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Relationships Between Medication Levels and Depressive Symptoms in Older Individuals








RELATIONSHIPS BETWEEN MEDICATION LEVELS AND DEPRESSIVE
SYMPTOMS IN OLDER INDIVIDUALS
















By

MOHAN KRISHNAN


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA


2006






























Copyright 2006

by

Mohan Krishnan






























This work is dedicated to all of the people who have blessed me with their love, helped
me find my way, and helped me see the value in the pursuit of wisdom.







ACKNOWLEDGMENTS

I would like to thank Dr. Michael Marsiske, for his guidance, support, and

mentorship throughout this project. I would like to thank all of the members of the

ACTIVE team, who were instrumental in collecting the data used in this project, and all

of the participants who volunteered their time and effort to help us understand the aging

process. I would also like to thank Dr. Peter Lichtenberg and Jean Gash for their support

in developing my understanding of and interest in gerontology.








TABLE OF CONTENTS



A C K N O W LED G M EN TS ........................... ... ..........................................................iv

L IST O F T A B LES ................... ............ ...... ........ ......................... ....................... vii

LIST O F FIG U RES........................................... .................................................viii

A B ST R A C T ...................... ............................................................. .......................... ix

CHAPTER

1 INTRODUCTION .............................. .... ....... .............................................. 1

2 REVIEW OF LITERATURE .................................................4

Depression in Older Individuals ..................................................................4
The Vascular Depression Hypothesis.....................................................5
Vascular Depression Within a Biopsychosocial Model of Depression....................7
Polypharm acy ....................... .......... ......................... ........... ................... 9

3 STATEMENT OF THE PROBLEM............................... ....................................... 13

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
D epressive Sym ptom s....................................................................................... 14
Aim 2. Relationships Between Medication Effects and Dimensions of Depression. 14

4 M E T H O D S ..................... ..................... ... ............ .. ...... .... ... ..... 15

Participants................. ........ ............ .............. ........................ 15
ACTIVE Pilot Study Participants.......................................... 15
Inclusion and Exclusion Criteria.................................................................. 15
M measures .............................................................. .... .. .. ............... ....... ... 16
Interview -Based M measures ........................................................ ................... 16
Self-Report Q questionnaires ...................................................... ................... 16
Procedures ............................................ ... ...................................................... 17
Categorization of Medications .............................. ................... 17
M missing D ata .............................. ..................... ......... ...................... 18
Statistical A analysis ........................................................... ..................... 19





5 RESULTS ................... ..... ........... ...................................... ................. ..20

Demographic Statistics ........................................................................................ 20
Medication Statistics ....................................................................... .................... 20
Correlational Analysis .......................................................................................... 22
Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms..................................................................................... 22
Aim 2. Relationships Between Medication Effects and Dimensions of Depression. 23

6 D ISC U S SIO N ................................................................................... .................... 25

Review of Study Findings.................................................................................... 25
Characterization of the Study Sample ............................................................ 25
Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms................................................................................25
Aim 2. Relationships Between Medication Effects and Dimensions of
Depression ..................... ......... ........................................................... 26
Synthesis of Findings..................................................................................... 26
Implications of Study........................................................................................... 27
Detrimental Polypharmacy for Depression..................................................... 27
Beneficial Effects of Polypharmacy of Cardiovascular Medication for
D expression ......................... ...... .... ........... .. ................... ................. ..... 2 8
Study Limitations ......................... ........ ....... ......... .......................................... 30
C conclusion .................... .... ... ............ .... .... .... .... ......... ................. .. 33

LIST OF REFERENCES........................................................................................... 34

BIOGRAPHICAL SKETCH .......................................................... ............................. 39








LIST OF TABLES


Table page

5-1 Correlations Among Predictor Variables ................................ ....................22

5-2 Regression of Predictor Variables Onto Depression Measures.............................. 23








LIST OF FIGURES


Figure page

1-1 Detrimental and Beneficial Polypharmacy in Depression in Older Individuals........2

5-1 Distribution of Participants' CES-D Total Scores................................................ 21

5-2 Frequency of Occurrence of Different Numbers of Medications Per Participant ... 21








Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Master of Science

RELATIONSHIPS BETWEEN MEDICATION LEVELS AND DEPRESSIVE
SYMPTOMS IN OLDER INDIVIDUALS

By

Mohan Krishnan

May 2006

Chair: Michael Marsiske
Major Department: Clinical and Health Psychology

Polypharmacy, the concurrent usage of multiple medications, is common in older

individuals, who often have many health conditions, and can result in detrimental effects

including increases in depressive symptoms. However, if polypharmacy in a functional

category of medication brings about the successful management of a health concern, such

as cardiovascular disease, which itself has a negative impact on mood, that polypharmacy

may also actually be beneficial in some circumstances. The present study sought to

determine whether overall polypharmacy had the detrimental effect of increasing

depressive symptomatology in older individuals, while polypharmacy in the area of

cardiovascular medication has the beneficial effect of reducing depressive symptoms,

which are hypothesized to have some vascular etiology in many older adults.

Analyses were conducted on data from 165 participants in the ACTIVE Pilot Study

(mean age 74 years, 83% female, 55% African-American). A multiple linear regression

model, controlling for participant demographics, was used to determine the effects of




polypharmacy on depression. As hypothesized, while overall polypharmacy was

associated with increased depressive symptoms, cardiovascular medication was

simultaneously associated with a decrease in depressive symptoms.

The findings are consistent with a model of negative polypharmacy effects,

representing underlying effects of multimorbidity, increased likelihood of adverse drug

reactions, central nervous system dysregulation, or some other process, on depression in

older individuals, with a simultaneous beneficial polypharmacy effect for cardiovascular

medication, through mechanisms such as a reduction in functional impairment due to

cardiovascular disease, or improvement in cerebrovascular functioning.







CHAPTER 1
INTRODUCTION

The purpose of the present study was to explore relationships between medication

levels and self-reported mood in older individuals. Depression, the persistent presence of

symptoms such as sadness or loss of pleasure, is observed at elevated rates in frail older

individuals, and is a major barrier to enjoying later life. It is a topic of major interest to

health care professionals and researchers from many different perspectives. Converging

lines of evidence have indicated that mechanisms related to physical frailty, medical

multimorbidity, and cardiovascular disease processes may underlie the elevated rates of

depression in this population. However, few of these studies have investigated

medication burdens related to these conditions and processes, although medication usage

is a frequent component of the care regimen for older individuals. To the extent that non-

psychological health concerns such as cardiovascular disease may be risk factors for

depression in later life, understanding the potentially beneficial impacts of aggressively

treating these disorders may be crucial in prevention of depression in this population. On

the other hand, if medication regimens, when taken as a whole, have iatrogenic effects,

manifested as increased depressive symptomatology, this would represent an additional

category of potentially modifiable risk factors for elders' mood disorders.

The current investigation is guided by the conceptual model depicted below, in

Figure 1-1, in which polypharmacy may be viewed as composed of both beneficial and

detrimental components, related to aspects that are able to manage medical conditions

aggressively, and elements that contribute to over-medication.
















Specific
medication
Effects
(CNS drugs,
etc)


Figure 1-1. Detrimental and Beneficial Polypharmacy in Depression in Older Individuals

The current investigation sought to expand the body of research on the effects of

multimorbidity and cardiovascular disease on depression in older individuals, by

investigating the role of general medication burden, and of medication management of

cardiovascular disease, on the presence of depressive symptoms in older individuals. It

was hypothesized that elders who take large numbers of medications, overall, would be

likely to show more signs of depression, but that those who receive more cardiovascular

medications, within the context of a polypharmacy regimen, would, in turn, be less likely

to show signs of depression.

These hypotheses have implications for our collective understanding of the

etiologies of depression in older individuals, and the possible relationship between

depressive symptoms and cardiovascular disease. It also has implications for prevention

and treatment of depression in the elderly, stressing the need for screening of depression






















3


in the context of evaluation for cardiovascular disease, and integration of services aimed

at improving psychological and physiological functioning.

In the subsequent chapters, an overview is provided of the existing body of

literature on the causes and progression of depression in older individuals, as well as the

impacts of general medication burden, followed by the aims, design, and results of the

present study. The results will then be analyzed and synthesized, and the limitations of

the present study will be considered. Finally, the contribution of this work to the study of

depression in older individuals will be summarized.







CHAPTER 2
REVIEW OF LITERATURE

Depression in Older Individuals

Improving quality of life for older individuals is a common goal for many health

care professionals (Borowiak & Kostka, 2004; Boyd et al., 2005). While this is broadly

true of health care for all populations, it is particularly important when working with

older individuals, because of the impacts of medical multimorbidity and the onset of

physical frailty (Gijsen et al., 2001; Mitnitski et al., 2002).

In addition to physical frailty and illness, research has also examined mental

illness in late life, with a particular emphasis on depression (Blazer & Hybels, 2005).

Two arguments initially posited that true depression would be rare in later life. One

argument made in favor of this view was that the ability to self-regulate negative affect,

and to selectively interact with the environment in such a way as to maintain affective

balance, were skills that continued to develop over the course of the lifespan, and that

older individuals would be more proficient at these skills, and thereby less susceptible to

depression, than their younger counterparts (see, for instance, Consedine & Magai, 2003).

Another argument was that perceived depression in older individuals is primarily the

result of somatic complaints such as "aches and pains," and does not truly represent the

syndrome of depression (see, for instance, the discussion in Blazer et al., 1998).

However, subsequent research has found that these explanations are not satisfactory in

describing the range of mood experiences of older individuals, that some older

individuals do indeed experience depression as it is traditionally conceived of, and that







this depression is not purely limited to the experience of somatic complaints (Blazer et

al., 1998).

This line of research indicated that the affective characteristics of depression in

older individuals are approximately comparable to depression in younger adult

populations, but studies also indicated vastly different rates of depression in certain sub-

populations of older individuals. This research indicated that, in community samples,

base rates are comparable to community samples of younger adults, but that in clinical

and institutional settings, they are substantially higher, with particularly high rates among

patients being seen for cardiovascular concerns and individuals in long-term care

facilities, which house frail older individuals more likely to have increased medical co-

morbidities (Kramer, 1988; Parmalee, 1989; Rapp, 1988; Taylor et al., 2004). In addition,

studies have indicated that physical and mental complaints are particularly likely to co-

occur in later life. For instance, one study indicated that, among elderly individuals

receiving inpatient treatment for depression (with a mean age of 76.2 years), more than

75% had at least one comorbid general medical condition, and almost half had two or

more, most commonly cardiovascular conditions such as hypertension and atherosclerosis

(Proctor et al., 2003).

The Vascular Depression Hypothesis

This pattern of high rates of depression among clinical populations and older

individuals with high levels of multi-morbidity, particularly in the area of cardiovascular

conditions, inspired the vascular depression hypothesis as an explanation for depression

in later life. This hypothesis stated that this form of depression might be the manifestation

of underlying neuropathology caused by cerebrovascular deficit (Alexopoulos, 1990).

This hypothesis was validated both by neuro-imaging and by postmortem techniques,








which found evidence of white matter pathology in depressed individuals who were

above the age of 60, but not in younger depressed individuals or non-depressed elders

(Krishnan et al., 1997). It was also validated by retrospective analyses of risk, which

found substantially increased rates of the development of depression in individuals who

had histories of risk factors for stroke or heart attack such as high blood pressure or

cholesterol, diabetes mellitus, or a history of smoking (Mast et al., 2004; Oldehinkel et

al., 2003). Krishnan et al. (2005) extended this research by demonstrating that, not only

did cardiovascular risk predict the onset of depression, but that depression was a

prominent indicator of the disease pathway leading to stroke, with individuals who had

similar cardiovascular risk histories much more likely to experience stroke if they first

developed depression than if they did not.

Taken together, this research indicates that, within the population of older

individuals, there may be unique neuropathological factors related to cardiovascular

health that help explain some cases of depression as part of a process which begins with

cardiovascular risk burden, progresses to cerebrovascular deficit, white matter pathology,

and concomitant depression, and eventually leads to an increased risk of stroke. The

exact mechanisms behind this process are not understood. Research has indicated that

patterns of vascularization of cerebral white matter may lead to areas, called "watershed

areas," in which small vessels are responsible for blood provision, that these small

vessels may be more vulnerable to the early effects of reduced vascular performance,

leading to increased vulnerability of specific regions of white matter, and that this process

may be an intermediate step in the development of cerebrovascular deficit that leads to

strokes (Inzitari, 2003; Pantoni & Garcia, 1997).







Vascular Depression Within a Biopsychosocial Model of Depression

The pattern described by research in vascular depression is not likely to underlie

all cases of depression beginning in late life, or to completely explain the prevalence of

late-life depression even within a specific individual. Rather, it must be considered as a

component of a biopsychosocial model of depression. Depression in later life is likely to

be determined by multiple factors, just as it is during other phases of life. One

contribution is likely to be that of stressful life events. Some researchers have proposed

that these have a cumulative burden in increasing the likelihood of depression, leading to

increased risk in older individuals, purely by virtue of a longer life in which to experience

stressful life events (O'Sullivan, 2004). While studies have provided some support for

this hypothesis, and have identified certain stressful life events, such as the loss of a

partner or a grandchild, as being particularly associated with depression in late life, they

have found modest overall increases in depression as a result of these types of life events

(Lindeboom et al., 2002). Another contributing factor is likely to be individual

differences in personality characteristics. Although researchers, as previously implicated,

have theorized that older individuals have better affective regulation, personality

characteristics such as neuroticism appear to play a role throughout the lifespan, and may

contribute to risk for depression (Consedine & Magai, 2003; Blazer & Hybels, 2005).

Finally, there are also likely to be other genetic and biological substrates for depression in

older individuals. One of these factors is likely to be the role of hormonal processes.

Some studies have indicated that estradiol hormone therapy may have beneficial impacts

on depressive symptoms (Dennerstein et al., 1979). Estrogen has also been identified as a

neuroprotective agent, with possible protective capabilities in the damage process

associated with stroke ischemia, although this research has been equivocal (Gibson et al.,








2006; Green & Simpkins, 2000). This suggests that estrogen and related hormones might

not only have independent roles in the development and maintenance of depression, but

may also have roles in the process underlying vascular depression. Other hormones,

including stress hormones, such as cortisol, may also play an important role in depression

throughout the lifespan (Blazer & Hybels, 2005). Another of these factors is likely to be

the contribution of the serotonin transporter gene, and particularly the region of this gene

known as 5-HTTLPR, which has been implicated in the development, maintenance, and

prognosis of depression in late life (Lenze et al., 2005). These factors may also interact to

produce additional risk for depression. For instance, researchers have demonstrated that

individuals homozygous for one version of the 5-HTTLPR allele are at greater risk for

developing depression in the wake of stressful life events than individuals expressing

other genotypes (Wilhelm et al., 2006).

Within this biopsychosocial model, however, vascular etiology appears to play an

important role in understanding depression that is unique to the population of older

individuals. Research in support of the vascular depression hypothesis has many

limitations. It has not yet been able to demonstrate explicitly that white matter deficits are

the cause depression in later life. It also has not been able to fully explain the underlying

neuropsychological basis for mood disturbances given this type of neuropathology. It

should also be noted that, while the vascular depression hypothesis considers a course in

which depression follows sub-acute cardiovascular conditions (e.g. those which may not

be immediately life threatening), there are also bi-directional relationships between

depression in older individuals and acute cardiovascular events. These relationships are

not limited to the context of stroke, as discussed above, but also include elevated rates of








depression in individuals recovering from myocardial infarctions and increased risk for

potentially fatal ventricular arrhythmias in depressed individuals (Ziegelstein, 2001;

Whang et al., 2005).

Nonetheless, this mechanism provides interesting insight into the interactions

among physical health, specifically cardiovascular health, the brain, and mood, and

provides a possible neurobiological basis for some cases of depression in later life.

Polypharmacy

While the research on vascular depression suggests a very specific relationship

between vascular comorbidities and the development of depression, a body of research

has also grown that demonstrates substantially more general correlates between

multimorbidity and cognitive functioning. Many of these effects are studied through the

phenomenon of polypharmacy, wherein elderly individuals are likely to take a large

number of different medications, frequently prescribed and managed by different

physicians and pharmacists, who may not have opportunities to communicate fully with

each other (Kingsbury et al., 2001). Polypharmacy can be measured as simply the total

number of prescription drugs an individual takes.

Rollason & Vogt investigated research in polypharmacy and concluded that 38-

52% of individuals in the US over the age of 65 take more than five different

prescriptions, and that an individual is likely to take 0.4 more prescriptions per decade of

age (2003). Beyond multimorbidity, patient and healthcare provider attitudes were also

cited as potential explanations for this phenomenon. Furthermore, Veehof et al.

investigated longitudinal polypharmacy in older individuals, and found that, particularly

for those individuals for whom the number of medications increased rapidly over time,








clear indications for additional medications, based on changes in disease severity or new

diagnoses, were frequently absent (2000).

While this method of characterizing the medication burden is very simplistic,

researchers have nonetheless been successful in demonstrating that polypharmacy,

measured in this way, is a predictor of a variety of concerns, including an increased

likelihood of falls, delirium, and reduced cognitive performance, and have also

implicated polypharmacy as an independent cause both of general adverse health events

and increased mortality (Field et al., 2001; Flaherty et al., 2000; Hogan, 1997; Klarin et

al., 2005; Mamun et al., 2004; Sloane et al., 2002; Starr et al., 2004; Weiner et al., 1998).

Polypharmacy can be conceptualized as arising from a number of different

mechanisms. The most basic explanation for polypharmacy is that an individual takes

more medications because they have more health conditions. In this model,

multimorbidity is a cause of polypharmacy, and detrimental effects such as those seen

above are not particularly surprising, since these kinds of broadly negative outcomes are

often seen in individuals struggling with multiple serious medical conditions. A second

model that helps to explain adverse events such as those described above is that, as the

medication burden increases, individuals seem to be more likely to receive medications

for multiple conditions from multiple health care practitioners, who are not necessarily in

close communication. In such a situation, the chances of inappropriate prescription

increases, including the initiation of medications that are likely to have adverse impacts,

either due to the frailty of ill older individuals, or through interactions with other

concurrently prescribed medications. A second possible impact of this model is the

prescription of medication for symptoms that are misunderstood because of a lack of








knowledge about existing medications and already diagnosed conditions, leading to

excess medication for which there is no medical indication, which may lead to

unpredictable changes in areas such as neurochemical or endocrine functioning. Indeed,

studies have shown at least preliminary support for both of these models, indicating that

the likelihood of adverse drug events and adverse drug-drug interactions do increase with

polypharmacy in older individuals, and that older individuals who have high medication

burdens are more likely to have one or more medications for which no clear medical

justification is documented (Hogan, 1997; Veehof et al., 2000).

At the same time, since the basis for medication is not only the treatment of

symptoms, but also the amelioration or prevention of serious medical conditions, a third

important model ofpolypharmacy's effects is that increased polypharmacy represents

aggressive treatment of general medical conditions, which should lead to reduced

negative impacts of multimorbidity and may play a beneficial role. Particularly in the

area of cardiovascular disease, many disease processes are often effectively managed in

early phases through aggressive treatment with medication, such as with the use of

angiotensin-converting enzyme inhibitors (ACE Inhibitors) in the case of congestive

heart failure, as well as medication-based management of related risk factors, such as

hypertension (Rich, 2005). Successful medication-based management can be an indicator

of early response, averting the need for hospitalization and more serious interventions,

such as cardiovascular bypass surgeries, with which a greater likelihood of adverse

outcomes and risk are associated.

While some discussion of this hypothesis, sometimes referred to as "beneficial

polypharmacy," has taken place, few studies have demonstrated support for this
























12


hypothesis, although researchers have begun to identify situations in which this model

might apply, such as combination drug therapies of conditions such as psychotic

disorders and, importantly, the treatment of cardiovascular conditions (Cleland et al.,

2000; Kingsbury et al., 2001). In these cases, polypharmacy was seen to be associated

with positive outcomes that were related to the aggressiveness of prevention and

treatment of identified conditions or risk factors.







CHAPTER 3
STATEMENT OF THE PROBLEM

The present study seeks to address these questions by examining relationships

between the number of medications an individual uses, both as a whole, and within

functional categories, and the symptoms of depression in a community sample of healthy

older individuals.

The usage of a community sample is important for a study of this kind. While rates

of clinical depression will tend to be low in healthy community samples, rates of

subsyndromal depression, or the presence of symptoms of depression that do not meet the

full criteria for a diagnosis of Major Depressive Disorder, are substantial (VanItallie,

2005). Although there is some controversy over the measurement or conceptualization of

subsyndromal depression, research has shown that it is a serious concern, both as a risk

factor for Major Depressive Disorder and as a predictor of related negative outcomes

such as perceived disability, increased utilization of medical services, and increased risk

of suicide (Chopra et al., 2005; Johnson et al., 1992). Specifically in the context of older

adults, minimal symptoms of depression, as measured by sub-clinical elevations in self-

report depression inventories, have been found to be strong indicators of adverse events,

such as myocardial infarction (Bush et al., 2001).

Furthermore, given that rates of depression are high in institutional populations of

older individuals, but low in the community, many individuals who are institutionalized

and depressed are likely to have previously been community-dwelling and experiencing

reduced levels of depression. The ability to detect a relationship between cardiovascular









medication regimens and depressive symptomatology prior to the onset of clinically

significant depression might therefore allow researchers to explore the possibility of

preventative measures. This is particularly critical if, as the vascular depression

hypothesis suggests, some cases of depression in late life are the result of organic

neuropathology, which is irreversible.

To begin to address these questions, in the present study, we address the following

three aims.

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

We hypothesize that, when demographics and the use of hormones, antidepressants,

and other central nervous system medications are controlled for, polypharmacy will be

associated with increased depressive symptoms, but that cardiovascular drugs will be

associated with reduced depressive symptoms. We hypothesize that these are

independent, simultaneously observable effects in opposite directions.

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

Since, as discussed above, previous research has implicated somatic complaints due

to physiological conditions as a source of apparent depressive symptomatology, and

warned that somatic complaints may not truly represent depression in the elderly, we

further hypothesize that these effects will exist not only for the somatic dimension of

depression, but also in other dimensions of depression. Stated in another way,

polypharmacy and cardiovascular medication levels will be predictors of not only the

overall level of depressive symptomatology, but also of multiple aspects of depression,

not limited to somatic complaints.







CHAPTER 4
METHODS

Participants

ACTIVE Pilot Study Participants

Data from the Pilot Study of the Advanced Cognitive Training for Independent and

Vital Elderly (ACTIVE) project were analyzed. The ACTIVE study is a randomized

clinical trial of targeted cognitive interventions, attempting to determine if cognitive

training can produce persistent improvements in the cognition of older adults, and if these

improvements lead to benefit in everyday life (Ball, 2002). In preparation for this study, a

smaller, non-longitudinal study was conducted to investigate psychometric properties of

the proposed instruments, to assess the ability to recruit participants to the trial, and to

test the feasibility of using the ACTIVE protocol with diverse populations. This study

was conducted on a community-based sample from six sites in the Northeast, Southeast

and Midwest United States.

Inclusion and Exclusion Criteria

Inclusion criteria for the study consisted of women and men aged at least 65 years

old, who had no functional disabilities at the beginning of the study, and a Mini-Mental

Status Examination (MMSE) score above 23. Individuals were also excluded if they had

a self-reported recent history of stroke, cancer or dementia diagnoses. A total of 168

participants were enrolled in the study.







Measures

Interview-Based Measures

Participants' demographic information and an assessment of their depressive

symptomatology were obtained in a phone-based interview. In addition to age, the

information recorded for each participant included gender, years of education, and race.

In addition, although a detailed checklist of prior health conditions was not available,

participants' cardiovascular risk was estimated by participant self-reported diagnosis of

Diabetes or Heart Disease (0, 1 or 2 total conditions).

During a subsequent in-person interview, a "brown-bag audit" of medication was

performed. This consisted of each participant bringing all medications they were

currently taking at the request of a health care provider (both over-the-counter and

prescription medications) to an interview. Medications provided during the audit were

documented by the interviewers. This method has been shown to be effective in

accurately portraying the medication status of older individuals (Caskie & Willis, 2004).

Medications were recorded by either brand or generic name, along with dosage route, and

frequency (or "as needed" status). All medications were later standardized into

therapeutic classes, as discussed in the Procedures section, below.

Self-Report Questionnaires

Depression was assessed using the Center for Epidemiological Studies Depression

Scale (CES-D(20)), a robust measure of depression that has been validated in adults,

including different age groups and races (Blazer et al., 1998; Wallace & O'Hara, 1992;

Weissman et al., 1977). This scale has a four-factor structure, consisting of Somatic

Complaints (such as sleep disturbance), Depressive Affect (feelings of sadness or

loneliness), Positive Affect (the absence of feelings of happiness or joy), and









Interpersonal Problems (the belief that others are unfriendly or dislike the individual),

and also provides a Total Score that represents overall depressive symptomatology

(Blazer et al., 1998; Roberts, 1980). While the CES-D total score can be compared to a

cut-off score (typically 16) to determine if an individual is clinically depressed, the

majority of individuals in this sample had low levels of depression, and so the actual

score was used instead of a diagnostic classification, a technique that has been used with

this instrument in the past, and has been effective in demonstrating the effects of minimal

symptoms of depression (Wallace & O'Hara, 1992).

Procedures

Categorization of Medications

After collection of medication information by interviewers, the medications were

coded into American Hospital Formulary Service (AHFS) classifications, a functional

classification that is widely used in the health care professions (McEvoy, 1996) by

researchers from the ACTIVE team. This formulary system provides hierarchical

classification of medications into broad functional categories (such as central nervous

system agents), as well as sub-classification into smaller functional categories (such as

anxiolytics), and therefore allows for analysis at multiple functional levels.

The number of drugs each participant took in several categories of interest was

then determined. The first of these categories consisted of medications used in response

to cardiovascular disease, formed from drugs in AHFS groups 20 (blood formation and

coagulation), 24 (cardiovascular drugs) and 40 (Electrolytic, Caloric, and Water

Balance). The numbers of different drugs in the relevant classes were summed to arrive at

this variable. These three functional categories were pooled together because all drugs in







these categories are commonly prescribed for the management of cardiovascular

conditions.

The number of drugs with primary central nervous system impacts (Group 28)

was also determined, in a similar fashion, with one subcategory, antidepressants,

considered separately, since, as previously indicated, drugs in these functional categories

are likely to have impacts on mood. Hormones and synthetic hormones (Group 68) were

also included in the analysis, since they have been implicated to have impacts both on

mood and on cardiovascular functioning.

Finally, the overall level of polypharmacy was computed as the number of

different drugs, irrespective of therapeutic class, for each participant. This variable

included contributions from the specific classes of drugs discussed above.

Missing Data

If a participant had missing data for two or fewer items on the CES-D, mean

scores were used to impute missing data (one participant was dropped for this reason);

participants with more than two items missing were excluded from subsequent analysis,

due to concerns of excessive distortion of the CES-D profile due to imputation of missing

responses from a limited number of available responses. For the computation of the CES-

D Total Score and its two larger subscales (the Somatic Complaints subscale and the

Depressive Affect subscale) missing items from the measure were replaced using mean

substitution. However, the remaining two subscales, Positive Affect and Interpersonal

Items, contain few items from the CES-D, and could be distorted considerably by mean

substitution; as a result, participants with missing values were excluded from analyses

using those two subscales as the dependent variable (relevant numbers of valid

participants are presented along with the results of these analyses). Two participants for

















whom medication data was not available (two participants) were also removed from

subsequent analyses. The final number of participants included in the main analyses was

165.

Statistical Analysis

Demographic statistics were computed, and a linear regression was performed for

the CES-D total score against demographics, cardiovascular risk, the levels of CNS,

antidepressant, hormonal and cardiovascular drugs, and the overall level of

polypharmacy. The predictors were entered in blocks into this regression, with

demographics and risk burden entered first, to control for the overlapping effect of these

variables and the medication variables of interest. Then, specific categories of drugs were

entered in the second block, to determine if these had an impact on mood above and

beyond demographics. Finally, polypharmacy was entered in the third block, to determine

if this had an additional impact that was distinct from the impact of medication in the

functional categories. The regression model was then repeated for each of the four

subscales of the CES-D.







CHAPTER 5
RESULTS

Demographic Statistics

For the 165 participants remaining after removal of individuals due to missing data

concerns, the mean age at the time of the study was 73.7 years (SD = 6.1), and 83% were

female. 55% of participants were African American, while the majority of the remainder

(42%) were European American. The mean education level was 12.1 years (SD = 3.0).

While few individuals in the sample endorsed a sufficient number of CES-D items

to meet the criteria for clinical depression (a total score of at least 16 points; 9% of the

sample endorsed this level of depressive symptomatology), the vast majority (86%) of

participants did endorse at least one symptom of depression. Figure 5-1 summarizes the

distribution of observed CES-D Total Scores, indicating the number of individuals

endorsing a clinically significant severity of depressive symptoms, as well as individuals

endorsing lesser levels of depressive symptoms, divided at arbitrary cut-points (0-4, 5-8,

and 9-15 total points). Most participants (78%) endorsed one or more somatic complaints

(e.g. sleep or appetite disturbances), while fewer (43%) endorsed depressive affect (e.g.

sadness or loneliness), a lack of positive affect (e.g. the absence of happiness or

enjoyment; 46%), or interpersonal symptoms (e.g. perception of others as unfriendly;

12%).

Medication Statistics

The mean number of medications per participant in the sample was 2.9, with 20.6%

of participants taking five or more medications, and only 13.9% reporting no current














18" o


51%


E0-4


M 5-8


9-15


*>16


Figure 5-1. Distribution of Participants' CES-D Total Scores medications.

Figure 5-2 depicts the distribution of overall numbers of medications for

participants.


25%

20%

15%

10%

5%

0%


0 1 2 3 4 5 6

Number of Medications


7 8 9 10


Figure 5-2. Frequency of Occurrence of Different Numbers of Medications Per
Participant








The most frequently endorsed categories of medications included Cardiovascular;

Hormones; Electrolytic, Caloric, and Water Balance; Central Nervous System;

Gastrointestinal; and Blood Formation.

Correlational Analysis

Correlations among the predictor variables are shown in Table 5-1, with

correlations significant at the p < 0.05 level shown in boldface. Notably, an increased

number of cardiovascular conditions from the screening instrument (which does not

necessarily represent all possible cardiovascular conditions) was associated with taking

fewer cardiovascular medications, as well as with fewer hormone medications.

Polypharmacy was significantly associated with a greater number of Cardiovascular,

Central Nervous System, and Hormone drugs.

Table 5-1. Correlations Among Predictor Variables
1 2 3 4 5 6 7 8 9 10 11
1. Age (years) 1.00
2. Gender 0.04 1.00
3. Education -0.19 -0.07 1.00
4. Race = White 0.28 -0.17 0.02 1.00
5. Race = Other 0.05 -0.11 0.09 -0.15 1.00
6. CVRFs 0.00 0.02 0.22 0.10 -0.05 1.00
7. Cardiovascular Drugs -0.02 -0.01 -0.12 -0.09 0.06 -0.53 1.00
8. CNS Drugs 0.00 0.01 -0.24 -0.04 0.02 -0.13 -0.05 1.00
9. Anti-Depressants -0.03 0.08 -0.09 -0.01 -0.03 0.01 -0.01 0.07 1.00
10. Hormones -0.04 -0.01 -0.10 -0.01 -0.01 -0.31 0.12 0.09 0.04 1.00
11. Polypharmacy -0.02 0.04 -0.23 -0.09 0.09 -0.57 0.77 0.35 0.12 0.47 1.00
Note: Correlations significant at the p < 0.05 level are boldfaced. Abbreviations: CVRFs -
Cardiovascular Risk Factors; CNS Drugs Agents acting primarily on the Central Nervous System

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

The linear regression of total CES-D score on the predictor variables is described in

Table 5-2. The overall model was significant (F(11, 153) = 3.270, p < 0.001), and

described 19% of the variance in CES-D score. Of this, 12.7% of unique variance, above

and beyond demographic variables, was described by the discrete drug categories, and an








additional 4.6% of variance was associated with polypharmacy, above and beyond the

individual effects of the drug categories and demographics. An increase in the number of

cardiovascular drugs was associated with a decrease in depressive symptoms (3 = -0.447,

p = 0.007; regression weights reported as standardized unless otherwise noted), as was an

increase in the number of hormonal drugs (3 = -0.237, p = 0.025); an increase in overall

polypharmacy was also separately associated with a substantial increase in depressive

symptomatology (P = 0.610, p = 0.004). No other variables reached significance as

predictors in this model.

Table 5-2. Regression of Predictor Variables Onto Depression Measures

Standardized Regression Coefficients*

CES-D Somatic Depressive Positive Interpersonal
Parameter Total Score Complaints Affect Affect Problems
Age (0=below median) 0.136 0.166 0.072 0.050 0.040
Gender (1=female) 0.024 0.044 0.021 0.001 0.065
Education (years) -0.052 -0.096 0.032 -0.037 -0.071
White race (l=true) -0.047 -0.101 0.040 -0.010 -0.096
Other race (1=true) -0.096 -0.063 -0.119 0.017 -0.056
# of CVRFs -0.149 -0.011 -0.083 -0.273 -0.071
Cardiovascular Drugs -0.477 -0.267 -0.716 0.048 -0.396
Other CNS Drugs 0.008 -0.010 -0.149 0.236 -0.080
Anti-Depressants 0.088 0.154 0.072 -0.023 -0.076
Hormone Therapy Drugs -0.237 -0.162 -0.331 0.000 -0.211
Polypharmacy 0.610 0.503 0.904 -0.225 0.513
Valid n** 165 165 165 154 160
Cumulative R2 0.190 0.187 0.180 0.098 0.078
Model F 3.270 3.191 3.046 1.405 1.133
Model Significance 0.001 0.001 0.001 0.177 0.078
Notes: (*) Regression coefficients result from five separate linear regression models for the total
CES-D score and the four sub-scales. Boldfaced coefficients were significant at the p < 0.05
level. (**) For the four subscales, missing values were not imputed due to the small number of
items on each scale, reducing the number of valid cases. Abbreviations: CVRFs Cardiovascular

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

The results of the regressions for the four subscales of the CES-D are also

presented in Table 5-2, above. The model for the Somatic Complaints subscale was








significant (F(11, 153) = 3.191, p = 0.001), and described 18.7% of the variance in the

subscale. In this model, increasing age was associated significantly, but slightly, with

increased Somatic Complaints (p = 0.166, p = 0.036), as was a larger number of Anti-

Depressant medications (3 = 0.154, p = 0.044), and, more substantially, an increase in

overall polypharmacy (P = 0.503, p = 0.016). The model for the Depressive Affect

subscale was also significant (F(11, 153) = 3.046, p = 0.001), describing 18% of the

variance in Depressive Affect. 11 additional participants were excluded from the

analysis, due to missing responses on this subscale of the CES-D, leading to a total of 154

participants in the analysis. An increased number of cardiovascular drugs was strongly

associated with decreased Depressive Affect ((3 = -0.716, p < 0.001), as was an increased

number of Hormone drugs, albeit at a weaker level (3 = -0.331, p = 0.002). At the same

time, an increase in overall polypharmacy was strongly associated with an increase in

Depressive Affect (p = 0.904, p < 0.001).

The model for Positive Affect, on the other hand, failed to reach significance (F(11,

142) = 1.405, p = 0.177). Five additional participants were excluded from this analysis

due to missing data on this subscale of the CES-D, leading to a total of 160 participants in

this analysis. However, the number of co-morbid cardiovascular conditions was mildly

associated with a reduction in this dimension of depression (3 = -0.273, p = 0.008), and

the number of CNS medications, not including anti-depressants, was mildly associated

with an increase in this dimension of depression (3 = 0.236, p = 0.048). The model for

Interpersonal Problems also failed to reach significance (F(11, 148) = 1.133, p = 0.340),

although overall polypharmacy was moderately associated with increases in this

dimension of depression ((3 = 0.513, p = 0.044).







CHAPTER 6
DISCUSSION

Review of Study Findings

Characterization of the Study Sample

The percentage of clinically depressed individuals (9%) in the present sample

compares favorably with that reported in a racially similar sample by Blazer et al. in

which a rate of clinically significant depression, as assessed by the CES-D, of 9% was

also found for community-dwelling elders above the age of 65 (Blazer et al., 1998). At

the same time, the mean number of medications per participant (2.9) was approximately

comparable to that reported by Veehof et al. (2000) for a similar age cohort in the

Netherlands (2.6 drugs per participant, at study onset, for a population with mean age 73

years), although somewhat lower than that reported for some other studies (Rollason &

Vogt, 2003). Differences between these studies may have been driven by broader

inclusion in some epidemiological studies the ACTIVE study did not include

participants who were community-dwelling, for instance, but functionally impaired.

However, taken as a whole, these findings indicate that the study sample is approximately

comparable, along the dimensions of depressive symptomatology and medication usage,

to other studied samples that are similar in age and/or racial demographics.

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

In the present study, overall polypharmacy was significantly associated with

increased depressive symptoms, as measured by the CES-D Total Score, even when







controlling for demographics, cardiovascular risk, and specific categories of drugs likely

to be related to depressive symptoms. At the same time, independently of the effect of

overall polypharmacy, the use of cardiovascular medications had a unique effect,

associated with reduced depressive symptoms, as measured by the CES-D Total Score,

providing support for the hypothesis that independent and opposing effects of beneficial

and detrimental polypharmacy impacts would be observable in the context of depressive

symptomatology.

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

When the detrimental impact of polypharmacy on depression was considered

within specific dimensions of depression represented in the CES-D, this effect was not

limited to the Somatic Complaints subscale of the CES-D, but was also present in the

Depressive Affect subscale, indicating that this effect existed in the context of the core

mood symptomatology of depression, as opposed to the existing solely as a projection of

somatic complaints due primarily to a general medical condition on the measure of

depression.

When the beneficial impact of cardiovascular medication was considered in the

context of the dimensions of depression, the effect was found to be primarily represented

in the Depressive Affect subscale, again demonstrating a link between the impacts of

medication and the core mood symptoms of depression.

Synthesis of Findings

The pattern of results presented above is consistent with the notion of simultaneous

overall detrimental impact of polypharmacy and beneficial impact of polypharmacy in

the case of cardiovascular medication, for the symptoms of depression, in older

individuals, although it is important to note that causation cannot be inferred either from







this relationship or from the relationship between cardiovascular medication and

increased depressive symptoms, and that overall polypharmacy cannot be made truly

independent of cardiovascular polypharmacy. This model of simultaneous detrimental

and beneficial polypharmacy is consistent with the hypothesized model presented earlier,

in Figure 1-1.

Implications of Study

Detrimental Polypharmacy for Depression

There are a number of possible explanations for the observed detrimental impact of

polypharmacy. Overall polypharmacy might lead to increased dysregulation of

neurotransmitters or endocrine processes, leading to adaptation difficulty. This may

proceed through a generalized route that involves cumulative effects of many drugs in a

non-specific way, particularly the unexpected impacts of drugs that are prescribed for

inappropriate reasons, or it may proceed through the increase in the likelihood of specific

adverse drug-drug interactions (Hogan, 1997; Veehof et al., 2000). Further understanding

of these mechanisms may lead to more effective intervention strategies for older

individuals with co-morbid cardiovascular disease and depressive symptomatology.

It is also possible that the detrimental effect of polypharmacy is mainly an effect of

multimorbidity, and not of the medication itself (i.e. the presence of multiple medications

serves as a proxy for the presence of multiple underlying medical conditions).

Differentiating this alternative explanation from a mechanism rooted in the effects of

polypharmacy on the central nervous system is difficult because no clear method exists

whereby the number and strength of medications can be meaningfully scaled by the

number and severity of the medical disorders that necessitate the medications in the first

place. Moreover, in this study, measurement of health conditions was not adequate to







permit the independent assessment of physical health conditions at the same level of

detail as was achieved in analysis of the available medication data. As previously

indicated, medication prescribed without clear indication is a serious concern within

observed polypharmacy, and partitioning its effect from the effect of additional

medications prescribed with clear indications may be important in understanding the

mechanism of polypharmacy's deleterious effects.

In either event, the suggestion that polypharmacy may carry affective concomitants

in the form of increased symptoms of depression adds to a growing body of literature

supporting the need for interdisciplinary interventions to attempt to reduce polypharmacy

in older individuals, without compromising the efficacy of treatment of the diagnosed

disorders for which they are being treated. Research on the benefits of such interventions

has focused primarily on cost savings, to date (Christensen et al., 2004). However, such

interventions already appear to be able to identify and act on individuals who are likely to

have inappropriately prescribed, unnecessary, or high-risk medication regimens, and may

represent an opportunity to improve the functioning of older individuals that carries with

it minimal risk and may have significant capacity to deliver improvements to quality of

life (Rollason & Vogt, 2003; Trygstad et al., 2005).

Beneficial Effects of Polypharmacy of Cardiovascular Medication for Depression

There are many potential mechanisms to explain the observed beneficial

polypharmacy relationship, in which individuals taking more cardiovascular medications

appear to be less depressed. Cardiovascular medication might be associated with the

prevention of white matter pathology, or may possibly aid compensatory mechanisms

such as increased cerebral blood flow and perfusion. At least one study has demonstrated

improvements in frontal white matter functioning, as a result of successful treatment of








depression in older individuals (in that case, through electro-convulsive therapy),

suggesting that improvements in white matter functioning may be an important pathway

to improvements in depressive mood in late life (Nobuhara et al., 2004).

On the other hand, it is also quite possible that the beneficial polypharmacy

associated with cardiovascular medications observed in the present study could be

explained through improvements in physical health by virtue of successful medical

management of cardiovascular disease. If it is the case that depression in cardiovascular

disease is not a specific neurological effect of the disease process, but is rather a

consequence of physical health impairment, then this depressive effect should be specific

to a level of physical health impairment, and not to a disease category. The present study

did not adequately assess physical health impairment as a potential mediator of drug

effects, although this may well be a fruitful area for future research. Furthermore,

successful treatments should improve depressive symptoms to the extent that they are

successful in treating the underlying disease.

Supporting this viewpoint is research that has demonstrated that depression in

individuals with organ failure requiring transplantation was not associated with the site of

failure (when comparing individuals with heart, lung, and kidney failure), but was

associated with the level of pain experienced (Forzberg et al., 1999). It is important to

note, however, that this research was not performed on older individuals, in whom the

associations among cardiovascular disease, white matter pathology, and depression, is

believed to exist. Another study indicated that individuals whose heart failure was

managed either by transplantation or by medication indicated that medication produced

both better improvements in physical health and a substantial decrement in depressive







symptoms (Evangelista et al., 2005). However, that study was not able to demonstrate

whether physical health management was a mediator of reduced depression in the

medication group. Indeed, it is difficult to isolate the success of treatment in managing

physical health from other benefits that are presumed to occur simultaneously in

individuals who respond to cardiovascular treatment, such as improved cerebrovascular

functioning.

Regardless of the relative power of the above explanations for the beneficial role of

cardiovascular polypharmacy on mood symptoms in this population, the facts that

individuals who received more cardiovascular medications showed fewer symptoms of

depression, and individuals who received fewer cardiovascular medications showed more

symptoms of depression is striking. Is it possible that cardiovascular disease may

continue to be under-treated in this population, and that at least some of those individuals

not receiving this medication might benefit from more aggressive treatment? Some

evidence looking purely at the issue of adequate diagnosis and treatment of

cardiovascular conditions in this population, suggests that this might, indeed, continue to

be the case, due to complicated clinical presentation, the non-specificity of symptoms,

access to care, particularly among impoverished elders, and other issues (Fitzpatrick et

al., 2004; Frasure-Smith et al., 1993; Rich, 2005). Complicating this issue is the fact that

not all individuals who are prescribed treatments for these conditions have the financial

ability to obtain all prescribed medications (Piette et al., 2004).

Study Limitations

There are several limitations to this study. First, the sample was relatively small,

and did not include frail or institutionalized elders. While the latter aspect makes this

study more representative of effects on community-dwelling elders, it also leads to









selecting individuals who are likely to be relatively less depressed and suffering from less

severe cardiovascular pathology. Conclusions about the process of decline within older

individuals that leads from low base rates of depression in the community to elevated

base rates in the institutional population are difficult to draw in the absence of data on

participants from both settings. In addition, since the present analysis is not longitudinal,

it is impossible to make causal inferences. It is not clear whether individuals who are less

depressed are more likely to need or use medication for cardiovascular conditions, for

instance, or whether individuals who use more cardiovascular medications are less likely

to become depressed.

This study utilized a method of operationalizing subsyndromal depression that has

been used with success in the extant literature namely, using scores from a self-report

depression instrument as continuous variables. It was nonetheless successful in finding

significant effects relating relatively low levels of depression and medication levels.

However, the exact relationship between this method and other methods of

conceptualizing depression below the level warranting a formal diagnosis of Major

Depressive Disorder, such as the research criteria proposed in the DSM-IV-TR for Minor

Depressive Disorder, remains unclear. The differences in the way this phenomenon is

defined in different research studies limit the ability of this body of literature, as a whole,

to make broad statements about sub-clinical, subsyndromal, minor, or minimal

depression. Each study, however, presents results that are potentially individually

meaningful, within the context of the definition adopted by the respective researchers, as

the present study also seeks to do.








Because of limitations in assessing existing physical health conditions, and the

longitudinal relationships between diagnoses of these conditions and prescription of

medications, the present study is limited in that an thorough assessment of each

participant's overall physical health and multimorbidity was not possible, and there is no

way to truly differentiate polypharmacy in the sense of aggressive treatment and

polypharmacy in the sense of overmedication. While it is implied here that cardiovascular

medication, with its beneficial impacts, represents the former, and not the latter, it is also

a component of polypharmacy, as measured, and is likely to contain, itself, both types of

polypharmacy.

The present study did not investigate the impacts of specific medicines in detail,

another technique that has provided compelling insight into changes in functioning in

older individuals. Several methods for doing this have been developed. One of these

methods is the investigation of relative risk associated with individual drugs (Dhondt et

al., 2002; Veehof et al., 2000). A second method is the consideration of lists of drugs,

such as the Beers Criteria, that are considered contra-indicated for older individuals in the

majority of cases, based on known anecdotal or empirical evidence of problems

associated with these medications in late life (Aparasu & Mort, 2000; Klarin et al., 2005).

These methods have strengths in their ability to identify specific mechanisms based on

the actions of individual drugs. However, the present method provides a complementary

line of evidence, in that large, significant effects of broad classes of medication suggest

the possibility of more basic mechanisms than those observed in studies of specific drugs.

Such mechanisms are not likely to rely on the site of action or chemistry of a specific,

individual drug, and may operate in parallel to the previously observed effects.














Finally, because this study did not make use of brain imaging techniques, no

conclusive statements can be made about the associations among polypharmacy, state

changes in the brain, and depression.

Conclusion

In spite of these limitations, the present research contributes to the body of

literature surrounding depression in older individuals by emphasizing the importance of

considering medication-based management of chronic health conditions, especially

cardiovascular conditions, within an integrated framework alongside other explanatory

variables in the creation and maintenance of depressive symptoms in older individuals.

This adds to the large body of literature that has demonstrated that elderly individuals

with a history of cardiovascular risk burden are more likely to become depressed, and

that these individuals are then likely to have white matter pathology and are at increased

risk for strokes and for mortality, as well as with research indicating that functional

disability due to chronic health concerns increases the risk of depression in the elderly,

and suggests further investigation of management of the overall medication burden, as

well as preventative and aggressive treatment of cardiovascular conditions, as possible

elements of an overall healthcare program for older individuals that may have the

capacity to prevent or eliminate some cases of depression in this population.








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BIOGRAPHICAL SKETCH

Mohan Krishnan graduated from the University of Michigan with a Bachelor of

Science in engineering physics, in 1997, and a Master of Science in nuclear engineering

and radiological sciences, in 1999. He then spent approximately 5 years working in

various engineering and business roles within the automotive industry. During this time,

he pursued coursework in psychology at Wayne State University, and participated in

research studying the relationship between cardiovascular disease and depression in the

elderly at the Wayne State University Institute of Gerontology. Currently, Mr. Krishnan

is working toward a doctorate in clinical and health psychology, with a specialization in

clinical neuropsychology, at the University of Florida.




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PAGE 1

R E L A T I O N S H I P S B E T W E E N M E D I C A T I O N L E V E L S A N D D E P R E S S I V E S Y M P T O M S I N O L D E R I N D I V I D U A L S B y M O H A N K R I S H N A N A T H E S I S P R E S E N T E D T O T H E G R A D U A T E S C H O O L O F T H E U N I V E R S I T Y O F F L O R I D A I N P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F M A S T E R O F S C I E N C E U N I V E R S I T Y O F F L O R I D A 2006

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C opyr i ght 2006 by M oha n K r i s hna n

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T hi s w or k i s de di c a t e d t o a l l of t he pe opl e w ho ha ve bl e s s e d m e w i t h t he i r l ove he l pe d m e f i nd m y w a y, a nd he l pe d m e s e e t he va l ue i n t h e pur s ui t of w i s dom

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i v A C K N O W L E D G M E N T S I w oul d l i ke t o t ha nk D r M i c ha e l M a r s i s ke f or hi s gui da nc e s uppor t a nd m e nt or s hi p t hr oughout t hi s pr oj e c t I w oul d l i ke t o t ha nk a l l of t he m e m be r s o f t he A C T I V E t e a m w ho w e r e i ns t r um e nt a l i n c ol l e c t i n g t he da t a us e d i n t hi s pr oj e c t a nd a l l of t he pa r t i c i pa nt s w ho vol unt e e r e d t he i r t i m e a nd e f f or t t o he l p us unde r s t a nd t he a gi ng pr oc e s s I w oul d a l s o l i ke t o t ha nk D r P e t e r L i c ht e nbe r g a nd J e a n G a s h f or t he i r s uppor t i n de ve l opi ng m y unde r s t a ndi ng of a nd i nt e r e s t i n ge r ont ol ogy.

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v T A B L E O F C O N T E N T S pa ge A C K N O W L E D G M E N T S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i v L I S T O F T A B L E S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi i L I S T O F F I G U R E S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi i i A B S T R A C T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i x C H A P T E R 1 I N T R O D U C T I O N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 R E V I E W O F L I T E R A T U R E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 D e pr e s s i on i n O l de r I ndi vi dua l s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 T he V a s c ul a r D e pr e s s i on H ypot he s i s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 V a s c ul a r D e pr e s s i on W i t hi n a B i ops yc hos oc i a l M ode l of D e pr e s s i on . . . . . . . . . . . 7 P ol ypha r m a c y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3 S T A T E M E N T O F T H E P R O B L E M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 A i m 1. R e l a t i ons hi ps A m ong P ol ypha r m a c y, C a r di ova s c ul a r M e di c a t i on, a nd D e pr e s s i ve S ym pt om s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 A i m 2. R e l a t i ons hi ps B e t w e e n M e di c a t i on E f f e c t s a nd D i m e ns i ons of D e pr e s s i on 14 4 M E T H O D S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 P a r t i c i pa nt s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 A C T I V E P i l ot S t udy P a r t i c i pa nt s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 I nc l us i on a nd E xc l us i on C r i t e r i a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 M e a s ur e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 I nt e r vi e w B a s e d M e a s ur e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 S e l f R e por t Q ue s t i onna i r e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 P r oc e dur e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 C a t e gor i z a t i on of M e di c a t i ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 M i s s i ng D a t a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 S t a t i s t i c a l A na l ys i s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

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vi 5 R E S U L T S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 D e m ogr a phi c S t a t i s t i c s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 M e di c a t i on S t a t i s t i c s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 C or r e l a t i ona l A na l ys i s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 A i m 1. R e l a t i ons hi ps A m ong P ol ypha r m a c y, C a r di ova s c ul a r M e di c a t i on, a nd D e pr e s s i ve S ym pt om s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 A i m 2. R e l a t i ons hi ps B e t w e e n M e di c a t i on E f f e c t s a nd D i m e ns i ons of D e pr e s s i on 23 6 D I S C U S S I O N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 R e vi e w of S t udy F i ndi ngs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 C ha r a c t e r i z a t i on of t he S t udy S a m p l e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 A i m 1 R e l a t i ons hi ps A m ong P ol ypha r m a c y, C a r di ova s c ul a r M e di c a t i on, a nd D e pr e s s i ve S ym pt om s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 A i m 2. R e l a t i ons hi ps B e t w e e n M e di c a t i on E f f e c t s a nd D i m e ns i ons of D e pr e s s i on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 S ynt he s i s of F i ndi ngs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 I m pl i c a t i ons of S t udy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 D e t r i m e nt a l P ol ypha r m a c y f or D e pr e s s i on . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 B e ne f i c i a l E f f e c t s of P ol ypha r m a c y of C a r di ova s c ul a r M e di c a t i on f or D e pr e s s i on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 S t udy L i m i t a t i ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 C onc l us i on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 L I S T O F R E F E R E N C E S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 B I O G R A P H I C A L S K E T C H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

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vi i L I S T O F T A B L E S T a bl e pa ge 5 1 C or r e l a t i ons A m ong P r e di c t o r V a r i a bl e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5 2 R e gr e s s i on of P r e di c t or V a r i a bl e s O nt o D e pr e s s i on M e a s ur e s . . . . . . . . . . . . . . . 23

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vi i i L I S T O F F I G U R E S F i gur e pa ge 1 1 D e t r i m e nt a l a nd B e ne f i c i a l P ol ypha r m a c y i n D e p r e s s i on i n O l de r I ndi vi dua l s . . . . 2 5 1 D i s t r i but i on of P a r t i c i pa nt s C E S D T ot a l S c or e s . . . . . . . . . . . . . . . . . . . . . . . . 21 5 2 F r e que nc y of O c c ur r e nc e of D i f f e r e nt N um be r s of M e di c a t i ons P e r P a r t i c i pa nt . 21

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i x A bs t r a c t of T he s i s P r e s e nt e d t o t he G r a dua t e S c hool of t he U ni ve r s i t y of F l or i da i n P a r t i a l F u l f i l l m e nt o f t he R e qui r e m e nt s f or t he M a s t e r of S c i e nc e R E L A T I O N S H I P S B E T W E E N M E D I C A T I O N L E V E L S A N D D E P R E S S I V E S Y M P T O M S I N O L D E R I N D I V I D U A L S B y M oha n K r i s hna n M a y 2006 C ha i r : M i c ha e l M a r s i s ke M a j or D e pa r t m e nt : C l i ni c a l a nd H e a l t h P s yc hol og y P ol ypha r m a c y, t he c onc ur r e nt us a ge of m ul t i pl e m e di c a t i ons i s c om m on i n ol de r i ndi vi dua l s w ho o f t e n ha ve m a ny he a l t h c ondi t i on s a nd c a n r e s ul t i n de t r i m e nt a l e f f e c t s i nc l udi ng i nc r e a s e s i n de pr e s s i ve s ym pt om s H ow e ve r i f pol ypha r m a c y i n a f unc t i ona l c a t e gor y of m e di c a t i on br i ngs a bout t he s uc c e s s f ul m a na ge m e nt of a he a l t h c onc e r n, s uc h a s c a r di ova s c ul a r di s e a s e w hi c h i t s e l f ha s a ne ga t i ve i m pa c t on m ood t ha t pol ypha r m a c y m a y a l s o a c t ua l l y be be ne f i c i a l i n s om e c i r c um s t a n c e s T he pr e s e nt s t udy s ought t o de t e r m i ne w he t he r ove r a l l pol ypha r m a c y ha d t he d e t r i m e nt a l e f f e c t of i nc r e a s i ng de pr e s s i ve s ym pt om a t ol ogy i n ol d e r i nd i vi dua l s w hi l e pol ypha r m a c y i n t he a r e a o f c a r di ova s c ul a r m e di c a t i on ha s t he be ne f i c i a l e f f e c t of r e duc i ng de pr e s s i ve s ym pt om s w hi c h a r e hypot he s i z e d t o ha ve s om e va s c ul a r e t i o l ogy i n m a ny ol de r a dul t s A na l ys e s w e r e c onduc t e d on da t a f r om 165 pa r t i c i pa nt s i n t he A C T I V E P i l ot S t udy ( m e a n a ge 74 ye a r s 83% f e m a l e 55% A f r i c a n A m e r i c a n) A m ul t i pl e l i ne a r r e gr e s s i on m ode l c ont r ol l i ng f or pa r t i c i pa nt de m ogr a phi c s w a s us e d t o de t e r m i ne t he e f f e c t s of

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x pol ypha r m a c y on de pr e s s i on. A s hypot he s i z e d, w h i l e ove r a l l pol ypha r m a c y w a s a s s oc i a t e d w i t h i nc r e a s e d de pr e s s i v e s ym pt om s c a r di ova s c ul a r m e di c a t i on w a s s i m ul t a ne ous l y a s s oc i a t e d w i t h a de c r e a s e i n de pr e s s i ve s ym pt om s T he f i ndi ngs a r e c ons i s t e nt w i t h a m ode l of ne ga t i ve pol ypha r m a c y e f f e c t s r e pr e s e nt i ng unde r l yi ng e f f e c t s of m ul t i m or bi d i t y, i nc r e a s e d l i ke l i hood of a dve r s e d r ug r e a c t i ons c e nt r a l ne r vous s ys t e m dys r e gul a t i on, or s om e ot he r p r oc e s s on de pr e s s i on i n ol de r i ndi vi dua l s w i t h a s i m ul t a ne ous be ne f i c i a l p ol ypha r m a c y e f f e c t f or c a r d i ova s c ul a r m e d i c a t i on, t hr ough m e c ha ni s m s s uc h a s a r e duc t i on i n f unc t i o na l i m pa i r m e nt due t o c a r di ova s c ul a r di s e a s e or i m pr ove m e nt i n c e r e br o va s c ul a r f unc t i oni ng.

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1 C H A P T E R 1 I N T R O D U C T I O N T he pur pos e of t he p r e s e nt s t udy w a s t o e xpl or e r e l a t i ons hi ps be t w e e n m e di c a t i on l e ve l s a nd s e l f r e por t e d m ood i n ol de r i nd i vi dua l s D e pr e s s i on, t he pe r s i s t e nt pr e s e nc e of s ym pt om s s uc h a s s a dne s s or l os s of pl e a s ur e i s o bs e r ve d a t e l e va t e d r a t e s i n f r a i l o l de r i ndi vi dua l s a nd i s a m a j or ba r r i e r t o e nj oyi ng l a t e r l i f e I t i s a t o p i c of m a j or i nt e r e s t t o he a l t h c a r e pr of e s s i ona l s a nd r e s e a r c he r s f r om m a ny di f f e r e nt pe r s pe c t i ve s C onve r gi ng l i ne s of e vi de nc e ha ve i ndi c a t e d t ha t m e c ha ni s m s r e l a t e d t o phys i c a l f r a i l t y, m e di c a l m ul t i m or bi di t y a nd c a r di ova s c ul a r di s e a s e pr oc e s s e s m a y u nde r l i e t he e l e va t e d r a t e s of de pr e s s i on i n t hi s popul a t i on. H ow e ve r f e w of t he s e s t udi e s ha ve i nve s t i ga t e d m e di c a t i on bur de ns r e l a t e d t o t he s e c ondi t i ons a nd pr oc e s s e s a l t hough m e di c a t i on us a ge i s a f r e que nt c om pone nt of t he c a r e r e gi m e n f o r ol de r i ndi v i dua l s T o t he e xt e nt t ha t non ps yc hol ogi c a l he a l t h c onc e r ns s uc h a s c a r di ova s c u l a r di s e a s e m a y be r i s k f a c t or s f or de pr e s s i on i n l a t e r l i f e unde r s t a ndi ng t he pot e nt i a l l y be ne f i c i a l i m pa c t s of a ggr e s s i ve l y t r e a t i ng t he s e di s or de r s m a y be c r uc i a l i n pr e ve n t i o n of de p r e s s i on i n t hi s popul a t i on O n t he ot he r ha nd i f m e di c a t i on r e gi m e ns w he n t a ke n a s a w hol e ha ve i a t r oge ni c e f f e c t s m a ni f e s t e d a s i nc r e a s e d de pr e s s i ve s ym pt om a t ol og y, t hi s w oul d r e pr e s e nt a n a ddi t i ona l c a t e gor y of pot e nt i a l l y m odi f i a bl e r i s k f a c t or s f o r e l de r s m ood di s or de r s T he c ur r e nt i nve s t i ga t i on i s gui de d by t he c onc e pt ua l m ode l de pi c t e d be l ow i n F i gur e 1 1 i n w hi c h pol ypha r m a c y m a y be vi e w e d a s c om pos e d of bot h be ne f i c i a l a nd de t r i m e nt a l c om pone nt s r e l a t e d t o a s pe c t s t ha t a r e a bl e t o m a na ge m e di c a l c ondi t i ons a ggr e s s i ve l y, a nd e l e m e nt s t ha t c ont r i but e t o ove r m e di c a t i on.

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2 F i gur e 1 1 D e t r i m e nt a l a nd B e ne f i c i a l P ol ypha r m a c y i n D e pr e s s i on i n O l de r I ndi vi dua l s T he c ur r e nt i nve s t i ga t i on s ought t o e xpa nd t he bod y of r e s e a r c h on t he e f f e c t s of m ul t i m or bi di t y a nd c a r di ova s c ul a r di s e a s e on de pr e s s i on i n ol de r i ndi vi dua l s by i nve s t i ga t i ng t he r ol e o f ge ne r a l m e di c a t i on bur de n a nd o f m e di c a t i on m a na ge m e nt of c a r di ova s c ul a r di s e a s e on t he pr e s e nc e of de pr e s s i ve s ym pt om s i n ol de r i ndi vi dua l s I t w a s hypot he s i z e d t ha t e l de r s w ho t a ke l a r ge nu m b e r s of m e di c a t i ons ove r a l l w oul d be l i ke l y t o s how m o r e s i gns of de pr e s s i on, but t ha t t h os e w ho r e c e i ve m or e c a r di ova s c ul a r m e di c a t i ons w i t hi n t he c ont e xt of a pol ypha r m a c y r e gi m e n, w oul d, i n t u r n, be l e s s l i ke l y t o s how s i gns of de pr e s s i on. T he s e hypot he s e s ha ve i m pl i c a t i ons f or ou r c ol l e c t i ve unde r s t a ndi ng of t he e t i ol ogi e s of de pr e s s i on i n ol de r i ndi vi dua l s a nd t he pos s i bl e r e l a t i ons hi p be t w e e n de pr e s s i ve s ym pt om s a nd c a r di ova s c ul a r di s e a s e I t a l s o ha s i m pl i c a t i ons f or pr e ve nt i on a nd t r e a t m e nt of de pr e s s i on i n t he e l de r l y, s t r e s s i ng t he ne e d f o r s c r e e ni ng o f de pr e s s i on

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3 i n t he c ont e xt o f e va l ua t i on f or c a r di ova s c ul a r di s e a s e a nd i nt e gr a t i on o f s e r vi c e s a i m e d a t i m pr ovi ng ps yc hol ogi c a l a nd phys i ol o gi c a l f unc t i oni ng. I n t he s ubs e que nt c ha pt e r s a n ove r vi e w i s pr ov i de d of t he e xi s t i ng body o f l i t e r a t ur e on t he c a us e s a nd pr ogr e s s i on of de p r e s s i on i n ol de r i ndi vi dua l s a s w e l l a s t he i m pa c t s of ge ne r a l m e di c a t i on bur de n, f ol l ow e d by t he a i m s de s i gn, a nd r e s ul t s of t he pr e s e nt s t udy. T he r e s ul t s w i l l t he n be a na l yz e d a n d s ynt he s i z e d, a nd t he l i m i t a t i ons of t he pr e s e nt s t udy w i l l be c ons i de r e d. F i na l l y, t he c ont r i but i on o f t hi s w o r k t o t he s t udy o f de pr e s s i on i n ol de r i ndi vi dua l s w i l l be s um m a r i z e d.

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4 C H A P T E R 2 R E V I E W O F L I T E R A T U R E D e p r e s s i on i n O l d e r I n d i vi d u al s I m pr ovi ng qua l i t y of l i f e f or ol de r i ndi vi dua l s i s a c om m on goa l f o r m a ny he a l t h c a r e pr of e s s i ona l s ( B or ow i a k & K os t ka 2004; B o yd e t a l 2005 ) W hi l e t hi s i s br oa dl y t r ue of he a l t h c a r e f or a l l popul a t i ons i t i s pa r t i c ul a r l y i m por t a nt w he n w or ki ng w i t h ol de r i ndi vi dua l s be c a us e of t he i m pa c t s o f m e di c a l m ul t i m or bi d i t y a nd t he ons e t of phys i c a l f r a i l t y ( G i j s e n e t a l 2001 ; M i t ni t s ki e t a l 2002) I n a ddi t i on t o phys i c a l f r a i l t y a nd i l l ne s s r e s e a r c h ha s a l s o e xa m i ne d m e nt a l i l l ne s s i n l a t e l i f e w i t h a pa r t i c ul a r e m pha s i s on de pr e s s i on ( B l a z e r & H ybe l s 2005 ) T w o a r gum e nt s i ni t i a l l y pos i t e d t ha t t r ue de pr e s s i on w oul d be r a r e i n l a t e r l i f e O ne a r gum e nt m a de i n f a vor of t hi s vi e w w a s t ha t t h e a bi l i t y t o s e l f r e gul a t e ne ga t i ve a f f e c t a nd t o s e l e c t i ve l y i nt e r a c t w i t h t he e nvi r onm e nt i n s uc h a w a y a s t o m a i nt a i n a f f e c t i ve ba l a nc e w e r e s ki l l s t ha t c ont i nue d t o de ve l op ove r t he c our s e of t he l i f e s pa n, a nd t ha t ol de r i ndi vi dua l s w oul d be m or e pr o f i c i e nt a t t he s e s ki l l s a nd t he r e by l e s s s us c e pt i bl e t o de pr e s s i on, t ha n t he i r younge r c ount e r pa r t s ( s e e f or i ns t a nc e C ons e di ne & M a ga i 2003 ) A not he r a r gum e nt w a s t ha t pe r c e i ve d de pr e s s i on i n ol de r i nd i vi dua l s i s pr i m a r i l y t he r e s ul t of s om a t i c c om pl a i nt s s uc h a s a c he s a nd pa i ns a nd doe s not t r ul y r e pr e s e nt t he s yndr om e of de pr e s s i on ( s e e f or i ns t a nc e t he di s c us s i on i n B l a z e r e t a l 1998 ) H ow e ve r s ubs e que nt r e s e a r c h ha s f ound t ha t t he s e e xpl a na t i ons a r e not s a t i s f a c t or y i n de s c r i bi ng t he r a nge o f m ood e xpe r i e nc e s of ol de r i ndi vi dua l s t ha t s om e ol de r i ndi vi dua l s do i nde e d e xpe r i e nc e de pr e s s i on a s i t i s t r a di t i ona l l y c onc e i ve d of a nd t ha t

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5 t hi s de pr e s s i on i s not pur e l y l i m i t e d t o t he e xpe r i e nc e of s om a t i c c om pl a i nt s ( B l a z e r e t a l 1998 ) T hi s l i ne of r e s e a r c h i ndi c a t e d t ha t t he a f f e c t i ve c h a r a c t e r i s t i c s of de pr e s s i on i n ol de r i ndi vi dua l s a r e a ppr oxi m a t e l y c om pa r a bl e t o de pr e s s i on i n younge r a dul t popul a t i ons but s t udi e s a l s o i ndi c a t e d va s t l y di f f e r e nt r a t e s of de p r e s s i on i n c e r t a i n s ub popul a t i ons of ol de r i ndi vi dua l s T hi s r e s e a r c h i ndi c a t e d t ha t i n c om m uni t y s a m pl e s ba s e r a t e s a r e c om pa r a bl e t o c om m uni t y s a m pl e s of younge r a dul t s but t ha t i n c l i ni c a l a nd i ns t i t ut i ona l s e t t i ngs t he y a r e s ubs t a nt i a l l y hi g he r w i t h pa r t i c ul a r l y hi gh r a t e s a m o ng pa t i e nt s be i ng s e e n f or c a r di ova s c ul a r c onc e r ns a n d i ndi vi dua l s i n l ong t e r m c a r e f a c i l i t i e s w hi c h hous e f r a i l ol de r i ndi vi dua l s m o r e l i ke l y t o ha ve i nc r e a s e d m e di c a l c o m or bi di t i e s ( K r a m e r 1988 ; P a r m a l e e 1989; R a pp, 1988; T a yl or e t a l 2004 ) I n a d di t i on, s t udi e s ha ve i ndi c a t e d t ha t phys i c a l a nd m e nt a l c o m pl a i nt s a r e pa r t i c ul a r l y l i ke l y t o c o oc c ur i n l a t e r l i f e F o r i ns t a nc e one s t udy i ndi c a t e d t ha t a m ong e l de r l y i ndi vi dua l s r e c e i vi ng i npa t i e nt t r e a t m e nt f o r de pr e s s i on ( w i t h a m e a n a ge of 76. 2 ye a r s ) m or e t ha n 75% ha d a t l e a s t one c om or bi d ge ne r a l m e di c a l c o ndi t i on, a nd a l m os t ha l f ha d t w o o r m or e m os t c om m onl y c a r di ova s c ul a r c ondi t i ons s uc h a s hype r t e ns i on a nd a t he r os c l e r os i s ( P r oc t or e t a l 2003) T h e V as c u l ar D e p r e s s i on H yp ot h e s i s T hi s pa t t e r n o f hi gh r a t e s of de pr e s s i on a m ong c l i n i c a l popul a t i ons a nd ol de r i ndi vi dua l s w i t h hi gh l e ve l s of m u l t i m o r bi di t y, pa r t i c ul a r l y i n t he a r e a of c a r d i ova s c ul a r c ondi t i ons i ns pi r e d t he va s c ul a r de pr e s s i on hypot he s i s a s a n e xpl a na t i on f or de pr e s s i on i n l a t e r l i f e T hi s hypot he s i s s t a t e d t ha t t h i s f or m o f de pr e s s i on m i ght be t he m a ni f e s t a t i on of unde r l yi ng ne ur opa t hol ogy c a us e d by c e r e b r ova s c ul a r de f i c i t ( A l e xopoul os 1990) T hi s hypot he s i s w a s va l i da t e d bot h by ne u r o i m a gi ng a nd by pos t m or t e m t e c hni que s

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6 w h i c h f ound e vi de nc e of w hi t e m a t t e r pa t hol ogy i n de pr e s s e d i ndi vi dua l s w ho w e r e a bove t he a ge of 60, but not i n younge r de pr e s s e d i ndi vi dua l s or non de p r e s s e d e l de r s ( K r i s hna n e t a l 1997 ) I t w a s a l s o va l i da t e d by r e t r os pe c t i ve a na l ys e s of r i s k, w hi c h f ou nd s ubs t a nt i a l l y i nc r e a s e d r a t e s of t he de ve l op m e nt of de p r e s s i on i n i ndi vi dua l s w ho ha d hi s t or i e s of r i s k f a c t or s f or s t r oke or he a r t a t t a c k s uc h a s hi gh bl ood p r e s s ur e or c hol e s t e r ol di a be t e s m e l l i t us o r a h i s t or y of s m oki ng ( M a s t e t a l 2004; O l de hi n ke l e t a l 2003 ) K r i s hna n e t a l ( 2005) e xt e nde d t hi s r e s e a r c h by de m ons t r a t i ng t ha t not onl y di d c a r di ova s c ul a r r i s k p r e di c t t he ons e t o f de pr e s s i on, but t ha t de pr e s s i on w a s a pr om i ne nt i ndi c a t or of t he di s e a s e pa t hw a y l e a di ng t o s t r oke w i t h i ndi vi dua l s w ho ha d s i m i l a r c a r di ova s c ul a r r i s k hi s t or i e s m uc h m or e l i k e l y t o e xpe r i e nc e s t r oke i f t he y f i r s t de ve l ope d de pr e s s i on t ha n i f t he y di d not T a ke n t oge t he r t hi s r e s e a r c h i ndi c a t e s t ha t w i t hi n t he popul a t i on of ol de r i ndi vi dua l s t he r e m a y be uni que n e ur opa t hol ogi c a l f a c t or s r e l a t e d t o c a r di ova s c ul a r he a l t h t ha t he l p e xpl a i n s om e c a s e s of de pr e s s i on a s pa r t of a pr oc e s s w hi c h be gi ns w i t h c a r di ova s c ul a r r i s k bur de n, pr ogr e s s e s t o c e r e br ov a s c ul a r de f i c i t w hi t e m a t t e r pa t ho l ogy, a nd c onc om i t a nt de pr e s s i o n, a nd e ve nt ua l l y l e a ds t o a n i nc r e a s e d r i s k of s t r oke T he e xa c t m e c ha ni s m s be hi nd t hi s pr oc e s s a r e not unde r s t ood. R e s e a r c h ha s i ndi c a t e d t ha t pa t t e r ns of va s c ul a r i z a t i on of c e r e br a l w hi t e m a t t e r m a y l e a d t o a r e a s c a l l e d w a t e r s he d a r e a s i n w hi c h s m a l l ve s s e l s a r e r e s pons i bl e f or b l ood pr ovi s i on, t ha t t he s e s m a l l ve s s e l s m a y be m or e vu l ne r a bl e t o t he e a r l y e f f e c t s of r e duc e d va s c ul a r pe r f or m a nc e l e a di ng t o i nc r e a s e d vul ne r a bi l i t y of s pe c i f i c r e gi o ns of w hi t e m a t t e r a nd t ha t t hi s pr oc e s s m a y be a n i nt e r m e di a t e s t e p i n t he de ve l opm e nt of c e r e br ova s c ul a r de f i c i t t ha t l e a ds t o s t r oke s ( I nz i t a r i 2003; P a nt oni & G a r c i a 1997)

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7 V as c u l ar D e p r e s s i on Wi t h i n a B i op s yc h os oc i al M od e l of D e p r e s s i on T he pa t t e r n de s c r i be d by r e s e a r c h i n va s c ul a r de pr e s s i on i s not l i ke l y t o unde r l i e a l l c a s e s of de pr e s s i on be gi nni ng i n l a t e l i f e or t o c om pl e t e l y e xpl a i n t he p r e va l e nc e of l a t e l i f e de pr e s s i on e ve n w i t hi n a s pe c i f i c i ndi vi du a l R a t he r i t m us t be c ons i de r e d a s a c om pone nt of a bi ops yc hos oc i a l m ode l of de pr e s s i on. D e pr e s s i on i n l a t e r l i f e i s l i ke l y t o be de t e r m i ne d by m ul t i pl e f a c t or s j us t a s i t i s du r i ng ot he r pha s e s of l i f e O ne c ont r i but i on i s l i ke l y t o be t ha t o f s t r e s s f ul l i f e e ve nt s S om e r e s e a r c he r s ha ve pr opos e d t ha t t he s e ha ve a c um ul a t i ve bu r de n i n i nc r e a s i ng t he l i ke l i hood of de pr e s s i on, l e a di ng t o i nc r e a s e d r i s k i n ol de r i ndi vi dua l s pur e l y by vi r t ue of a l onge r l i f e i n w hi c h t o e xpe r i e nc e s t r e s s f ul l i f e e ve nt s ( O S ul l i va n, 2004 ) W hi l e s t ud i e s ha ve pr ovi de d s om e s uppor t f or t hi s hypot he s i s a nd ha ve i de nt i f i e d c e r t a i n s t r e s s f u l l i f e e ve nt s s uc h a s t he l os s of a pa r t ne r or a gr a ndc hi l d a s be i ng pa r t i c ul a r l y a s s oc i a t e d w i t h de pr e s s i on i n l a t e l i f e t he y ha ve f ound m ode s t ove r a l l i nc r e a s e s i n de pr e s s i on a s a r e s ul t of t he s e t ype s of l i f e e ve nt s ( L i nde boom e t a l 2002 ) A not he r c ont r i but i ng f a c t or i s l i ke l y t o be i ndi vi dua l di f f e r e nc e s i n pe r s ona l i t y c ha r a c t e r i s t i c s A l t hough r e s e a r c he r s a s pr e vi ous l y i m pl i c a t e d ha ve t he or i z e d t ha t ol de r i ndi vi dua l s ha ve be t t e r a f f e c t i ve r e gul a t i on, pe r s ona l i t y c ha r a c t e r i s t i c s s uc h a s ne ur ot i c i s m a ppe a r t o pl a y a r ol e t h r oughout t he l i f e s pa n, a nd m a y c ont r i but e t o r i s k f o r de pr e s s i on ( C ons e di ne & M a ga i 2003; B l a z e r & H ybe l s 2005) F i na l l y, t he r e a r e a l s o l i ke l y t o be ot he r ge ne t i c a n d bi ol ogi c a l s ubs t r a t e s f or de pr e s s i on i n ol de r i ndi vi dua l s O ne of t he s e f a c t or s i s l i ke l y t o be t he r ol e of ho r m ona l p r oc e s s e s S om e s t udi e s ha ve i ndi c a t e d t ha t e s t r a di ol hor m on e t he r a py m a y ha ve be ne f i c i a l i m pa c t s on de pr e s s i ve s ym pt om s ( D e nne r s t e i n e t a l 1979) E s t r oge n ha s a l s o be e n i de nt i f i e d a s a ne ur opr ot e c t i ve a ge nt w i t h pos s i bl e pr ot e c t i ve c a p a bi l i t i e s i n t he da m a ge p r oc e s s a s s oc i a t e d w i t h s t r oke i s c he m i a a l t hough t hi s r e s e a r c h ha s be e n e qui voc a l ( G i bs on e t a l

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8 2006; G r e e n & S i m pki ns 2000) T hi s s ugge s t s t ha t e s t r oge n a nd r e l a t e d h or m one s m i ght not onl y ha ve i nde pe nde nt r ol e s i n t he de ve l opm e n t a nd m a i nt e na nc e of de pr e s s i on, but m a y a l s o ha ve r ol e s i n t he pr oc e s s unde r l yi ng va s c ul a r de pr e s s i on. O t he r hor m one s i nc l udi ng s t r e s s hor m one s s uc h a s c or t i s ol m a y a l s o pl a y a n i m por t a nt r ol e i n de pr e s s i on t hr oughout t he l i f e s pa n ( B l a z e r & H ybe l s 2005 ) A not he r of t he s e f a c t or s i s l i ke l y t o be t he c ont r i but i on of t he s e r ot oni n t r a ns por t e r ge ne a nd pa r t i c ul a r l y t he r e gi on of t hi s ge ne know n a s 5 H T T L P R w hi c h ha s be e n i m pl i c a t e d i n t he de v e l opm e nt m a i nt e na nc e a nd pr ognos i s of de pr e s s i on i n l a t e l i f e ( L e nz e e t a l 2 005) T he s e f a c t or s m a y a l s o i n t e r a c t t o pr oduc e a ddi t i ona l r i s k f or de pr e s s i on. F o r i ns t a nc e r e s e a r c he r s ha ve de m ons t r a t e d t ha t i ndi vi dua l s hom oz ygous f or one ve r s i on of t he 5 H T T L P R a l l e l e a r e a t gr e a t e r r i s k f or de ve l opi ng de pr e s s i on i n t he w a ke of s t r e s s f ul l i f e e ve nt s t ha n i ndi vi dua l s e xpr e s s i ng ot he r ge not ype s ( W i l he l m e t a l 2006 ) W i t hi n t hi s bi ops yc hos oc i a l m ode l how e ve r va s c ul a r e t i ol ogy a ppe a r s t o pl a y a n i m por t a n t r o l e i n unde r s t a ndi ng de pr e s s i on t ha t i s uni que t o t he popu l a t i on of ol de r i ndi vi dua l s R e s e a r c h i n s uppor t o f t he va s c ul a r de pr e s s i on hypot he s i s ha s m a ny l i m i t a t i ons I t ha s not ye t be e n a bl e t o de m ons t r a t e e xpl i c i t l y t ha t w hi t e m a t t e r de f i c i t s a r e t he c a us e de pr e s s i on i n l a t e r l i f e I t a l s o ha s not be e n a bl e t o f ul l y e xpl a i n t he unde r l yi ng ne ur ops yc hol ogi c a l ba s i s f or m ood di s t ur ba nc e s gi ve n t hi s t ype of ne ur opa t hol ogy I t s houl d a l s o be not e d t ha t w hi l e t he va s c ul a r de pr e s s i on hypot he s i s c ons i de r s a c our s e i n w hi c h de pr e s s i on f ol l ow s s ub a c ut e c a r di ova s c ul a r c ondi t i ons ( e g t h os e w hi c h m a y not be i m m e di a t e l y l i f e t hr e a t e ni ng) t he r e a r e a l s o bi di r e c t i ona l r e l a t i ons hi ps be t w e e n de pr e s s i on i n ol de r i ndi vi dua l s a nd a c ut e c a r di ova s c ul a r e ve nt s T he s e r e l a t i ons hi ps a r e not l i m i t e d t o t he c ont e xt of s t r oke a s di s c us s e d a b ove but a l s o i nc l ude e l e va t e d r a t e s of

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9 de pr e s s i on i n i ndi vi dua l s r e c ove r i ng f r om m yoc a r d i a l i nf a r c t i ons a nd i nc r e a s e d r i s k f o r pot e nt i a l l y f a t a l ve nt r i c ul a r a r r hyt hm i a s i n de pr e s s e d i ndi v i dua l s ( Z i e ge l s t e i n, 2001; W ha ng e t a l 2005) N one t he l e s s t hi s m e c ha ni s m pr ovi de s i nt e r e s t i ng i ns i ght i nt o t he i nt e r a c t i ons a m ong phys i c a l he a l t h, s pe c i f i c a l l y c a r di ova s c ul a r he a l t h, t he b r a i n, a nd m ood a nd pr ovi de s a pos s i bl e ne ur obi ol ogi c a l ba s i s f or s om e c a s e s of de pr e s s i on i n l a t e r l i f e P ol yp h ar m ac y W hi l e t he r e s e a r c h on va s c ul a r de pr e s s i on s ugge s t s a ve r y s pe c i f i c r e l a t i ons hi p be t w e e n va s c ul a r c om or bi di t i e s a nd t he de ve l opm e nt of de p r e s s i on, a body o f r e s e a r c h ha s a l s o gr ow n t ha t de m ons t r a t e s s ubs t a nt i a l l y m or e ge ne r a l c or r e l a t e s be t w e e n m ul t i m or bi di t y a nd c ogni t i ve f unc t i oni ng M a ny o f t he s e e f f e c t s a r e s t udi e d t hr ough t he phe nom e non of pol ypha r m a c y, w he r e i n e l de r l y i n di vi dua l s a r e l i ke l y t o t a ke a l a r ge num be r of di f f e r e nt m e di c a t i ons f r e que nt l y p r e s c r i be d a nd m a na ge d by di f f e r e nt phys i c i a ns a nd pha r m a c i s t s w ho m a y not ha ve op por t uni t i e s t o c om m uni c a t e f ul l y w i t h e a c h ot he r ( K i ngs bur y e t a l 2001 ) P ol ypha r m a c y c a n be m e a s ur e d a s s i m pl y t he t ot a l num be r of pr e s c r i pt i on d r ugs a n i ndi vi dua l t a ke s R ol l a s on & V ogt i nve s t i ga t e d r e s e a r c h i n po l ypha r m a c y a nd c onc l ude d t ha t 38 52% of i ndi vi dua l s i n t he U S ove r t he a ge of 65 t a ke m or e t ha n f i ve di f f e r e nt pr e s c r i pt i ons a nd t ha t a n i ndi vi dua l i s l i ke l y t o t a k e 0. 4 m o r e pr e s c r i pt i ons pe r de c a de of a ge ( 20 03) B e yond m ul t i m o r bi di t y pa t i e nt a nd he a l t hc a r e pr ovi de r a t t i t ude s w e r e a l s o c i t e d a s pot e nt i a l e xpl a na t i ons f or t hi s phe nom e no n. F u r t he r m or e V e e hof e t a l i nve s t i ga t e d l ongi t udi na l pol ypha r m a c y i n ol de r i n di vi dua l s a nd f ound t ha t pa r t i c ul a r l y f or t h os e i ndi v i dua l s f or w hom t he num be r o f m e d i c a t i ons i nc r e a s e d r a pi dl y ove r t i m e

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10 c l e a r i ndi c a t i ons f or a ddi t i ona l m e di c a t i ons ba s e d on c ha nge s i n di s e a s e s e ve r i t y or ne w di a gnos e s w e r e f r e que nt l y a bs e nt ( 2000 ) W hi l e t hi s m e t hod o f c ha r a c t e r i z i ng t he m e di c a t i o n bur de n i s ve r y s i m pl i s t i c r e s e a r c he r s ha ve none t he l e s s be e n s uc c e s s f ul i n de m ons t r a t i ng t ha t pol ypha r m a c y, m e a s ur e d i n t hi s w a y, i s a pr e di c t o r of a va r i e t y of c onc e r ns i nc l udi ng a n i nc r e a s e d l i ke l i hood of f a l l s de l i r i um a nd r e duc e d c ogni t i ve pe r f or m a nc e a nd ha ve a l s o i m pl i c a t e d pol ypha r m a c y a s a n i nde pe nde nt c a us e bot h of ge ne r a l a dve r s e he a l t h e ve nt s a nd i nc r e a s e d m or t a l i t y ( F i e l d e t a l 2001; F l a he r t y e t a l 2000; H oga n, 1997; K l a r i n e t a l 2005 ; M a m un e t a l 2004; S l oa ne e t a l 2002; S t a r r e t a l 2004; W e i ne r e t a l 1998) P ol ypha r m a c y c a n be c onc e pt ua l i z e d a s a r i s i ng f r o m a num be r of di f f e r e nt m e c ha ni s m s T he m os t ba s i c e xpl a na t i on f o r pol yp ha r m a c y i s t ha t a n i ndi vi dua l t a ke s m or e m e di c a t i ons be c a us e t he y ha ve m or e he a l t h c ondi t i ons I n t hi s m ode l m ul t i m or bi di t y i s a c a us e of pol ypha r m a c y, a nd de t r i m e nt a l e f f e c t s s uc h a s t hos e s e e n a bove a r e not pa r t i c ul a r l y s ur p r i s i ng, s i nc e t he s e ki nds of br oa dl y ne ga t i ve out c om e s a r e of t e n s e e n i n i ndi vi dua l s s t r uggl i ng w i t h m ul t i pl e s e r i ous m e di c a l c ondi t i ons A s e c ond m ode l t ha t he l ps t o e xpl a i n a dve r s e e ve nt s s uc h a s t hos e de s c r i be d a bove i s t ha t a s t he m e di c a t i on bur de n i nc r e a s e s i ndi vi dua l s s e e m t o b e m or e l i ke l y t o r e c e i ve m e di c a t i ons f or m ul t i pl e c ondi t i ons f r om m ul t i pl e he a l t h c a r e p r a c t i t i one r s w ho a r e not ne c e s s a r i l y i n c l os e c om m uni c a t i on. I n s uc h a s i t ua t i on, t he c ha n c e s of i na ppr opr i a t e p r e s c r i pt i on i nc r e a s e s i nc l udi ng t he i ni t i a t i on of m e di c a t i ons t h a t a r e l i ke l y t o ha ve a dve r s e i m pa c t s e i t he r due t o t he f r a i l t y o f i l l ol de r i ndi v i dua l s or t hr ough i nt e r a c t i ons w i t h ot he r c onc ur r e nt l y pr e s c r i be d m e di c a t i ons A s e c ond pos s i bl e i m pa c t of t h i s m ode l i s t he pr e s c r i pt i on of m e di c a t i on f o r s ym pt om s t ha t a r e m i s unde r s t ood be c a us e of a l a c k of

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11 know l e dge a bout e xi s t i ng m e di c a t i ons a nd a l r e a dy di a gnos e d c ondi t i ons l e a di ng t o e xc e s s m e di c a t i on f or w hi c h t he r e i s no m e di c a l i n di c a t i on, w hi c h m a y l e a d t o unpr e di c t a bl e c ha nge s i n a r e a s s uc h a s ne ur oc he m i c a l or e ndoc r i ne f unc t i oni ng I nde e d, s t udi e s ha ve s how n a t l e a s t pr e l i m i na r y s uppor t f o r bot h of t he s e m ode l s i nd i c a t i ng t ha t t he l i ke l i hood o f a dve r s e dr ug e ve nt s a nd a dve r s e dr ug dr ug i nt e r a c t i ons do i nc r e a s e w i t h pol ypha r m a c y i n ol de r i ndi vi dua l s a nd t ha t ol de r i ndi vi dua l s w ho ha ve hi gh m e di c a t i on bur de ns a r e m or e l i ke l y t o ha ve one o r m o r e m e di c a t i ons f or w hi c h no c l e a r m e di c a l j us t i f i c a t i on i s doc um e nt e d ( H oga n 1997; V e e hof e t a l 2000) A t t he s a m e t i m e s i nc e t he ba s i s f or m e di c a t i on i s not onl y t he t r e a t m e nt o f s ym pt om s but a l s o t he a m e l i o r a t i on o r p r e ve nt i on of s e r i ous m e di c a l c ondi t i ons a t hi r d i m por t a nt m ode l of pol ypha r m a c y s e f f e c t s i s t ha t i nc r e a s e d pol ypha r m a c y r e pr e s e nt s a ggr e s s i ve t r e a t m e nt of ge ne r a l m e di c a l c ondi t i ons w hi c h s houl d l e a d t o r e duc e d ne ga t i ve i m pa c t s of m ul t i m or bi di t y a nd m a y pl a y a be ne f i c i a l r ol e P a r t i c ul a r l y i n t he a r e a of c a r di ova s c ul a r di s e a s e m a ny di s e a s e pr oc e s s e s a r e of t e n e f f e c t i ve l y m a na ge d i n e a r l y pha s e s t hr ough a ggr e s s i ve t r e a t m e nt w i t h m e di c a t i on, s uc h a s w i t h t he us e of a ngi ot e ns i n c onve r t i ng e nz ym e i nhi bi t or s ( A C E I n hi bi t or s ) i n t he c a s e of c o nge s t i ve he a r t f a i l ur e a s w e l l a s m e di c a t i on ba s e d m a na ge m e nt of r e l a t e d r i s k f a c t or s s uc h a s hype r t e ns i on ( R i c h, 2005 ) S uc c e s s f ul m e di c a t i on ba s e d m a na ge m e nt c a n be a n i ndi c a t or of e a r l y r e s pons e a ve r t i ng t he ne e d f or hos pi t a l i z a t i on a nd m o r e s e r i ous i nt e r ve nt i ons s uc h a s c a r di ova s c ul a r bypa s s s ur ge r i e s w i t h w hi c h a gr e a t e r l i ke l i hood o f a dve r s e out c om e s a nd r i s k a r e a s s oc i a t e d. W hi l e s om e di s c us s i on of t hi s hypot he s i s s om e t i m e s r e f e r r e d t o a s be ne f i c i a l pol ypha r m a c y, ha s t a ke n pl a c e f e w s t udi e s ha ve de m ons t r a t e d s uppor t f or t hi s

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12 hypot he s i s a l t hough r e s e a r c he r s ha ve be gun t o i de nt i f y s i t ua t i ons i n w hi c h t hi s m ode l m i ght a ppl y, s uc h a s c om bi na t i on dr ug t he r a pi e s o f c ondi t i ons s uc h a s ps yc hot i c di s or de r s a nd, i m po r t a nt l y, t he t r e a t m e nt of c a r di o va s c ul a r c ondi t i ons ( C l e l a nd e t a l 2000; K i ngs bur y e t a l 2001) I n t he s e c a s e s pol y pha r m a c y w a s s e e n t o be a s s oc i a t e d w i t h pos i t i ve out c om e s t ha t w e r e r e l a t e d t o t he a gg r e s s i ve ne s s of pr e ve nt i on a nd t r e a t m e nt of i de nt i f i e d c ondi t i ons or r i s k f a c t or s

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13 C H A P T E R 3 S T A T E M E N T O F T H E P R O B L E M T he pr e s e nt s t udy s e e ks t o a ddr e s s t he s e que s t i ons by e xa m i ni ng r e l a t i ons hi ps be t w e e n t he num be r o f m e di c a t i ons a n i ndi v i dua l us e s bot h a s a w hol e a nd w i t hi n f unc t i ona l c a t e gor i e s a nd t he s ym pt om s of de pr e s s i on i n a c om m uni t y s a m pl e o f he a l t hy ol de r i ndi vi dua l s T he us a ge of a c om m uni t y s a m pl e i s i m por t a nt f or a s t udy of t h i s ki nd. W hi l e r a t e s of c l i ni c a l de pr e s s i on w i l l t e nd t o be l ow i n he a l t h y c om m uni t y s a m pl e s r a t e s of s ubs yndr om a l de pr e s s i on, or t he p r e s e nc e of s y m pt om s of de pr e s s i on t ha t do not m e e t t he f ul l c r i t e r i a f o r a di a gnos i s of M a j or D e pr e s s i ve D i s or de r a r e s ubs t a nt i a l ( V a nI t a l l i e 2005) A l t ho ugh t he r e i s s om e c ont r ove r s y ove r t h e m e a s ur e m e nt or c onc e pt ua l i z a t i on of s ubs yndr om a l de pr e s s i on, r e s e a r c h ha s s how n t ha t i t i s a s e r i ous c onc e r n, bot h a s a r i s k f a c t or f o r M a j or D e pr e s s i ve D i s or de r a nd a s a pr e d i c t or of r e l a t e d ne ga t i ve ou t c om e s s uc h a s pe r c e i ve d di s a bi l i t y, i nc r e a s e d ut i l i z a t i on o f m e di c a l s e r vi c e s a nd i nc r e a s e d r i s k of s ui c i de ( C hopr a e t a l 2 005; J ohns on e t a l 199 2) S pe c i f i c a l l y i n t he c ont e xt o f ol de r a dul t s m i ni m a l s ym pt om s o f de pr e s s i on, a s m e a s u r e d by s ub c l i ni c a l e l e va t i ons i n s e l f r e por t de pr e s s i on i nve nt or i e s ha ve be e n f ound t o be s t r ong i ndi c a t or s o f a dve r s e e ve nt s s uc h a s m yoc a r di a l i nf a r c t i on ( B us h e t a l 2001 ) F ur t he r m or e gi ve n t ha t r a t e s o f de pr e s s i on a r e hi g h i n i ns t i t ut i ona l popul a t i ons of ol de r i ndi vi dua l s but l ow i n t he c om m uni t y m a ny i ndi vi dua l s w ho a r e i ns t i t ut i ona l i z e d a nd de pr e s s e d a r e l i ke l y t o ha ve pr e vi ous l y b e e n c om m uni t y dw e l l i ng a nd e xpe r i e nc i ng r e duc e d l e ve l s of de pr e s s i on. T he a bi l i t y t o de t e c t a r e l a t i ons hi p be t w e e n c a r di ova s c ul a r

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14 m e di c a t i on r e gi m e ns a nd de pr e s s i ve s ym pt om a t ol ogy pr i or t o t he ons e t of c l i ni c a l l y s i gni f i c a nt de pr e s s i on m i ght t he r e f o r e a l l o w r e s e a r c he r s t o e xpl or e t he pos s i bi l i t y of pr e ve nt a t i ve m e a s ur e s T hi s i s pa r t i c ul a r l y c r i t i c a l i f a s t he va s c ul a r de pr e s s i on hypot he s i s s ugge s t s s om e c a s e s of de pr e s s i on i n l a t e l i f e a r e t he r e s ul t o f o r ga ni c ne ur opa t hol ogy, w hi c h i s i r r e ve r s i bl e T o be gi n t o a ddr e s s t he s e que s t i ons i n t he pr e s e nt s t udy, w e a ddr e s s t he f ol l ow i ng t hr e e a i m s A i m 1. R e l at i on s h i p s A m on g P ol yp h ar m ac y, C a r d i ovas c u l ar M e d i c at i on an d D e p r e s s i ve S ym p t om s W e hypot he s i z e t ha t w he n de m ogr a phi c s a nd t he us e of hor m one s a nt i de p r e s s a nt s a nd ot he r c e nt r a l ne r vous s ys t e m m e di c a t i ons a r e c ont r ol l e d f o r pol ypha r m a c y w i l l be a s s oc i a t e d w i t h i nc r e a s e d de pr e s s i v e s ym pt om s but t ha t c a r di ova s c ul a r d r ugs w i l l be a s s oc i a t e d w i t h r e duc e d de pr e s s i ve s ym pt om s W e hypot he s i z e t ha t t he s e a r e i nde pe nde nt s i m ul t a ne ous l y obs e r va bl e e f f e c t s i n oppos i t e di r e c t i ons A i m 2. R e l at i on s h i p s B e t w e e n M e d i c a t i on E f f e c t s an d D i m e n s i on s of D e p r e s s i on S i nc e a s di s c us s e d a bove pr e vi ous r e s e a r c h ha s i m pl i c a t e d s om a t i c c om pl a i nt s due t o phys i ol ogi c a l c ondi t i o ns a s a s our c e of a ppa r e nt de pr e s s i ve s ym pt om a t ol ogy, a nd w a r ne d t ha t s om a t i c c om pl a i nt s m a y no t t r ul y r e pr e s e nt de pr e s s i on i n t he e l de r l y, w e f ur t he r hypo t he s i z e t ha t t he s e e f f e c t s w i l l e xi s t not onl y f or t he s om a t i c di m e ns i on o f de pr e s s i on, but a l s o i n o t he r di m e ns i ons of de pr e s s i on. S t a t e d i n a not he r w a y, pol ypha r m a c y a nd c a r di ova s c ul a r m e di c a t i on l e ve l s w i l l be pr e di c t o r s of not onl y t he ove r a l l l e ve l of de pr e s s i ve s ym pt om a t ol ogy, but a l s o of m ul t i pl e a s pe c t s of de pr e s s i on, not l i m i t e d t o s om a t i c c om pl a i nt s

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15 C H A P T E R 4 M E T H O D S P ar t i c i p an t s A C T I V E P i l ot S t u d y P ar t i c i p an t s D a t a f r om t he P i l ot S t udy of t he A dva nc e d C ogni t i ve T r a i ni ng f or I nde pe nde nt a nd V i t a l E l de r l y ( A C T I V E ) pr oj e c t w e r e a na l yz e d. T h e A C T I V E s t udy i s a r a ndom i z e d c l i ni c a l t r i a l o f t a r ge t e d c ogni t i ve i nt e r ve nt i ons a t t e m pt i ng t o de t e r m i ne i f c ogni t i ve t r a i ni ng c a n pr o duc e pe r s i s t e nt i m pr ove m e nt s i n t h e c ogni t i on of ol de r a dul t s a nd i f t he s e i m pr ove m e nt s l e a d t o be ne f i t i n e ve r yda y l i f e ( B a l l 2002) I n p r e pa r a t i on f o r t h i s s t udy, a s m a l l e r non l ongi t udi na l s t udy w a s c onduc t e d t o i nve s t i ga t e ps yc hom e t r i c pr ope r t i e s of t he pr opos e d i ns t r um e nt s t o a s s e s s t he a bi l i t y t o r e c r ui t pa r t i c i pa nt s t o t he t r i a l a nd t o t e s t t he f e a s i bi l i t y of us i ng t he A C T I V E pr ot oc ol w i t h di ve r s e popul a t i ons T hi s s t udy w a s c onduc t e d on a c om m uni t y ba s e d s a m pl e f r o m s i x s i t e s i n t he N o r t he a s t S out he a s t a nd M i dw e s t U ni t e d S t a t e s I n c l u s i on an d E xc l u s i on C r i t e r i a I nc l us i on c r i t e r i a f or t he s t udy c ons i s t e d of w om e n a nd m e n a ge d a t l e a s t 65 ye a r s ol d, w ho ha d no f unc t i o na l di s a bi l i t i e s a t t he be gi n ni ng of t he s t udy, a nd a M i ni M e nt a l S t a t us E xa m i na t i on ( M M S E ) s c or e a bove 23 I ndi vi dua l s w e r e a l s o e xc l ude d i f t he y ha d a s e l f r e por t e d r e c e nt hi s t or y o f s t r oke c a nc e r o r d e m e nt i a di a gnos e s A t ot a l of 168 pa r t i c i pa nt s w e r e e nr ol l e d i n t he s t udy

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16 M e as u r e s I n t e r vi e w B as e d M e as u r e s P a r t i c i pa nt s de m ogr a phi c i n f or m a t i on a nd a n a s s e s s m e nt of t he i r de p r e s s i ve s ym pt om a t ol ogy w e r e obt a i ne d i n a phone ba s e d i nt e r vi e w I n a ddi t i on t o a ge t he i nf or m a t i on r e c or de d f o r e a c h pa r t i c i pa nt i nc l ude d ge nde r ye a r s of e duc a t i on, a nd r a c e I n a ddi t i on a l t hough a de t a i l e d c he c kl i s t of pr i o r h e a l t h c ondi t i ons w a s not a va i l a bl e pa r t i c i pa nt s c a r di ova s c ul a r r i s k w a s e s t i m a t e d by pa r t i c i pa nt s e l f r e por t e d di a gnos i s of D i a be t e s or H e a r t D i s e a s e ( 0, 1 or 2 t ot a l c ondi t i on s ) D ur i ng a s ubs e que nt i n pe r s on i nt e r vi e w a br ow n ba g a udi t of m e di c a t i on w a s pe r f or m e d. T hi s c ons i s t e d of e a c h pa r t i c i pa nt b r i ng i ng a l l m e di c a t i ons t he y w e r e c ur r e nt l y t a ki ng a t t he r e que s t of a he a l t h c a r e p r ov i de r ( bot h ove r t he c ount e r a nd pr e s c r i pt i on m e di c a t i ons ) t o a n i nt e r vi e w M e di c a t i ons pr ovi de d dur i ng t he a udi t w e r e doc um e nt e d by t he i nt e r vi e w e r s T hi s m e t hod ha s be e n s how n t o be e f f e c t i ve i n a c c ur a t e l y por t r a yi ng t he m e di c a t i on s t a t us of ol de r i ndi vi dua l s ( C a s ki e & W i l l i s 2004 ) M e di c a t i ons w e r e r e c or de d by e i t he r br a nd o r ge ne r i c na m e a l ong w i t h dos a ge r out e a nd f r e que nc y ( or a s ne e de d s t a t us ) A l l m e di c a t i ons w e r e l a t e r s t a nda r di z e d i nt o t he r a pe ut i c c l a s s e s a s di s c us s e d i n t he P r oc e dur e s s e c t i on, be l ow S e l f R e p or t Q u e s t i on n ai r e s D e pr e s s i on w a s a s s e s s e d us i ng t he C e nt e r f or E pi d e m i ol ogi c a l S t udi e s D e pr e s s i on S c a l e ( C E S D ( 20) ) a r obus t m e a s ur e of de pr e s s i on t ha t ha s be e n va l i da t e d i n a dul t s i nc l udi ng di f f e r e nt a ge g r oups a nd r a c e s ( B l a z e r e t a l 1998; W a l l a c e & O H a r a 1992; W e i s s m a n e t a l 1977) T hi s s c a l e ha s a f ou r f a c t o r s t r uc t ur e c ons i s t i ng of S om a t i c C om pl a i nt s ( s uc h a s s l e e p di s t ur ba nc e ) D e pr e s s i ve A f f e c t ( f e e l i ngs of s a dne s s or l one l i ne s s ) P os i t i ve A f f e c t ( t he a bs e nc e of f e e l i ng s of ha ppi ne s s or j o y ) a nd

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17 I nt e r pe r s ona l P r obl e m s ( t he be l i e f t ha t o t he r s a r e u nf r i e ndl y o r di s l i ke t he i ndi vi dua l ) a nd a l s o pr ovi de s a T o t a l S c or e t ha t r e pr e s e nt s ove r a l l de pr e s s i ve s ym pt om a t ol ogy ( B l a z e r e t a l 1998; R obe r t s 1980 ) W hi l e t he C E S D t ot a l s c or e c a n be c om pa r e d t o a c ut of f s c or e ( t ypi c a l l y 16 ) t o de t e r m i ne i f a n i ndi v i dua l i s c l i ni c a l l y de pr e s s e d, t he m a j or i t y of i ndi vi dua l s i n t hi s s a m pl e ha d l ow l e ve l s of de pr e s s i on, a nd s o t he a c t ua l s c or e w a s us e d i ns t e a d of a di a gnos t i c c l a s s i f i c a t i on, a t e c hni que t ha t ha s be e n us e d w i t h t hi s i ns t r um e nt i n t he pa s t a nd ha s be e n e f f e c t i ve i n de m ons t r a t i ng t he e f f e c t s of m i ni m a l s ym pt om s of de pr e s s i on ( W a l l a c e & O H a r a 1992 ) P r oc e d u r e s C at e gor i z at i on of M e d i c at i on s A f t e r c ol l e c t i on o f m e di c a t i on i nf or m a t i on by i nt e r v i e w e r s t he m e di c a t i ons w e r e c ode d i nt o A m e r i c a n H os pi t a l F or m ul a r y S e r vi c e ( A H F S ) c l a s s i f i c a t i ons a f unc t i o na l c l a s s i f i c a t i on t ha t i s w i de l y us e d i n t he he a l t h c a r e pr of e s s i ons ( M c E voy, 1996) by r e s e a r c he r s f r om t he A C T I V E t e a m T hi s f o r m ul a r y s ys t e m pr o vi de s hi e r a r c hi c a l c l a s s i f i c a t i on of m e di c a t i ons i nt o b r oa d f unc t i ona l c a t e gor i e s ( s uc h a s c e nt r a l ne r vous s ys t e m a ge nt s ) a s w e l l a s s ub c l a s s i f i c a t i on i nt o s m a l l e r f unc t i ona l c a t e gor i e s ( s uc h a s a nxi ol yt i c s ) a nd t he r e f or e a l l ow s f or a na l ys i s a t m ul t i pl e f unc t i ona l l e ve l s T he num be r of d r ugs e a c h pa r t i c i pa nt t ook i n s e ve r a l c a t e gor i e s of i nt e r e s t w a s t he n de t e r m i ne d. T he f i r s t o f t he s e c a t e gor i e s c ons i s t e d of m e di c a t i ons us e d i n r e s pons e t o c a r di ova s c ul a r di s e a s e f or m e d f r om dr ugs i n A H F S gr oups 20 ( bl ood f or m a t i on a nd c oa gul a t i on) 24 ( c a r di ova s c ul a r dr ugs ) a nd 40 ( E l e c t r ol yt i c C a l or i c a nd W a t e r B a l a nc e ) T he num be r s o f di f f e r e nt dr ugs i n t he r e l e va nt c l a s s e s w e r e s um m e d t o a r r i ve a t t hi s va r i a bl e T he s e t hr e e f unc t i ona l c a t e gor i e s w e r e pool e d t oge t h e r be c a us e a l l d r ugs i n

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18 t he s e c a t e gor i e s a r e c om m onl y pr e s c r i be d f o r t he m a na ge m e nt of c a r di ova s c ul a r c ondi t i ons T he num be r of d r ugs w i t h p r i m a r y c e nt r a l ne r vous s ys t e m i m pa c t s ( G r oup 28 ) w a s a l s o de t e r m i ne d, i n a s i m i l a r f a s hi on, w i t h one s ubc a t e gor y, a nt i de pr e s s a nt s c ons i de r e d s e pa r a t e l y, s i nc e a s pr e vi ous l y i ndi c a t e d, dr ugs i n t he s e f unc t i ona l c a t e gor i e s a r e l i ke l y t o ha ve i m pa c t s on m ood. H or m one s a nd s ynt he t i c hor m one s ( G r oup 68) w e r e a l s o i nc l ude d i n t he a na l ys i s s i nc e t he y ha ve be e n i m pl i c a t e d t o ha ve i m pa c t s bot h on m ood a nd on c a r d i ova s c ul a r f unc t i oni ng. F i na l l y, t he ove r a l l l e ve l of pol ypha r m a c y w a s c o m put e d a s t he num be r of di f f e r e nt d r ugs i r r e s pe c t i ve of t he r a pe ut i c c l a s s f o r e a c h pa r t i c i pa nt T hi s va r i a bl e i nc l ude d c ont r i but i ons f r om t he s pe c i f i c c l a s s e s of dr ugs di s c us s e d a bove M i s s i n g D at a I f a pa r t i c i pa nt ha d m i s s i ng da t a f or t w o o r f e w e r i t e m s on t he C E S D m e a n s c or e s w e r e us e d t o i m put e m i s s i ng da t a ( one pa r t i c i pa nt w a s dr oppe d f or t hi s r e a s on) ; pa r t i c i pa nt s w i t h m or e t ha n t w o i t e m s m i s s i ng w e r e e xc l ude d f r om s ubs e que nt a na l ys i s due t o c onc e r ns of e xc e s s i ve di s t or t i on of t he C E S D pr of i l e due t o i m put a t i on of m i s s i ng r e s pons e s f r om a l i m i t e d num be r o f a va i l a bl e r e s pons e s F or t he c om put a t i on of t he C E S D T ot a l S c or e a nd i t s t w o l a r ge r s ubs c a l e s ( t he S o m a t i c C om pl a i nt s s ubs c a l e a nd t he D e pr e s s i ve A f f e c t s ubs c a l e ) m i s s i ng i t e m s f r om t h e m e a s ur e w e r e r e pl a c e d us i ng m e a n s ubs t i t ut i on. H ow e ve r t he r e m a i ni ng t w o s ubs c a l e s P os i t i ve A f f e c t a nd I n t e r pe r s ona l I t e m s c ont a i n f e w i t e m s f r om t he C E S D a nd c oul d be di s t or t e d c ons i de r a bl y by m e a n s ubs t i t ut i on; a s a r e s ul t pa r t i c i pa nt s w i t h m i s s i ng va l ue s w e r e e xc l ude d f r om a na l ys e s us i ng t hos e t w o s ubs c a l e s a s t he de pe nde nt va r i a bl e ( r e l e va nt num be r s of va l i d pa r t i c i pa nt s a r e pr e s e nt e d a l ong w i t h t he r e s ul t s of t he s e a na l ys e s ) T w o pa r t i c i pa nt s f o r

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19 w hom m e di c a t i on da t a w a s not a va i l a bl e ( t w o pa r t i c i pa nt s ) w e r e a l s o r e m ove d f r om s ubs e que nt a na l ys e s T he f i na l num be r o f pa r t i c i pa nt s i nc l ude d i n t he m a i n a na l ys e s w a s 165. S t at i s t i c al A n al ys i s D e m og r a phi c s t a t i s t i c s w e r e c om put e d, a nd a l i ne a r r e gr e s s i on w a s pe r f o r m e d f o r t he C E S D t ot a l s c or e a ga i ns t de m ogr a phi c s c a r di ova s c ul a r r i s k, t he l e ve l s of C N S a nt i de pr e s s a nt hor m ona l a nd c a r di ova s c ul a r d r ugs a nd t he ove r a l l l e ve l of pol ypha r m a c y. T he pr e di c t or s w e r e e nt e r e d i n bl oc ks i nt o t hi s r e g r e s s i on, w i t h de m ogr a phi c s a nd r i s k bur de n e nt e r e d f i r s t t o c ont r ol f o r t he ove r l a ppi ng e f f e c t of t he s e va r i a bl e s a nd t he m e di c a t i on va r i a bl e s o f i nt e r e s t T he n, s pe c i f i c c a t e gor i e s o f dr ugs w e r e e nt e r e d i n t he s e c ond bl oc k t o de t e r m i ne i f t he s e h a d a n i m pa c t on m ood a bove a nd be yond de m ogr a phi c s F i na l l y pol ypha r m a c y w a s e nt e r e d i n t he t hi r d bl oc k, t o de t e r m i ne i f t hi s ha d a n a ddi t i ona l i m pa c t t ha t w a s di s t i nc t f r om t he i m pa c t of m e di c a t i on i n t he f unc t i ona l c a t e gor i e s T he r e gr e s s i on m ode l w a s t he n r e pe a t e d f or e a c h of t he f ou r s ubs c a l e s of t he C E S D

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20 C H A P T E R 5 R E S U L T S D e m ogr ap h i c S t a t i s t i c s F or t he 165 pa r t i c i pa nt s r e m a i ni ng a f t e r r e m ova l o f i ndi vi dua l s due t o m i s s i ng da t a c onc e r ns t he m e a n a ge a t t he t i m e of t he s t udy w a s 73. 7 ye a r s ( S D = 6 1) a nd 83% w e r e f e m a l e 55% of pa r t i c i pa nt s w e r e A f r i c a n A m e r i c a n, w hi l e t he m a j or i t y of t he r e m a i nde r ( 42% ) w e r e E u r ope a n A m e r i c a n. T he m e a n e duc a t i on l e ve l w a s 12. 1 ye a r s ( S D = 3 0) W hi l e f e w i ndi vi dua l s i n t he s a m pl e e ndor s e d a s uf f i c i e nt num be r of C E S D i t e m s t o m e e t t he c r i t e r i a f or c l i ni c a l de pr e s s i on ( a t o t a l s c or e of a t l e a s t 16 poi nt s ; 9% o f t he s a m pl e e ndor s e d t hi s l e ve l of de p r e s s i ve s ym pt om a t ol ogy) t he va s t m a j or i t y ( 86 % ) o f pa r t i c i pa nt s di d e ndor s e a t l e a s t one s ym pt om of d e pr e s s i on. F i gur e 5 1 s um m a r i z e s t he di s t r i but i on of obs e r ve d C E S D T ot a l S c or e s i ndi c a t i ng t he num be r of i ndi vi dua l s e ndor s i ng a c l i ni c a l l y s i gni f i c a nt s e ve r i t y of de pr e s s i ve s ym pt om s a s w e l l a s i ndi vi dua l s e ndor s i ng l e s s e r l e ve l s o f de pr e s s i ve s ym pt om s di vi de d a t a r bi t r a r y c ut poi nt s ( 0 4, 5 8, a nd 9 15 t ot a l poi nt s ) M os t pa r t i c i pa nt s ( 78 % ) e ndor s e d one or m or e s om a t i c c om pl a i nt s ( e g. s l e e p or a ppe t i t e di s t ur ba nc e s ) w hi l e f e w e r ( 43% ) e ndor s e d de pr e s s i ve a f f e c t ( e g s a dne s s or l one l i ne s s ) a l a c k of pos i t i ve a f f e c t ( e g t he a bs e nc e of ha ppi ne s s or e nj oym e nt ; 46% ) o r i nt e r pe r s ona l s ym pt om s ( e g pe r c e pt i on of ot he r s a s unf r i e ndl y; 12% ) M e d i c at i on S t a t i s t i c s T he m e a n num be r of m e di c a t i ons pe r pa r t i c i pa nt i n t he s a m pl e w a s 2. 9 w i t h 20. 6 % of pa r t i c i pa nt s t a ki ng f i ve o r m o r e m e di c a t i ons a nd onl y 13 9% r e por t i ng no c ur r e nt

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21 F i gur e 5 1 D i s t r i bu t i on o f P a r t i c i pa nt s C E S D T o t a l S c or e s m e di c a t i ons F i gur e 5 2 de pi c t s t he di s t r i bu t i on of ove r a l l num b e r s of m e di c a t i ons f o r pa r t i c i pa nt s F i gur e 5 2 F r e que nc y of O c c ur r e nc e of D i f f e r e nt N um be r s of M e di c a t i ons P e r P a r t i c i pa nt

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22 T he m os t f r e que nt l y e ndor s e d c a t e gor i e s of m e di c a t i ons i nc l ude d C a r di ova s c ul a r ; H or m one s ; E l e c t r ol yt i c C a l or i c a nd W a t e r B a l a nc e ; C e nt r a l N e r vous S ys t e m ; G a s t r oi nt e s t i na l ; a nd B l ood F or m a t i on C or r e l at i on al A n al ys i s C or r e l a t i ons a m ong t he p r e di c t or va r i a bl e s a r e s how n i n T a bl e 5 1 w i t h c or r e l a t i ons s i gni f i c a nt a t t he p < 0. 05 l e ve l s how n i n bol d f a c e N ot a bl y, a n i nc r e a s e d num be r of c a r di ova s c ul a r c ondi t i on s f r om t he s c r e e ni ng i ns t r um e nt ( w hi c h doe s not ne c e s s a r i l y r e pr e s e nt a l l pos s i bl e c a r di ova s c ul a r c o ndi t i ons ) w a s a s s oc i a t e d w i t h t a ki ng f e w e r c a r di ova s c ul a r m e di c a t i ons a s w e l l a s w i t h f e w e r hor m one m e di c a t i ons P ol ypha r m a c y w a s s i gni f i c a nt l y a s s oc i a t e d w i t h a gr e a t e r num be r of C a r di ova s c ul a r C e nt r a l N e r vous S ys t e m a nd H or m one d r ugs T a bl e 5 1 C or r e l a t i ons A m ong P r e di c t or V a r i a bl e s A i m 1. R e l at i on s h i p s A m on g P ol yp h ar m ac y, C a r d i ovas c u l ar M e d i c at i on an d D e p r e s s i ve S ym p t om s T he l i ne a r r e gr e s s i on of t o t a l C E S D s c or e on t he pr e di c t or va r i a bl e s i s de s c r i be d i n T a bl e 5 2 T he ove r a l l m ode l w a s s i gni f i c a nt ( F ( 11 153) = 3 270, p < 0. 001) a nd de s c r i be d 19% of t he va r i a nc e i n C E S D s c or e O f t hi s 12. 7 % of uni que va r i a nc e a bove a nd be yond de m ogr a phi c va r i a bl e s w a s de s c r i be d by t he di s c r e t e dr ug c a t e gor i e s a nd a n

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23 a ddi t i ona l 4. 6% of va r i a nc e w a s a s s oc i a t e d w i t h pol ypha r m a c y, a bove a nd be yond t he i ndi vi dua l e f f e c t s of t he d r ug c a t e gor i e s a nd de m o gr a phi c s A n i nc r e a s e i n t he num be r of c a r di ova s c ul a r dr ugs w a s a s s oc i a t e d w i t h a de c r e a s e i n de pr e s s i ve s ym pt om s ( = 0 447, p = 0. 007; r e gr e s s i on w e i ght s r e por t e d a s s t a nda r di z e d unl e s s ot he r w i s e not e d) a s w a s a n i nc r e a s e i n t he num be r of ho r m ona l d r ugs ( = 0. 237, p = 0. 025 ) ; a n i nc r e a s e i n ove r a l l pol ypha r m a c y w a s a l s o s e pa r a t e l y a s s oc i a t e d w i t h a s ubs t a nt i a l i nc r e a s e i n de pr e s s i ve s ym pt om a t ol ogy ( = 0 610, p = 0. 004) N o ot he r va r i a bl e s r e a c he d s i gni f i c a nc e a s pr e di c t or s i n t hi s m ode l T a bl e 5 2 R e gr e s s i on of P r e di c t or V a r i a bl e s O nt o D e pr e s s i on M e a s ur e s A i m 2. R e l at i on s h i p s B e t w e e n M e d i c a t i on E f f e c t s an d D i m e n s i on s of D e p r e s s i on T he r e s ul t s of t he r e g r e s s i ons f or t he f our s ubs c a l e s of t he C E S D a r e a l s o pr e s e nt e d i n T a bl e 5 2, a bove T he m ode l f or t he S om a t i c C om pl a i nt s s ubs c a l e w a s

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24 s i gni f i c a nt ( F ( 11 153 ) = 3. 191 p = 0. 001 ) a nd de s c r i be d 18. 7% of t he va r i a nc e i n t he s ubs c a l e I n t hi s m ode l i nc r e a s i ng a ge w a s a s s oc i a t e d s i gni f i c a nt l y, b ut s l i ght l y w i t h i nc r e a s e d S om a t i c C om pl a i nt s ( = 0 166, p = 0 03 6) a s w a s a l a r ge r num be r of A nt i D e pr e s s a nt m e di c a t i ons ( = 0. 154, p = 0 044) a n d, m or e s ubs t a nt i a l l y, a n i nc r e a s e i n ove r a l l pol ypha r m a c y ( = 0. 503 p = 0 016) T he m ode l f or t he D e pr e s s i ve A f f e c t s ubs c a l e w a s a l s o s i gni f i c a nt ( F ( 11 153 ) = 3 046, p = 0. 001 ) de s c r i bi ng 18% of t he va r i a nc e i n D e pr e s s i ve A f f e c t 11 a ddi t i ona l pa r t i c i pa nt s w e r e e xc l ude d f r om t he a na l ys i s due t o m i s s i ng r e s pons e s on t hi s s ubs c a l e of t he C E S D l e a di ng t o a t ot a l o f 154 pa r t i c i pa nt s i n t he a na l ys i s A n i nc r e a s e d num be r o f c a r di ova s c ul a r dr ugs w a s s t r ongl y a s s oc i a t e d w i t h de c r e a s e d D e pr e s s i ve A f f e c t ( = 0. 716, p < 0 001) a s w a s a n i nc r e a s e d num be r of H or m one d r ugs a l be i t a t a w e a ke r l e ve l ( = 0. 331 p = 0. 002 ) A t t he s a m e t i m e a n i nc r e a s e i n ove r a l l pol ypha r m a c y w a s s t r o ngl y a s s oc i a t e d w i t h a n i nc r e a s e i n D e pr e s s i ve A f f e c t ( = 0. 904 p < 0 001) T he m ode l f or P os i t i ve A f f e c t on t he ot he r ha nd, f a i l e d t o r e a c h s i gni f i c a nc e ( F ( 11 142) = 1 405, p = 0. 177) F i ve a ddi t i ona l pa r t i c i pa nt s w e r e e xc l ude d f r om t hi s a na l ys i s due t o m i s s i ng da t a on t hi s s ubs c a l e of t he C E S D l e a di ng t o a t ot a l o f 160 pa r t i c i pa nt s i n t hi s a na l ys i s H ow e ve r t he nu m be r o f c o m o r bi d c a r di ova s c ul a r c ondi t i ons w a s m i l dl y a s s oc i a t e d w i t h a r e duc t i on i n t h i s di m e ns i on of de pr e s s i on ( = 0. 273 p = 0 008) a nd t he num be r o f C N S m e di c a t i ons not i nc l ud i ng a nt i de pr e s s a nt s w a s m i l dl y a s s oc i a t e d w i t h a n i nc r e a s e i n t h i s di m e ns i on of de pr e s s i on ( = 0. 236 p = 0 048) T he m ode l f or I nt e r pe r s ona l P r obl e m s a l s o f a i l e d t o r e a c h s i gni f i c a nc e ( F ( 11, 148) = 1 133, p = 0 340) a l t hough ove r a l l pol ypha r m a c y w a s m ode r a t e l y a s s oc i a t e d w i t h i nc r e a s e s i n t hi s di m e ns i on of de pr e s s i on ( = 0 513, p = 0. 044 )

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25 C H A P T E R 6 D I S C U S S I O N R e vi e w of S t u d y F i n d i n gs C h ar ac t e r i z at i on of t h e S t u d y S a m p l e T he pe r c e nt a ge of c l i ni c a l l y de pr e s s e d i ndi vi dua l s ( 9% ) i n t he pr e s e nt s a m p l e c om pa r e s f a vor a bl y w i t h t ha t r e po r t e d i n a r a c i a l l y s i m i l a r s a m pl e by B l a z e r e t a l i n w hi c h a r a t e o f c l i ni c a l l y s i gni f i c a nt de pr e s s i on, a s a s s e s s e d by t he C E S D of 9% w a s a l s o f ound f o r c om m uni t y dw e l l i ng e l de r s a bove t he a ge of 65 ( B l a z e r e t a l 19 98) A t t he s a m e t i m e t he m e a n num be r of m e di c a t i ons pe r pa r t i c i pa nt ( 2. 9 ) w a s a ppr oxi m a t e l y c om pa r a bl e t o t ha t r e por t e d by V e e hof e t a l ( 2000 ) f o r a s i m i l a r a ge c ohor t i n t he N e t he r l a nds ( 2. 6 d r ugs pe r pa r t i c i pa nt a t s t udy ons e t f o r a popu l a t i on w i t h m e a n a ge 73 ye a r s ) a l t hough s om e w ha t l ow e r t ha n t ha t r e por t e d f or s om e ot he r s t udi e s ( R ol l a s on & V ogt 2003) D i f f e r e nc e s be t w e e n t he s e s t udi e s m a y ha ve be e n dr i ve n by br oa de r i nc l us i on i n s om e e pi de m i ol ogi c a l s t udi e s t he A C T I V E s t udy di d not i nc l ude pa r t i c i pa nt s w ho w e r e c om m uni t y dw e l l i ng, f or i n s t a nc e but f unc t i ona l l y i m pa i r e d. H ow e ve r t a ke n a s a w hol e t he s e f i ndi ngs i ndi c a t e t ha t t he s t udy s a m pl e i s a ppr oxi m a t e l y c om pa r a bl e a l ong t he di m e ns i ons of de pr e s s i ve s ym pt om a t ol ogy a nd m e di c a t i on us a ge t o ot he r s t udi e d s a m pl e s t ha t a r e s i m i l a r i n a ge a nd / or r a c i a l de m og r a phi c s A i m 1. R e l at i on s h i p s A m on g P ol yp h ar m ac y, C a r d i ovas c u l ar M e d i c at i on an d D e p r e s s i ve S ym p t om s I n t he p r e s e nt s t udy, ove r a l l pol ypha r m a c y w a s s i g ni f i c a nt l y a s s oc i a t e d w i t h i nc r e a s e d d e pr e s s i ve s ym pt om s a s m e a s ur e d by t he C E S D T ot a l S c or e e ve n w he n

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26 c ont r ol l i ng f o r de m og r a phi c s c a r di ova s c ul a r r i s k, a nd s pe c i f i c c a t e gor i e s of dr ugs l i ke l y t o be r e l a t e d t o de pr e s s i ve s ym pt om s A t t he s a m e t i m e i nde pe nde nt l y o f t he e f f e c t o f ove r a l l po l ypha r m a c y, t he us e of c a r di ova s c ul a r m e di c a t i ons ha d a uni que e f f e c t a s s oc i a t e d w i t h r e duc e d de pr e s s i ve s ym pt om s a s m e a s ur e d by t he C E S D T o t a l S c or e pr ovi di ng s uppor t f or t he hypot he s i s t ha t i nde pe nde nt a nd oppos i ng e f f e c t s o f be ne f i c i a l a nd de t r i m e nt a l pol ypha r m a c y i m pa c t s w oul d be o bs e r va bl e i n t he c ont e xt o f de pr e s s i ve s ym pt om a t ol ogy. A i m 2. R e l at i on s h i p s B e t w e e n M e d i c a t i on E f f e c t s an d D i m e n s i on s of D e p r e s s i on W he n t he de t r i m e nt a l i m pa c t of pol ypha r m a c y on de pr e s s i on w a s c ons i de r e d w i t hi n s pe c i f i c di m e ns i ons of de p r e s s i on r e pr e s e nt e d i n t he C E S D t hi s e f f e c t w a s not l i m i t e d t o t he S om a t i c C om pl a i nt s s ubs c a l e of t he C E S D but w a s a l s o pr e s e nt i n t he D e pr e s s i ve A f f e c t s ubs c a l e i ndi c a t i ng t ha t t hi s e f f e c t e xi s t e d i n t he c ont e xt of t he c or e m ood s ym p t om a t ol ogy of de pr e s s i on, a s oppos e d t o t he e xi s t i ng s ol e l y a s a p r oj e c t i on o f s om a t i c c om pl a i nt s due pr i m a r i l y t o a ge ne r a l m e d i c a l c ondi t i on on t he m e a s ur e of de pr e s s i on. W he n t he be ne f i c i a l i m pa c t o f c a r di ova s c ul a r m e di c a t i on w a s c ons i de r e d i n t he c ont e xt of t he di m e ns i ons of de pr e s s i on, t he e f f e c t w a s f ound t o be pr i m a r i l y r e p r e s e nt e d i n t he D e pr e s s i ve A f f e c t s ubs c a l e a ga i n de m ons t r a t i ng a l i nk be t w e e n t he i m pa c t s of m e di c a t i on a nd t he c or e m ood s ym pt om s o f de pr e s s i on. S yn t h e s i s of F i n d i n gs T he pa t t e r n o f r e s ul t s pr e s e nt e d a bove i s c ons i s t e nt w i t h t he not i on o f s i m ul t a ne ous ove r a l l de t r i m e nt a l i m pa c t of pol ypha r m a c y a nd b e ne f i c i a l i m pa c t of pol ypha r m a c y i n t he c a s e of c a r di ova s c ul a r m e di c a t i on, f or t he s ym pt om s of de pr e s s i on, i n ol de r i ndi vi dua l s a l t h ough i t i s i m po r t a nt t o not e t ha t c a us a t i on c a nnot be i nf e r r e d e i t he r f r om

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27 t hi s r e l a t i ons hi p or f r om t he r e l a t i ons hi p be t w e e n c a r di ova s c ul a r m e di c a t i on a nd i nc r e a s e d de pr e s s i ve s ym pt om s a nd t ha t ove r a l l p ol ypha r m a c y c a nnot be m a de t r ul y i nde pe nde nt of c a r di ova s c ul a r pol ypha r m a c y T hi s m ode l of s i m ul t a ne ous de t r i m e nt a l a nd be ne f i c i a l pol ypha r m a c y i s c ons i s t e nt w i t h t he hypot he s i z e d m ode l pr e s e nt e d e a r l i e r i n F i gur e 1 1. I m p l i c at i on s of S t u d y D e t r i m e n t al P ol yp h ar m ac y f or D e p r e s s i on T he r e a r e a num be r of pos s i bl e e xpl a na t i ons f o r t h e obs e r ve d de t r i m e nt a l i m pa c t of pol ypha r m a c y. O ve r a l l pol ypha r m a c y m i gh t l e a d t o i nc r e a s e d dys r e gul a t i on of ne ur ot r a ns m i t t e r s or e ndoc r i ne pr oc e s s e s l e a di ng t o a da pt a t i on di f f i c ul t y. T hi s m a y pr oc e e d t hr ough a ge ne r a l i z e d r out e t ha t i nvol ve s c um ul a t i ve e f f e c t s of m a ny dr ugs i n a non s pe c i f i c w a y, pa r t i c ul a r l y t he une xpe c t e d i m p a c t s of dr ugs t ha t a r e pr e s c r i be d f or i na ppr opr i a t e r e a s ons or i t m a y pr oc e e d t h r ough t he i nc r e a s e i n t he l i ke l i hood of s pe c i f i c a dve r s e dr ug dr ug i nt e r a c t i ons ( H oga n, 1997; V e e hof e t a l 2000) F u r t he r unde r s t a ndi ng of t he s e m e c ha ni s m s m a y l e a d t o m o r e e f f e c t i ve i n t e r ve nt i on s t r a t e gi e s f or ol de r i ndi vi dua l s w i t h c o m o r bi d c a r di ova s c ul a r di s e a s e a nd de pr e s s i ve s ym pt om a t ol ogy. I t i s a l s o pos s i bl e t ha t t he de t r i m e nt a l e f f e c t o f pol ypha r m a c y i s m a i nl y a n e f f e c t o f m ul t i m or bi di t y a nd not o f t he m e di c a t i on i t s e l f ( i e t he p r e s e nc e of m ul t i pl e m e di c a t i ons s e r ve s a s a pr oxy f or t he p r e s e nc e of m ul t i pl e unde r l yi ng m e di c a l c ondi t i ons ) D i f f e r e nt i a t i ng t hi s a l t e r na t i ve e xpl a na t i on f r om a m e c ha ni s m r oot e d i n t he e f f e c t s of pol ypha r m a c y on t he c e nt r a l ne r vous s ys t e m i s di f f i c ul t be c a us e no c l e a r m e t hod e xi s t s w he r e by t he num be r a nd s t r e ngt h o f m e di c a t i ons c a n be m e a ni ngf ul l y s c a l e d by t he num be r a nd s e ve r i t y o f t he m e d i c a l di s or de r s t ha t ne c e s s i t a t e t he m e di c a t i ons i n t he f i r s t pl a c e M or e ove r i n t hi s s t udy m e a s ur e m e nt of he a l t h c ondi t i ons w a s not a de qua t e t o

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28 pe r m i t t he i nde pe nde nt a s s e s s m e nt of phys i c a l he a l t h c ondi t i ons a t t he s a m e l e ve l of de t a i l a s w a s a c hi e ve d i n a na l ys i s of t he a va i l a bl e m e di c a t i on da t a A s pr e vi ous l y i ndi c a t e d, m e di c a t i on p r e s c r i be d w i t hout c l e a r i ndi c a t i on i s a s e r i ous c onc e r n w i t hi n obs e r ve d pol ypha r m a c y, a nd pa r t i t i oni ng i t s e f f e c t f r om t he e f f e c t o f a ddi t i ona l m e di c a t i ons pr e s c r i be d w i t h c l e a r i ndi c a t i ons m a y be i m por t a nt i n unde r s t a ndi ng t he m e c ha ni s m of pol ypha r m a c y s de l e t e r i ous e f f e c t s I n e i t he r e ve nt t he s ugge s t i on t ha t pol ypha r m a c y m a y c a r r y a f f e c t i ve c onc om i t a nt s i n t he f o r m o f i nc r e a s e d s ym pt om s of de pr e s s i on a dds t o a gr ow i ng body o f l i t e r a t ur e s uppor t i ng t he ne e d f or i nt e r di s c i pl i na r y i nt e r ve nt i ons t o a t t e m pt t o r e duc e pol ypha r m a c y i n ol de r i ndi vi dua l s w i t hout c om pr om i s i ng t he e f f i c a c y of t r e a t m e nt of t he di a gnos e d di s or de r s f or w hi c h t he y a r e be i ng t r e a t e d. R e s e a r c h on t he be ne f i t s of s uc h i nt e r ve nt i ons ha s f oc us e d pr i m a r i l y on c os t s a vi ngs t o da t e ( C hr i s t e ns e n e t a l 2004 ) H ow e ve r s uc h i nt e r ve nt i ons a l r e a dy a ppe a r t o be a bl e t o i de nt i f y a nd a c t on i ndi vi dua l s w ho a r e l i ke l y t o ha ve i na ppr opr i a t e l y p r e s c r i be d, unne c e s s a r y, or hi gh r i s k m e di c a t i on r e gi m e ns a nd m a y r e pr e s e nt a n oppor t uni t y t o i m pr ove t he f unc t i oni n g of ol de r i ndi vi dua l s t ha t c a r r i e s w i t h i t m i ni m a l r i s k a nd m a y ha ve s i gni f i c a nt c a pa c i t y t o de l i ve r i m p r ove m e nt s t o qua l i t y of l i f e ( R ol l a s on & V ogt 2003; T r ygs t a d e t a l 2005) B e n e f i c i al E f f e c t s of P ol yp h ar m ac y o f C ar d i ova s c u l ar M e d i c at i on f or D e p r e s s i on T he r e a r e m a ny pot e nt i a l m e c ha ni s m s t o e xpl a i n t h e obs e r ve d be ne f i c i a l pol ypha r m a c y r e l a t i ons hi p, i n w hi c h i ndi vi dua l s t a ki ng m or e c a r di ova s c ul a r m e di c a t i ons a pp e a r t o be l e s s de pr e s s e d. C a r di ova s c ul a r m e di c a t i on m i ght be a s s oc i a t e d w i t h t he pr e ve nt i on of w hi t e m a t t e r pa t hol ogy, or m a y pos s i bl y a i d c om pe ns a t or y m e c ha ni s m s s uc h a s i nc r e a s e d c e r e br a l bl ood f l ow a nd pe r f us i o n. A t l e a s t one s t udy ha s de m ons t r a t e d i m pr ove m e nt s i n f r ont a l w hi t e m a t t e r f unc t i oni ng a s a r e s ul t of s uc c e s s f ul t r e a t m e nt o f

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29 de pr e s s i on i n ol de r i ndi vi dua l s ( i n t ha t c a s e t hr ou gh e l e c t r o c onvul s i ve t he r a py) s ugge s t i ng t ha t i m pr ove m e nt s i n w hi t e m a t t e r f unc t i oni ng m a y be a n i m por t a nt pa t hw a y t o i m pr ove m e nt s i n de pr e s s i ve m ood i n l a t e l i f e ( N obuha r a e t a l 2004 ) O n t he ot he r ha nd, i t i s a l s o qui t e pos s i bl e t ha t t he be ne f i c i a l pol ypha r m a c y a s s oc i a t e d w i t h c a r di ova s c ul a r m e di c a t i ons obs e r v e d i n t he p r e s e nt s t udy c oul d be e xpl a i ne d t hr ough i m p r ove m e nt s i n phys i c a l he a l t h by vi r t ue of s uc c e s s f ul m e di c a l m a na ge m e nt of c a r di ova s c ul a r di s e a s e I f i t i s t he c a s e t ha t de pr e s s i on i n c a r di ova s c ul a r di s e a s e i s not a s pe c i f i c ne ur ol ogi c a l e f f e c t of t he d i s e a s e pr oc e s s but i s r a t he r a c ons e que nc e of phys i c a l he a l t h i m pa i r m e nt t he n t hi s de pr e s s i ve e f f e c t s houl d be s pe c i f i c t o a l e ve l o f phys i c a l he a l t h i m pa i r m e nt a nd not t o a di s e a s e c a t e gor y. T he pr e s e nt s t udy di d not a de qua t e l y a s s e s s phys i c a l he a l t h i m pa i r m e nt a s a pot e nt i a l m e di a t o r o f dr ug e f f e c t s a l t h ough t h i s m a y w e l l be a f r ui t f ul a r e a f o r f ut u r e r e s e a r c h. F ur t he r m o r e s uc c e s s f ul t r e a t m e nt s s houl d i m pr ove de p r e s s i ve s ym pt om s t o t he e xt e nt t ha t t he y a r e s uc c e s s f ul i n t r e a t i ng t he unde r l yi ng di s e a s e S uppor t i ng t h i s vi e w poi nt i s r e s e a r c h t ha t ha s de m o ns t r a t e d t ha t de pr e s s i on i n i ndi vi dua l s w i t h or ga n f a i l ur e r e qui r i ng t r a ns pl a nt a t i on w as not a s s oc i a t e d w i t h t he s i t e o f f a i l ur e ( w he n c om pa r i ng i nd i vi dua l s w i t h he a r t l u ng, a nd ki dne y f a i l ur e ) but w as a s s oc i a t e d w i t h t he l e ve l of pa i n e xpe r i e nc e d ( F o r z b e r g e t a l 1999) I t i s i m po r t a nt t o not e how e ve r t ha t t h i s r e s e a r c h w a s not pe r f or m e d on ol de r i ndi vi dua l s i n w hom t he a s s oc i a t i on s a m ong c a r di ova s c ul a r di s e a s e w hi t e m a t t e r pa t hol ogy, a nd de pr e s s i on, i s be l i e ve d t o e xi s t A not he r s t udy i ndi c a t e d t ha t i ndi vi dua l s w hos e he a r t f a i l ur e w a s m a na ge d e i t he r by t r a ns pl a nt a t i on or by m e di c a t i o n i ndi c a t e d t ha t m e di c a t i on pr oduc e d bot h be t t e r i m pr ove m e nt s i n phys i c a l he a l t h a nd a s ubs t a nt i a l de c r e m e nt i n de pr e s s i ve

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30 s ym pt om s ( E va nge l i s t a e t a l 2005 ) H ow e ve r t ha t s t udy w a s not a bl e t o de m ons t r a t e w he t he r phys i c a l he a l t h m a na ge m e nt w a s a m e di a t or of r e duc e d de pr e s s i on i n t he m e di c a t i on gr oup. I nde e d, i t i s di f f i c ul t t o i s ol a t e t he s uc c e s s of t r e a t m e nt i n m a na gi ng phys i c a l he a l t h f r om ot he r be ne f i t s t ha t a r e pr e s um e d t o oc c ur s i m ul t a ne ous l y i n i ndi vi dua l s w ho r e s pond t o c a r di ova s c ul a r t r e a t m e nt s uc h a s i m pr ove d c e r e br ova s c ul a r f unc t i oni ng. R e ga r dl e s s of t he r e l a t i ve pow e r of t he a bove e xpl a na t i ons f or t he be ne f i c i a l r ol e of c a r di ova s c ul a r pol ypha r m a c y on m ood s y m pt om s i n t hi s popul a t i on, t he f a c t s t ha t i ndi vi dua l s w ho r e c e i ve d m or e c a r di ova s c ul a r m e d i c a t i ons s how e d f e w e r s ym pt om s of de pr e s s i on, a nd i ndi vi dua l s w ho r e c e i ve d f e w e r c a r di ova s c ul a r m e di c a t i ons s how e d m or e s ym pt om s of de pr e s s i on i s s t r i ki ng. I s i t pos s i bl e t ha t c a r di ova s c ul a r di s e a s e m a y c ont i nue t o be unde r t r e a t e d i n t hi s popul a t i on a nd t ha t a t l e a s t s om e of t hos e i ndi vi dua l s not r e c e i vi ng t hi s m e di c a t i on m i ght be ne f i t f r om m or e a ggr e s s i ve t r e a t m e nt ? S om e e vi de nc e l ooki ng pur e l y a t t he i s s ue of a de qu a t e di a gnos i s a nd t r e a t m e nt of c a r di ova s c ul a r c ondi t i ons i n t hi s popul a t i on s ugge s t s t ha t t hi s m i ght i nde e d, c ont i nue t o be t he c a s e due t o c om pl i c a t e d c l i ni c a l p r e s e nt a t i on, t he non s pe c i f i c i t y of s ym pt om s a c c e s s t o c a r e pa r t i c ul a r l y a m ong i m pove r i s h e d e l de r s a nd ot he r i s s ue s ( F i t z pa t r i c k e t a l 2004 ; F r a s ur e S m i t h e t a l 1993; R i c h, 2005) C om pl i c a t i ng t hi s i s s ue i s t he f a c t t ha t not a l l i ndi vi dua l s w ho a r e p r e s c r i be d t r e a t m e nt s f or t he s e c ondi t i ons ha ve t he f i na nc i a l a bi l i t y t o obt a i n a l l p r e s c r i be d m e di c a t i ons ( P i e t t e e t a l 2004) S t u d y L i m i t at i on s T he r e a r e s e ve r a l l i m i t a t i ons t o t hi s s t udy. F i r s t t h e s a m pl e w a s r e l a t i ve l y s m a l l a nd di d not i nc l ude f r a i l or i ns t i t ut i ona l i z e d e l de r s W hi l e t he l a t t e r a s pe c t m a ke s t hi s s t udy m or e r e pr e s e nt a t i ve of e f f e c t s on c om m uni t y dw e l l i ng e l de r s i t a l s o l e a ds t o

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31 s e l e c t i ng i ndi vi dua l s w ho a r e l i ke l y t o be r e l a t i ve l y l e s s de pr e s s e d a nd s uf f e r i ng f r o m l e s s s e ve r e c a r di ova s c ul a r pa t hol ogy. C onc l us i ons a bout t he pr oc e s s of de c l i ne w i t hi n ol de r i ndi vi dua l s t ha t l e a ds f r om l ow ba s e r a t e s o f de pr e s s i on i n t he c om m uni t y t o e l e va t e d ba s e r a t e s i n t he i ns t i t ut i ona l popul a t i on a r e di f f i c ul t t o d r a w i n t he a bs e nc e of da t a on pa r t i c i pa nt s f r om bot h s e t t i ngs I n a ddi t i on s i nc e t he pr e s e nt a na l ys i s i s not l ongi t udi na l i t i s i m pos s i bl e t o m a ke c a us a l i nf e r e nc e s I t i s not c l e a r w he t he r i ndi vi dua l s w ho a r e l e s s de pr e s s e d a r e m or e l i ke l y t o ne e d or us e m e di c a t i o n f or c a r di ova s c ul a r c ondi t i ons f or i ns t a nc e or w he t he r i ndi vi dua l s w ho us e m o r e c a r di ova s c ul a r m e di c a t i ons a r e l e s s l i ke l y t o be c om e de pr e s s e d. T hi s s t udy ut i l i z e d a m e t hod o f ope r a t i ona l i z i ng s ubs yndr om a l de pr e s s i on t ha t ha s be e n us e d w i t h s uc c e s s i n t he e xt a nt l i t e r a t ur e na m e l y, us i ng s c or e s f r o m a s e l f r e por t de pr e s s i on i ns t r um e nt a s c ont i nuous va r i a bl e s I t w a s none t he l e s s s u c c e s s f ul i n f i ndi ng s i gni f i c a nt e f f e c t s r e l a t i ng r e l a t i ve l y l ow l e ve l s of de pr e s s i on a nd m e di c a t i on l e ve l s H ow e ve r t he e xa c t r e l a t i ons hi p be t w e e n t hi s m e t h od a nd ot he r m e t hods of c onc e pt ua l i z i ng de pr e s s i on be l ow t he l e ve l w a r r a n t i ng a f o r m a l di a gnos i s of M a j or D e pr e s s i ve D i s or de r s uc h a s t he r e s e a r c h c r i t e r i a pr opos e d i n t he D S M I V T R f or M i nor D e pr e s s i ve D i s or de r r e m a i ns unc l e a r T he d i f f e r e nc e s i n t he w a y t hi s phe nom e non i s de f i ne d i n di f f e r e nt r e s e a r c h s t udi e s l i m i t t he a bi l i t y of t h i s body of l i t e r a t u r e a s a w hol e t o m a ke br oa d s t a t e m e nt s a bout s ub c l i ni c a l s ubs yndr om a l m i nor or m i ni m a l de pr e s s i on. E a c h s t udy, how e ve r p r e s e nt s r e s ul t s t ha t a r e pot e nt i a l l y i ndi vi dua l l y m e a ni ngf ul w i t h i n t he c ont e xt of t he de f i ni t i on a d opt e d by t he r e s pe c t i ve r e s e a r c he r s a s t he pr e s e nt s t udy a l s o s e e ks t o do.

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32 B e c a us e of l i m i t a t i ons i n a s s e s s i ng e xi s t i ng phys i c a l he a l t h c ondi t i ons a nd t he l ongi t udi na l r e l a t i ons hi ps be t w e e n di a gnos e s of t h e s e c ondi t i ons a nd pr e s c r i pt i on of m e di c a t i ons t he pr e s e nt s t udy i s l i m i t e d i n t ha t a n t hor ough a s s e s s m e nt of e a c h pa r t i c i pa nt s ove r a l l phys i c a l he a l t h a nd m ul t i m o r b i di t y w a s not pos s i bl e a nd t he r e i s no w a y t o t r ul y di f f e r e nt i a t e pol ypha r m a c y i n t he s e ns e of a ggr e s s i ve t r e a t m e nt a nd pol ypha r m a c y i n t he s e ns e of ove r m e di c a t i on. W hi l e i t i s i m pl i e d he r e t ha t c a r di ova s c ul a r m e di c a t i on, w i t h i t s be ne f i c i a l i m pa c t s r e pr e s e nt s t he f or m e r a nd not t he l a t t e r i t i s a l s o a c om pone nt of pol ypha r m a c y, a s m e a s ur e d, a nd i s l i ke l y t o c ont a i n, i t s e l f bot h t ype s o f pol yp ha r m a c y. T he pr e s e nt s t udy di d not i nve s t i ga t e t he i m pa c t s o f s pe c i f i c m e di c i ne s i n de t a i l a not he r t e c hni que t ha t ha s p r ovi de d c om pe l l i ng i ns i ght i nt o c ha nge s i n f unc t i oni ng i n ol de r i ndi vi dua l s S e ve r a l m e t hods f or do i ng t hi s h a ve be e n de ve l ope d. O ne of t he s e m e t hods i s t he i nve s t i ga t i on of r e l a t i ve r i s k a s s oc i a t e d w i t h i ndi vi dua l dr ugs ( D hondt e t a l 2002 ; V e e hof e t a l 2000 ) A s e c ond m e t hod i s t he c ons i de r a t i on of l i s t s of dr ugs s uc h a s t he B e e r s C r i t e r i a t ha t a r e c ons i de r e d c ont r a i ndi c a t e d f or ol de r i ndi vi dua l s i n t he m a j or i t y of c a s e s ba s e d on know n a ne c dot a l or e m pi r i c a l e vi de nc e of pr obl e m s a s s oc i a t e d w i t h t he s e m e di c a t i ons i n l a t e l i f e ( A pa r a s u & M or t 2000; K l a r i n e t a l 2005 ) T he s e m e t hods ha ve s t r e ngt hs i n t he i r a bi l i t y t o i de nt i f y s pe c i f i c m e c ha ni s m s ba s e d on t he a c t i ons of i ndi v i dua l dr ugs H ow e ve r t he pr e s e nt m e t hod p r ovi de s a c om pl e m e nt a r y l i ne of e vi de nc e i n t ha t l a r ge s i gni f i c a nt e f f e c t s of br oa d c l a s s e s of m e di c a t i on s ugge s t t he pos s i bi l i t y of m or e ba s i c m e c ha ni s m s t ha n t hos e ob s e r ve d i n s t udi e s of s pe c i f i c d r ugs S uc h m e c ha ni s m s a r e not l i ke l y t o r e l y on t he s i t e of a c t i on o r c he m i s t r y o f a s pe c i f i c i ndi vi dua l dr ug a nd m a y ope r a t e i n pa r a l l e l t o t he pr e vi ous l y obs e r ve d e f f e c t s

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33 F i na l l y, be c a us e t hi s s t udy di d not m a ke us e of b r a i n i m a gi ng t e c hni que s n o c onc l us i ve s t a t e m e nt s c a n be m a de a bout t he a s s oc i a t i ons a m ong pol ypha r m a c y, s t a t e c ha nge s i n t he br a i n, a nd de pr e s s i on. C on c l u s i on I n s pi t e of t he s e l i m i t a t i ons t he pr e s e nt r e s e a r c h c ont r i but e s t o t he body of l i t e r a t ur e s ur r o undi ng de pr e s s i on i n ol de r i ndi vi du a l s by e m pha s i z i ng t he i m por t a nc e o f c ons i de r i ng m e di c a t i on ba s e d m a na ge m e nt of c hr o ni c he a l t h c ondi t i ons e s pe c i a l l y c a r di ova s c ul a r c ondi t i ons w i t hi n a n i nt e gr a t e d f r a m e w or k a l ongs i de ot he r e xpl a na t or y va r i a bl e s i n t he c r e a t i on a nd m a i nt e na nc e of de pr e s s i ve s ym pt om s i n ol de r i ndi vi dua l s T hi s a dds t o t he l a r ge body of l i t e r a t ur e t ha t ha s de m ons t r a t e d t ha t e l de r l y i ndi vi dua l s w i t h a hi s t or y of c a r di ova s c ul a r r i s k bur de n a r e m o r e l i ke l y t o be c om e de pr e s s e d, a nd t ha t t he s e i ndi vi dua l s a r e t he n l i ke l y t o ha ve w hi t e m a t t e r pa t hol ogy a nd a r e a t i nc r e a s e d r i s k f or s t r oke s a nd f o r m o r t a l i t y, a s w e l l a s w i t h r e s e a r c h i ndi c a t i ng t ha t f unc t i ona l di s a bi l i t y due t o c h r oni c he a l t h c onc e r ns i nc r e a s e s t he r i s k of de pr e s s i on i n t he e l de r l y, a nd s ugge s t s f ur t he r i nve s t i ga t i on of m a na ge m e nt of t he ove r a l l m e di c a t i on bu r de n, a s w e l l a s pr e ve nt a t i ve a nd a ggr e s s i ve t r e a t m e nt o f c a r di ova s c ul a r c ondi t i ons a s pos s i bl e e l e m e nt s of a n ove r a l l he a l t hc a r e pr og r a m f o r ol de r i ndi vi dua l s t ha t m a y ha ve t he c a pa c i t y t o pr e ve nt o r e l i m i na t e s om e c a s e s of de pr e s s i on i n t hi s popul a t i on.

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34 L I S T O F R E F E R E N C E S A l e xopoul os G S ( 1990) C l i ni c a l a nd B i ol ogi c a l F i ndi ngs i n L a t e O ns e t D e pr e s s i on. A m e r i c an P r e s s R e v i e w of P s y c hi at r y 9, 249 262. A pa r a s u, R R & M or t J R ( 2000) I na ppr opr i a t e P r e s c r i bi ng f or t he E l de r l y: B e e r s C r i t e r i a B a s e d R e vi e w T he A nnal s o f P har m ac ot he r apy 34, 338 346. B l a z e r D G & H ybe l s C F ( 2005) O r i gi ns o f D e pr e s s i on i n L a t e r L i f e P s y c hol ogi c al M e di c i ne 35 1241 1252 B l a z e r D G L a nde r m a n L R H a ys J C S i m o ns i c k, E M & S a unde r s W B ( 1998) S ym pt om s o f D e pr e s s i on A m ong C om m u ni t y D w e l l i ng E l de r l y A f r i c a n A m e r i c a n a nd W hi t e O l de r A dul t s P s y c hol ogi c al M e di c i ne 28 1311 1320 B or ow i a k, E & K os t ka T ( 2004) P r e di c t or s o f Q ua l i t y of L i f e A m ong O l de r P e opl e L i vi ng a t H om e a nd i n I ns t i t ut i ons A gi ng C l i ni c al and E x pe r i m e nt al R e s e ar c h 16, 212 220 B oyd, C M D a r e r J B oul t C F r i e d L P B ou l t L & W u, A W ( 2005) C l i ni c a l P r a c t i c e G ui de l i ne s a nd Q ua l i t y o f C a r e f or O l de r P a t i e nt s W i t h M ul t i pl e C om or bi d D i s e a s e s J A M A 294 716 724. B us h, D E Z i e ge l s t e i n, R C T a yba c k, M R i c ht e r D S t e ve ns S Z a ha l s ky, H & F a ue r ba c h, J A ( 2001) E ve n M i ni m a l S ym p t om s of D e pr e s s i on I nc r e a s e M or t a l i t y R i s k A f t e r A c ut e M yoc a r di a l I nf a r c t i on. T he A m e r i c an J our nal of C ar di ol ogy 88, 337 341. C a s ki e G I L & W i l l i s S L ( 2004) C ongr ue nc e of S e l f R e por t e d M e di c a t i ons W i t h P ha r m a c y P r e s c r i pt i on R e c or ds i n L ow I nc om e O l de r A dul t s T he G e r ont ol ogi s t 44, 176 185 C hopr a M P Z ubr i t s ky, C K not t K T e n H a ve T H a dl e y T C oyne J C & O s l i n D W ( 2005) I m por t a nc e o f S ubs yndr om a l S ym pt om s of D e pr e s s i on i n E l de r l y P a t i e nt s A m e r i c an J our nal of G e r i at r i c P s y c hi at r y 13 597 606 C hr i s t e ns e n, D T r ys t a d, T S ul l i va n, R G a r m i s e J & W e gne r S E ( 20 04) A P ha r m a c y M a na ge m e nt I nt e r ve nt i on f or O pt i m i z i n g D r ug T he r a py f or N u r s i ng H om e P a t i e nt s T he A m e r i c an J our nal of G e r i at r i c P har m ac ot he r apy 2, 248 256. C l e l a nd, J G B a ks h, A & L oui s A ( 2000 ) P o l y pha r m a c y ( or P ol yt he r a py) i n t he T r e a t m e nt of H e a r t F a i l ur e H e ar t F ai l ur e M oni t or 1 8 13

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39 B I O G R A P H I C A L S K E T C H M oha n K r i s hna n gr a dua t e d f r om t he U ni ve r s i t y of M i c hi ga n w i t h a B a c he l or of S c i e nc e i n e ngi ne e r i ng phys i c s i n 1997, a nd a M a s t e r of S c i e nc e i n nuc l e a r e n gi ne e r i ng a nd r a di ol ogi c a l s c i e nc e s i n 1999 H e t he n s pe nt a ppr oxi m a t e l y 5 ye a r s w o r ki ng i n va r i ous e ngi ne e r i ng a nd bus i ne s s r ol e s w i t hi n t he a ut om ot i ve i ndus t r y. D ur i ng t hi s t i m e he pur s ue d c our s e w or k i n ps yc hol ogy a t W a yne S t a t e U ni ve r s i t y, a nd pa r t i c i pa t e d i n r e s e a r c h s t udyi ng t he r e l a t i ons hi p be t w e e n c a r di ov a s c ul a r di s e a s e a nd de pr e s s i on i n t he e l de r l y a t t he W a yne S t a t e U ni ve r s i t y I ns t i t ut e of G e r ont ol ogy. C ur r e nt l y, M r K r i s hna n i s w or ki ng t ow a r d a doc t or a t e i n c l i ni c a l a nd he a l t h ps yc hol ogy, w i t h a s pe c i a l i z a t i on i n c l i ni c a l ne ur ops yc hol ogy, a t t he U ni ve r s i t y o f F l or i da


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Title: Relationships Between Medication Levels and Depressive Symptoms in Older Individuals
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Title: Relationships Between Medication Levels and Depressive Symptoms in Older Individuals
Physical Description: Mixed Material
Copyright Date: 2008

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Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
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RELATIONSHIPS BETWEEN MEDICATION LEVELS AND DEPRESSIVE
SYMPTOMS IN OLDER INDIVIDUALS
















By

MOHAN KRISHNAN


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA


2006

































Copyright 2006

by

Mohan Krishnan
































This work is dedicated to all of the people who have blessed me with their love, helped
me find my way, and helped me see the value in the pursuit of wisdom.















ACKNOWLEDGMENTS

I would like to thank Dr. Michael Marsiske, for his guidance, support, and

mentorship throughout this project. I would like to thank all of the members of the

ACTIVE team, who were instrumental in collecting the data used in this project, and all

of the participants who volunteered their time and effort to help us understand the aging

process. I would also like to thank Dr. Peter Lichtenberg and Jean Gash for their support

in developing my understanding of and interest in gerontology.
















TABLE OF CONTENTS

page

A C K N O W L E D G M E N T S ...................................................................... ...................iv

L IST O F T A B L E S ..........................................................................vii

L IST O F FIG U R E S ...................................................viii

A B STR A C T ................. ..... ... .. ........... .......... ....... ...................... ix

CHAPTER

1 INTRODUCTION .................................................................. ... ......... 1

2 REVIEW OF LITERATURE ........................................................................... 4

Depression in Older Individuals............................ ............... 4
The Vascular Depression Hypothesis ............. ......... ............................... ...... 5
Vascular Depression Within a Biopsychosocial Model of Depression .......................7
P olypharm acy ................................................................................................. 9

3 STATEMENT OF THE PROBLEM .............................13

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
D expressive Sym ptom s......................................... ... ...... ...... ........ 14
Aim 2. Relationships Between Medication Effects and Dimensions of Depression. 14

4 M E T H O D S ...................................................................................... .......... 1 5

P articip ants .......................................... ................... .......... 15
A CTIV E Pilot Study Participants.................................................................. 15
Inclusion and Exclusion Criteria ............................... .............. 15
M easu re s ......................................................... ......... ...................................... 16
Interview-Based M measures ................................. ........................... .. 16
Self-R report Q uestionnaires...................................................... ...... ... .. 16
P ro c e d u re s ................................................. .................... ............................... 17
Categorization of Medications ........................ ................................ 17
M missing D ata ...................... .......... ........ .......... .... ........ .... 18
Statistical A analysis ............ .................... .......... ................ .............. 19









5 R E SU L T S ......................... .....20.......... ................

D em graphic Statistics .......... .............................. .......................... .............. 20
M education Statistics ...................... .... ........................................ .............. 20
C orrelational A naly sis ................ ...... ... ... .. ............................. .. .............22
Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
D epressive Sym ptom s.................................................................. ............... ... 22
Aim 2. Relationships Between Medication Effects and Dimensions of Depression .23

6 DISCUSSION ................................................................... .... ......... 25

R eview of Study Findings....................................................................................... 25
Characterization of the Study Sample .......................................................... 25
Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Sym ptom s ............................................. ............ ................ 25
Aim 2. Relationships Between Medication Effects and Dimensions of
D expression ................................................. .......................... ........ 26
Synthesis of F indings.............................................. .................... ... ...... 26
Im plications of Study......................................................................... ....... 27
Detrimental Polypharmacy for Depression..................................................... 27
Beneficial Effects of Polypharmacy of Cardiovascular Medication for
D expression ................................................. .......................... ........ 28
Study Limitations .................................... ....................................... 30
C conclusion ..................................................... ................... ....... ....... 33

L IST O F R E FE R E N C E S............................................................................. ..............34

BIOGRAPHICAL SKETCH .......................................................... .............. .. 39
















LIST OF TABLES

Table pge

5-1 Correlations Among Predictor Variables ............................ .... ........... 22

5-2 Regression of Predictor Variables Onto Depression Measures............................ 23















LIST OF FIGURES


Figure page

1-1 Detrimental and Beneficial Polypharmacy in Depression in Older Individuals........2

5-1 Distribution of Participants' CES-D Total Scores ....................................... 21

5-2 Frequency of Occurrence of Different Numbers of Medications Per Participant ... 21















Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Master of Science

RELATIONSHIPS BETWEEN MEDICATION LEVELS AND DEPRESSIVE
SYMPTOMS IN OLDER INDIVIDUALS

By

Mohan Krishnan

May 2006

Chair: Michael Marsiske
Major Department: Clinical and Health Psychology

Polypharmacy, the concurrent usage of multiple medications, is common in older

individuals, who often have many health conditions, and can result in detrimental effects

including increases in depressive symptoms. However, if polypharmacy in a functional

category of medication brings about the successful management of a health concern, such

as cardiovascular disease, which itself has a negative impact on mood, that polypharmacy

may also actually be beneficial in some circumstances. The present study sought to

determine whether overall polypharmacy had the detrimental effect of increasing

depressive symptomatology in older individuals, while polypharmacy in the area of

cardiovascular medication has the beneficial effect of reducing depressive symptoms,

which are hypothesized to have some vascular etiology in many older adults.

Analyses were conducted on data from 165 participants in the ACTIVE Pilot Study

(mean age 74 years, 83% female, 55% African-American). A multiple linear regression

model, controlling for participant demographics, was used to determine the effects of









polypharmacy on depression. As hypothesized, while overall polypharmacy was

associated with increased depressive symptoms, cardiovascular medication was

simultaneously associated with a decrease in depressive symptoms.

The findings are consistent with a model of negative polypharmacy effects,

representing underlying effects of multimorbidity, increased likelihood of adverse drug

reactions, central nervous system dysregulation, or some other process, on depression in

older individuals, with a simultaneous beneficial polypharmacy effect for cardiovascular

medication, through mechanisms such as a reduction in functional impairment due to

cardiovascular disease, or improvement in cerebrovascular functioning.














CHAPTER 1
INTRODUCTION

The purpose of the present study was to explore relationships between medication

levels and self-reported mood in older individuals. Depression, the persistent presence of

symptoms such as sadness or loss of pleasure, is observed at elevated rates in frail older

individuals, and is a major barrier to enjoying later life. It is a topic of major interest to

health care professionals and researchers from many different perspectives. Converging

lines of evidence have indicated that mechanisms related to physical frailty, medical

multimorbidity, and cardiovascular disease processes may underlie the elevated rates of

depression in this population. However, few of these studies have investigated

medication burdens related to these conditions and processes, although medication usage

is a frequent component of the care regimen for older individuals. To the extent that non-

psychological health concerns such as cardiovascular disease may be risk factors for

depression in later life, understanding the potentially beneficial impacts of aggressively

treating these disorders may be crucial in prevention of depression in this population. On

the other hand, if medication regimens, when taken as a whole, have iatrogenic effects,

manifested as increased depressive symptomatology, this would represent an additional

category of potentially modifiable risk factors for elders' mood disorders.

The current investigation is guided by the conceptual model depicted below, in

Figure 1-1, in which polypharmacy may be viewed as composed of both beneficial and

detrimental components, related to aspects that are able to manage medical conditions

aggressively, and elements that contribute to over-medication.

















Specific
medication
Effects
(CNS drugs,
etc)


Figure 1-1. Detrimental and Beneficial Polypharmacy in Depression in Older Individuals

The current investigation sought to expand the body of research on the effects of

multimorbidity and cardiovascular disease on depression in older individuals, by

investigating the role of general medication burden, and of medication management of

cardiovascular disease, on the presence of depressive symptoms in older individuals. It

was hypothesized that elders who take large numbers of medications, overall, would be

likely to show more signs of depression, but that those who receive more cardiovascular

medications, within the context of a polypharmacy regimen, would, in turn, be less likely

to show signs of depression.

These hypotheses have implications for our collective understanding of the

etiologies of depression in older individuals, and the possible relationship between

depressive symptoms and cardiovascular disease. It also has implications for prevention

and treatment of depression in the elderly, stressing the need for screening of depression









in the context of evaluation for cardiovascular disease, and integration of services aimed

at improving psychological and physiological functioning.

In the subsequent chapters, an overview is provided of the existing body of

literature on the causes and progression of depression in older individuals, as well as the

impacts of general medication burden, followed by the aims, design, and results of the

present study. The results will then be analyzed and synthesized, and the limitations of

the present study will be considered. Finally, the contribution of this work to the study of

depression in older individuals will be summarized.














CHAPTER 2
REVIEW OF LITERATURE

Depression in Older Individuals

Improving quality of life for older individuals is a common goal for many health

care professionals (Borowiak & Kostka, 2004; Boyd et al., 2005). While this is broadly

true of health care for all populations, it is particularly important when working with

older individuals, because of the impacts of medical multimorbidity and the onset of

physical frailty (Gijsen et al., 2001; Mitnitski et al., 2002).

In addition to physical frailty and illness, research has also examined mental

illness in late life, with a particular emphasis on depression (Blazer & Hybels, 2005).

Two arguments initially posited that true depression would be rare in later life. One

argument made in favor of this view was that the ability to self-regulate negative affect,

and to selectively interact with the environment in such a way as to maintain affective

balance, were skills that continued to develop over the course of the lifespan, and that

older individuals would be more proficient at these skills, and thereby less susceptible to

depression, than their younger counterparts (see, for instance, Consedine & Magai, 2003).

Another argument was that perceived depression in older individuals is primarily the

result of somatic complaints such as "aches and pains," and does not truly represent the

syndrome of depression (see, for instance, the discussion in Blazer et al., 1998).

However, subsequent research has found that these explanations are not satisfactory in

describing the range of mood experiences of older individuals, that some older

individuals do indeed experience depression as it is traditionally conceived of, and that









this depression is not purely limited to the experience of somatic complaints (Blazer et

al., 1998).

This line of research indicated that the affective characteristics of depression in

older individuals are approximately comparable to depression in younger adult

populations, but studies also indicated vastly different rates of depression in certain sub-

populations of older individuals. This research indicated that, in community samples,

base rates are comparable to community samples of younger adults, but that in clinical

and institutional settings, they are substantially higher, with particularly high rates among

patients being seen for cardiovascular concerns and individuals in long-term care

facilities, which house frail older individuals more likely to have increased medical co-

morbidities (Kramer, 1988; Parmalee, 1989; Rapp, 1988; Taylor et al., 2004). In addition,

studies have indicated that physical and mental complaints are particularly likely to co-

occur in later life. For instance, one study indicated that, among elderly individuals

receiving inpatient treatment for depression (with a mean age of 76.2 years), more than

75% had at least one comorbid general medical condition, and almost half had two or

more, most commonly cardiovascular conditions such as hypertension and atherosclerosis

(Proctor et al., 2003).

The Vascular Depression Hypothesis

This pattern of high rates of depression among clinical populations and older

individuals with high levels of multi-morbidity, particularly in the area of cardiovascular

conditions, inspired the vascular depression hypothesis as an explanation for depression

in later life. This hypothesis stated that this form of depression might be the manifestation

of underlying neuropathology caused by cerebrovascular deficit (Alexopoulos, 1990).

This hypothesis was validated both by neuro-imaging and by postmortem techniques,









which found evidence of white matter pathology in depressed individuals who were

above the age of 60, but not in younger depressed individuals or non-depressed elders

(Krishnan et al., 1997). It was also validated by retrospective analyses of risk, which

found substantially increased rates of the development of depression in individuals who

had histories of risk factors for stroke or heart attack such as high blood pressure or

cholesterol, diabetes mellitus, or a history of smoking (Mast et al., 2004; Oldehinkel et

al., 2003). Krishnan et al. (2005) extended this research by demonstrating that, not only

did cardiovascular risk predict the onset of depression, but that depression was a

prominent indicator of the disease pathway leading to stroke, with individuals who had

similar cardiovascular risk histories much more likely to experience stroke if they first

developed depression than if they did not.

Taken together, this research indicates that, within the population of older

individuals, there may be unique neuropathological factors related to cardiovascular

health that help explain some cases of depression as part of a process which begins with

cardiovascular risk burden, progresses to cerebrovascular deficit, white matter pathology,

and concomitant depression, and eventually leads to an increased risk of stroke. The

exact mechanisms behind this process are not understood. Research has indicated that

patterns of vascularization of cerebral white matter may lead to areas, called "watershed

areas," in which small vessels are responsible for blood provision, that these small

vessels may be more vulnerable to the early effects of reduced vascular performance,

leading to increased vulnerability of specific regions of white matter, and that this process

may be an intermediate step in the development of cerebrovascular deficit that leads to

strokes (Inzitari, 2003; Pantoni & Garcia, 1997).









Vascular Depression Within a Biopsychosocial Model of Depression

The pattern described by research in vascular depression is not likely to underlie

all cases of depression beginning in late life, or to completely explain the prevalence of

late-life depression even within a specific individual. Rather, it must be considered as a

component of a biopsychosocial model of depression. Depression in later life is likely to

be determined by multiple factors, just as it is during other phases of life. One

contribution is likely to be that of stressful life events. Some researchers have proposed

that these have a cumulative burden in increasing the likelihood of depression, leading to

increased risk in older individuals, purely by virtue of a longer life in which to experience

stressful life events (O'Sullivan, 2004). While studies have provided some support for

this hypothesis, and have identified certain stressful life events, such as the loss of a

partner or a grandchild, as being particularly associated with depression in late life, they

have found modest overall increases in depression as a result of these types of life events

(Lindeboom et al., 2002). Another contributing factor is likely to be individual

differences in personality characteristics. Although researchers, as previously implicated,

have theorized that older individuals have better affective regulation, personality

characteristics such as neuroticism appear to play a role throughout the lifespan, and may

contribute to risk for depression (Consedine & Magai, 2003; Blazer & Hybels, 2005).

Finally, there are also likely to be other genetic and biological substrates for depression in

older individuals. One of these factors is likely to be the role of hormonal processes.

Some studies have indicated that estradiol hormone therapy may have beneficial impacts

on depressive symptoms (Dennerstein et al., 1979). Estrogen has also been identified as a

neuroprotective agent, with possible protective capabilities in the damage process

associated with stroke ischemia, although this research has been equivocal (Gibson et al.,









2006; Green & Simpkins, 2000). This suggests that estrogen and related hormones might

not only have independent roles in the development and maintenance of depression, but

may also have roles in the process underlying vascular depression. Other hormones,

including stress hormones, such as cortisol, may also play an important role in depression

throughout the lifespan (Blazer & Hybels, 2005). Another of these factors is likely to be

the contribution of the serotonin transporter gene, and particularly the region of this gene

known as 5-HTTLPR, which has been implicated in the development, maintenance, and

prognosis of depression in late life (Lenze et al., 2005). These factors may also interact to

produce additional risk for depression. For instance, researchers have demonstrated that

individuals homozygous for one version of the 5-HTTLPR allele are at greater risk for

developing depression in the wake of stressful life events than individuals expressing

other genotypes (Wilhelm et al., 2006).

Within this biopsychosocial model, however, vascular etiology appears to play an

important role in understanding depression that is unique to the population of older

individuals. Research in support of the vascular depression hypothesis has many

limitations. It has not yet been able to demonstrate explicitly that white matter deficits are

the cause depression in later life. It also has not been able to fully explain the underlying

neuropsychological basis for mood disturbances given this type of neuropathology. It

should also be noted that, while the vascular depression hypothesis considers a course in

which depression follows sub-acute cardiovascular conditions (e.g. those which may not

be immediately life threatening), there are also bi-directional relationships between

depression in older individuals and acute cardiovascular events. These relationships are

not limited to the context of stroke, as discussed above, but also include elevated rates of









depression in individuals recovering from myocardial infarctions and increased risk for

potentially fatal ventricular arrhythmias in depressed individuals (Ziegelstein, 2001;

Whang et al., 2005).

Nonetheless, this mechanism provides interesting insight into the interactions

among physical health, specifically cardiovascular health, the brain, and mood, and

provides a possible neurobiological basis for some cases of depression in later life.

Polypharmacy

While the research on vascular depression suggests a very specific relationship

between vascular comorbidities and the development of depression, a body of research

has also grown that demonstrates substantially more general correlates between

multimorbidity and cognitive functioning. Many of these effects are studied through the

phenomenon of polypharmacy, wherein elderly individuals are likely to take a large

number of different medications, frequently prescribed and managed by different

physicians and pharmacists, who may not have opportunities to communicate fully with

each other (Kingsbury et al., 2001). Polypharmacy can be measured as simply the total

number of prescription drugs an individual takes.

Rollason & Vogt investigated research in polypharmacy and concluded that 38-

52% of individuals in the US over the age of 65 take more than five different

prescriptions, and that an individual is likely to take 0.4 more prescriptions per decade of

age (2003). Beyond multimorbidity, patient and healthcare provider attitudes were also

cited as potential explanations for this phenomenon. Furthermore, Veehof et al.

investigated longitudinal polypharmacy in older individuals, and found that, particularly

for those individuals for whom the number of medications increased rapidly over time,









clear indications for additional medications, based on changes in disease severity or new

diagnoses, were frequently absent (2000).

While this method of characterizing the medication burden is very simplistic,

researchers have nonetheless been successful in demonstrating that polypharmacy,

measured in this way, is a predictor of a variety of concerns, including an increased

likelihood of falls, delirium, and reduced cognitive performance, and have also

implicated polypharmacy as an independent cause both of general adverse health events

and increased mortality (Field et al., 2001; Flaherty et al., 2000; Hogan, 1997; Klarin et

al., 2005; Mamun et al., 2004; Sloane et al., 2002; Starr et al., 2004; Weiner et al., 1998).

Polypharmacy can be conceptualized as arising from a number of different

mechanisms. The most basic explanation for polypharmacy is that an individual takes

more medications because they have more health conditions. In this model,

multimorbidity is a cause of polypharmacy, and detrimental effects such as those seen

above are not particularly surprising, since these kinds of broadly negative outcomes are

often seen in individuals struggling with multiple serious medical conditions. A second

model that helps to explain adverse events such as those described above is that, as the

medication burden increases, individuals seem to be more likely to receive medications

for multiple conditions from multiple health care practitioners, who are not necessarily in

close communication. In such a situation, the chances of inappropriate prescription

increases, including the initiation of medications that are likely to have adverse impacts,

either due to the frailty of ill older individuals, or through interactions with other

concurrently prescribed medications. A second possible impact of this model is the

prescription of medication for symptoms that are misunderstood because of a lack of









knowledge about existing medications and already diagnosed conditions, leading to

excess medication for which there is no medical indication, which may lead to

unpredictable changes in areas such as neurochemical or endocrine functioning. Indeed,

studies have shown at least preliminary support for both of these models, indicating that

the likelihood of adverse drug events and adverse drug-drug interactions do increase with

polypharmacy in older individuals, and that older individuals who have high medication

burdens are more likely to have one or more medications for which no clear medical

justification is documented (Hogan, 1997; Veehof et al., 2000).

At the same time, since the basis for medication is not only the treatment of

symptoms, but also the amelioration or prevention of serious medical conditions, a third

important model of polypharmacy's effects is that increased polypharmacy represents

aggressive treatment of general medical conditions, which should lead to reduced

negative impacts of multimorbidity and may play a beneficial role. Particularly in the

area of cardiovascular disease, many disease processes are often effectively managed in

early phases through aggressive treatment with medication, such as with the use of

angiotensin-converting enzyme inhibitors (ACE Inhibitors) in the case of congestive

heart failure, as well as medication-based management of related risk factors, such as

hypertension (Rich, 2005). Successful medication-based management can be an indicator

of early response, averting the need for hospitalization and more serious interventions,

such as cardiovascular bypass surgeries, with which a greater likelihood of adverse

outcomes and risk are associated.

While some discussion of this hypothesis, sometimes referred to as "beneficial

polypharmacy," has taken place, few studies have demonstrated support for this






12


hypothesis, although researchers have begun to identify situations in which this model

might apply, such as combination drug therapies of conditions such as psychotic

disorders and, importantly, the treatment of cardiovascular conditions (Cleland et al.,

2000; Kingsbury et al., 2001). In these cases, polypharmacy was seen to be associated

with positive outcomes that were related to the aggressiveness of prevention and

treatment of identified conditions or risk factors.














CHAPTER 3
STATEMENT OF THE PROBLEM

The present study seeks to address these questions by examining relationships

between the number of medications an individual uses, both as a whole, and within

functional categories, and the symptoms of depression in a community sample of healthy

older individuals.

The usage of a community sample is important for a study of this kind. While rates

of clinical depression will tend to be low in healthy community samples, rates of

subsyndromal depression, or the presence of symptoms of depression that do not meet the

full criteria for a diagnosis of Major Depressive Disorder, are substantial (VanItallie,

2005). Although there is some controversy over the measurement or conceptualization of

subsyndromal depression, research has shown that it is a serious concern, both as a risk

factor for Major Depressive Disorder and as a predictor of related negative outcomes

such as perceived disability, increased utilization of medical services, and increased risk

of suicide (Chopra et al., 2005; Johnson et al., 1992). Specifically in the context of older

adults, minimal symptoms of depression, as measured by sub-clinical elevations in self-

report depression inventories, have been found to be strong indicators of adverse events,

such as myocardial infarction (Bush et al., 2001).

Furthermore, given that rates of depression are high in institutional populations of

older individuals, but low in the community, many individuals who are institutionalized

and depressed are likely to have previously been community-dwelling and experiencing

reduced levels of depression. The ability to detect a relationship between cardiovascular









medication regimens and depressive symptomatology prior to the onset of clinically

significant depression might therefore allow researchers to explore the possibility of

preventative measures. This is particularly critical if, as the vascular depression

hypothesis suggests, some cases of depression in late life are the result of organic

neuropathology, which is irreversible.

To begin to address these questions, in the present study, we address the following

three aims.

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

We hypothesize that, when demographics and the use of hormones, antidepressants,

and other central nervous system medications are controlled for, polypharmacy will be

associated with increased depressive symptoms, but that cardiovascular drugs will be

associated with reduced depressive symptoms. We hypothesize that these are

independent, simultaneously observable effects in opposite directions.

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

Since, as discussed above, previous research has implicated somatic complaints due

to physiological conditions as a source of apparent depressive symptomatology, and

warned that somatic complaints may not truly represent depression in the elderly, we

further hypothesize that these effects will exist not only for the somatic dimension of

depression, but also in other dimensions of depression. Stated in another way,

polypharmacy and cardiovascular medication levels will be predictors of not only the

overall level of depressive symptomatology, but also of multiple aspects of depression,

not limited to somatic complaints.














CHAPTER 4
METHODS

Participants

ACTIVE Pilot Study Participants

Data from the Pilot Study of the Advanced Cognitive Training for Independent and

Vital Elderly (ACTIVE) project were analyzed. The ACTIVE study is a randomized

clinical trial of targeted cognitive interventions, attempting to determine if cognitive

training can produce persistent improvements in the cognition of older adults, and if these

improvements lead to benefit in everyday life (Ball, 2002). In preparation for this study, a

smaller, non-longitudinal study was conducted to investigate psychometric properties of

the proposed instruments, to assess the ability to recruit participants to the trial, and to

test the feasibility of using the ACTIVE protocol with diverse populations. This study

was conducted on a community-based sample from six sites in the Northeast, Southeast

and Midwest United States.

Inclusion and Exclusion Criteria

Inclusion criteria for the study consisted of women and men aged at least 65 years

old, who had no functional disabilities at the beginning of the study, and a Mini-Mental

Status Examination (MMSE) score above 23. Individuals were also excluded if they had

a self-reported recent history of stroke, cancer or dementia diagnoses. A total of 168

participants were enrolled in the study.









Measures

Interview-Based Measures

Participants' demographic information and an assessment of their depressive

symptomatology were obtained in a phone-based interview. In addition to age, the

information recorded for each participant included gender, years of education, and race.

In addition, although a detailed checklist of prior health conditions was not available,

participants' cardiovascular risk was estimated by participant self-reported diagnosis of

Diabetes or Heart Disease (0, 1 or 2 total conditions).

During a subsequent in-person interview, a "brown-bag audit" of medication was

performed. This consisted of each participant bringing all medications they were

currently taking at the request of a health care provider (both over-the-counter and

prescription medications) to an interview. Medications provided during the audit were

documented by the interviewers. This method has been shown to be effective in

accurately portraying the medication status of older individuals (Caskie & Willis, 2004).

Medications were recorded by either brand or generic name, along with dosage route, and

frequency (or "as needed" status). All medications were later standardized into

therapeutic classes, as discussed in the Procedures section, below.

Self-Report Questionnaires

Depression was assessed using the Center for Epidemiological Studies Depression

Scale (CES-D(20)), a robust measure of depression that has been validated in adults,

including different age groups and races (Blazer et al., 1998; Wallace & O'Hara, 1992;

Weissman et al., 1977). This scale has a four-factor structure, consisting of Somatic

Complaints (such as sleep disturbance), Depressive Affect (feelings of sadness or

loneliness), Positive Affect (the absence of feelings of happiness or joy), and









Interpersonal Problems (the belief that others are unfriendly or dislike the individual),

and also provides a Total Score that represents overall depressive symptomatology

(Blazer et al., 1998; Roberts, 1980). While the CES-D total score can be compared to a

cut-off score (typically 16) to determine if an individual is clinically depressed, the

majority of individuals in this sample had low levels of depression, and so the actual

score was used instead of a diagnostic classification, a technique that has been used with

this instrument in the past, and has been effective in demonstrating the effects of minimal

symptoms of depression (Wallace & O'Hara, 1992).

Procedures

Categorization of Medications

After collection of medication information by interviewers, the medications were

coded into American Hospital Formulary Service (AHFS) classifications, a functional

classification that is widely used in the health care professions (McEvoy, 1996) by

researchers from the ACTIVE team. This formulary system provides hierarchical

classification of medications into broad functional categories (such as central nervous

system agents), as well as sub-classification into smaller functional categories (such as

anxiolytics), and therefore allows for analysis at multiple functional levels.

The number of drugs each participant took in several categories of interest was

then determined. The first of these categories consisted of medications used in response

to cardiovascular disease, formed from drugs in AHFS groups 20 (blood formation and

coagulation), 24 (cardiovascular drugs) and 40 (Electrolytic, Caloric, and Water

Balance). The numbers of different drugs in the relevant classes were summed to arrive at

this variable. These three functional categories were pooled together because all drugs in









these categories are commonly prescribed for the management of cardiovascular

conditions.

The number of drugs with primary central nervous system impacts (Group 28)

was also determined, in a similar fashion, with one subcategory, antidepressants,

considered separately, since, as previously indicated, drugs in these functional categories

are likely to have impacts on mood. Hormones and synthetic hormones (Group 68) were

also included in the analysis, since they have been implicated to have impacts both on

mood and on cardiovascular functioning.

Finally, the overall level of polypharmacy was computed as the number of

different drugs, irrespective of therapeutic class, for each participant. This variable

included contributions from the specific classes of drugs discussed above.

Missing Data

If a participant had missing data for two or fewer items on the CES-D, mean

scores were used to impute missing data (one participant was dropped for this reason);

participants with more than two items missing were excluded from subsequent analysis,

due to concerns of excessive distortion of the CES-D profile due to imputation of missing

responses from a limited number of available responses. For the computation of the CES-

D Total Score and its two larger subscales (the Somatic Complaints subscale and the

Depressive Affect subscale) missing items from the measure were replaced using mean

substitution. However, the remaining two subscales, Positive Affect and Interpersonal

Items, contain few items from the CES-D, and could be distorted considerably by mean

substitution; as a result, participants with missing values were excluded from analyses

using those two subscales as the dependent variable (relevant numbers of valid

participants are presented along with the results of these analyses). Two participants for









whom medication data was not available (two participants) were also removed from

subsequent analyses. The final number of participants included in the main analyses was

165.

Statistical Analysis

Demographic statistics were computed, and a linear regression was performed for

the CES-D total score against demographics, cardiovascular risk, the levels of CNS,

antidepressant, hormonal and cardiovascular drugs, and the overall level of

polypharmacy. The predictors were entered in blocks into this regression, with

demographics and risk burden entered first, to control for the overlapping effect of these

variables and the medication variables of interest. Then, specific categories of drugs were

entered in the second block, to determine if these had an impact on mood above and

beyond demographics. Finally, polypharmacy was entered in the third block, to determine

if this had an additional impact that was distinct from the impact of medication in the

functional categories. The regression model was then repeated for each of the four

subscales of the CES-D.














CHAPTER 5
RESULTS

Demographic Statistics

For the 165 participants remaining after removal of individuals due to missing data

concerns, the mean age at the time of the study was 73.7 years (SD = 6.1), and 83% were

female. 55% of participants were African American, while the majority of the remainder

(42%) were European American. The mean education level was 12.1 years (SD = 3.0).

While few individuals in the sample endorsed a sufficient number of CES-D items

to meet the criteria for clinical depression (a total score of at least 16 points; 9% of the

sample endorsed this level of depressive symptomatology), the vast majority (86%) of

participants did endorse at least one symptom of depression. Figure 5-1 summarizes the

distribution of observed CES-D Total Scores, indicating the number of individuals

endorsing a clinically significant severity of depressive symptoms, as well as individuals

endorsing lesser levels of depressive symptoms, divided at arbitrary cut-points (0-4, 5-8,

and 9-15 total points). Most participants (78%) endorsed one or more somatic complaints

(e.g. sleep or appetite disturbances), while fewer (43%) endorsed depressive affect (e.g.

sadness or loneliness), a lack of positive affect (e.g. the absence of happiness or

enjoyment; 46%), or interpersonal symptoms (e.g. perception of others as unfriendly;

12%).

Medication Statistics

The mean number of medications per participant in the sample was 2.9, with 20.6%

of participants taking five or more medications, and only 13.9% reporting no current












9%


18c"




51%



22%


m0-4 I5-8 -9-15 0>16




Figure 5-1. Distribution of Participants' CES-D Total Scores medications.

Figure 5-2 depicts the distribution of overall numbers of medications for

participants.


25%


20%

15%

1 10%

5%

0%


0 1 2 3 4 5 6

Number of Medications


7 8 9 10


Figure 5-2. Frequency of Occurrence of Different Numbers of Medications Per
Participant










The most frequently endorsed categories of medications included Cardiovascular;

Hormones; Electrolytic, Caloric, and Water Balance; Central Nervous System;

Gastrointestinal; and Blood Formation.

Correlational Analysis

Correlations among the predictor variables are shown in Table 5-1, with

correlations significant at the p < 0.05 level shown in boldface. Notably, an increased

number of cardiovascular conditions from the screening instrument (which does not

necessarily represent all possible cardiovascular conditions) was associated with taking

fewer cardiovascular medications, as well as with fewer hormone medications.

Polypharmacy was significantly associated with a greater number of Cardiovascular,

Central Nervous System, and Hormone drugs.

Table 5-1. Correlations Among Predictor Variables
1 2 3 4 5 6 7 8 9 10 11
1. Age (years) 1.00
2. Gender 0.04 1.00
3. Education -0.19 -0.07 1.00
4. Race = White 0.28 -0.17 0.02 1.00
5. Race = Other 0.05 -0.11 0.09 -0.15 1.00
6. CVRFs 0.00 0.02 0.22 0.10 -0.05 1.00
7. Cardiovascular Drugs -0.02 -0.01 -0.12 -0.09 0.06 -0.53 1.00
8. CNS Drugs 0.00 0.01 -0.24 -0.04 0.02 -0.13 -0.05 1.00
9. Anti-Depressants -0.03 0.08 -0.09 -0.01 -0.03 0.01 -0.01 0.07 1.00
10. Hormones -0.04 -0.01 -0.10 -0.01 -0.01 -0.31 0.12 0.09 0.04 1.00
11. Polypharmacy -0.02 0.04 -0.23 -0.09 0.09 -0.57 0.77 0.35 0.12 0.47 1.00
Note: Correlations significant at the p < 0.05 level are boldfaced. Abbreviations: CVRFs -
Cardiovascular Risk Factors; CNS Drugs Agents acting primarily on the Central Nervous System

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

The linear regression of total CES-D score on the predictor variables is described in

Table 5-2. The overall model was significant (F(11, 153) = 3.270,p < 0.001), and

described 19% of the variance in CES-D score. Of this, 12.7% of unique variance, above

and beyond demographic variables, was described by the discrete drug categories, and an










additional 4.6% of variance was associated with polypharmacy, above and beyond the

individual effects of the drug categories and demographics. An increase in the number of

cardiovascular drugs was associated with a decrease in depressive symptoms (3 = -0.447,

p = 0.007; regression weights reported as standardized unless otherwise noted), as was an

increase in the number of hormonal drugs (3 = -0.237, p = 0.025); an increase in overall

polypharmacy was also separately associated with a substantial increase in depressive

symptomatology (P3 = 0.610, p = 0.004). No other variables reached significance as

predictors in this model.

Table 5-2. Regression of Predictor Variables Onto Depression Measures

Standardized Regression Coefficients*

CES-D Somatic Depressive Positive Interpersonal
Parameter Total Score Complaints Affect Affect Problems
Age (0=below median) 0.136 0.166 0.072 0.050 0.040
Gender (1=female) 0.024 0.044 0.021 0.001 0.065
Education (years) -0.052 -0.096 0.032 -0.037 -0.071
White race (1=true) -0.047 -0.101 0.040 -0.010 -0.096
Other race (1=true) -0.096 -0.063 -0.119 0.017 -0.056
# of CVRFs -0.149 -0.011 -0.083 -0.273 -0.071
Cardiovascular Drugs -0.477 -0.267 -0.716 0.048 -0.396
Other CNS Drugs 0.008 -0.010 -0.149 0.236 -0.080
Anti-Depressants 0.088 0.154 0.072 -0.023 -0.076
Hormone Therapy Drugs -0.237 -0.162 -0.331 0.000 -0.211
Polypharmacy 0.610 0.503 0.904 -0.225 0.513
Valid n** 165 165 165 154 160
Cumulative R2 0.190 0.187 0.180 0.098 0.078
Model F 3.270 3.191 3.046 1.405 1.133
Model Significance 0.001 0.001 0.001 0.177 0.078
Notes: (*) Regression coefficients result from five separate linear regression models for the total
CES-D score and the four sub-scales. Boldfaced coefficients were significant at the p < 0.05
level. (**) For the four subscales, missing values were not imputed due to the small number of
items on each scale, reducing the number of valid cases. Abbreviations: CVRFs Cardiovascular

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

The results of the regressions for the four subscales of the CES-D are also

presented in Table 5-2, above. The model for the Somatic Complaints subscale was









significant (F(11, 153) = 3.191, p = 0.001), and described 18.7% of the variance in the

subscale. In this model, increasing age was associated significantly, but slightly, with

increased Somatic Complaints (P3 = 0.166, p = 0.036), as was a larger number of Anti-

Depressant medications (3 = 0.154, p = 0.044), and, more substantially, an increase in

overall polypharmacy (3 = 0.503, p = 0.016). The model for the Depressive Affect

subscale was also significant (F(11, 153) = 3.046,p = 0.001), describing 18% of the

variance in Depressive Affect. 11 additional participants were excluded from the

analysis, due to missing responses on this subscale of the CES-D, leading to a total of 154

participants in the analysis. An increased number of cardiovascular drugs was strongly

associated with decreased Depressive Affect (3 = -0.716, p < 0.001), as was an increased

number of Hormone drugs, albeit at a weaker level (3 = -0.331, p = 0.002). At the same

time, an increase in overall polypharmacy was strongly associated with an increase in

Depressive Affect (P3 = 0.904, p < 0.001).

The model for Positive Affect, on the other hand, failed to reach significance (F(11,

142) = 1.405, p = 0.177). Five additional participants were excluded from this analysis

due to missing data on this subscale of the CES-D, leading to a total of 160 participants in

this analysis. However, the number of co-morbid cardiovascular conditions was mildly

associated with a reduction in this dimension of depression (3 = -0.273, p = 0.008), and

the number of CNS medications, not including anti-depressants, was mildly associated

with an increase in this dimension of depression (3 = 0.236, p = 0.048). The model for

Interpersonal Problems also failed to reach significance (F(11, 148) = 1.133, p = 0.340),

although overall polypharmacy was moderately associated with increases in this

dimension of depression (3 = 0.513,p = 0.044).














CHAPTER 6
DISCUSSION

Review of Study Findings

Characterization of the Study Sample

The percentage of clinically depressed individuals (9%) in the present sample

compares favorably with that reported in a racially similar sample by Blazer et al. in

which a rate of clinically significant depression, as assessed by the CES-D, of 9% was

also found for community-dwelling elders above the age of 65 (Blazer et al., 1998). At

the same time, the mean number of medications per participant (2.9) was approximately

comparable to that reported by Veehof et al. (2000) for a similar age cohort in the

Netherlands (2.6 drugs per participant, at study onset, for a population with mean age 73

years), although somewhat lower than that reported for some other studies (Rollason &

Vogt, 2003). Differences between these studies may have been driven by broader

inclusion in some epidemiological studies the ACTIVE study did not include

participants who were community-dwelling, for instance, but functionally impaired.

However, taken as a whole, these findings indicate that the study sample is approximately

comparable, along the dimensions of depressive symptomatology and medication usage,

to other studied samples that are similar in age and/or racial demographics.

Aim 1. Relationships Among Polypharmacy, Cardiovascular Medication, and
Depressive Symptoms

In the present study, overall polypharmacy was significantly associated with

increased depressive symptoms, as measured by the CES-D Total Score, even when









controlling for demographics, cardiovascular risk, and specific categories of drugs likely

to be related to depressive symptoms. At the same time, independently of the effect of

overall polypharmacy, the use of cardiovascular medications had a unique effect,

associated with reduced depressive symptoms, as measured by the CES-D Total Score,

providing support for the hypothesis that independent and opposing effects of beneficial

and detrimental polypharmacy impacts would be observable in the context of depressive

symptomatology.

Aim 2. Relationships Between Medication Effects and Dimensions of Depression

When the detrimental impact of polypharmacy on depression was considered

within specific dimensions of depression represented in the CES-D, this effect was not

limited to the Somatic Complaints subscale of the CES-D, but was also present in the

Depressive Affect subscale, indicating that this effect existed in the context of the core

mood symptomatology of depression, as opposed to the existing solely as a projection of

somatic complaints due primarily to a general medical condition on the measure of

depression.

When the beneficial impact of cardiovascular medication was considered in the

context of the dimensions of depression, the effect was found to be primarily represented

in the Depressive Affect subscale, again demonstrating a link between the impacts of

medication and the core mood symptoms of depression.

Synthesis of Findings

The pattern of results presented above is consistent with the notion of simultaneous

overall detrimental impact of polypharmacy and beneficial impact of polypharmacy in

the case of cardiovascular medication, for the symptoms of depression, in older

individuals, although it is important to note that causation cannot be inferred either from









this relationship or from the relationship between cardiovascular medication and

increased depressive symptoms, and that overall polypharmacy cannot be made truly

independent of cardiovascular polypharmacy. This model of simultaneous detrimental

and beneficial polypharmacy is consistent with the hypothesized model presented earlier,

in Figure 1-1.

Implications of Study

Detrimental Polypharmacy for Depression

There are a number of possible explanations for the observed detrimental impact of

polypharmacy. Overall polypharmacy might lead to increased dysregulation of

neurotransmitters or endocrine processes, leading to adaptation difficulty. This may

proceed through a generalized route that involves cumulative effects of many drugs in a

non-specific way, particularly the unexpected impacts of drugs that are prescribed for

inappropriate reasons, or it may proceed through the increase in the likelihood of specific

adverse drug-drug interactions (Hogan, 1997; Veehof et al., 2000). Further understanding

of these mechanisms may lead to more effective intervention strategies for older

individuals with co-morbid cardiovascular disease and depressive symptomatology.

It is also possible that the detrimental effect of polypharmacy is mainly an effect of

multimorbidity, and not of the medication itself (i.e. the presence of multiple medications

serves as a proxy for the presence of multiple underlying medical conditions).

Differentiating this alternative explanation from a mechanism rooted in the effects of

polypharmacy on the central nervous system is difficult because no clear method exists

whereby the number and strength of medications can be meaningfully scaled by the

number and severity of the medical disorders that necessitate the medications in the first

place. Moreover, in this study, measurement of health conditions was not adequate to









permit the independent assessment of physical health conditions at the same level of

detail as was achieved in analysis of the available medication data. As previously

indicated, medication prescribed without clear indication is a serious concern within

observed polypharmacy, and partitioning its effect from the effect of additional

medications prescribed with clear indications may be important in understanding the

mechanism of polypharmacy's deleterious effects.

In either event, the suggestion that polypharmacy may carry affective concomitants

in the form of increased symptoms of depression adds to a growing body of literature

supporting the need for interdisciplinary interventions to attempt to reduce polypharmacy

in older individuals, without compromising the efficacy of treatment of the diagnosed

disorders for which they are being treated. Research on the benefits of such interventions

has focused primarily on cost savings, to date (Christensen et al., 2004). However, such

interventions already appear to be able to identify and act on individuals who are likely to

have inappropriately prescribed, unnecessary, or high-risk medication regimens, and may

represent an opportunity to improve the functioning of older individuals that carries with

it minimal risk and may have significant capacity to deliver improvements to quality of

life (Rollason & Vogt, 2003; Trygstad et al., 2005).

Beneficial Effects of Polypharmacy of Cardiovascular Medication for Depression

There are many potential mechanisms to explain the observed beneficial

polypharmacy relationship, in which individuals taking more cardiovascular medications

appear to be less depressed. Cardiovascular medication might be associated with the

prevention of white matter pathology, or may possibly aid compensatory mechanisms

such as increased cerebral blood flow and perfusion. At least one study has demonstrated

improvements in frontal white matter functioning, as a result of successful treatment of









depression in older individuals (in that case, through electro-convulsive therapy),

suggesting that improvements in white matter functioning may be an important pathway

to improvements in depressive mood in late life (Nobuhara et al., 2004).

On the other hand, it is also quite possible that the beneficial polypharmacy

associated with cardiovascular medications observed in the present study could be

explained through improvements in physical health by virtue of successful medical

management of cardiovascular disease. If it is the case that depression in cardiovascular

disease is not a specific neurological effect of the disease process, but is rather a

consequence of physical health impairment, then this depressive effect should be specific

to a level of physical health impairment, and not to a disease category. The present study

did not adequately assess physical health impairment as a potential mediator of drug

effects, although this may well be a fruitful area for future research. Furthermore,

successful treatments should improve depressive symptoms to the extent that they are

successful in treating the underlying disease.

Supporting this viewpoint is research that has demonstrated that depression in

individuals with organ failure requiring transplantation was not associated with the site of

failure (when comparing individuals with heart, lung, and kidney failure), but was

associated with the level of pain experienced (Forzberg et al., 1999). It is important to

note, however, that this research was not performed on older individuals, in whom the

associations among cardiovascular disease, white matter pathology, and depression, is

believed to exist. Another study indicated that individuals whose heart failure was

managed either by transplantation or by medication indicated that medication produced

both better improvements in physical health and a substantial decrement in depressive









symptoms (Evangelista et al., 2005). However, that study was not able to demonstrate

whether physical health management was a mediator of reduced depression in the

medication group. Indeed, it is difficult to isolate the success of treatment in managing

physical health from other benefits that are presumed to occur simultaneously in

individuals who respond to cardiovascular treatment, such as improved cerebrovascular

functioning.

Regardless of the relative power of the above explanations for the beneficial role of

cardiovascular polypharmacy on mood symptoms in this population, the facts that

individuals who received more cardiovascular medications showed fewer symptoms of

depression, and individuals who received fewer cardiovascular medications showed more

symptoms of depression is striking. Is it possible that cardiovascular disease may

continue to be under-treated in this population, and that at least some of those individuals

not receiving this medication might benefit from more aggressive treatment? Some

evidence looking purely at the issue of adequate diagnosis and treatment of

cardiovascular conditions in this population, suggests that this might, indeed, continue to

be the case, due to complicated clinical presentation, the non-specificity of symptoms,

access to care, particularly among impoverished elders, and other issues (Fitzpatrick et

al., 2004; Frasure-Smith et al., 1993; Rich, 2005). Complicating this issue is the fact that

not all individuals who are prescribed treatments for these conditions have the financial

ability to obtain all prescribed medications (Piette et al., 2004).

Study Limitations

There are several limitations to this study. First, the sample was relatively small,

and did not include frail or institutionalized elders. While the latter aspect makes this

study more representative of effects on community-dwelling elders, it also leads to









selecting individuals who are likely to be relatively less depressed and suffering from less

severe cardiovascular pathology. Conclusions about the process of decline within older

individuals that leads from low base rates of depression in the community to elevated

base rates in the institutional population are difficult to draw in the absence of data on

participants from both settings. In addition, since the present analysis is not longitudinal,

it is impossible to make causal inferences. It is not clear whether individuals who are less

depressed are more likely to need or use medication for cardiovascular conditions, for

instance, or whether individuals who use more cardiovascular medications are less likely

to become depressed.

This study utilized a method of operationalizing subsyndromal depression that has

been used with success in the extant literature namely, using scores from a self-report

depression instrument as continuous variables. It was nonetheless successful in finding

significant effects relating relatively low levels of depression and medication levels.

However, the exact relationship between this method and other methods of

conceptualizing depression below the level warranting a formal diagnosis of Major

Depressive Disorder, such as the research criteria proposed in the DSM-IV-TR for Minor

Depressive Disorder, remains unclear. The differences in the way this phenomenon is

defined in different research studies limit the ability of this body of literature, as a whole,

to make broad statements about sub-clinical, subsyndromal, minor, or minimal

depression. Each study, however, presents results that are potentially individually

meaningful, within the context of the definition adopted by the respective researchers, as

the present study also seeks to do.









Because of limitations in assessing existing physical health conditions, and the

longitudinal relationships between diagnoses of these conditions and prescription of

medications, the present study is limited in that an thorough assessment of each

participant's overall physical health and multimorbidity was not possible, and there is no

way to truly differentiate polypharmacy in the sense of aggressive treatment and

polypharmacy in the sense of overmedication. While it is implied here that cardiovascular

medication, with its beneficial impacts, represents the former, and not the latter, it is also

a component of polypharmacy, as measured, and is likely to contain, itself, both types of

polypharmacy.

The present study did not investigate the impacts of specific medicines in detail,

another technique that has provided compelling insight into changes in functioning in

older individuals. Several methods for doing this have been developed. One of these

methods is the investigation of relative risk associated with individual drugs (Dhondt et

al., 2002; Veehof et al., 2000). A second method is the consideration of lists of drugs,

such as the Beers Criteria, that are considered contra-indicated for older individuals in the

majority of cases, based on known anecdotal or empirical evidence of problems

associated with these medications in late life (Aparasu & Mort, 2000; Klarin et al., 2005).

These methods have strengths in their ability to identify specific mechanisms based on

the actions of individual drugs. However, the present method provides a complementary

line of evidence, in that large, significant effects of broad classes of medication suggest

the possibility of more basic mechanisms than those observed in studies of specific drugs.

Such mechanisms are not likely to rely on the site of action or chemistry of a specific,

individual drug, and may operate in parallel to the previously observed effects.









Finally, because this study did not make use of brain imaging techniques, no

conclusive statements can be made about the associations among polypharmacy, state

changes in the brain, and depression.

Conclusion

In spite of these limitations, the present research contributes to the body of

literature surrounding depression in older individuals by emphasizing the importance of

considering medication-based management of chronic health conditions, especially

cardiovascular conditions, within an integrated framework alongside other explanatory

variables in the creation and maintenance of depressive symptoms in older individuals.

This adds to the large body of literature that has demonstrated that elderly individuals

with a history of cardiovascular risk burden are more likely to become depressed, and

that these individuals are then likely to have white matter pathology and are at increased

risk for strokes and for mortality, as well as with research indicating that functional

disability due to chronic health concerns increases the risk of depression in the elderly,

and suggests further investigation of management of the overall medication burden, as

well as preventative and aggressive treatment of cardiovascular conditions, as possible

elements of an overall healthcare program for older individuals that may have the

capacity to prevent or eliminate some cases of depression in this population.
















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BIOGRAPHICAL SKETCH

Mohan Krishnan graduated from the University of Michigan with a Bachelor of

Science in engineering physics, in 1997, and a Master of Science in nuclear engineering

and radiological sciences, in 1999. He then spent approximately 5 years working in

various engineering and business roles within the automotive industry. During this time,

he pursued coursework in psychology at Wayne State University, and participated in

research studying the relationship between cardiovascular disease and depression in the

elderly at the Wayne State University Institute of Gerontology. Currently, Mr. Krishnan

is working toward a doctorate in clinical and health psychology, with a specialization in

clinical neuropsychology, at the University of Florida.