Increased risk of depressive and anxiety disorders in relatives of patients with Parkinson disease.

Abstract

Relatives of patients with Parkinson disease (PD) have an increased risk of PD and other neurologic disorders; however, their risk of psychiatric disorders remains uncertain.
To study the risk of depressive disorders and anxiety disorders among first-degree relatives of patients with PD compared with first-degree relatives of controls.
In a population-based, historical cohort study, we included 1000 first-degree relatives of 162 patients with PD and 850 first-degree relatives of 147 controls. Both patients with PD and controls were representative of the population of Olmsted County, Minnesota.
Documentation of psychiatric disorders was obtained for each relative separately through a combination of telephone interviews with the relatives (or their proxies) and review of their medical records from a records-linkage system (family study method). Psychiatric disorders were defined using clinical criteria from the DSM-IV or routine diagnoses.
We found an increased risk of several psychiatric disorders in first-degree relatives of patients with PD compared with first-degree relatives of controls (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.21-1.95; P <.001). In particular, we found an increased risk of depressive disorders (HR, 1.45; 95% CI, 1.11-1.89; P = .006) and anxiety disorders (HR, 1.55; 95% CI, 1.05-2.28; P = .03). The results were consistent in analyses that adjusted for type of interview, excluded relatives who developed parkinsonism, or excluded relatives who developed both a depressive disorder and an anxiety disorder.
These findings suggest that depressive disorders and anxiety disorders may share familial susceptibility factors with PD.

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ORIGINAL ARTICLE
Increased Risk of Depressive and Anxiety Disorders
in Relatives of Patients With Parkinson Disease
Gennarina Arabia, MD, MSc; Brandon R. Grossardt, MS; Yonas E. Geda, MD, MSc; Justin M. Carlin, BA;
James H. Bower, MD; J. Eric Ahlskog, PhD, MD; Demetrius M. Maraganore, MD; Walter A. Rocca, MD, MPH
Context: Relatives of patients with Parkinson disease
(PD) have an increased risk of PD and other neurologic
disorders;however,theirriskofpsychiatricdisordersre-
mains uncertain.
Objective:Tostudytheriskofdepressivedisordersand
anxiety disorders among first-degree relatives of patients
with PD compared with first-degree relatives of controls.
Design, Setting, and Participants: In a population-
based, historical cohort study, we included 1000 first-
degree relatives of 162 patients with PD and 850 first-
degree relatives of 147 controls. Both patients with PD
andcontrolswererepresentativeofthepopulationofOlm-
sted County, Minnesota.
Main Outcome Measures: Documentation of psy-
chiatric disorders was obtained for each relative sepa-
ratelythroughacombinationoftelephoneinterviewswith
the relatives (or their proxies) and review of their medi-
cal records from a records-linkage system (family study
method).Psychiatricdisordersweredefinedusingclini-
cal criteria from the DSM-IV or routine diagnoses.
Results: We found an increased risk of several psychiat-
ric disorders in first-degree relatives of patients with PD
compared with first-degree relatives of controls (hazard
ratio [HR], 1.54; 95% confidence interval [CI], 1.21-
1.95; P?.001). In particular, we found an increased risk
of depressive disorders (HR, 1.45; 95% CI, 1.11-1.89;
P=.006) and anxiety disorders (HR, 1.55; 95% CI, 1.05-
2.28;P=.03).Theresultswereconsistentinanalysesthat
adjustedfortypeofinterview,excludedrelativeswhode-
veloped parkinsonism, or excluded relatives who devel-
oped both a depressive disorder and an anxiety disorder.
Conclusion:Thesefindingssuggestthatdepressivedis-
orders and anxiety disorders may share familial suscep-
tibility factors with PD.
Arch Gen Psychiatry. 2007;64(12):1385-1392
D
In addition, symptoms of depression and
anxiety not only occur after the onset of
motor symptoms but also may develop
many years, even decades, before the on-
setofPD.7-9Onepossibleinterpretationof
these findings is that depressive disor-
ders and anxiety disorders are not simply
reactions to the disability caused by PD,
but they share genetic susceptibility fac-
tors with PD.8If we assume that there are
shared genetic factors, we would expect
relatives of patients with PD to have a
higher risk of these psychiatric disorders
thanrelativesofcontrols.Therefore,aspart
of the Mayo Clinic Family Study of Par-
kinson’s Disease,10-15we investigated the
EPRESSIVE DISORDERS AND
anxiety disorders are
commoninpatientswith
Parkinson disease (PD),
particularlyinpatientsaf-
fected by the akinetic-rigid form of PD.1-6
risk of depressive disorders and anxiety
disorders among first-degree relatives of
patients with PD compared with first-
degree relatives of controls.
METHODS
STUDY DESIGN
This study included 2 cohorts of relatives: (1)
first-degreerelativesofpatientswithincidentPD
fromOlmstedCounty,Minnesota,and(2)first-
degree relatives of controls free of PD, parkin-
sonism, or tremor from the same Olmsted
County population. The first-degree relatives
frombothcohortswerefollowedupfrombirth
to onset of psychiatric disorders, death, tele-
phone interview for the study, or last medical
record information. Documentation of psychi-
atric disorders was obtained through tele-
phone interviews and review of medical rec-
ords (family study method). Details about the
overall study design were reported else-
where.10,12All aspects of the study that in-
Author Affiliations:
Department of Health Sciences
Research, Divisions of
Epidemiology (Drs Arabia,
Geda, and Rocca) and
Biostatistics (Messrs Grossardt
and Carlin), Department of
Psychiatry and Psychology
(Dr Geda), and Department of
Neurology (Drs Bower,
Ahlskog, Maraganore, and
Rocca), Mayo Clinic College of
Medicine, Rochester,
Minnesota. Dr Arabia was on
leave from the Institute of
Neurological Sciences, Italian
National Research Council,
Cosenza, Italy, at the time
of the study.
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volved contact with participants were approved by the institu-
tionalreviewboardsoftheMayoClinicandtheOlmstedMedical
Center. Relatives examined as part of the study (to assess neu-
rologicoutcomes)signedaninformedconsentform.Mostrela-
tives included in this study classified themselves as white when
presented with the standard US Census options.12Information
on ethnicity was collected because it was considered related to
genetic or nongenetic familial susceptibility factors.
PATIENTS WITH PD AND CONTROLS
The medical records–linkage system of the Rochester Epidemi-
ologyProjectwasusedtoidentifyallindividualswhoresidedin
Olmsted County who developed PD from 1976 through 1995.
Details about the study population, the identification of inci-
dent cases, and the diagnostic criteria for PD are reported else-
where.16,17OurclinicalclassificationofpatientswithPDthrough
medical record review was found to be valid compared with a
direct examination by a movement disorders specialist.18Each
patient with PD was individually matched by age (±1 year) and
sex to a general population control who resided in Olmsted
County and was free of PD, other parkinsonism, or tremor of
any type in the index year (year of onset of PD in the matched
case).Recordsofpotentialcontrolswerereviewedbyaneurolo-
gist (D.M.M.) to confirm their eligibility. Our exclusion of par-
kinsonismincontrolsthroughmedicalrecordreviewwasfound
to be valid compared with a direct examination by a movement
disordersspecialist.18Thepresenceofdementiaorotherneuro-
logicdiseaseswasnotanexclusioncriterion.Similarly,thepres-
enceofdepressivedisorders,anxietydisorders,orotherpsychi-
atricdisorderswasnotanexclusioncriterion.Furtherdetailsabout
the selection of controls have been reported elsewhere.12,18
WeaskedpatientswithPDandcontrols(ortheirproxies)to
provide a full listing and contact information of all first-degree
relatives.12For some of the families who resided in Olmsted
Countyandwhohadnoavailableinformant,thepedigreecom-
position was obtained from the obituaries archived at the Olm-
sted County Historical Society and the records-linkage system,
asdescribedelsewhere.12,19Becausethe2cohortsofrelativeswere
originally designed to investigate the risk of parkinsonism and
becauseparkinsonismisrareinindividualsyoungerthan40years,
weexcludedrelativeswhowereyoungerthan40yearsatthetime
of the study. However, for those relatives who were included,
we studied the onset of psychiatric disorders at any time from
birth onward. In addition, we excluded stepparents, stepsib-
lings, and adopted relatives because they were not biologically
related. We also excluded half-siblings.
ASCERTAINMENT OF PSYCHIATRIC
DISORDERS AMONG RELATIVES
Psychiatric disorders were ascertained using a combination of
2 methods: (1) telephone interviews and (2) review of medi-
calrecordsfromarecords-linkagesystem.Thetelephonecon-
tact was made by 1 of 3 specifically trained research assistants
and was direct whenever possible; for deceased or otherwise
incapacitated relatives (eg, deaf, cognitively impaired, or ter-
minallyill),wecontactedthebestavailableproxy(mostknowl-
edgeable person in the family).12
The interview included a structured questionnaire for de-
pressivedisorders.Wefirstasked,“Haveyoueversuffered(Did
he or she ever suffer) from a depression that interfered with
your (his or her) work or daily activities?” Relatives or their
proxies who reported depression were asked details about age
atoccurrence,treatments(drugsorelectroconvulsivetherapy),
and hospitalizations. Information about other psychiatric dis-
eases, including anxiety disorders, was collected through an
open-ended question: “Have you ever had (has he or she ever
had) any psychiatric disease or psychiatric problem?” We also
administered the Geriatric Depression Scale (GDS; short ver-
sion with 15 items) to all relatives interviewed directly. This
scale has been previously validated.20
Independentoftheinterviewdescribedherein,relativeswho
had resided in Olmsted County for part or all of their life were
studiedthroughreviewofinpatientandoutpatientmedicalrec-
ords in the records-linkage system of the Rochester Epidemi-
ology Project.12,19In addition, for relatives who resided out-
sideOlmstedCountyandreportedapsychiatricdisease(directly
or by proxy), we obtained written authorization, and we re-
quested copies of their pertinent medical records from physi-
cians or medical institutions throughout the United States to
strengthen the diagnostic certainty. All medical records from
within or outside the records-linkage system were abstracted
by a trained neurologist (G.A.) with the assistance of a board-
certified psychiatrist (Y.E.G.).
The relatives (or their proxies), the 3 telephone interview-
ers, and both physicians (G.A. and Y.E.G.) involved in medi-
cal records abstracting were kept uninformed of the relation
ofrelativestopatientswithPDorcontrolstopreventbias(mask-
ing). In particular, the scripted introductory telephone con-
versation between the interviewers and the relatives (or their
proxies) described the study only in general terms (“a family
study of neurological diseases”), specified that the study in-
volved relatives of individuals both with and without neuro-
logicdiseases,anddidnotrevealwhethertheindividualswere
or were not affected by a neurologic disease (to protect confi-
dentiality within the family and to maintain masking). Simi-
larly, the abstracting of medical records was kept masked by
involving a study coordinator who organized the abstracting.
DIAGNOSTIC CRITERIA
FOR PSYCHIATRIC DISORDERS
Fordepressivedisorders,werequiredthatthepsychiatricsymp-
toms documented in the medical records of the patient met the
criteriaoftheDSM-IVformajordepressivedisorder,dysthymic
disorder, or depressive disorder not otherwise specified or that
the physician had made an explicit diagnosis of depression or
dysthymia.21Foranxietydisorders,werequiredthatthepsychi-
atric symptoms documented in the medical records of the pa-
tient met DSM-IV criteria for 1 specific type of anxiety disorder
orthatthephysicianhadmade1ofthefollowingdescriptivedi-
agnoses: anxiety neurosis, anxiety state, anxiety reaction, ner-
voustension,nervousexhaustion,tensionstate,generalizedanxi-
ety disorder, psychoneurosis, nervousness, obsessive-
compulsivedisorderorneurosis,phobiasofanytype,andpanic
attacks or disorder. These terms were used historically by phy-
sicians involved in the records-linkage system to describe anxi-
etydisorders.8Forotherpsychiatricdisorders,werequiredthat
the psychiatric symptoms documented in the medical records
ofthepatientmetDSM-IVcriteriaorthatthephysicianhadmade
anexplicitdiagnosisofschizophrenia,somatoformdisorder,per-
sonalitydisorder,dissociativedisorder,oradjustmentdisorder.
For individuals who had no pertinent medical record, psy-
chiatric disorders were defined as a previous diagnosis re-
ported by the individual or proxy at interview. As markers of
severity of the psychiatric symptoms, we obtained informa-
tionondiagnosisbyapsychiatristandonuseofspecificmedi-
cations(eg,antidepressants).Forrelativeswithmultiplesources
of information, the final diagnosis was based on the best avail-
ableevidence.Forrelativeswithpositiveinformationfromboth
theinterviewandmedicalrecord,wegaveprioritytothemedi-
cal record; however, for relatives with discordant informa-
tion, a positive report was given priority regardless of source.
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RELIABILITY AND VALIDITY
The ascertainment of depressive disorders relied on both medi-
cal records and interviews (Table 1). To assess the reliability
ofourmethodtoascertaindepressivedisorders(acombination
of telephone interview and medical records), all relatives who
resided within driving distance (a 120-mile radius centered in
Rochester,Minnesota)andwere60yearsorolderatthetimeof
interview were invited to undergo an independent clinical ex-
amination (at Mayo Clinic or at home).12One of 3 neurologists
(J.H.B.,J.E.A.,andD.M.M.)whowerekeptunawareofthepsy-
chiatric diagnosis assigned by our method examined 139 rela-
tives, of whom 132 were previously interviewed directly and 7
via proxy. Both current and past depression were investigated
during the clinical examination. The agreement between our
method and a direct examination was adequate (agree-
ment=83.5%; ?=0.51; 95% confidence interval [CI], 0.34-
0.68).Theagreementwassimilarwhenconsideringrelativesof
patients with PD and relatives of controls separately.
In addition, agreement on the diagnosis of depressive dis-
orders between telephone interview (direct or proxy) and in-
dependentreviewofmedicalrecordsfromtherecords-linkage
system was 80.7% (?=0.32; 95% CI, 0.23-0.42) in a sample of
610 relatives who had both sources of data. The limited agree-
ment was partly due to the inadequacy of some medical rec-
ords to document current depression. However, the agree-
ment was similar when considering relatives of patients with
PD and relatives of controls separately.
Finally, we compared the performance on the GDS (score
?6) with our method of ascertainment of depressive disor-
ders (a combination of telephone interview and medical rec-
ords)in320relativeswithadequateinformation.Althoughthe
overallagreementwasgood(85.3%),the?wasonly0.15(95%
CI, 0.005-0.30). The disagreement was partly due to the as-
certainment of past depression by our method but not by the
GDS. Therefore, we did not use the GDS score to define de-
pressive disorders.
Contrarytodepressivedisorders,theascertainmentofanxi-
etydisorderswasbasedalmostcompletelyonthereviewofmedi-
cal records (98.9% in relatives of patients with PD and 100.0%
in relatives of controls; Table 1). Therefore, a comparison of
methods of ascertainment could not be performed.
STATISTICAL ANALYSIS
First-degree relatives of patients with PD or controls were in-
cluded in the analyses from birth through the onset of a spe-
cificpsychiatricdisorder(eg,depressivedisorder),death,tele-
phoneinterviewforthestudy,orlastmedicalrecordinformation,
whichever came first. For 56 relatives of patients with PD and
32 relatives of controls with unknown age at onset of depres-
sive disorders and for 1 relative of a patient with PD with un-
known age at onset of anxiety disorders, we used age at death,
age at telephone interview, or age at last medical record infor-
mation (carry-forward imputation).
Weobtainedcumulativeincidencecurvesofpsychiatricdis-
orders using the Kaplan-Meier method and estimated hazard
ratios (HRs) and their 95% CIs using Cox proportional haz-
ardsmodelswithageasthetimescale.22Becausethestudyout-
comes clustered in some of the families of patients with PD or
controls,weaccountedfortheclusteringinallstatisticalmod-
els.23The proportionality assumption in the Cox proportional
hazardsmodelswastestedgraphicallyandbyintroducingatime-
dependent coefficient.22Primary analyses were conducted on
the overall sample and in strata defined by age at onset of pa-
tients with PD (in tertiles), clinical type of PD (tremor-
dominant vs akinetic-rigid), presence of depressive disorders
or anxiety disorders, type of relative, and sex of the relative.
Stratification by clinical type of PD was prompted by findings
from previous studies5,6and was based on clinical features ab-
stracted from medical records, as detailed elsewhere.24
We also conducted secondary analyses restricted to out-
comes confirmed by a psychiatrist or that required treatment
as well as several sets of sensitivity analyses. Data were ana-
lyzed with SAS statistical software, version 8.2 (SAS Institute
Inc, Cary, North Carolina), and all statistical testing was per-
formed at the conventional 2-tailed ? level of .05.
RESULTS
Details about the participation of the 162 patients with
PD and the 147 controls in the construction of pedi-
grees and the identification of first-degree relatives have
beenreportedelsewhere.12Table1givesdetailsaboutthe
inclusionoffirst-degreerelativesofpatientswithPDand
Table 1. Inclusion of First-Degree Relatives in the Study
and Documentation of Psychiatric Diagnoses
Variable
Inclusion of first-degree relatives
All relatives identified
Relatives includeda
Direct interview
With medical records
Without medical records
Proxy interview
With medical records
Without medical records
Only medical records
Documentation of psychiatric
diagnoses among first-degree
relatives
All relatives with depressionc
Medical records
Only direct interview
Only proxy interview
All relatives with anxietyc
Medical recordse
No. (%) of Patients
P
Value
Patients
With PD Controls
1278 (100.0) 1207 (100.0)
1000 (78.2)
412 (41.2)
362 (36.2)
50 (5.0)
506 (50.6)
226 (22.6)
280 (28.0)
82 (8.2)
850 (70.4)
274 (32.2)
227 (26.7)
47 (5.5)
491 (57.8)
231 (27.2)
260 (30.6)
85 (10.0)
?.001
?.001
?.001b
. . .
.002
. . .
. . .
. . .
200 (100.0)
88 (44.0)
65 (32.5)
47 (23.5)
90 (100.0)
89 (98.9)
125 (100.0)
45 (36.0)
51 (40.8)
29 (23.2)
52 (100.0)
52 (100.0)
.26d
. . .
. . .
.45
Abbreviation: PD, Parkinson disease.
aWe explored the variables that influenced the inclusion of relatives in the
study with multivariable stepwise logistic regression models. We considered
family size (?7 members vs otherwise), sex of relative, vital status of relative
(dead vs alive), relationship of relative (parent, sibling, or offspring), age of
patient with PD or control (in tertiles), year of birth of patient with PD or control
(in tertiles), and relative of patient with PD or relative of control status. The final
model showed higher inclusion for relatives from smaller families, women
relatives, living relatives, siblings and offspring (compared with parents), and
relatives of younger patients. Even after accounting for all of these variables,
relatives of patients with PD were included more frequently than relatives of
controls (odds ratio, 1.37; 95% confidence interval, 1.13-1.68; P = .002).
bP value comparing frequencies of relatives with direct interview with
medical records, direct interview without medical records, proxy interview with
medical records, proxy interview without medical records, and relatives with
only medical records.
cFor the documentation of psychiatric diagnoses, medical records were given
priority. For relatives with diagnoses from both record and interview, only
record was counted.
dP value comparing frequencies of diagnoses confirmed by medical records,
with only direct interview, or with only proxy interview.
eOnly 1 relative of a patient with PD and no relatives of controls had anxiety
disorders documented only via interview (direct interview).
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controls via interview or medical record review. First-
degree relatives of patients with PD were included more
frequently (78.2% vs 70.4%; P?.001) and had more di-
rect interviews (41.2% vs 32.2%; P?.001) than first-
degreerelativesofcontrols.Inamultivariablelogisticre-
gression model, we found higher inclusion in the study
Table 2. Risk of Psychiatric Disorders Among First-degree Relatives of Patients With PD Compared With Relatives of Controls
Psychiatric Disorder
Any psychiatric disorder
Any mood disorder
Depressive disordersa
Bipolar disorders
Anxiety disorders
Schizophrenia
Somatoform disorders
Personality disorders
Dissociative disorders
Adjustment disorders
No. (%) of Events
HR (95% CI)
1.54 (1.21-1.95)
1.46 (1.12-1.90)
1.45 (1.11-1.89)
1.53 (0.37-6.37)
1.55 (1.05-2.28)
2.64 (0.88-7.90)
3.93 (1.36-11.36)
1.63 (0.61-4.37)
NAb
2.16 (1.04-4.50)
P Value
?.001
.005
.006
.56
.03
.08
.01
.33
. . .
.04
Relatives of Patients
With PD (n=1000)
257 (25.7)
207 (20.7)
200 (20.0)
7 (0.7)
90 (9.0)
12 (1.2)
18 (1.8)
13 (1.3)
1 (0.1)
24 (2.4)
Relatives of Controls
(n=850)
154 (18.1)
129 (15.2)
125 (14.7)
4 (0.5)
52 (6.1)
4 (0.5)
4 (0.5)
7 (0.8)
0
10 (1.2)
Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not available; PD, Parkinson disease.
aDepressive disorders included major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Results were consistent after
excluding depressive disorder not otherwise specified (HR, 1.41; 95% CI, 1.02-1.94; P=.04).
bThe HR could not be estimated because no relatives of controls had a dissociative disorder.
Table 3. Risk of Depressive Disorders Among First-degree Relatives of Patients With PD Compared With Relatives of Controls
Type of Relatives
Analyses stratified by type of diagnosisa
Relatives of controls, all diagnoses
Relatives of patients with PD, all diagnoses
Relatives of controls, by psychiatrist
Relatives of patients with PD, by psychiatrist
Relatives of controls, ever treated
Relatives of patients with PD, ever treated
Analyses stratified by relatives of patients with PD
with the following characteristics:c
Onset ?66 yd
Onset from 67-75 y
Onset ?75 y
Tremor-dominant typee
Akinetic-rigid type
Depressive disordersf
No depressive disorders
Analyses stratified by type of relative
Parents of controls
Parents of patients with PD
Siblings of controls
Siblings of patients with PD
Offspring of controls
Offspring of patients with PD
No. of Relatives
at Risk
No. (%) With
Depressive DisordersHR (95% CI)P Value
850
1000
850
1000
850
1000
125 (14.7)
200 (20.0)
22 (2.6)
47 (4.7)
53 (6.2)
91 (9.1)
1 [Reference]
1.45 (1.11-1.89)b
1 [Reference]
1.87 (1.11-3.17)
1 [Reference]
1.53 (1.03-2.27)
. . .
.006
. . .
.02
. . .
.04
344
324
332
754
246
212
731
83 (24.1)
62 (19.1)
55 (16.6)
150 (19.9)
50 (20.3)
41 (19.3)
153 (20.9)
1.95 (1.36-2.78)
1.43 (0.98-2.07)
1.06 (0.76-1.48)
1.41 (1.06-1.89)
1.57 (1.06-2.32)
1.39 (0.95-2.03)
1.54 (1.15-2.06)
?.001
.06
.74
.02
.02
.09
.004
174
217
425
457
251
326
14 (8.1)
29 (13.4)
45 (10.6)
84 (18.4)
66 (26.3)
87 (26.7)
1 [Reference]
1.81 (0.96-3.43)
1 [Reference]
1.84 (1.22-2.77)
1 [Reference]
1.04 (0.72-1.49)
. . .
.07
. . .
.004
. . .
.85
Abbreviations: CI, confidence interval; HR, hazard ratio; PD, Parkinson disease.
aAnalyses were conducted including all relatives with all levels of diagnostic certainty and were repeated including only diagnoses confirmed by a psychiatrist or
only relatives ever treated with antidepressant medications.
bAnalyses adjusted by type of interview (direct, proxy, or only medical record) were consistent (HR, 1.30; 95% CI, 1.00-1.69; P=.05). A sensitivity analysis that
excluded the 72 relatives who developed PD or parkinsonism (43 relatives of patients with PD and 29 relatives of controls) was consistent (HR, 1.47; 95% CI,
1.12-1.94; P=.006). A sensitivity analysis that removed the 80 relatives who had both depression and anxiety was also consistent (HR, 1.44; 95% CI, 1.07-1.94;
P=.02). Finally, a sensitivity analysis that removed the 88 relatives with unknown age at onset of depressive disorders yielded an HR of 1.41 (95% CI, 1.04-1.91;
P=.03).
cRelatives of patients with PD stratified by age at onset of PD (in tertiles), clinical type of PD, or presence of depressive disorders were compared with the
overall group of relatives of controls (reference).
dResults of a test for linear trend in the log HRs were statistically significant (P?.001).
eResults of a formal test of interaction were not statistically significant (P=.60).
fRelatives of patients with PD with a history of depressive disorders preceding the onset of motor symptoms.8Depression status was unknown for 7 patients
with PD (with 57 relatives). Results of a formal test of interaction were not statistically significant (P=.59).
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for relatives from smaller families, women relatives, liv-
ingrelatives,siblingsandoffspring(comparedwithpar-
ents), and relatives of younger patients (Table 1, foot-
note a). Even after accounting for all of these variables,
relatives of patients with PD were included more fre-
quently than relatives of controls (odds ratio, 1.37; 95%
CI, 1.13-1.68; P=.002). Table 1 also gives the degree of
clinicalinformationobtainedforrelativesaffectedbyde-
pressive disorders or anxiety disorders.
ThesizeoffamiliesofpatientswithPD(median,8rela-
tives; interquartile range, 5-10 relatives) was similar to
thatofcontrols(median,7relatives;interquartilerange,
6-11 relatives; P=.48). We investigated the clustering of
depressive and anxiety disorders in families of patients
with PD or controls. For the controls, we observed 125
relativesaffectedbydepressivedisordersclusteredwithin
76families(51.7%ofall147families).Atotalof43fami-
lieshad1relativeaffected,20had2,and13had3ormore
relatives affected. Similarly, we observed 52 relatives af-
fected by anxiety disorders clustered within 37 families
(25.2% of all 147 families). A total of 25 families had 1
relative affected, 9 had 2, and 3 had 3 relatives affected.
For the patients with PD, we observed 200 relatives af-
fected by depressive disorders clustered within 96 fami-
lies(59.3%ofall162families).Atotalof38familieshad
1 relative affected, 30 had 2, and 28 had 3 or more rela-
tives affected. Similarly, we observed 90 relatives af-
fected by anxiety disorders clustered within 63 families
(38.9% of all 162 families). A total of 44 families had 1
relative affected, 12 had 2, and 7 had 3 or more relatives
affected.
Tables 2, 3, and 4, and the Figure show our re-
sults. We found an increased risk of several psychiatric
disordersinrelativesofpatientswithPDcomparedwith
relatives of controls. In particular, we found an in-
creased risk of depressive disorders, anxiety disorders,
somatoform disorders, and adjustment disorders. Re-
sultsfordepressivedisordersandanxietydisorderswere
consistent after restricting the analyses to disorders di-
agnosedbyapsychiatristorevertreated.BecausePDag-
gregates in families11and because depression and anxi-
ety are more frequent in patients with PD than in the
general population,9,25-27we also performed sensitivity
analyses that excluded the 72 relatives who developed
PDorparkinsonism.Theassociationsdidnotchangeno-
ticeably (Table 3 and Table 4, footnotes).
Table 4. Risk of Anxiety Disorders Among First-degree Relatives of Patients With PD Compared With Relatives of Controls
Type of Relatives
Analyses stratified by type of diagnosisa
Relatives of controls, all diagnoses
Relatives of patients with PD, all diagnoses
Relatives of controls, by psychiatrist
Relatives of patients with PD, by psychiatrist
Relatives of controls, ever treated
Relatives of patients with PD, ever treated
Analyses stratified by relatives of patients with PD
with the following characteristics:c
Onset ?66 yd
Onset 67-75 y
Onset ?75 y
Tremor-dominant typee
Akinetic-rigid type
Anxiety disordersf
No anxiety disorders
Analyses stratified by type of relative
Parents of controls
Parents of patients with PD
Siblings of controls
Siblings of patients with PD
Offspring of controls
Offspring of patients with PD
No. of Relatives
at Risk
No. (%) With
Anxiety DisordersHR (95% CI)P Value
850
1000
850
1000
850
1000
52 (6.1)
90 (9.0)
8 (0.9)
32 (3.2)
30 (3.5)
49 (4.9)
1 [Reference]
1.55 (1.05-2.28)b
1 [Reference]
3.49 (1.63-7.48)
1 [Reference]
1.45 (0.88-2.38)
.03
.001
.15
344
324
332
754
246
432
511
29 (8.4)
34 (10.5)
27 (8.1)
70 (9.3)
20 (8.1)
50 (11.6)
38 (7.4)
1.55 (0.90-2.67)
1.86 (1.14-3.04)
1.29 (0.78-2.14)
1.58 (1.05-2.36)
1.45 (0.76-2.76)
2.00 (1.26-3.16)
1.29 (0.82-2.03)
.12
.01
.33
.03
.26
.003
.27
174
217
425
457
251
326
0 1 [Reference]
12 (5.5)
26 (6.1)
38 (8.3)
26 (10.4)
40 (12.3)
NAg
. . .
1 [Reference]
1.42 (0.83-2.43)
1 [Reference]
1.19 (0.73-1.96)
.20
.48
Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not available; PD, Parkinson disease.
aAnalyses were conducted including all relatives with all levels of diagnostic certainty and were repeated including only diagnoses confirmed by a psychiatrist or
only relatives ever treated.
bAnalyses adjusted by type of interview (direct, proxy, or only medical record) were consistent (HR, 1.46; 95% CI, 1.00-2.13; P=.05). A sensitivity analysis that
excluded the 72 relatives who developed PD or parkinsonism (43 relatives of PD patients and 29 relatives of controls) was consistent (HR, 1.58; 95% CI,
1.05-2.36; P=.03). A sensitivity analysis that removed the 80 relatives who had both anxiety and depression was also consistent (HR, 1.64; 95% CI, 0.96-2.82;
P=.07).
cRelatives of patients with PD stratified by age at onset of PD (in tertiles), by clinical type of PD, or by presence of anxiety disorders were compared with the
overall group of relatives of controls (reference).
dResults of a test for linear trend in the log HRs were statistically significant (P=.03).
eResults of a formal test of interaction were not statistically significant (P=.81).
fRelatives of patients with a history of anxiety disorders preceding the onset of motor symptoms.8Anxiety status was unknown for 7 patients with PD (with 57
relatives). Results of a formal test of interaction were not statistically significant (P=.07).
gThe HR could not be estimated because no parents of controls had an anxiety disorder.
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Relatives of patients with younger age at onset of PD
(first tertile) had a particularly increased risk of depres-
sive disorders, and we found a trend of increasing risk
of depressive disorders in relatives with decreasing age
at onset of PD in the patients (test for linear trend of the
logHRs;P?.001;Table3).However,thetrendforanxi-
ety disorders in relatives was less pronounced (P=.03;
Table 4). We did not find statistically significant differ-
encesinHRsfordepressivedisorders(interactionP=.83)
oranxietydisorders(interactionP=.29)comparingmale
relatives with female relatives (data not shown). Results
were consistent in several sets of sensitivity analyses
(Table 3 and Table 4, footnotes). In particular, because
anxietydisordersanddepressivedisordersmayoccurin
the same person,28,29we repeated our analyses after re-
moving all relatives who had both outcomes. The re-
sults were consistent.
The risk of depressive disorders or anxiety disorders
in relatives did not vary across strata of relatives of pa-
tientswithPDwiththetremor-dominantortheakinetic-
rigid form. Similarly, the risk did not vary across strata
of relatives of patients with PD with or without depres-
sivedisordersoranxietydisorders(Table3andTable4).
COMMENT
Weobservedanincreasedriskofdepressivedisordersand
anxiety disorders in first-degree relatives of patients with
PD compared with first-degree relatives of controls. In-
terestingly, the increased risk of depressive disorders or
anxiety disorders was not restricted to those families of
patients with PD who had experienced depressive disor-
ders or anxiety disorders before the onset of their motor
symptoms. In addition, we observed an increased risk of
somatoform disorders and adjustment disorders among
relatives of patients with PD; however, our analyses for
those conditions had limited statistical power.
Ourfindingsarenovelbecauseevidenceislimitedfor
theoccurrenceofpsychiatricdisordersinrelativesofpa-
tients with PD. We are aware of only 1 previous study
that addressed the association from a different perspec-
tive. Fahim et al30compared the family history of PD in
patients with self-reported depression with that in con-
trols without depression and found inconclusive re-
sults. Another study31that focused on dementia showed
a higher frequency of family history of major depres-
sion in patients with Alzheimer disease and depression
compared with patients with Alzheimer disease but no
depression. Therefore, our findings cannot be directly
compared with previous data. We discuss several com-
parisonsbasedontheassumptionthatclinicalanddemo-
graphic characteristics associated with a higher risk of
anxietydisordersordepressivedisordersinpatientswith
PD are also associated with a higher risk of psychiatric
disorders among relatives.
First, we found the risk of depressive disorders to be
particularlyincreasedforrelativesofpatientswithyounger
age at onset of PD (?66 years, first tertile). These find-
ings are consistent with a study32that showed a higher
risk of depression in patients with younger age at onset
of PD (ie, before 50 years of age). Second, some stud-
ies33,34showed no difference in the frequency of depres-
sion in men and women with PD, whereas other stud-
ies35showedapreponderanceinwomen.Weobserveda
higherfrequencyofdepressivedisordersandanxietydis-
orders in women than in men in both relatives of pa-
35
30
25
20
15
10
5
0 10 2030 40
Age, y Age, y
5060 70 80
35
30
25
20
15
10
5
0 1020 3040 50 6070 80
1000Relatives at Risk
Cumulative Events
Relatives of Controls
989
12
940
60
645
116
256
1770
Relatives of Patients With PD
Relatives of patients with PD
Relatives of patients with PD
850 Relatives at Risk
Cumulative Events
848 819
33
590
77
252
11102
1000997971
32
630
75
256
8805
850849837
14
592
41
252
5003
Relatives of controls
Relatives of controls
AB
Cumulative Incidence in Relatives, %
Figure. Cumulative incidence of disorders among first-degree relatives of patients with Parkinson disease compared with first-degree relatives of controls.
A, Depressive disorders. B, Anxiety disorders.
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tientswithPDandrelativesofcontrols.However,theHRs
were similar in men and women (data not shown).
Third,2studiesshowedahigherfrequencyofdepres-
sion in patients with a postural instability-gait difficulty
typeofPDcomparedwithtremor-dominantpatients5or
in patients with akinetic-rigid PD compared with the
tremor-dominant type.6By contrast, we did not observe
a higher risk of depressive disorders or anxiety disor-
ders among relatives of patients with the akinetic-rigid
type of PD compared with relatives of patients with the
tremor-dominant type of PD.
This study has several strengths. First, using a popu-
lation-basedsampleofpatientswithincidentPDandcon-
trols, we avoided possible biases related to survival (in-
cidence-prevalence bias) and to selection of cases and
controls for inclusion in the study (referral bias).36Sec-
ond, we used the medical records-linkage system of the
Rochester Epidemiology Project to increase the assess-
mentofpsychiatricdisordersviapassivesurveillancefol-
low-up. Third, we used a family study method and con-
firmed the presence of psychiatric disorders in a large
proportion of relatives (Table 1).10,37,38As evidence for
the completeness of our outcome assessment, the crude
frequencyofdepressivedisordersamongrelativesofcon-
trols (14.7%) was almost identical to the frequency ob-
servedamongthecontrolsthemselvesinapreviouscase-
control study (14.8%).8We also observed some degree
of familial clustering of depressive disorders or, sepa-
rately,ofanxietydisordersinfamiliesofcontrols.These
findings confirm previous evidence of the familial ag-
gregationofdepressivedisordersoranxietydisordersin
the general population.39-41
However, our study has several limitations, and not
allpotentialbiasescouldbecontrolled.First,despiteour
ability to supplement a traditional family study method
withaccesstoarecords-linkagesystem,first-degreerela-
tives of patients with PD were included more frequently
and had more direct interviews than first-degree rela-
tives of controls. In addition, living relatives were in-
cluded more frequently than deceased relatives for both
patientswithPDandcontrols(Table1,footnotea).How-
ever,theoverallmortalitywassimilarforrelativesofpa-
tients with PD and relatives of controls (HR, 1.00; 95%
CI,0.88-1.14;P=.98;datanotshown).Inaddition,analy-
ses adjusted for type of interview (direct, proxy, or only
medicalrecord)yieldedconsistentresults.Finally,toad-
dress the approximately 8% lower participation rate of
relatives of controls compared with relatives of patients
withPD,weconductedasensitivityanalysisinwhichwe
imputed a corresponding number of relatives of con-
trols, assuming that they had the same risk as relatives
ofpatientswithPD(worst-casescenario).Theresultsre-
mained consistent in 500 repeated random simulations.
Second, our structured telephone interview to detect
psychiatricdisordershadlimitations.Inparticular,some
relatives with a diagnosis of psychiatric disorders docu-
mentedonlyviaproxyinterviewmayhavebeenmisclas-
sified.Inaddition,theopen-endedquestionaboutother
psychiatric disorders may have caused some underre-
portingoflessseverepsychiatricdisorders.However,the
misclassification should be similar for relatives of pa-
tients with PD and relatives of controls. In fact, analyses
restrictedtorelativeswithadiagnosisconfirmedbyapsy-
chiatrist or to relatives who were treated for their psy-
chiatricdisorderwereconsistent.Forapproximately28%
of relatives of patients with PD and 26% of relatives of
controls with depressive disorders, the age at onset was
unknown,andweusedacarry-forwardimputation.How-
ever,asensitivityanalysisthatexcludedallrelativeswith
missing age at onset yielded consistent results.
Third, we considered ineligible relatives who were
youngerthan40yearsatthetimeofthestudy;however,
most relatives excluded were sons or daughters, and we
excluded both relatives of patients with PD and rela-
tives of controls in a symmetric way. The percentage of
relatives excluded because they were younger than 40
yearswas9.7%forrelativesofpatientswithPDand9.3%
forrelativesofcontrols(P=.74).Fourth,despitethelarge
number of first-degree relatives studied, the number of
outcome events was small for rare psychiatric disorders
and in some stratified analyses, and the study had lim-
ited power. On the other hand, some of the significant
findings may be due to chance (multiple testing).
This study provides evidence that first-degree rela-
tives of patients with PD have an increased risk of de-
pressive disorders and anxiety disorders. These associa-
tions are primarily driven by relatives of patients with
youngerageatonsetofPD.Ourfindingssuggestthatde-
pressive disorders and anxiety disorders may share fa-
milial susceptibility factors (genetic or nongenetic) and
common pathogenetic mechanisms with PD. If con-
firmed, these findings may have both clinical and re-
search implications.
Submitted for Publication: April 26, 2007; final revi-
sion received June 25, 2007; accepted July 9, 2007.
Correspondence: Walter A. Rocca, MD, MPH, Division
of Epidemiology, Department of Health Sciences Re-
search, Mayo Clinic, 200 First St SW, Rochester, MN
55905 (rocca@mayo.edu).
Author Contributions: Dr Rocca (the principal investi-
gator,whoisafull-timeemployeeoftheMayoClinicCol-
legeofMedicine)hadfullaccesstoallthedatainthestudy
and takes responsibility for the integrity of the data and
the accuracy of the data analysis.
Financial Disclosure: Dr Maraganore reports a US pro-
visional patent application for a method of treating neu-
rodegenerative disease, which has been licensed to Al-
nylam Pharmaceuticals Inc; a provisional patent
application for PD-related compositions and methods,
which is owned by Perlegen Sciences Inc; and a provi-
sional patent application for predicting PD, which is
owned by the Mayo Foundation for Medical Education
and Research. In addition, Dr Maraganore reports con-
sulting for Merck and Pfizer, for which he received no
compensation.
Funding/Support: This study was supported by grants
R01 NS33978 and R01 AR30582 from the National In-
stitutes of Health, Bethesda, Maryland.
RoleoftheSponsors:Thesponsorsofthisstudyhadno
role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; or
preparation, review, or approval of the manuscript.
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