The Fuzzy World of Subsyndromal
Depression: And Epidemiologic Challenge
Dan G. Blazer MD, PHD
JP Gibbons Professor of Psychiatry
and Behavioral Sciences
The Modern Epidemiologic
Assumptions
Human pathophysiology should be studied as
discrete entities - diseases.
The phenotypic expressions of these discrete
entities represent underlying discrete
pathophysiological processes.
These pathophysiological processes result from
the interaction of the genetic make-up of the
individual with specific environmental
challenges or support to the individual.
The Modern Epidemiologic
Assumptions
The study of the causes of disease has shifted
away from the environment as a whole to
specific factors within the environment (e.g.
biological organisms) and to the behaviors of
individuals (e.g. smoking).
All variables are thus best measured at the
individual level for it is the individual who is
truly important in the causation of disease
Diez - Roux, 1998
The Modern Epidemiologic
Assumptions (cont.)
Phenylketoneuria (PKU) represents the
classic example of this
genetic/environmental interaction.
“Treatment” of disease consists of specific
environmental interventions, such as the
change of a subject’s diet or the
prescription of a specific drug.
Some have labeled this view as
methodological individualism.
The Modern Epidemiologic
Conclusion
A combination of symptoms, signs, clinical
course, family history, biological markers and
response to treatment (?) will enable the
epidemiologist to develop the criteria for
identifying a case of the discrete entity (the
disease)
Methods will be established which will become
the “gold standard” for identifying the case.
Screening methods will emerge which can be
tested for sensitivity and specificity
The Modern Epidemiologic
Conclusion
Risk should be individualized. Risk is
individually determined rather than socially
determined. (e.g. stressful life events)
“Lifestyle and behaviors” are matters of free
individual choice.
Therefore facts about society and social
phenomenon are to be explained solely in terms
of facts about the individual.
Duncan et al, 1996; Lukes, 1970; Diez-Roux, 1998
The “Case” for Subsyndromal
or Minor Depression
The Case for Subsyndromal
Depression - Clinical Experience
Persons are receiving treatment for depression
which does not meet criteria for major
depression in primary care
Primary care physicians see much more in the
way of subthreshold conditions, whereas
specialty clinicians see the more severe end of
the spectrum. This leads to varying views
regarding the prevalence of depression across
the life cycle.
Pincus et al, 1999
Score
The Case for Subsyndromal
Depression - Prevalence Studies
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
65
70
75
80
Age
Mean CES-D Scores (modified) by Age in the Duke EPESE sample in 1986-87
Blazer et al, 1991
85
The Case for Subsyndromal
Depression - Prevalence Studies
Many depressive symptoms are not captured by
DSM in community based epidemiologic
surveys
Minimal or no symptoms - 75%
Dysphoric symptoms - 19%
Symptomatic (minor) Depression - 4%
Mixed depression/anxiety - 1.2%
Dysthymia - 2.1%
Major Depression - 0.7%
Blazer et al, 1987
The Case for Subsyndromal Depression
Outcome Studies
Wave I
Wave II
Asymptomatic
Major Depression
Dysthymia
Minor Depression
without mood
disturbance
Minor depression
with mood
disturbance
Broadhead et al.,
Minor Depression Minor Depression
Major
with Mood
without Mood
Depression
Disturbance
Disturbance
35.4
23.7
2.6
37.2
10.3
2.4
65.1
1.8
2.0
17.6
16.0
5.6
20.8
34.2
25.5
The Case for Subsyndromal Depression
Case Identification
Of five pure types in grade of membership
analysis (GOM), one approximated major
depression and older persons loaded on this
pure type.
Symptoms which loaded included depressed
mood, decreased appetite, psychomotor
retardation anxiety and memory loss.
There was a smooth distribution of subjects who
loaded upon this pure type. Blazer et al, 1988
The Case for Subsyndromal Depression
Case Identification
Among persons studied in the ECA survey,
more than 50% of cases of first onset major
depression in the community were
associated with prior depressive symptoms
Horwarth, 1992
Many persons only experience partial
recovery from major depression.
Keller et al, 1981; Angst and Merikangas,
1997
The Case for Subsyndromal
Depression - Family History
In a study of 1420 subjects with
subsyndromal depression compared to
hypertensives and major depression,
family history of 41% in subsyndromal
group compared to 59% in major
depressive group and higher than among
hypertensives for both depressive groups.
Shelbourne, 1994
The Case for Subsyndromal Depression
Risk Factor Profiles
Subsyndromal depression and major
depression associated with functional
impairment, financial impairment, bed
days, high levels of functional strain and
limitations in job functioning.
Conclusion - subsyndromal depression is a
clinically significant variant of unipolar
major depression
Judd et al, 1996
The Case for Subsyndromal Depression
Risk Factor Profiles
In a community based survey of older adults, the
prevalence of CES-D was 9.1% and the
prevalence of subthreshold depression was
9.9%. In ordinal logistic regression, both were
associated with impaired physical functioning,
disability days, poorer self-rated health, use of
psychotropic medications, perceived low social
support, female gender and being unmarried.
Hybels et al, 2001
The Case for Subsyndromal
Depression - Treatment Studies
Pharmacologic therapy is effective for treating
minor depression
Paroxetine was superior to placebo in treating
415 primary care patients experiencing
minor depression and dysthymia in a
clinical trial (HSCL-D-20; MOS ShortForm 36; HDRS).
Williams et al, JAMA, 2000
The Emergence of
Subsyndromal Depression
DSM-IV Criteria for Minor Depressive
Disorder (Appendix)
• Depressed moon or loss of
interest/pleasure.
• Other symptoms may include sleep
disturbance, weight loss, agitation or
retardation, fatigue, feelings of
worthlessness, decreased ability to
concentrate
• At least two weeks duration
• Cause clinically significant distress
The Frequency of Minor Depression in
Late Life in the Community
• 4 - 8% using the DIS - some functional
impairment (Blazer et al, 1987)
• 14.6% using the DIS - two or more
depressive symptoms (Judd et al, 1994)
• 11% using the CES-D (Kennedy 1990)
• 12.9% using the CES-D (Beekman et al,
1995)
• 8.3% using the GMS/AGECAT (Copeland
et al, 1987)
Prevalence (%) of Minor Depression by
Age and Gender
(Beekman et al, 1995)
25
20
15
Prevalence
Men
Women
10
5
0
55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 80 - 85
Age
Prevalence Studies in Inpatient
Settings
• Koenig et al, 1988 - 11.5% of hospitalized
elderly diagnosed with major depression. 23%
had clinically significant depressive symptoms.
• O’Riordan et al, 1989 - 23% of patients
admitted to an acute medical geriatric
assessment unit screened positive for
depression, 10.8% had comorbid
depression/dementia and 13.5% were judged to
need antidepressant medication.
Prevalence in Outpatient
Settings
20.2% using RDC (Oxmam et al,
1990)
Prevalence Studies in LongTerm Care
• Parmelee et al, 1989 - 12.4% of subjects met
criteria for MDE. 30.5% reported less severe
but clinically significant depressive symptoms.
• Ames, 1990 - 24% of residents in homes for the
elderly screened positive for depression. 12%
had evidence of a mood disorder and 8% had
comorbid depression/dementia. At one year,
25% had died and 28% had recovered.
Risk Factors for Major Depression, Minor
Depression, and Dysthymia in Late Life
Major Depression
Not married
Female gender
Younger age
Low SES
Cognitive
impairment
Comorbid anxiety
Internal locus of
control
Loneliness
Functional
impairment
Beekman et al., in
press
Minor Depression
Perceived poor health
Functional limitations
Loneliness
Internal locus on
control
Not/no longer married
History of major
depression
Cognitive impairment
Functional impairment
Stressful life events
(Beekman et al., in
press
Blazer et al., 1991
Dysthymia
No gender
difference
Stressful life
events
Comorbid disorders
less common
Devenand et al.,
1994
Proportion of Elderly Community Sample
followed for 10 Years Taking Different Categories
of Antidepressant Medications
1986 1989 1992 1996
SSRI 0
s
TCAs 3.4
0.4
0.5
4.8
4.3
4.9
4.5
Total
5.5
6.4
11.0
3.8
Blazer et al, 2000
Conclusion
Subsyndromal or minor Depression
has been reified by clinicians as an
entity.
Therefore
The Resulting Epidemiologic
Questions
How can we better develop criteria for a case of
subsyndromal depression?
What is the frequency and distribution of
subsyndromal depression?
What are the correlates ( individual risk factors)
of subsyndromal depression?
What is the treatment of subsyndromal
depression?
Caveat - Subsyndromal depression may be a
variant of unipolar depressive disorder
Has the research agenda
therefore been set in stone for
subsyndromal or minor
depression?
The Case Against
Subsyndromal Depression as
an Entity (a thing)
The Case Against Subsyndromal or
Minor Depression
“…the authors ...want to apply their medical
interpretations and their pharmacological
treatment across the board, beyond the socalled clinically depressed ...to those who are
unhappy without apparent reason, the theory
being that ‘these conditions [i.e. minor
depressions] negatively affect quality of life and
are associated with increased risk of comorbid
medical illness and clinical depression.’…[on
the other hand], a depressive reaction to life
The Case Against Subsyndromal or
Minor Depression (cont.)
experience is one thing, and vulnerability to a
diagnosable disease called depression is
another…[consider] depression as a personality
train, a tendency to experience feelings which
varies in strength from person to person. The
disposition is not pathological but normally
distributed, stable personality trait that neither
increases nor declines with age.”
Stanley Jacobson, Atlantic Monthly , April, 1995,
pp 46-51 (in response to a consensus statement
regarding minor depression in the elderly)
What is a Case of
Subsyndromal Depression?
Research Diagnostic Criteria
for Minor Depression
An Episode with relatively persistent
depressed mood.
Two or more criteria symptoms, such as
poor appetite or sleep difficulty
Duration of at least one week
May be superimposed on another disorder
such as alcoholism
Must result in impairment and/or use of
health services
ICD-10 Proposed Criteria for
Mild Depression
• Lowering of mood, reduction of energy
and decreased activity
• Self-esteem reduced and ideas of guilt
and worthlessness.
• Biological symptoms mild or absent
• Causes distress and interference with
normal activity
• Duration of at least two weeks
Examples of Other Operational
Definitions Used in Research Studies
• Two or more current depressive
symptoms lasting for at least two weeks
excluding major depression. (Judd et al,
1994, Kessler et al, 1997)
• A score of >15 on the CES-D but not
meeting criteria for major depression.
(Beekman et al, 1997)
• Scores of 12 -15 on the CES-D (Hybels, et
al, 2000)
Snaith Criteria (1987)
Snaith proposes a biogenic from of mild
depression. Anhedonia is the central and
reliable symptm of “hypomelancholia”
(or mild biogenic depression
Differences Between Community Based
and Clinic Based Cases (unpublished data)
19 subjects who met CIDI criteria for major depression
were assessed by clinical examination. 80% were
determined to meet criteria following the clinical
examination.
These 19 subjects were further evaluated for dysfunction
and health service use. None reported work days
missed during the episode nor other significant physical
or social impairment. All had recovered from the
episode within one month. None sought professional
consultation for the episode.
Blazer, Kessler and Swartz (unpublished data)
What is a Case of
Subsyndromal Depression?
Except for the fact that the symptoms are
less severe than “major depression” yet
can be disabling, we don’t know the
answer to this question.
We can operationalize criteria, yet no one
set of operational criteria appears to
trump the others.
What is the Frequency and
Distribution of Subsyndromal
Depression?
The Epidemiologic Quagmire
of Subsyndromal Depression
• Community prevalence of 2.2% (Skodol et
al, 1994)
• mD without mood disturbance of 23.4%
(Broadhead et al, 1990)
• Depressive symptom community prevalence
of 23.1% (Johnson et al, 1992)
• Episodic mD community prevalence of
52.6% of elderly patients (Oxman et al,
1990)
What is the Frequency and Distribution of
Subsyndromal Depression?
If we cannot agree upon a definition of a
case, we cannot determine the frequency
and distribution of subsyndromal
depression.
What are the Risk Factors for
Subsyndromal Depression?
All the risk factors for major depression
“and more”.
What is the Outcome of
Subsyndromal Depression?
The Outcome of Subsyndromal
Depression
In a longitudinal study over 15 years of young
adults, few subjects with depression meet the
criteria for only one depressive subtype.
One third of the subjects eventually develop a
major depressive disorder (MDD).
One-half of persons with MDD meet criteria for
subsyndromal depression at follow-up. (Angst
and Merikangas, 1997)
Most cases do not evolve into a clearly defined
entity
Odds of Mortality in Females in
Controlled Analyses
CES-D Score 9+
CES-D Score 6-8
Age
Chronic Health
Katz
Rosow-Breslau
Small BMI
Cognitive Impairment
Low Income
Hx of Smoking
0.94
0.63
1.05
1.93
1.61
2.21
1.61
1.45
1.52
1.48
*
***
***
**
***
***
*
**
**
Hybels et al, in preparation
What are We Treating with
What?
“…the current antidepressants [SSRIs] are at
present all but misbranded as antidepressants.
They are effective for a wide range of ‘neurotic’
conditions. Kline’s term, psychic energizer
seems much more appropriate” (David Healey:
The Antidepressant Era, 1997)
Are we treating symptoms not fully explained
with tonics and energizers or symptoms of a
specific disorder with a specific, targeted
therapy?
Are we asking the wrong
questions? Are we looking in
the wrong place?
A Brief History of the
Diagnosis of Depression
A Brief History of the
Diagnosis of Depression
• Melancholia and underactive madness (from
Hippocrates, the two sides of the maniac, the
wholly mad person)
• Religious melancholia (1650 - 1800) - sickness
of the soul (the entire soul)
• Lypemania (Esquirol, 1838, a partial insanity
dominated by sadness, a specific disorder)
• Manic Depressive psychoses (from Kraepelin,
1899, one of the two forms of mental illness)
A Brief History of the
Diagnosis of Depression
Depression and the depressive neuroses as distinct
from melancholia, was introduced by Adolf Meyer
(early 1900s), a depression of mental energies.
“Neurosis” derived from the late 18th century to
refer to a presumed disorder of the nerves. Meyer
distinguished a constitutional depression
(pessimistic temperament), simple melancholic
(much like our major depression) and other forms
characterized by neurasthenic malaise and
hypochondriacal complaints.
A Brief History of the
Diagnosis of Depression
• Depressive psychoneuroses distinguishes
melancholia from mourning (Freud, 1917, the
neurotic variant of a normal adaptation to a
stressful event, a psychoneurisis - the rigid
distinction between personalities or
constitutions and diseases was not drawn)
• Endogenous (autonomous) and reactive
depression distinguished (Mobius, 1893;
Gillespie, 1929)
A Brief History of the
Diagnosis of Depression
• Major affective disorders (involutional
melancholia and manic-depressive illness)
distinguished from depressive neuroses in DSM
II (1968)
• Major Depression (Feighner, 1972; DSM -III,
1980) • The ECA Epidemiologic “gap” and Depression
NOS (Myers et al, 1984)
• Minor Depression (Broadhead et al, 1990)
A Brief History of the
Diagnosis of Depression
The evolution of the diagnosis of
depression, especially over the past 30
years, has contributed in part to the
emergence of the “diagnosis” of minor or
subsyndromal depression.
A Brief History of Unexplained
Psychiatric and Medical Symptoms
A Brief History of Unexplained
Psychiatric and Medical Symptoms
• War syndromes (Hyams, 1998)
– Da Costra’s irritable heart syndrome (Civil
War) - shortness of breath, palpitations,
chest pain, fatigability, headache, diarrhea,
dizziness and disturbed sleep
– The Effort Syndrome (World War I) fatigue, headache, dizziness, confusion,
concentration problems, forgetfulness,
nightmares
A Brief History of Unexplained
Psychiatric and Medical Symptoms
• War Syndromes
– Battle Fatigue (World War II) - fatigue,
palpitations, diarrhea, headache, impaired
concentration, forgetfulness, and disturbed
sleep.
– Gulf War Syndrome (Persian Gulf War) sleep disturbances, impaired concentration,
forgetfulness, irritability, muscle and joint
pain, and depression
A Brief History of Unexplained
Psychiatric and Medical Symptoms
• Other syndromes
– Neurasthenia (1870s to 1880s) - anxiety,
chronic disposition to irritability, fatigue
(especially mental fatigue), lethargy,
exhaustion
– Hysteroid dysphoria - histrionic patients
with chronic dispositions to depression.
Impaired anticipatory pleasure, what
appears to be character pathology is
secondary to a biological disturbance
A Brief History of Unexplained
Psychiatric and Medical Symptoms
• Demoralization (Frank, 1973;
Dohrenwend, 1980) - poor self-esteem,
helplessness-hopelessness, dread, sadness,
anxiety, confused thinking,
psychophysiologic symptoms, perceived
poor physical health
Common Symptoms Across
Multiple Syndromes
Depression*
Anxiety (agitation)*
Sleep disturbance*
Psychophysiological complaints (or medically
unexplained physical symptoms)
Problems with concentration*
Fatigue*
*DSM-IV Criteria for Minor Depressive Disorder
The Past and Present History
of Subsyndromal Depression
What we currently diagnose as minor or
subsyndromal depression probably was
captured in a number of diagnostic categories
in the past, most of which were considered a
response to general environmental stressors or
overwhelming specific stressors, such as war.
The fact that we label these symptoms minor or
subsyndromal depression shapes both our view
of the origin of the symptoms and their
treatment.
If we have identified a non-specific symptom
complex, what can we learn about the etiology?
“Epidemiology has become excessively
concerned with individual risks and
inadequately engaged with the social
production of disease.” Smith, 2001
This sounds very much like a message from
psychiatric epidemiology’s past - Stirling
County
Multilevel or Contextual
Analysis
• Lives of individuals are affected not only
by their personal characteristics but also
by characteristics of the social groups to
which they belong.
• The proposal has been made that, in
developing causal models, we should
include group- or macro- level variables
along with individual-level variables in
public health research. Dies-Roux, 1998
Multilevel or Contextual
Analysis
• Variables that reflect characteristics of
groups can be either:
– Derived or aggregate variables (also
contextual), that is, summarized characteristics
of individuals in groups such as average income
in a neighborhood.
– Integral variables are characteristics of the
group not derived from characteristics of its
members, such as availability of health care
Dies-Roux, 1998
Conclusions and Implications
• Psychiatric epidemiology should for the
time being abandon its assumption that
there is a specific disease subsyndromal
depression (or a variant of major
depression) and take an honest, empirical
view of our data regarding
“subsyndromal” symptoms
We don’t have to name everything!
Conclusions and Implications
• A focus upon specific symptoms (such as
sleep disturbance) or small clusters of
symptoms (such as the melancholic
symptoms of depression) with the use of
cluster and factor analytic studies should
assist psychiatric epidemiology to focus
down upon manageable (though perhaps
not all inclusive) syndromes for future
studies.
Conclusions and Implications
• Psychiatric epidemiology should take full
advantage of the rich data sets available,
such as the ECA and NCS, to further
study more focused groups of symptoms.
• Psychiatric epidemiology might do well to
revisit novel groupings of symptoms, such
as Dohrenwend’s “demoralization” but
again we must take care not to reify such
groupings prematurely.
Conclusions and Implications
• Psychiatric epidemiology should consider
bringing context back into its studies, perhaps
through multilevel analysis, again taking
advantage of existing data sets for preliminary
analyses.
• Psychiatric epidemiology should be more
sanguine regarding the nature of human nature
and avoid the modern day myth that happiness
is the natural state of our species
We don’t have to explain everything!
Conclusions and Implications
• The need to diagnose and treat specific
disorders, which dominates clinical
medicine (and psychiatry) currently,
should not unduly influence our
explorations of emotional suffering in the
community.
• Nevertheless, we must never take lightly
the reality of emotional suffering among
the depressed.