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Depression as a risk factor for dementia
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Depression as a risk factor for dementia
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Content
DEPRESSION AS A RISK FACTOR FOR DEMENTIA
by
Jessica Anne Brommelhoff
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF ARTS
(CLINICAL PSYCHOLOGY)
August 2006
Copyright 2006 Jessica Anne Brommelhoff
UMI Number: 1438544
1438544
2007
UMI Microform
Copyright
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
ProQuest Information and Learning Company
300 North Zeeb Road
P.O. Box 1346
Ann Arbor, MI 48106-1346
by ProQuest Information and Learning Company.
ii
Acknowledgements
I would like to gratefully acknowledge Margaret Gatz, Ph.D. for her
dedicated support and supervision throughout every step of this project. In addition
to Dr. Gatz, I would like to also thank Nancy Pedersen, Ph.D. for allowing me access
to the Swedish Twin Registry data.
Thank you as well to all past and present Gatz Lab members (Amy Fiske,
Ph.D., Cynthia Pearson, Ph.D., Barbara Yuen, Maggi Mackintosh, Poorni Otilingam,
Randi Jones, Emily Schoenhofen, Priya Hanson, and Amber Hall), as well as my
committee members (Bob Knight, Ph.D., John Horn, Ph.D., and Jack McArdle
Ph.D.), for their support (moral and otherwise), comments, and suggestions over the
past two years.
Additionally, I would like to thank my friends and classmates, especially
Lara Heflin, Kent Holmes, Jenny Stevens, Anne Hong, and Carrie Ryan for keeping
me “well-rounded” and helping me maintain a sense of humor. Finally, I would like
to thank my parents, Jurgen and Gretchen Brommelhoff, and my family for their love
and constant support.
iii
List of Tables
Table 1: ICD Diagnostic Codes for Depressive Disorders 11
Table 2: Sample Demographics for Case-Control Analysis Covariates 19
Table 3: Risk for Dementia Stratified by Early and Recent Depression Onset 20
Table 4: Risk for AD Stratified by Early and Recent Depression Onset 21
Table 5: Sample Demographics for Co-Twin Control Covariates 23
Table 6: Risk for Dementia for Co-Twin Control Analyses 23
iv
Table of Contents
Acknowledgements ii
List of Tables iii
Abstract v
Introduction 1
Research Design and Methods 4
Research Design 4
Measures 6
Figure 1: Case Identification 9
Combining Sources of Depression 13
Years Since Age of Onset of Depression 15
Covariates 16
Analyses 16
Results 18
Case-Control Analysis 18
Co-Twin Control Analysis 22
Discussion 24
Limitations 28
Conclusion 30
References 31
Appendix 35
v
Abstract
Studies have shown that depression and dementia frequently coexist, but
whether depression is a risk factor or prodrome of dementia remains controversial.
This study used a co-twin control design to test whether a history of depression was
associated with a significant increase in the risk of developing dementia. We also
examined whether those with a greater time difference between age of onset of
depressive episodes and onset of dementia were at a greater or lesser risk for
developing dementia compared with those who either had no prior depressive
episodes or who had a first depressive episode occurring closer in time to dementia
onset. We found that individuals with a history of depression were more likely to
develop dementia, and that with each one-year increase in depression onset prior to
dementia onset or censored age, the risk of developing dementia decreased by eight
percent. These findings suggest that depression is a prodrome, rather than a risk
factor for dementia.
1
Introduction
Studies have shown that depression and dementia frequently coexist (Jorm,
2001). Whether or not a history of depression leads to an increased risk of dementia,
however, remains controversial. Several case-control studies have tested the
connection between dementia and depression. An early analysis (Agbayewa, 1986)
found that patients with Alzheimer’s disease (AD) were 2.77 times more likely than
nondemented patients to have a history of psychiatric illness, with depression being
the most frequent diagnosis. A later study by Speck, Kukull, Brenner, Bowen,
McCormick, Teri, et al. (1995) specifically looked at depression that was not related
to loss or grief and found an odds ratio of 2.0 (95% CI = 1.1, 3.5) for a history of
depression in participants with AD. When the results were stratified by year of
depression onset, they observed an odds ratio of 2.4 (95% CI = 1.2, 4.5) for
depression occurring more than 10 years before the onset of dementia, but an odds
ratio of 0.9 (95% CI = 0.3, 2.8) for depression occurring within 10 years before
dementia onset. In other words, an early history of depression rather than a later-life
diagnosis of depression was more associated with the risk of developing dementia.
In contrast to the findings by Speck et al. (1995), several studies have found a
higher risk of depressive episodes developing for the first time closer in time to
dementia onset (Chen, Ganguli, Mulasnt, & DeKosky, 1999; Wetherell, Gatz,
Johansson, & Pedersen, 1999; Yaffe et al., 1999), and therefore concluded that
depression is a prodromal feature of dementia, rather than a risk factor for dementia.
2
These studies all suggest that depression manifests itself as an early symptom of
dementia.
A meta-analysis by Jorm (2001) suggested that a history of depression nearly
doubles the risk of dementia, as found by both case-control studies (RR=2.01, 1.16-
3.50) and prospective studies (RR=1.87, 1.09-3.20). Of the 14 studies he included,
seven showed that a history of depression significantly increased the relative risk for
dementia (Buntinx, Kester, Bergers, & Knottnerus, 1996; Cooper & Holmes, 1998;
Devanand et al., 1996; Geerlings et al., 2000; Jorm et al., 1991; Kessing, Mortensen,
& Bolwig, 1998; Steffens et al., 1997), while the other seven studies did not find the
relationship statistically significant (Agbayewa, 1986; Chen et al., 1999; Henderson
et al., 1997; Palsson, Aevarsson, & Skoog, 1999; Speck et al., 1995; Wetherell et al.,
1999; Zalsman et al., 2000). The meta-analysis yielded a gain in power that separate
small studies would obscure.
Depression can also be co-morbid with dementia. Bassuk, Berkman, and
Wypij (1998) found that depression did not significantly precede cognitive
impairment, but instead was present in those participants who had already
experienced a reduction in cognitive abilities. Thus, they concluded that depression
was more likely to be a reaction to an individual’s insight about decline in cognitive
functioning.
In Jorm’s meta-analysis (2001), he concluded that there were three
hypotheses that may explain the association between depression and risk of
dementia: 1) depression is a prodrome of dementia, 2) depression and dementia are
3
independent illnesses, but depression affects the threshold for developing dementia,
or in other words the cognitive deficits caused by depression might lead to an earlier
diagnosis for dementia and 3) depression causes damage to the hippocampus, leading
to dementia, via a glucocorticoid cascade. While most of these explanations are not
mutually exclusive, the current study tests whether a history of depression is a risk
factor for dementia, and whether the timing of onset of depression is related to this
risk, a factor that Jorm (2001) did not take into account in his meta-analysis.
Using a co-twin control design, we tested whether a history of depression
significantly increased the risk of developing dementia later in life among twin pairs
discordant for dementia. Additionally we examined the difference between age of
first depressive episode and age of onset of dementia. In other words, we tested
whether those with a greater time difference between onset of depressive episodes
and onset of dementia were at a greater risk for developing dementia compared with
those who either had no prior depressive episodes or those who had a first depressive
episode occurring closer in time to dementia onset. On the one hand, an earlier
depression diagnosis implicates depression as a risk factor for dementia. On the
other hand, if depression only occurs close in time to dementia onset, then the
hypothesis of depression as a prodromal feature of dementia cannot be refuted.
The proposed study has several advantages over past investigations. First,
because each person with a dementia diagnosis was paired with a non-demented
twin, this study will control for genetic and early environmental risk factors. Also,
sample sizes for previous studies of similar design have been a great deal smaller
4
than the current study’s sample. This study additionally has the advantage of having
several sources from which to gain information regarding the history of depression
for each person, including sources that do not rely on the self-reports of participants.
Research Design and Methods
Research Design
This study used two designs—the co-twin control method (also called
internal control) and the case-control method (also called external control). The co-
twin control method is used to examine the importance of a risk factor after
controlling for genetic background and early environmental experiences
(Lichtenstein, De Faire, Floderus, Svartengren, Svedberg, & Pedersen, 2002),
through comparing twins with a disorder to their unaffected twin siblings. In the
internal control group design, in order to control for most genetic and early
environmental experiences, both monozygotic (MZ) and dizygotic (DZ) twin pairs
discordant for dementia were used, and the non-demented co-twin served as the
control. In the case-control group design twins diagnosed with dementia are
compared with unrelated external controls, and the design is in essence a typical
case-control design, with the results indicating the association between the exposure,
in this case depression, and the outcome, dementia.
Participants
Participants in the study took part in the Study of Dementia in Swedish Twins
(HARMONY; Gatz et al., 2005). The study population included all the twins in the
5
Swedish Twin Registry (STR; Lichtenstein et al., 2002) who were aged 65 and older
and alive during the telephone screening phase. Of the 20,269 twins, 14,435 (71.2%)
agreed to participate, 4,314 (21.3%) refused, 1,190 (5.9%) were not able to be traced,
and 267 (1.3%) died between selection and screening. Additionally 63 individuals
were members of a previous longitudinal cohort study of aging (Gatz et al., 1997), in
which they had already been screened for dementia. Therefore, the total number of
participants was 14,498. A total of 13,693 participants finished the cognitive
screening process, 712 were not interviewable due to deafness or physical illness, 23
were not administered the cognitive screening questions due to administrative error,
and seven individuals gave insufficient answers to obtain a score.
Case-control (external control) sample. This sample consisted of all
individuals aged 65 and older who completed the screening process and had
information about both their lifetime history of depression and their dementia status.
Those who screened positive during the screening phase and later were diagnosed
with dementia during the clinical phase were considered cases (N=547) and those
who screened negative for dementia were controls (N=12,133). Those not included
in the analyses were individuals who screened positive, but were not visited for a
diagnostic evaluation because of refusal to participate in the clinical phase, or by
design because their co-twin had died before age 65.
Co-twin control (internal control) sample. This sample consisted of 146 twin
pairs discordant for clinically diagnosed dementia, where there is information about
depression for both individuals.
6
Measures
Dementia Diagnosis. Dementia was diagnosed in two phases, a screening
phase and a clinical phase. In the screening phase, cognitive status was assessed
over a 2.5-year period starting March 1998. The TELE cognitive screening
instrument (Gatz, Reynolds, Nikolic, Lowe, & Karel, 1995) was used to screen for
cognitive dysfunction. If an individual performed poorly on the TELE, a relative
was subsequently interviewed with the Blessed Dementia Rating Scale (BDRS;
Blessed, Tomlinson, & Roth, 1968) to determine if the twin’s cognitive status
affected functioning on a daily basis. The scores from the TELE and BDRS were
then combined to create a cognitive status score of 0 (cognitively intact), 1 (errors on
one domain of the TELE), 2 (poor performance on the TELE, i.e., errors in two or
more domains, but no confirmation of functional impairment due to cognitive
decline by an informant on the BDRS), or 3 (cognitive dysfunction—poor
performance on the TELE and confirmation of functional impairment by an
informant). Those who obtained a score of 3 were then invited to the clinical phase,
wherein a clinical work up was performed to determine a clinical diagnosis. Of the
1569 participants who obtained a score of 3, 1101 proceeded to the clinical phase.
The remaining 468 did not proceed either by design because the twin’s partner would
not be informative or because they refused.
After the assessment team made a preliminary assessment that a twin was
demented, their co-twin was referred for clinical evaluation, regardless of whether
the co-twin had screened positive or negative for cognitive impairment.
7
Clinical evaluations involved a visit by the assessment team, comprised of a
nurse and a physician, typically occurring in the twin’s home. To ensure that the
assessment team was blind to twin zygosity, the same team did not visit both twins in
a pair. The evaluation protocol generally followed the Consortium to Establish a
Registry for Alzheimer’s Disease (CERAD; Morris, Heyman, Mohs, Hughes,
vanBelle, Fillenbaum, et al., 1989), including a physical and neurological
examination, a complete medical history based on medical record review and
informant interview, a neuropsychological evaluation, a collection of blood for
laboratory tests, and a referral for neuroimaging.
Dementia was clinically diagnosed using the DSM-IV criteria. Differential
diagnoses were made using the NINCDS/ADRDA criteria for Alzheimer’s disease
(McKhann, Drachman, Folstein, Katzman, Price, & Stadlan, 1984), NINDS-AIREN
criteria for vascular dementia (Roman, Tatemichi, Erkinjuntti, Cummings, Madseu,
Garcia, et al, 1993), Lund and Manchester criteria for frontal temporal dementia
(Lund and Manchester Groups, 1994; Neary, Snowden, Gustafson, Passant, Stuss,
Black, et al., 1998), and consensus criteria for dementia with Lewy bodies (McKeith,
Galasko, Kosaka, Perry, Dickson, Hansen, et al., 1996).
Diagnostic procedure followed three steps. First, based on workup and
review of medical records, the assessment team completed an initial diagnosis. Next,
the assessment information was given to a diagnostic review board, comprised of a
psychologist and neurologist, who independently constructed a clinical dementia
diagnosis, including differential diagnosis of type of dementia. Finally,
8
disagreements between board members as well as disagreements between assessment
teams and board members were submitted back to the diagnostic review board for
resolution, which was determined by consensus. The consensus diagnosis is used in
this study. (See Figure 1 for frequencies and outline of screening and diagnostic
procedure.)
The HARMONY study used two sources of information to estimate the age
of dementia onset: informant reporting and medical records (Fiske, Gatz, Aadnoy, &
Pedersen, 2005). During the clinical phase, to assess age of onset and course of
dementia, an in-depth, semi-structured interview, designed specifically for the
HARMONY study was administered to an informant by trained nurses. Informants
were usually either children or spouses, had a long history with the proband, and
were in at least weekly contact with the proband. Information was also extracted
from medical records, including the dates of any prior workup conducted to assess
dementia, which indicated some level of cognitive impairment. Based on the
informant interview and the information from medical records, the assessment team
determined the age of onset for dementia.
Lifetime History of Depression. Depression information, including
occurrence and age of onset, was collected from four sources: 1) the inpatient
hospital discharge registry, 2) the inpatient psychiatric hospital discharge registry, 3)
the medical history for cases and co-twin controls who received the in-person
diagnostic visit, and 4) medical records for cases and co-twin controls who received
the in-person diagnostic visit. The last two sources were not available for external
9
Figure 1. Case Identification
Cognitive
Screening
FINISHED
N= 13,693
No Cognitive
Screening
(refused or not
contacted)
N=805
Cognitive dysfunction
N=1569 (11.5%)
Poor performance
N=2117 (15.5%)
Minor errors
N=2969 (21.7%)
Cognitively intact
N=7038 (51.4%)
Proceeded to
clinical phase
N=1101
Did not proceed
N=468
Clinical diagnosis
available
N=1557
Questionable
Dementia
N=185
Not Demented
N=752
Demented
N=620
Alzheimer’s
Disease
N=384
Frontotemporal
dementia
N=10
Dementia
w/ Lewy
bodies
N=5
Vascular
dementia
N=146
Alcoholic
dementia
N=7
Secondary
dementia
N=25
Dementia
N.O.S.
N=43
Normal control
twin pairs
N=60
Normal co-
twin partner
N=319
Assessed in
previous study
N=77
Probable AD
N=271
Possible AD
N=113
Possible vascular
dementia
N=124
Mixed AD and
vascular dementia
N=22
10
controls as they were collected during the clinical workup phase, so this information
was only used for comparing cases with their co-twin control. Depression was
considered to be absent if the earliest onset of depression was after the onset of
dementia.
Inpatient hospital discharge registry. The Swedish Twin Registry (STR) is
linked to the national hospital discharge registry (HDR) that records inpatient
discharges every time any individual leaves a hospital in Sweden. The HDR was
begun in 1964, but 100% coverage throughout Sweden was not achieved until 1987,
three years after reporting to the HDR became mandatory. The discharge diagnosis
is given in terms of an International Classification of Disease (ICD) code. (See
Table 1.) The ICD-7 was used prior to 1969, the ICD-8 was used from 1969 to1986,
the ICD-9 was used from 1987 to 1996, and beginning in 1997 the ICD-10 was used.
A total of 284 participants had at least one depression-related discharge diagnosis
between the years of 1964 and 2002, a span of 38 years.
Psychiatric hospital discharge registry. The STR has also been linked to a
national registry of inpatient psychiatric hospital services for depression between
1967 and 1983. For each person entered in this registry, there is a record of the
discharge diagnosis and the date of hospitalization. All discharge diagnoses are
given in terms of an ICD-8 diagnosis (See Table 1). A comparison of inpatient
psychiatric discharge codes with the inpatient hospital discharge codes between 1967
and 1983 showed overall high rates of agreement. Of the 186 individuals with
depression diagnoses in the psychiatric hospital discharge registry, 153 individuals
11
Table 1. ICD Diagnostic Codes for Depressive Disorders
ICD-7 ICD-8 ICD-9 ICD-10
Manic-depressive reaction (bipolar
affective disorder), depressed type
301.1 296.2 296.5
F31.3 –
F31.5
Involutional melancholia 302 296.0 -- --
Neurotic-depressive reaction
(dysthymia)
314.9 298
300.4
301.1
F34.1
Other recurrent depressive disorder 790.2 790.2 -- --
Affective personality disorder -- 301.1 -- --
Other affective psychosis -- 296.8 -- F39.9
Unspecified affective psychosis -- 296.9 -- F39.9
Depressive neurosis -- 300.4 -- --
Depressive psychosis (depressive
episode)
-- --
296.2,
298.0
F32
Recurrent depressive psychosis
(recurrent depressive disorder)
-- -- 296.3 F33
Atypical Depression -- -- 296.8 --
Depression, NOS -- -- 311 --
Brief Depressive Reaction -- -- 309.0 --
Schizoaffective disorder, depressed
type
-- -- -- F25.1
Persistent mood disorder -- -- -- F34.9
Other specified mood disorder -- -- -- F38.8
had depression-related diagnoses in both registries, though there was some
discrepancy as to specific diagnosis. Most of the discrepancies, however, were due
to multiple diagnoses being listed in one registry, but only one or two diagnoses
listed in the other registry. There were 33 individuals with records of a depression-
related diagnosis in the psychiatric discharge registry who did not have a depression-
related discharge diagnosis in the inpatient discharge registry. There were only three
cases in which there was no overlap in specific diagnoses. The inpatient discharge
registry coverage was not 100% until 1987, so it is possible that this is the reason for
12
these disagreements, since all records in the psychiatric discharge registry are prior
to that year.
Medical history for cases and co-twin controls (cases and internal controls
only). Medical history was collected during the clinical evaluation. For two-thirds
of the co-twin pairs, information was obtained from an informant for each twin, in
order to avoid biases that might come from comparing self-report for controls to
proxy-report for cases. Twins were never informants for each other, and different
informants were sought for each twin, so the same informant was not reporting on
both members of a pair. The history includes whether the individual had any history
of “major depressive disorder” or “reactive depression,” and if so, what was the date
of onset. Also included in medical history is information regarding the use of
antidepressant medication. If the medical history indicated any depressive disorder
or the use of antidepressants, the participant was considered to have a history of
depression. The first depressive episode according to the medical history was
determined by taking the earliest date recorded for either the onset of a depressive
disorder or the start date for initiating the use of an antidepressant medication.
Medical records for cases and co-twin controls (cases and internal controls
only). Medical records, ordered during the clinical evaluation phase, were coded by
the assessment team to reflect whether the twin had been diagnosed with depression.
Records typically go back approximately ten years or until the general time of onset
of symptoms of cognitive dysfunction. Thus, these records were most helpful in
knowing whether there was depression just prior to the dementia and concurrently
13
with the dementia. Also listed is the onset and dates of the illnesses, the source of
information, as well as the date the records were taken. There is also information
regarding the use of antidepressant medication, the date of first recorded use, and
whether they had ever received electroconvulsive therapy (ECT) for depression. The
first depressive episode according to the medical records was determined by taking
the earliest date recorded for either onset of depression, use of antidepressant
medication, or treatment of depression with ECT.
Combining Sources of Depression
For the case-control analysis all information regarding a history of depression
came from the hospital discharge registries. Because the age of dementia onset for
cases was prior to their study age (age at the time of assessment for dementia during
the clinical phase), a potential bias was introduced wherein controls had a longer
time frame in which they could be considered to have a history of depression. Since
the median for length of time between age of onset of dementia and study age for
cases was four years, we censored depression for the controls at four years prior to
their study age. This ensured that both the cases and the controls had approximately
the same length of time in which they had the “opportunity” to have depression.
For the co-twin control analysis, the hospital discharge registries, medical
history, and medical records were all used to assess whether each participant had a
history of depression. The co-twin control was considered to have a history of
depression if depression occurred prior to the proband’s age of dementia onset. Of
the 43 participants with a history of depression prior to the onset of dementia or to
14
the co-twin’s onset of dementia, three individuals had evidence of depression in all
sources, two had evidence of depression in the hospital discharge registries only,
seven had evidence of depression in the medical history source only, 12 had
evidence of depression in the medical records only, and 19 had evidence of
depression in both their medical records and medical history, but not in the hospital
discharge registries. These numbers are consistent with the fact that most people
who have a history of depression will have never been hospitalized for the disorder,
and therefore will only have evidence of a history of depression in a source that is
not limited to hospitalization diagnosis data.
Among all individuals in the co-twin control analysis, medical history and
medical records agreed 82.5% of the time, with 70.6% of the disagreement being
instances where the medical records indicated depression, but the medical history did
not. When stratified by dementia status, agreement between sources was 71.9% for
probands, with 75.7% of the disagreement being instances where the medical records
indicated depression, but the medical history did not. For the controls, agreement
between sources was 93.1%, and there was no difference between which source was
more likely to indicate depression when there was disagreement between sources.
Kappa values indicated that the agreement between sources was higher for the
controls (kappa value = 0.6050) than for the probands (kappa value = 0.3682). This
suggests that depression was more likely to have been reported in the medical
records, rather than in the medical history, for the individuals diagnosed with
dementia.
15
Another consideration when combining sources of information regarding
history of depression was to confirm whether probands and controls had the same
number of sources of information. A paired t-test showed that the mean difference in
number of sources of information on depression between probands and controls was
0.25, where probands had a greater number of sources of depression history
information. It further indicated that the number of sources providing information
about depression was significantly different between probands and controls (p <
0.0001). Therefore for our co-twin control model, the number of sources of
depression was included as a covariate.
Years Since Age of Onset of Depression
For cases, the years since first episode of depression was determined by
discerning the age at earliest reported occurrence of depression and calculating the
number of years from that age until the age of dementia onset. For external controls,
years since first episode was the difference between the age at first episode of
depression and four years prior to study age, at which age depression was censored.
For the co-twin control analysis, the number of years since the first episode
of depression for the co-twin controls was determined by discerning the earliest
reported occurrence of depression and calculating the number of years from that date
until the date of the demented twin’s age of dementia onset. If different sources
indicated different dates or ages for the earliest reported occurrence of depression,
the earliest date or age was used.
16
Covariates
Potential confounders included age, gender, zygosity, and number of years of
education completed. All of these variables were primarily measured during the
telephone screening phase, which began in March 1998 (Lichtenstein et al., 2002).
These data were supplemented with information from other sources (i.e. other studies
based on the STR) if available. Zygosity was determined by a developed algorithm
that was based on the answers to questions such as, “During childhood, were you and
your twin partner as like as ‘two peas in a pod’ or not more alike than siblings in
general” and “How often did strangers have difficulty in distinguishing between you
and your twin partner when you were children.” The algorithm was validated by
testing 13 DNA markers on 199 adult pairs, proving to be correct in 99% of the
pairs. Only one pair classified as MZ was misclassified (Lichtenstein et al., 2002).
In our analyses we collapsed zygosity into two levels: MZ and not MZ (dizygotic or
unknown).
Analyses
Case-Control (External Control) Analyses. Logistic regression models
(LOGISTIC procedure in SAS; version 8.2; SAS Institute, Inc., Cary, North
Carolina) were used to assess association between history of depression and risk of
dementia. Because members of twin pairs were included in the analyses in the same
way as single participants, confidence intervals were corrected using robust standard
errors for having two members from the same family included (Moradi, Adami,
Ekrom, Wendren, Terry, Floderus et al., 2002). Primary analyses indicated that age,
17
gender, education, and zygosity differed significantly by dementia status. However,
164 individuals (41 cases; 123 controls) were missing information regarding years of
education. For these individuals, we estimated their education level based upon
gender and year of birth. Our final model adjusted for age, education, gender, and
zygosity.
Additionally we conducted separate analyses for recent onset of depression
and early onset of depression, using 10 years to differentiate between recent and
early onset to parallel previous studies. One aspect unique to this study was that we
also analyzed the timing of the onset of depression as a continuous construct using a
Cox regression model (PHREG procedure in SAS). Finally we also conducted
analyses to assess the association between a history of depression and risk of
Alzheimer’s disease. We included age, education, gender, and zygosity as covariates
in all models.
Co-Twin Control (Internal Control) Analyses. Conditional logistic regression
models (PHREG procedure in SAS) were used to investigate the association between
history of depression and risk of dementia in twin pairs discordant for dementia. We
also examined the association between history of depression and risk of Alzheimer’s
disease in pairs discordant for Alzheimer’s disease. Using conditional logistic
regression with twin pair as the stratum compares each dementia case to his or her
co-twin. Gender, level of education, and number of sources of information regarding
a history of depression were considered as possible covariates and were included in
the final conditional logistic regression model.
18
Results
Case-Control Analysis
Dementia cases. There were 547 individuals diagnosed with dementia who
also had information about their lifetime history of depression. Alzheimer’s disease
was the most common diagnosis (62%), followed by vascular dementia (23.5%),
dementia NOS (7%), and secondary dementia (4%). The remaining 3.5% of the
cases had diagnoses of frontotemporal dementia, dementia with Lewy bodies, or
alcoholic dementia. The average age of onset for dementia was 76.98 years (SD =
8.10), and ranged from age 45.5 to 96.5 years of age (Table 2). Females made up
68.0% of this group, and 29.1% of the individuals were an MZ twin. The average
years of education obtained by the cases was 7.26 years (SD = 2.25). Twenty-one
individuals with dementia had records in the inpatient discharge registry indicating
that they had been hospitalized for depression. The average age at first
hospitalization for depression was 66.58 (SD = 11.83). The mean for the first
episode of depression was 9.70 years prior to the onset of the dementia (SD = 9.59),
and ranged from 31 years prior to dementia onset to the same year as dementia onset.
Finally the mean number of separate hospitalizations for separate episodes of
depression among this group was 2.86 (SD = 4.36).
Controls. There were 12,133 participants who had information about their
lifetime history of depression, who were determined to be non-demented. The mean
age of these individuals was 72.84 (SD = 6.17). Females made up 55.7% of this
group, and 23.5% of the individuals were an MZ twin. The average years of
19
education obtained by the controls was 8.72 years (SD = 3.02). For the 296
individuals who reported a history of depression, the average age of first
hospitalization for depression was 52.45 years (SD = 9.50). The mean for the
earliest hospitalization of depression was 15.45 (SD = 7.57) years prior to censored
age, and ranged from 30 years prior to censored age to the same year as censored
age. Finally, the mean number of separate hospitalizations for depression among this
group was 4.07 (SD = 5.27).
Table 2: Sample Demographics for Case-Control Analysis Covariates
No Dementia Dementia
N 12,133 547
Mean Age (SD) 72.84 (6.17) 76.98 (8.10) p < 0.0001
Education (SD) 8.72 (3.02) 7.26 (2.25) p < 0.0001
% Female 55.7 % 68.0 % p < 0.0001
% MZ Twins 23.5% 29.1% p = 0.0030
Bivariate analyses indicated that the mean age at first hospitalization and the
mean years between the first episode of depression and onset of dementia for cases
or censored age for controls differed significantly by dementia status. Age at first
hospitalization was significantly earlier for the controls compared with the cases (p <
0.0001). Additionally, the time between the first reported episode of depression and
the censored age for the controls was significantly longer than the time between the
first reported episode of depression and onset of dementia for cases (p = 0.0011).
An initial logistic regression model without covariates indicated that among
our participants, individuals with a history of depression were 1.6 times more likely
20
to have dementia than those without a history of depression (CI = 1.02, 2.51, p =
0.0421). After controlling for gender, age, education and zygosity in our
multivariate model, the effect remained (OR = 1.72, CI = 1.07, 2.76, p = 0.0212). To
determine if timing of depression acted as an effect modifier, we ran a logistic
regression model comparing the reference group (individuals with no history of
depression) with individuals having an onset of depression within the previous 10
years and individuals with an onset of depression more than 10 years prior to either
the onset of dementia or censored age. These analyses indicated that individuals
with a later onset of depression (within the past 10 years) were 3.87 times more
likely than those with no depression to have dementia (CI = 2.10, 7.14, p < 0.0001).
In contrast, an earlier onset of depression (more than 10 years prior to age of
dementia onset of censored age) was not associated with an increased risk of
dementia (OR = 0.90, CI = 0.44, 1.85, p = 0.7786). (See Table 3.)
Table 3: Risk for Dementia Stratified by Early and Recent Depression Onset
1
Cases Controls
Dep No
Dep
Dep No
Dep
OR 95% CI p-value
All Depression
vs.
No Depression
21 526 296 11,837 1.72
1.07 –
2.76
p =
0.0212
Recent Onset of
Depression vs.
No Depression
13 526 83 11,837 3.87
2.10 –
7.14
p <
0.0001
Earlier Onset of
Depression vs.
No Depression
8 526 213 11,837 0.90
0.44 –
1.85
p =
0.7786
1
Covariates for all case-control group models included age, education, gender, and zygosity.
21
We used the same multivariate model to test whether the effect remained if
the group with dementia was narrowed to only include individuals with AD. When
we ran a model to determine if ever having a history of depression was a risk factor
for AD, we found no association (OR = 1.20, CI = 0.63, 2.30, p = 0.5792).
However, when we compared the reference group to individuals having an onset of
depression within the previous 10 years and to individuals having an onset of
depression more than 10 years prior to either the onset of AD or censored age, we
found that the individuals with the later onset of depression were 2.62 times more
likely that those without a history of depression to be diagnosed with AD (CI = 1.12,
6.17, p = 0.0269). In contrast, AD was not associated with an earlier history of
depressive episodes (OR = 0.66, CI = 0.24, 1.81, p = 0.4211). (See Table 4.)
Table 4: Risk for AD Stratified by Early and Recent Depression Onset
AD Only Controls
Dep No
Dep
Dep No
Dep
OR 95% CI p-value
All Depression
vs.
No Depression
10 360 296 11,821 1.20
0.63,
2.30
p =
0.5772
Recent Onset of
Depression vs.
No Depression
6 360 83 11,821 2.62
1.12,
6.17
p =
0.0269
Earlier Onset of
Depression vs.
No Depression
4 360 213 11,821 0.66
0.24,
1.81
p =
0.4211
In order to analyze the timing of the onset of depression as a continuous
construct, a survival analysis using a Cox regression model was used. Controlling
for age, education, gender, and zygosity, we found that each one-year increase in the
22
length of time between first depressive episode and age of dementia onset or
censored age decreased the hazard of developing dementia by 8.1% (p = 0.0031).
Finally, we ran a t-test to determine whether the estimated age of dementia
onset was significantly earlier in cases with a history of depression compared with
cases without a history of depression. We found that there was no difference
between cases with and cases without depression in either age of dementia onset (p =
0.6880) or length of time between dementia onset and study age (p = 0.8179).
Co-Twin Control Analysis
There were 146 pairs of twins discordant for dementia. (See Table 5.)
Females comprised 59.6% of the probands and 58.9% of the control group. MZ
twins made up 22.6% of the pairs, DZ same sex twins made up 42.4% of the pairs,
DZ opposite sex twins made up 33.6% of the pairs, and 1.4% of the pairs were of
indeterminate zygosity. The average years of education for the probands was 7.86
years (SD = 2.55) and 8.24 years (SD = 2.87) for the controls. Among the probands,
the average age of first episode of depression was 61.93 years (SD = 15.92) and the
average age among the controls was 56.61 (SD = 16.94) for the first episode of
depression. Finally, the mean for the first episode of depression was 11.80 years (SD
= 13.77) prior to dementia onset for the probands and 20.65 years prior to the
proband’s onset of dementia for the controls.
There were 30 twins with a diagnosis of dementia who also had a history of
depression and 13 co-twin controls with a history of depression. Without controlling
for any covariates, an initial conditional logistic regression model indicated that
23
Table 5: Sample Demographics for Co-Twin Control Covariates
No Dementia Dementia
N 146 146
% Female 58.9% 59.6% p = 0.9054
Education (SD) 8.24 (2.87) 7.86 (2.55) p = 0.1334
# of Sources of Depression
Information (SD)
4.03 (1.03) 3.56 (1.79) p < 0.0001
individuals with a history of depression were 3.43 times more likely than their co-
twin to develop dementia (CI = 1.48, 7.96, p = 0.0041). After controlling for gender,
education, and number of sources of depression in our conditional logistic regression
model, we found that individuals with a history of depression were 3.19 times more
likely than their co-twin to develop dementia (CI = 1.35, 7.55, p = 0.0082; Table 6).
We used the same conditional logistic regression model to test whether the
effect remained if the group with dementia was narrowed to only include individuals
with AD. When we ran a model to determine if ever having a history of depression
Table 6: Risk for Dementia for Co-twin Control Analysis
2
Cases Controls
Dep No Dep Dep No Dep OR 95% CI p-value
Depression
vs. No
Depression
30 116 13 133 3.19 1.35, 7.55
p =
0.0082
Depression
vs. No
Depression
*AD Only
13 73 7 79 2.53 0.66, 9.72
p =
0.1742
2
Covariates for all co-twin control models included gender, education, and number of sources of
depression information.
24
was a risk factor for AD, we found that there was not a significant association
between a history of depression and the risk of AD (OR = 2.53, CI = 0.66, 9.72, p =
0.1742).
It was not feasible to use a survival approach in analyzing the co-twin control
sample. However, we found that 66.7% of the probands with a history of depression
had their first episode of depression sometime during the 10-years preceding
dementia onset, and 46.7% had their first episode within five years prior to dementia
onset, with the median being 6 years prior to dementia onset. Among the controls
with a history of depression, 30.8% had their first episode of depression within the
10-years preceding their twin’s dementia onset, and 15.4% had their first episode of
depression within five years prior to dementia onset, with the median being 17 years
prior to dementia onset.
Discussion
This study provides evidence for the relationship between dementia and
depression. Specifically we found that individuals with a history of depression were
more than one and a half times more likely to develop dementia. In our co-twin
control analysis, which controlled for genetic and environmental risk factors, we
found that individuals with a history of depression were over three times more likely
to develop dementia. Furthermore this association was strengthened in our case
control group when the onset of depression was considered, wherein depression
onset occurring more than 10 years before dementia onset or censored age was no
25
longer associated with an increased risk of dementia, but depression onset occurring
within 10 years of dementia onset or censored age was associated with a nearly four
times greater risk of developing dementia. We also found that depression occurring
within 10 years of dementia onset or censored age was associated with a more than
two and a half times greater risk of developing AD. These findings suggest that
rather than being a risk factor for dementia, depression is more likely a prodrome of
dementia.
The hypothesis that depression is a prodrome of dementia is further supported
by our findings from the case control group, in which those without dementia had a
much earlier age of first episode of depression compared with the cases. Also
supporting the prodrome hypothesis is the fact the cases had their first episode of
depression, on average, less than 10 years before dementia onset. The controls, on
the other hand, had their first episode of depression, on average, more than 15 years
before censored age. Furthermore as indicated by our proportional hazard regression
model, with each one-year increase in depression onset prior to dementia onset or
censored age, the risk of developing dementia decreased by eight percent. Therefore,
individuals having an onset of depression less than five years prior to dementia onset
or censored age are at an even higher risk of developing dementia than those having
an onset of depression between five and 10 years prior to dementia onset or censored
age.
Contrary to our findings, one study had found that an early history of
depression was more associated with the risk of developing AD (Speck et al., 1995).
26
For their study, however, Speck et al. (1995) relied solely on interviews with
informants to determine whether a participant had a history of depression. Our study
used multiple sources of gathering information regarding history of depression,
which may partially explain the differences in results. Our findings are consistent
with the findings by Steffens et al. (1997), who observed that late-onset depression
was associated with a higher risk of AD, while an earlier onset of depression was not
associated with an elevated risk. This pattern of depression onset closer in proximity
to the onset of dementia on the whole supports a construal of depression as
prodromal in relation to dementia.
Among Jorm’s (2001) hypotheses, our results most strongly support the
prodromal hypothesis. Because the age of dementia onset for cases did not differ
significantly by depression status, it is less likely that our results indicate that
depression affects the threshold for developing dementia, leading to an earlier
diagnosis. However, without specifically testing whether the participants were
cognizant of their declining cognitive abilities, we cannot definitively state whether
the depression in the cases was a reaction to the development of dementia.
Jorm (2001) and others (e.g. Sheline, Gado, & Kraemer, 2003) have
suggested that dementia might be the result of damage to the hippocampus through a
glucocorticoid cascade brought on by depression. In an article summarizing findings
of structural changes in the brain due to depression, Kanner (2004) reported that
decreases in hippocampal volume is directly associated with chronicity, severity, and
duration of depression. Since atrophy of structures in the temporal lobe, especially
27
the hippocampus, is also often found in patients with AD (Schweitzer, Tuckwell,
Ames, & O’Brien, 2001), it is plausible that depression could affect subsequent risk
of AD. Studies have also suggested that decreases in the volumes of the caudate
nuclei (Krishnan et al., 1992) and the basal ganglia (Zubenko & Moossey, 1998)
found in depressed individuals may also play a role in linking depression with
dementia.
Our results are not consistent with this hypothesis, for two reasons
specifically. First, our controls had a longer standing history of depression,
including on average, more hospitalizations for depression. If depression played a
role in causing dementia, or in other words, depression was a specific risk factor,
then we would have expected to find that earlier onset depression was more
associated with dementia than later onset. Secondly, we did not specifically test for
varying levels of depression severity. However, since depression was measured
solely by hospitalization in our case-control analyses, it was not the case that those
who became demented had a higher level of depression severity, as depression that
requires hospitalization is no doubt severe. Therefore, our results do not suggest that
depression “dosage” on the severe end of the depression spectrum mediates whether
changes in the brain will lead to dementia.
However, depression could be due to changes to the brain caused by
dementia, rather than the other way around. One study by Almeida, Burton, Ferrier,
McKeith, and O’Brien (2003) found that participants with late-onset depression
(onset after age 60) had greater reduction in frontal lobe volume than participants
28
with early-onset depression (before age 60) and controls. They also suggested that
changes in brain volume or structure have a role in late-onset depression. In addition
to atrophy of structures in the temporal lobe in patients with Alzheimer’s disease,
van der Flier et al. (2002) found that atrophy was also pronounced in the frontal lobe.
Therefore the frontal lobe volume reduction seen in late-onset depression might also
be associated with dementia.
Another study found that older adult patients with late-onset depression had
significantly more white matter hyperintensity than older adult patients with early-
onset depression or no depression (Lesser, Boone, Mehringer, Wohl, Miller, &
Berman, 1996). Additionally, those with late-onset depression showed degeneration
in executive functions and information processing speed. This is consistent with our
finding that there was a stronger association between history of later onset
depression and dementia in general, than in history of later onset depression and
Alzheimer’s disease specifically.
Limitations
This study has several limitations. Because our measures of depression were
dichotomous, it was infeasible to assess severity of depression, which would be more
congruent with the general consensus that depression is a continuous, rather than
discrete construct. One approximation of severity could be inferred from whether or
not an individual was hospitalized for their depression, as it is likely that only severe
depression would necessitate inpatient care. Since our case-control measure of
depression was based solely on those who were hospitalized for depression, our
29
results do not indicate whether milder forms of depression within 10 years of
dementia would also increase one’s risk for dementia. Additionally, most of this
study’s measures of depression, with the exception of the medical history, would
miss whether a person had depression that was treated in other settings such as
outpatient psychotherapy. However, because depression in our co-twin control
group, which was indicated by medical records and medical history, in addition to
hospitalization, was associated with a higher risk of dementia, our results do indicate
that there is at least some spectrum of depression severity that is associated with a
higher risk of dementia.
Another limitation stems from the fact that dementia has an insidious onset,
which leads to imprecision in determining exact age of onset. Because symptoms of
depression can often mimic symptoms of dementia, it is possible that the estimated
age of onset for those with depression was earlier than it would have been had they
not been depressed. However, we did not find any difference between cases with
and cases without depression in either age of dementia onset or length of time
between dementia onset and study age.
Another limitation inherent in any study involving individuals with dementia,
is that a case’s ability to self-report is greatly impaired. For example, the CIDI-SF
was administered to every twin during the screening phase. However, among those
who had missing data for this portion of the screening, 79% were diagnosed with
dementia during the clinical phase. Not only could these data not be used to measure
depression in our analyses, there was no other self-report measure of depression that
30
may pick up milder cases of depression, or cases that did not require medical
attention.
Conclusions
Our results strongly support previous findings that a later-life diagnosis of
depression is associated with an increased risk of dementia and furthermore that
depression is a prodrome of dementia. Our co-twin control analyses further suggest
that the mechanism is not just the shared genetic and environmental effects of each
disorder. On a clinical level, late-life depression should be carefully assessed, and
when appropriate, treated. Treatment is not just important for attending to the
depressive symptoms, but it may also be important in the improvement of some
cognitive abilities as some symptoms of depression may exacerbate cognitive
impairment (Raskind, 1998). Finally, it is possible that the association we observed
between dementia and depression is not specific to depression. Future studies could
look at psychiatric history in general, or account for co-morbid disorders such as
anxiety.
31
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35
Appendix
SAS Scripts Used for Multivariate Models Used In Study
Case Control Group Multivariate Logistic Regression Models
Model for risk of dementia as predicted by hospitalization for depression,
age, education, gender, and zygosity:
proc logistic descending;
class cc_icd4 sex mzzyg /ref=first;
model dementia = cc_icd4 age educ3 sex mzzyg/
risklimits;
run;
Model to find risk of dementia by depression status (early first episode, late
first episode, or no depression), age, education, gender, and zygosity:
proc logistic descending data = rerun1;
class depstat10 (ref = '1')/ param = ref;
model dementia = depstat10 age educ3 sex mzzyg/rl;
run;
Model for risk of Alzheimer’s disease as predicted by hospitalization for
depression, age, education, gender, and zygosity:
proc logistic descending;
class cc_icd4 sex mzzyg /ref=first;
model alz = cc_icd4 age educ3 sex mzzyg/ risklimits;
run;
Model to find risk of Alzheimer’s disease by depression status (early first
episode, late first episode, or no depression), age, education, gender, and zygosity:
proc logistic descending;
class depstat10 (ref = '1')/ param = ref;
36
model alz = depstat10 age educ3 sex mzzyg/rl;
run;
Case Control Group Cox Regression Model
Model for risk of dementia as predicted by time since first hospitalization for
depression, age, education, gender, and zygosity:
proc phreg;
model time*dementia(0) = newlength4 age educ3 sex mzzyg/
ties = exact risklimits;
run;
Co-twin Control Group Multivariate Conditional Logistic Regression Models
Model for risk of dementia as predicted by depression, education, gender, and
number of sources of information regarding history of depression:
proc phreg;
model time*dementia(0) = cens_any educ3 sex sumin/ ties
= discrete risklimits;
strata pairid;
run;
Model for risk of Alzheimer’s disease as predicted by depression, education,
gender, and number of sources of information regarding history of depression:
proc phreg;
model time*alz(0) = cens_any educ3 sex sumin/ ties =
discrete risklimits;
strata pairid;
run;
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Asset Metadata
Creator
Brommelhoff, Jessica Anne
(author)
Core Title
Depression as a risk factor for dementia
School
Graduate School
Degree
Master of Arts
Degree Program
Clinical Psychology
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
Gerontology,OAI-PMH Harvest,Psychology, clinical
Language
English
Contributor
Digitized by ProQuest
(provenance)
Advisor
Gatz, Margaret (
committee chair
), Horn, John (
committee member
), Knight, Bob G. (
committee member
)
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c16-56353
Unique identifier
UC11327655
Identifier
1438544.pdf (filename),usctheses-c16-56353 (legacy record id)
Legacy Identifier
1438544.pdf
Dmrecord
56353
Document Type
Thesis
Rights
Brommelhoff, Jessica Anne
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA