Transcript Document

Subjectivity: Lessons from
Epidemiology of Psychiatric Comorbidities of RLS
Hochang Benjamin Lee, MD
Assistant Professor of Psychiatry
and Behavioral Sciences
Johns Hopkins University School of Medicine
Baltimore, Maryland
Objectives
• Discuss why RLS interests psychiatrists
• Summarize the currently available crosssectional data on RLS and mood disorders
• Highlight the results from the two studies
– RLS in Baltimore ECA (RiBECA) study
– Korean ECA-RLS Study
• Future Directions
2
“Subjectivity”
• Definition: a subject's perspective,
particularly feelings, beliefs, and desires.
• It is often used casually to refer to
unjustified personal opinions, in contrast
to knowledge and justified belief.
• In philosophy, the term is often
contrasted with objectivity
3
Why RLS Interests Psychiatrists:
Similarities to Mood Disorders
• Epidemiologic similarities
– Similar 5%-10% prevalence rate in community1
– Female preponderance2: 2:1
– Mean age of onset: late 30s3
– Family history as a risk factor4,5
1. Allen RP et al. Sleep Med. 2003;4:101-109; 2. Berger K et al. Arch Intern Med. 2004;164:196-202; 3. Allen RP et al. Arch
Intern Med. 2005;165:1286-1292; 4. Walters AS et al. Neurology. 1996;46:92-95; 5. Winkelman JW et al. Ann Neurol.
2002;52:297-302.
4
Why RLS Interests Psychiatrists:
Similarities to Mood Disorders
• Clinical similarities
– Diagnosis and treatment based on
subjective report
– High placebo response rate in clinical trials1
– Treatment: Role of dopamine agonist (eg,
bupropion) and psychotherapy (CBT) in
treatment2,3,5
– Potential symptomatic overlap between RLS
and depression4
1. Trenkwalder C et al. J Neurol Neurosurg Psychiatry. 2004;75:92-97; 2. Feighner JP et al. Am J Psychiatry. 1984;141:525-529;
3. Kim SW et al. Clin Neuropharmacol. 2005;28:298-301; 4. Pichietti D, Winkelman JW. Sleep. 2005;28:891-898.; 5. Hornyak M
et al. J Neurol Neurosurg Psychiatry. 2008;79:823-5
5
Depressive Symptoms and RLS
in Clinic-Based Studies
Sample
RLS
Diagnosis
Depression
Measure
Results
Winkelman et al,
2005
130 in Germany
IRLSSG
CIDI (structured
interview)
18% in 1 year
37% in lifetime
Vandeputte et al,
2003
154 at sleep clinic
ICSD-R
BDI
53% with BDI >10
Saletu et al, 2002
33 RLS, 26 PLMD
IRLSSG and
ICSD-R
SDS
Elevated depressive
symptoms
Basetti et al, 2001
55 at sleep clinic
IRLSSG
Medical history
of depression
33% with depression
7 pregnant women
One
question
POMS, CES-D
Elevated depressive
symptoms
45% with depression
Reference
Lee et al, 2001
Banno et al, 2000
218 at sleep clinic
IRLSSG
Medical
diagnosis of
depression
Mosko et al, 1999
31 at sleep clinic
ICSD
DSM III-R
71% met criteria
129 on dialysis
IRLSSG
Medical history
of depression
16% had history
Gigli et al, 2004
Pichietti D, Winkelman JW. SLEEP. 2005;28:891-898.
6
“Anxietas Tibiarum”: Depression and Anxiety
Disorders in Patients With Restless Legs Syndrome
• Methods
– Standardized diagnostic
interview
• (Munich-Composite
International
Diagnostic Interview
for DSM-IV)
• Compared rates of
anxiety and depressive
disorders between 130
RLS patients and 2265
community resident
respondents
Winkelman J et al. J Neurol. 2005;252:67-71.
• Results
– Strong association between
RLS and DSM-IV diagnoses
during past 12 months
• Panic disorder
(OR=4.7; 95% CI, 2.1-10.1)
• Generalized anxiety
disorder (OR=3.5; 95% CI,
1.7-7.1)
• Major depression
(OR=2.6; 95% CI, 1.5-4.4)
– Limitation: sample bias
7
Depressive Symptoms and RLS
in Population-Based Studies
Depression
Measure
Sample
RLS Diagnosis
Sevim
et al, 2004
3234
Turkish
Questionnaire;
IRLSSG
HAM-D
Elevated
depressive
symptoms
Sukegawa
et al, 2003
2023
Japanese
Questionnaire;
IRLSSG
GDS
Only in men aged
65-75 years
Single item
More frequent
CES-D
Elevated only in
men
2608
Questionnaire;
Ulfberg
et al, 2001 Swedish men
IRLSSG
Rothdach
et al, 2000
369
Germans
Questionnaire;
IRLSSG
Pichietti D, Winkelman JW. SLEEP. 2005;28:891-898.
Results
8
Baltimore Epidemiologic Catchment Area
(ECA) Follow-up Study (1981-2005)
• Baltimore ECA site (Johns Hopkins) — one of five
epidemiologic study sites established by NIMH in 19811
– Goal: to assess prevalence of psychiatric disorders in
the United States
• Wave IV of Baltimore ECA follow-up study2 (23-year
follow-up of original cohort) was completed in 2005
– 1071 (or 75%) of surviving cohort of Wave III (19931996) participated in Wave IV
– 7 item RLS questionnaire
– Structured Psychiatric Interview (Diagnostic
Interview Schedule.
1. Regier D et al. Arch Gen Psychiatry. 1984;41:934-941.
2. Lee HB et al. Sleep Med. 2006;7:642-645.
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RiBECA Questionnaire
• Revised from the three item -RLS diagnostic instrument
from the MEMO study (Berger K, et al. 2000)
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RLS in Baltimore Epidemiologic Catchment Area (RiBECA) Study Two-stage Study Design (PI: Lee HB)
• Stage 1:
Secondary analysis
based on 7-item
RLS Q.
• Stage 2: Direct
examination based
on Structured
interview for RLS
and Consensus
Panel Diagnosis
11
Validation Study - Preliminary
•
164 people for clinical interview (38
with RLS + on 7 Question and 126 with
RLS-)
•
Hopkins Telephone Diagnostic
Interview (IN PERSON) – blind to the
RLSQ status – by a Trained clinician
•
•
•
•
Full Neurological Exam
2 hour cognitive battery
SCAN Clinician Psychiatric Interview
Consensus Diagnostic Panel
– LEE HB, Hening W, Allen P.
•
•
•
•
Sensitivity: 0.88
Specificity: 0.95
Positive- Predictive Value: 0.82
Negative- Predictive value: 0.97
•
Kappa: 0.81
Consensus
Diagnosis
+
Consensus
Diagnosis
-
7 Item
RLS Q +
31
7
7 Item
RLS Q -
4
122
12
RiBECA Study Results:
Baseline Variables by RLS Diagnosis and Race
Sociodemographic and Health-Related Variables
Age (y)
Education (y)
Female gender
Race
African American
White
Other
Self-health rating
Excellent
Good
Fair
Poor
Heart disease
Diabetes
On SSRI or TCA
RLS (n=42)
Mean
SD
Controls (n=982)
Mean
SD
P Value*
Total (n=1024)
Mean
SD
58.11
12.1
n
34
12.2
2.6
%
81
57.98
12.42
n
606
11.2
2.8
%
61.7
.943
.286
P Value*
.012
58.11
12.4
n
640
11.13
2.77
%
62.5
17
24
1
40.5
57.1
2.4
341
609
32
34.7
62.0
3.3
.694
358
633
33
35.0
61.8
3.1
4
15
13
6
8
9
9
10.5
395
34.2
15.8
19.0
22.0
19.0
136
455
251
51
123
178
107
15.2
40.1
28.1
5.7
12.3
18.1
10.9
.046
140
470
264
57
131
187
115
15.0
50.7
28.4
6.1
12.9
18.3
11.2
.222
.535
.128
* Results from a t-test for continuous variables and chi-square for categorical variables.
Percent
Race and RLS Among
East Baltimore Adult Residents
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
RLS
"Clinical RLS"
Black
White
Black
(n=358)
RLS
RLS of clinical significance
Total
White (n=633)
Non-black,
Non-white (n=33)
Total
(N=1024)
17 (4.7%)
24 (3.8%)
1 (3%)
42 (4.1%)
9 (2.5%)
9 (1.4%)
0
18 (1.8%)
Diagnosis
Lee HB et al. Sleep Med. 2006;7:642-645.
14
Prevalence and Crude and Adjusted Odds
Ratios for DSM-IV Psychiatric Disorders
RLS
(n=42)
No RLS
(n=982)
RLS vs Controls
RLS vs Controls
n
%
n
%
Crude
OR
95% CI
P Value
Adj.
OR*
95% CI
P Value
Lifetime
8
19.0
81
8.4
2.6
1.2-5.5
.005
2.7
1.1-6.7
.031
12-month
4
9.5
21
2.2
4.7
1.6-14.5
.006
4.7
1.2-18.3
.026
Lifetime
7
16.7
40
4.1
4.7
2.0-11.1
.001
5.3
2.0-14.0
.001
12-month
5
11.9
13
1.3
9.5
3.2-27.8
.001
12.9
3.6-46.0
.001
Lifetime
3
7.1
19
2.0
3.8
1.1-13.4
.037
4.0
1.0-16.5
.055
12-month
2
4.8
6
0.6
7.9
1.5-40.6
.013
9.7
1.4-69.0
.002
GAD
3
7.9
31
3.5
2.4
0.7-8.1
.189
2.0
0.6-7.3
.288
OCD
3
7.3
13
1.3
5.8
1.6-21.3
.008
5.6
1.4-21.9
.013
Lifetime
14
36.8
129
14.6
2.5
1.3-4.8
.007
3.6
1.7-7.6
.001
12-month
8
21.1
39
4.5
5.7
2.4-13.2
.001
6.2
2.2-17.4
.001
MDD
Panic disorder
Panic disorder
and MDD
Any diagnosis
* Adjusted for age, gender, health rating, and use of antidepressants (SSRIs or TCAs).
GAD=generalized anxiety disorder; MDD=major depressive disorder; OCD=obsessive-compulsive disorder.
Lee HB et al. J Neuropsychiatry Clin Neurosci. 2008.
RLS Is Associated With MDD
and Panic Disorder in the Community
1-Year Prevalence of
DSM-IV Diagnoses
Lifetime Prevalence of
DSM-IV Diagnoses
40
25
35
No RLS
30
Percent
Percent
20
RLS
15
10
5
RLS
No RLS
25
20
15
10
5
0
0
MDD
Panic
Any
Lee HB et al. J Neuropsychiatry Clin Neurosci. 2008.
MDD
Panic
Any
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Restless Legs Syndrome in a community sample of Korean adults:
Prevalence, Impact on Quality of Life, and Association between
DSM-IV Psychiatric Disorders.
Cho SJ, Hong JP, Hahm BJ, Jeon HJ, Chang SM, Cho MJ, Lee HB. (poster, APM 2008)
• Design/setting: Cross-sectional nationwide survey.
• Participants: Nationally representative sample of
6,510 Korean adults aged 18-64.
• Method: Face-to-face interviews
• RLS Assessment: Korean translation of IRLSSG-Criteria
based 4 questions – Similar process as the INSTANT
study in France
• Psychiatric Assessment: Korean version of Composite
International Diagnostic Interview (K-CIDI)
• Other Measures: CES-D, EuroQol (EQ-5D), and select
questions form the Pittsburgh Sleep Quality Index.
17
Prevalence of RLS based on 4 Questions
in South Korea
• Prevalence rate: 0.9%
• Substantially lower than previous
reported rates in South Korea
likely due to different assessment
method and sampling strategy
– Cho et al 2008
• Prevalence: 7.5%
• Telephone survey
• 11.8% response rate.
– Kim et al 2005
• Prevalence: 12.1%
• Single item Question
• Similar to previous reports of
prevalence from Singapore (0.6%)
and Japan (1.0%)
18
Comparison of Rates of RLS
• Similar 4-item questionnaire and sampling strategies with the
INSTANT Study and the REST General study.
• RLS prevalence (0.9%) in South Korea is also substantially lower
than the 8.5% prevalence among the adult French population in the
INSTANT study or the 7.9 % in the REST study
12
10.8
10
9
Percentage
8.5
8
REST study
7.2
6
5.4
Instatant study
5.8
KECA-R
4
2
0.9
0.6
1.2
0
Total
Male
Female
19
Similarities with comparison of MDD prevalence
in South Korea (2.9%) and in France (16.4%)
(Weissman et al, JAMA1996)
Lifetime rate %
(s.e.)
Female:male ratio Mean
(s.e.)
Age at onset (year
(s.e.)
USA
5.2 (0.24)
2.6 (0.11)
25.6 (0.30)
Canada (Edmonton)
9.6 (0.60)
1.9 (0.13)
24.8 (0.52)
Puerto Rico
4.3 (0.59)
1.8 (0.29)
29.5 (1.19)
France (Paris)
16.4 (1.16)
2.1 (0.16)
29.2 (0.52)
West Germany
9.2 (1.50)
3.1 (0.39)
29.7 (1.18)
Italy (Florence)
12.4 (1.33)
3.0 (0.26)
34.8 (1.12)
Lebanon (Beirut)
19.0 (1.76)
1.6 (0.19)
25.2 (1.00)
Taiwan
1.5 (0.12)
1.6 (0.17)
29.3 (0.88)
Korea
2.9 (0.24)
2.0 (0.18)
29.3 (0.88)
New Zealand
(Christchurch)
11.6 (0.96)
2.1 (0.18)
27.3 (0.58)
s) Mean
20
21
22
23
Summary of Korean-ECA –RLS Study
• RLS Prevalence based on 4-item IRLSSG Questionnaire is
substantially lower in South Korea than in Western
Countries
• Despite low prevalence, risk factors (e.g. gender) and
impact on daily lives (e.g. sleep and quality of life) are
similar
• Cross-sectional association between RLS and DSM IV
mood disorders are replicated.
24
Co-occurrence of Depression and RLS:
Symptomatic Overlap?
• Depressed mood—possibly common in RLS
• Diminished interest
• Feelings of worthlessness
• Thoughts of death
• Weight gain or loss
• Fatigue or loss of energy—common in RLS
• Diminished concentration—common in RLS
• Psychomotor retardation—possibly common in RLS
• Insomnia or excessive sleepiness—common in RLS
Pichietti D, Winkelman JW. SLEEP. 2005;28:891-898..
25
Comparison of MDD Symptoms Profile
Symptom
Dysphoria
Appetite changes
Sleep problems
Fatigue
Slow/restless
Anhedonia
Worthless/sinful feelings
Troubles concentrating
Suicidal ideation/attempts
Fisher’s exact test-no significant differences
.
Lifetime History of Major Depressive Disorder
With Comorbid RLS
Without Comorbid
(n=9)
RLS (n=80)
n (%)
n (%)
8 (88.9)
73 (91.3)
9 (100)
62 (77.5)
8 (88.9)
68 (85.0)
8 (88.9)
72 (90.0)
7 (77.8)
47 (58.8)
8 (88.9)
71 (88.8)
6 (66.7)
50 (62.5)
7 (77.8)
69 (86.3)
8 (88.9)
57 (71.3)
26
If Not Symptomatic, What Is the
Potential Pathophysiologic Overlap
Between RLS and MDD or Panic Disorder?
• Overlapping role of personality in RLS and depression
• Overlapping role of dopamine in pathophysiology of
RLS and depression
– Multiple studies support a role for diminished
dopaminergic neurotransmission in major
depression (Dunlop BW, Nemeroff CB. Arch Gen
Psychiatry. 2007).
• Overlapping role of insomnia? (Hornyak M et al,
2005)
• Potential role of genetics?
27
Restless Legs Syndrome and the Five-factor Model of Personality:
Results from a Community Sample.
(Kalaydjian A, Bienvenu OJ, Hening WA, Allen RP, Eaton WW, Lee HB, Sleep Med, 2008, in press)
Personality Profile of Restless Legs Syndrome
Factor Score
55
50
RLS
Non-RLS Controls
45
40
N
O
A
C
E
NEO Personality Inventory Factors
•
•
Total N = 1024 Comparison between RLS (n =41) and non RLS (n = 982)
NEO-PI-R: 240-question personality measure of the Five Factor Model: Extraversion,
Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience.
• High neuroticism is associated with RLS. However, adjusting for
neuroticism does not account for association between depression
and RLS or panic disorder and RLS.
28
Summary
• Cross-sectional association between RLS and DSM IV Mood
(i.e. depression and anxiety) disorders are wellestablished.
• Longitudinal studies are needed to establish the
underlying relationship between RLS and mood disorders.
• Subjective nature of RLS case ascertainment underscores
the need for validation studies for diagnostic instruments
– especially in cross-cultural setting.
• Future studies should be longitudinal and include
potential objective measures to improve diagnostic
validity of case ascertainment.
29
Acknowledgment
• Funding
– NIA R03: Restless legs risk in the biracial East Baltimore cohort
– NIMH K23: Cognitive sequelae of early and midlife depression
– GSK IIS: Race, pathophysiology, and neuropsychiatry of RLS
– Korean Ministry for Health, Welfare and Family Affairs
• Co-Investigators
– Wayne Hening (Rutgers)
–
–
–
–
–
–
–
Constantine Lyketsos (JHH)
Christopher Earley (JHH)
William Eaton (JHH)
Richard Allen (JHH)
Amanda Kalajdian (NIH)
Seongjin Cho (Gil Hospital, South Korea)
Christine Ramsey (JHH)
30