 1.68 [95% CI, 1.15-2.53]; ≥ 2 interactions: HR = 1.96 [95% CI, 0.90-4.25]).

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Figure 1 shows the survival curves according to potential antipsychotic drug interactions. A significant increase in mortality among residents potentially exposed to antipsychotic drug interactions was observed as compared with the unexposed residents (P = .02).

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DISCUSSION

The present study documented that nearly half of the nursing home residents with cognitive impairment treated with antipsychotics were also prescribed at least 1 drug potentially interacting with these agents. According to our findings, among elderly individuals with cognitive impairment in long-term care, those potentially exposed to antipsychotic drug interactions had a nearly 70% increased risk of death compared to those receiving antipsychotics without potentially interacting concomitant medications.

To our knowledge, the current study is the first study investigating the risk of death associated with antipsychotic drug interaction in a cognitively impaired elderly population.

In April 2005, the US Food and Drug Administration (FDA) issued a black-box warning based on the reanalysis of 17 randomized controlled trials that showed a nearly 1.7 times increased risk of all-cause death associated with the use of atypical antipsychotics compared to placebo in elderly individuals with dementia.27 In June 2008, the warning was extended by the FDA to conventional antipsychotics.28 Specifically, the most frequent causes of death documented in those trials included cardiovascular events such as sudden death and heart failure and infections such as pneumonia.27,28 Some of these negative effects might be related to drug interactions often involving antipsychotics. In the current study, we have reported that over 40% of potential adverse effects due to antipsychotic drug interactions were cardiovascular effects including decreased blood pressure and QT prolongation. The concomitant use of antihypertensive medications may contribute to an increased risk of falls and syncope in elderly patients treated with antipsychotics. Similarly, the concomitant treatment with drugs potentially prolonging the QT interval may increase the risk of life-threatening arrhythmias potentially associated with many antipsychotic medications. There is evidence that the excess risk of cardiac arrest, ventricular arrhythmias, and ischemic stroke associated with antipsychotics is highest among those patients with a previous history of cardiac or cerebrovascular disease and being treated with cardiovascular medications.29,30 Finally, it is believed that the anticholinergic and antihistaminergic action of antipsychotics may contribute to increased risk of swallowing disturbances and aspiration pneumonia.10 Concomitant medications with potential anticholinergic effects, such as several common antiparkinsonian drugs and antidepressants, may interact with antipsychotics in determining the onset of such adverse effects.

Different mechanisms of antipsychotic drug interactions have been described.21 Most of the reported antipsychotic drug interactions, including QT prolongation, sedation, decreased blood pressure, and anticholinergic side effects, have a pharmacodynamic mechanism. Among the pharmacokinetic interactions, the most frequently observed are caused by drugs that affect the metabolism of antipsychotics in the liver through the inhibition or induction of the cytochromeP450 family of enzymes. A recent large population-based study31 has shown that relative to healthy controls of similar age, elderly patients newly prescribed with quetiapine, risperidone, or olanzapine have over 70% increased risk of acute loss of kidney function. As the authors suggest, such adverse influence on renal function may actually be the result of other specific adverse effects related to antipsychotics such as acute urinary retention, rhabdomyolysis, pneumonia, acute myocardial infarction, and ventricular arrhythmias. The sudden loss of renal function may have an impact on the pharmacokinetics of concomitant medications ultimately leading to an increase in the risk of medication adverse effects and drug interactions.

This study has several limitations. No data were available before the baseline assessment of participants, and this made it impossible to assess the time of initiation of antipsychotic treatment. Similarly, it was not possible to ascertain for all participants that they were still taking antipsychotics at the time of death or at the end of follow-up since data were not available. No information was collected regarding the specific cause of death. It would have been of interest to estimate the effect of each single potential interaction on the risk of death. However, we could not provide such information because single-interaction groups resulted too small in size to be analyzed separately. Finally, although the role of numerous potential confounders was taken into account in the analysis, residual confounding is always possible. The study was conducted in a population of elderly nursing home residents with cognitive impairment, and findings can not be generalized to other populations.

Adverse drug reactions are an important medical problem accounting for nearly 10% of in-hospital costs and being associated with increased morbidity and mortality.32 The continuous assessment of potential drug-drug interactions and the implementation of tools for the identification of inappropriate drugs, such as the Beers criteria33 and the Screening Tool of Older Person’s Prescriptions (STOPP) criteria,34 might represent a valuable strategy to reduce the risk of adverse drug reactions. Limited data are available on the impact of such a strategy on clinical and economic outcomes, and future research should focus on deprescribing to avoid drug-drug interactions and reduce the prescription of inappropriate drugs.

The findings of this study add a piece of knowledge to the ongoing debate on the safety of antipsychotic medications in the elderly population with cognitive impairment. The possibility of antipsychotic drug interaction should be carefully evaluated especially among those patients receiving concomitant cardiovascular or psychotropic medications.

Submitted: August 5, 2015; accepted March 31, 2016.

Drug names: carbamazepine (Tegretol, Epitol, and others), citalopram (Celexa and others), ciprofloxacin (Cipro and others), chlorpromazine (Thorazine and others), clozapine (Clozaril, FazaClo, and others), digoxin (Lanoxin and others), escitalopram (Lexapro and others), olanzapine (Zyprexa and others), paroxetine (Paxil, Pexeva, and others), phenytoin (Dilantin, Phenytek, and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), sertraline (Zoloft and others), sulfamethoxazole/trimethoprim (Bactrim, Septra, and others), tamoxifen (Soltamox and others), theophylline (Aerolate and others), warfarin (Coumadin, Jantoven, and others), zolpidem (Ambien, Edluar, and others).

Disclosure of off-label usage: The authors have determined that, to the best of their knowledge, chlorpromazine, clozapine, olanzapine, quetiapine, risperidone, haloperidol, tiapride, and thioridazine are not approved by the US Food and Drug Administration (FDA) for the treatment of behavioral and psychological symptoms of dementia, and melperone is not approved by the FDA.

Author contributions: Rosa Liperoti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The manuscript is an honest, accurate, and transparent account of the study being reported; no important aspects of the study have been omitted.

Financial disclosure: The authors have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.

Funding/support: This study was funded by the European Union 7th Framework Programme.

Role of the sponsor: The funding organization had no role in the design or conduct of the study; in the collection, management, analysis or interpretation of the data; or in the preparation, review, or approval of the manuscript.

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