**1. Introduction**

This chapter builds upon findings from retrospective studies described in a previous chapter by Stones, Worobetz, Randle, Marchese, Fossum, Ostrum and Brink [1]. Those studies examine associations between mortality in long-term care home (LTHC) residents in the Canadian province of Ontario and the reported use of psychotropic medications. Regulations in Section 155 of the Canadian province of Ontario's *Long-Term Care Homes Act* of 2007 specifies that the residents of LTCH should be (1) 18+ years of age; (2) insured under the *Health Insurance Act*; (3) in need of 24-hours on-site nursing care, or (4) frequent daily assistance with activities of daily living (ADL), or (5) on-site monitoring or supervision in order to ensure safety and well-being. Alternative terms for LTCH in other dominions and countries include nursing homes and homes for the aged. Such homes contrast with supportive housing and continuing care hospitals that respectively provide lesser or greater levels of health care provision.

The impetus for what became our research program concerns the allegedly harmful effects of antipsychotic medication on mortality and medical conditions that potentially precipitate mortality. Although the research we describe in this chapter relates specifically to the effects of antipsychotics, our overall research program evolved to focus more generally on associations between mortality and the reported usage of any type of psychotropic medication. The latter includes not only antipsychotics but also anxiolytics, analgesics, antidepressants and hypnotics. The primary instrumentation deployed in these studies is the Resident Assessment Instrument 2.0 (RAI 2.0). This tool provides standardized clinical assessment and good data quality [2], with widespread adoption throughout the world. The measure of psychotropic usage on the RAI 2.0 is the number of days of delivery during the week preceding an assessment.

The findings described in the earlier chapter indicate strongest associations with mortality for intermittent usage of 1–6 days per week when compared with no use or daily use. These findings are significant for each type of psychotropic medication in both univariate and multivariate analyses, where the latter attempts to control for potentially confounding effects and interactions. We refer to intermittent prescribing as *pro re nata* (PRN, or 'as needed') prescription in order to be consistent with recent regulatory initiatives to curb hazardous effects associated with 'as needed' prescribing practices [3].

In contrast to augmented mortality with PRN prescribing, our earlier findings indicate lower mortality associated with daily usage of antidepressant and antipsychotic medications when compared to an absence of usage. The findings on daily usage of antipsychotic medication depart from expectations in the existing literature of its hazardous effects on mortality. This finding is also surprising because the database is among the most all-encompassing of any used in previous studies. It includes consensus level, yearly incidence data on all new admissions to all LTCHs in Ontario (i.e., over 20,000 new admissions to over 600 LTCHs during a given year, with each resident followed up for 1-year). The purpose of the research in this chapter is to explore reasons for this discrepancy.

#### **1.1 Caregiving for behavioral and psychological symptoms of dementia**

The context of our research concerns caregiving for residents of long-term care homes with behaviors that generally fall under the rubric of behavioral and psychological symptoms of dementia (BPSD). A consensus conference of the International Psychogeriatric Association in 1976 defined BPSD as "symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia" [4]. These symptoms include physical aggression, loud vocalization, restlessness, agitation, wandering, anxiety, depressive mood, hallucinations, and delusions [5]. Not all residents with dementia exhibit such symptoms, which usually emerge during the middle and later stages of the illness. Previous estimates indicate that BPSD characterizes nearly 40% of residents in Ontario's LTCHs [1].

By far the most frequent treatment for residents of LTCHs is chemical management. Of the five types of psychotropic medication, the main purposes are to alleviate pain and discomfort (i.e., analgesics), depression (i.e., antidepressants), anxiety (i.e., anxiolytics), sleeplessness (i.e., hypnotics) and BPSD (i.e., antipsychotics). The two categories of antipsychotic medication are termed *typical* and *atypical*. The latter were introduced in attempt to intent reduce adverse side-effects associated with the former [6].

The first columns in **Figure 1**, which is adapted from our previous chapter [1], shows more than double the usage of antipsychotic medication for male and female LTCH residents with than without diagnosed dementia. The findings for no other form of psychotropic medication approach this level of discrepancy. Consequently, antipsychotic medication is the most frequently used psychotropic medication

**187**

**relationships**

*Effects of Antipsychotic Medication on Mortality in Long-Term Care Home Residents*

specifically used with demented individuals, which is a conclusion consistent with

*Percentage of PRN or daily use of psychotropic medications for residents with or without diagnosed dementia.*

Concerns arose early in this millennium about adverse effects associated with the use of antipsychotic medications for the management of dementia. Such effects include cardiovascular and cerebrovascular events, cardiac arrythmia, cognitive decline, extrapyramidal symptoms, falls, fractures, pneumonia and elevated mortality [8]. Levels of the preceding for people with antipsychotic prescriptions exceed those among elderly people in general, people with dementia but without antipsychotic prescriptions, and those exhibiting BPSD without antipsychotic

From 2002 onwards, manufacturers of antipsychotic medications issued warnings about health and mortality risks when prescribed for elderly people. In 2005, the USA's Federal Food and Drug Administration required "black box" warnings on packages of atypical antipsychotics, which in 2008 was extended to typical antipsychotics. This warning reads: "WARNING: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death." Health

Recent meta-analysis [10] and scoping reviews [11] draw the following conclusions about mortality and antipsychotic usage in elderly people. The mortality risks are comparable between typical and atypical antipsychotics, and approximately twice that of people without such usage. The risks are comparable between individuals with or without dementia; they increase with dosage, and are highest during with first month(s) of usage. The latter suggests to authors of the scoping review [11] that factors other than antipsychotic medication may contribute to findings of elevated mortality. The authors of the meta-analytic study [10] recommend restric-

The findings discussed in our earlier chapter [1] indicate that, after control for variables that include gender, age, activities of daily living, level of cognition and

authorities in other countries subsequently issued comparable warnings.

**1.2 Methodology of retrospective studies of antipsychotic-mortality** 

tion and de-prescribing of antipsychotics with older people.

*DOI: http://dx.doi.org/10.5772/intechopen.95388*

that reported in previous publications [7].

prescriptions [9].

**Figure 1.**

*Effects of Antipsychotic Medication on Mortality in Long-Term Care Home Residents DOI: http://dx.doi.org/10.5772/intechopen.95388*

#### **Figure 1.**

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

the week preceding an assessment.

chapter is to explore reasons for this discrepancy.

prescribing practices [3].

that potentially precipitate mortality. Although the research we describe in this chapter relates specifically to the effects of antipsychotics, our overall research program evolved to focus more generally on associations between mortality and the reported usage of any type of psychotropic medication. The latter includes not only antipsychotics but also anxiolytics, analgesics, antidepressants and hypnotics. The primary instrumentation deployed in these studies is the Resident Assessment Instrument 2.0 (RAI 2.0). This tool provides standardized clinical assessment and good data quality [2], with widespread adoption throughout the world. The measure of psychotropic usage on the RAI 2.0 is the number of days of delivery during

The findings described in the earlier chapter indicate strongest associations with mortality for intermittent usage of 1–6 days per week when compared with no use or daily use. These findings are significant for each type of psychotropic medication in both univariate and multivariate analyses, where the latter attempts to control for potentially confounding effects and interactions. We refer to intermittent prescribing as *pro re nata* (PRN, or 'as needed') prescription in order to be consistent with recent regulatory initiatives to curb hazardous effects associated with 'as needed'

In contrast to augmented mortality with PRN prescribing, our earlier findings indicate lower mortality associated with daily usage of antidepressant and antipsychotic medications when compared to an absence of usage. The findings on daily usage of antipsychotic medication depart from expectations in the existing literature of its hazardous effects on mortality. This finding is also surprising because the database is among the most all-encompassing of any used in previous studies. It includes consensus level, yearly incidence data on all new admissions to all LTCHs in Ontario (i.e., over 20,000 new admissions to over 600 LTCHs during a given year, with each resident followed up for 1-year). The purpose of the research in this

**1.1 Caregiving for behavioral and psychological symptoms of dementia**

that BPSD characterizes nearly 40% of residents in Ontario's LTCHs [1].

The context of our research concerns caregiving for residents of long-term care homes with behaviors that generally fall under the rubric of behavioral and psychological symptoms of dementia (BPSD). A consensus conference of the International Psychogeriatric Association in 1976 defined BPSD as "symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia" [4]. These symptoms include physical aggression, loud vocalization, restlessness, agitation, wandering, anxiety, depressive mood, hallucinations, and delusions [5]. Not all residents with dementia exhibit such symptoms, which usually emerge during the middle and later stages of the illness. Previous estimates indicate

By far the most frequent treatment for residents of LTCHs is chemical management. Of the five types of psychotropic medication, the main purposes are to alleviate pain and discomfort (i.e., analgesics), depression (i.e., antidepressants), anxiety (i.e., anxiolytics), sleeplessness (i.e., hypnotics) and BPSD (i.e., antipsychotics). The two categories of antipsychotic medication are termed *typical* and *atypical*. The latter were introduced in attempt to intent reduce adverse side-effects associated

The first columns in **Figure 1**, which is adapted from our previous chapter [1], shows more than double the usage of antipsychotic medication for male and female LTCH residents with than without diagnosed dementia. The findings for no other form of psychotropic medication approach this level of discrepancy. Consequently, antipsychotic medication is the most frequently used psychotropic medication

**186**

with the former [6].

*Percentage of PRN or daily use of psychotropic medications for residents with or without diagnosed dementia.*

specifically used with demented individuals, which is a conclusion consistent with that reported in previous publications [7].

Concerns arose early in this millennium about adverse effects associated with the use of antipsychotic medications for the management of dementia. Such effects include cardiovascular and cerebrovascular events, cardiac arrythmia, cognitive decline, extrapyramidal symptoms, falls, fractures, pneumonia and elevated mortality [8]. Levels of the preceding for people with antipsychotic prescriptions exceed those among elderly people in general, people with dementia but without antipsychotic prescriptions, and those exhibiting BPSD without antipsychotic prescriptions [9].

From 2002 onwards, manufacturers of antipsychotic medications issued warnings about health and mortality risks when prescribed for elderly people. In 2005, the USA's Federal Food and Drug Administration required "black box" warnings on packages of atypical antipsychotics, which in 2008 was extended to typical antipsychotics. This warning reads: "WARNING: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death." Health authorities in other countries subsequently issued comparable warnings.

Recent meta-analysis [10] and scoping reviews [11] draw the following conclusions about mortality and antipsychotic usage in elderly people. The mortality risks are comparable between typical and atypical antipsychotics, and approximately twice that of people without such usage. The risks are comparable between individuals with or without dementia; they increase with dosage, and are highest during with first month(s) of usage. The latter suggests to authors of the scoping review [11] that factors other than antipsychotic medication may contribute to findings of elevated mortality. The authors of the meta-analytic study [10] recommend restriction and de-prescribing of antipsychotics with older people.

#### **1.2 Methodology of retrospective studies of antipsychotic-mortality relationships**

The findings discussed in our earlier chapter [1] indicate that, after control for variables that include gender, age, activities of daily living, level of cognition and

mortality risk, mortality was (1) significantly elevated with PRN use for each type of psychotropic medication (2) significantly attenuated with daily use of antipsychotic and antidepressant medications, (3) significantly elevated for combinations of psychotropic medications that include PRN use and (4) significantly attenuated for combinations of psychotropic medications that include their daily use. These findings are consistent with and build upon unpublished thesis research on antipsychotic medication use by Worobetz [12]. Differences and confounds that might relate to discrepancies between our findings and previous reports of excessive mortality associated with antipsychotic medication use include the following.

First, the analyses in our chapter use generalized linear mixed modeling (GLMM) procedures. Such modeling includes a random variable that encompasses clustering of observations within that variable. This structure is appropriate for the analysis of LTCH data, with the individual homes assumed to be a random variable (i.e., the homes are independent and uncorrelated entities). In contrast, observations of residents living within a given home have commonalities because of localized admission practices, treatment preferences that differ in content and/or frequency from those in other homes, the mutual interactions of residents, etc. Traditional regression and survival analyses fail to account for such commonalities, thereby violating assumptions of independence of observations of residents, which adds to correlated error, potentially with adverse implications for the correctness of analytic outcomes. Unfortunately, it appears that the majority of studies of LTCH residents fail to address this problem. The specific form of mixed modeling used in our earlier [1] and present studies is interval censored survival (i.e., a binomial distribution with a complementary log–log link), which is appropriate for analysis of clustered observations, some of which are without a terminal event.

Second, the majority of studies of relationships between antipsychotic medication and mortality report the type and dosage of medication but not the frequency of usage [11]. Although a few studies treat PRN use as an exclusionary criterion [11], it is more likely grouped with daily use in the majority of studies. The implications of such inclusion include augmented mortality beyond that associated with daily use.

Third, our earlier study indicates augmented mortality associated with PRN use of any psychotropic but ameliorated mortality associated with daily use of certain psychotropics (e.g., antidepressants) [1]. Consequently, combinations that include PRN or daily use of other psychotropics have respective implications for increased or decreased mortality levels associated with antipsychotic use.

Fourth, compliance and adherence to medication regimens are problematic among older people with chronic illness [13]. Anyone with work experience in long-term care settings knows that "residents who put pills into their mouths do not necessarily swallow them" [1]. Some residents chose to hide those pills, others throw them away. In effect, such 'hidden' non-compliance transforms daily prescriptions to intermittent usage, potentially with adverse effects on the estimated risk of mortality.

#### **2. The present study**

The motivation that underlies the present research is to explain our earlier finding that daily use of antipsychotic medication ameliorates mortality, which contradicts conclusions reported in the majority of previous studies [9–11]. The research that follows analyzes the same database as our earlier chapter [1] to answer

**189**

**Table 1.**

*final assessment.*

daily use.

**Antipsychotic prescription**

*Effects of Antipsychotic Medication on Mortality in Long-Term Care Home Residents*

questions about the frequencies of concurrent combinations of antipsychotic with other psychotropic usage and their associations with subsequent mortality. As in the earlier study, the target variable is mortality within 90 days following the final RAI 2.0 assessment. The reason for this duration is that successive RAI 2.0 assessments

To simplify the presentation of results, we limit the control variables in analyses of mortality to the *Changes in Health, End-Stage Disease, Signs, and Symptoms Scale* (CHESS), which is an established indicator of mortality risk [14]. Although preliminary analyses also included demographic measures of age, gender and objective scales from the RAI 2.0 that include the Cognitive Performance Scale, the Activities of Daily Living Hierarchy and the Aggressive Behavior Scale (ABS), their inclusion fails to add appreciably to an interpretation of effects associated with the primary predictor variable. The latter is represented in **Table 1** by concurrent combinations

The 1st and 2nd columns in **Table 1** represent combinations of concurrent usage of antipsychotic and other psychotropic medications. The frequencies for antipsychotics include no use, PRN use and daily use. The inclusive frequencies all other types of psychotropic are no use, PRN and daily use, only PRN use and only daily use. The 3rd, 4th, 5th and 6th columns represent possible combinations of antipsychotics with antidepressant, analgesic, anxiolytic or hypnotic medications, respectively. The possible frequencies for each of the latter are no use, PRN use and

The main hypotheses derive from our previous findings that, after control of the major risk factor for mortality, daily use of psychotropic medication ameliorates risk, whereas PRN use exacerbates risk. Consequently, we anticipate that combinations of antipsychotics with the daily use of other psychotropics ameliorate mortality to levels below that associated with absence of psychotropic use. In contrast, we predict augmented mortality associated with combinations of antipsychotic and

None None None None None None None PRN & Daily . . . . None PRN PRN PRN PRN PRN None Daily Daily Daily Daily Daily PRN None None None None None PRN PRN & Daily . . . . PRN PRN PRN PRN PRN PRN PRN Daily Daily Daily Daily Daily Daily None None None None None Daily PRN & Daily . . . . Daily PRN PRN PRN PRN PRN Daily Daily Daily Daily Daily Daily

*Antipsychotic prescription frequencies combined with frequencies for other antipsychotic medications on the* 

**All psychotropics Antidepressant Analgesic Anxiolytic Hypnotic**

*DOI: http://dx.doi.org/10.5772/intechopen.95388*

occur at approximately 90-day intervals.

of antipsychotic use and other psychotropic use.

other psychotropics that involve PRN use.

**Prescriptions for other psychotropics**

#### *Effects of Antipsychotic Medication on Mortality in Long-Term Care Home Residents DOI: http://dx.doi.org/10.5772/intechopen.95388*

questions about the frequencies of concurrent combinations of antipsychotic with other psychotropic usage and their associations with subsequent mortality. As in the earlier study, the target variable is mortality within 90 days following the final RAI 2.0 assessment. The reason for this duration is that successive RAI 2.0 assessments occur at approximately 90-day intervals.

To simplify the presentation of results, we limit the control variables in analyses of mortality to the *Changes in Health, End-Stage Disease, Signs, and Symptoms Scale* (CHESS), which is an established indicator of mortality risk [14]. Although preliminary analyses also included demographic measures of age, gender and objective scales from the RAI 2.0 that include the Cognitive Performance Scale, the Activities of Daily Living Hierarchy and the Aggressive Behavior Scale (ABS), their inclusion fails to add appreciably to an interpretation of effects associated with the primary predictor variable. The latter is represented in **Table 1** by concurrent combinations of antipsychotic use and other psychotropic use.

The 1st and 2nd columns in **Table 1** represent combinations of concurrent usage of antipsychotic and other psychotropic medications. The frequencies for antipsychotics include no use, PRN use and daily use. The inclusive frequencies all other types of psychotropic are no use, PRN and daily use, only PRN use and only daily use. The 3rd, 4th, 5th and 6th columns represent possible combinations of antipsychotics with antidepressant, analgesic, anxiolytic or hypnotic medications, respectively. The possible frequencies for each of the latter are no use, PRN use and daily use.

The main hypotheses derive from our previous findings that, after control of the major risk factor for mortality, daily use of psychotropic medication ameliorates risk, whereas PRN use exacerbates risk. Consequently, we anticipate that combinations of antipsychotics with the daily use of other psychotropics ameliorate mortality to levels below that associated with absence of psychotropic use. In contrast, we predict augmented mortality associated with combinations of antipsychotic and other psychotropics that involve PRN use.


#### **Table 1.**

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

of which are without a terminal event.

mortality risk, mortality was (1) significantly elevated with PRN use for each type of psychotropic medication (2) significantly attenuated with daily use of antipsychotic and antidepressant medications, (3) significantly elevated for combinations of psychotropic medications that include PRN use and (4) significantly attenuated for combinations of psychotropic medications that include their daily use. These findings are consistent with and build upon unpublished thesis research on antipsychotic medication use by Worobetz [12]. Differences and confounds that might relate to discrepancies between our findings and previous reports of excessive mortality associated with antipsychotic medication use include the following. First, the analyses in our chapter use generalized linear mixed modeling (GLMM) procedures. Such modeling includes a random variable that encompasses clustering of observations within that variable. This structure is appropriate for the analysis of LTCH data, with the individual homes assumed to be a random variable (i.e., the homes are independent and uncorrelated entities). In contrast, observations of residents living within a given home have commonalities because of localized admission practices, treatment preferences that differ in content and/or frequency from those in other homes, the mutual interactions of residents, etc. Traditional regression and survival analyses fail to account for such commonalities, thereby violating assumptions of independence of observations of residents, which adds to correlated error, potentially with adverse implications for the correctness of analytic outcomes. Unfortunately, it appears that the majority of studies of LTCH residents fail to address this problem. The specific form of mixed modeling used in our earlier [1] and present studies is interval censored survival (i.e., a binomial distribution with a complementary log–log link), which is appropriate for analysis of clustered observations, some

Second, the majority of studies of relationships between antipsychotic medication and mortality report the type and dosage of medication but not the frequency of usage [11]. Although a few studies treat PRN use as an exclusionary criterion [11], it is more likely grouped with daily use in the majority of studies. The implications of such inclusion include augmented mortality beyond that associated with

Third, our earlier study indicates augmented mortality associated with PRN use of any psychotropic but ameliorated mortality associated with daily use of certain psychotropics (e.g., antidepressants) [1]. Consequently, combinations that include PRN or daily use of other psychotropics have respective implications for increased

Fourth, compliance and adherence to medication regimens are problematic among older people with chronic illness [13]. Anyone with work experience in long-term care settings knows that "residents who put pills into their mouths do not necessarily swallow them" [1]. Some residents chose to hide those pills, others throw them away. In effect, such 'hidden' non-compliance transforms daily prescriptions to intermittent usage, potentially with adverse effects on the estimated

The motivation that underlies the present research is to explain our earlier finding that daily use of antipsychotic medication ameliorates mortality, which contradicts conclusions reported in the majority of previous studies [9–11]. The research that follows analyzes the same database as our earlier chapter [1] to answer

or decreased mortality levels associated with antipsychotic use.

**188**

daily use.

risk of mortality.

**2. The present study**

*Antipsychotic prescription frequencies combined with frequencies for other antipsychotic medications on the final assessment.*
