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

The Case for Subsyndromal Depression - Prevalence Studies

00.5

11.5

22.5

33.5

44.5

65 70 75 80 85

Age

Scor

e

Mean CES-D Scores (modified) by Age in the Duke EPESE sample in 1986-87Blazer et al, 1991

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

Asymptomatic 35.4 37.2 65.1Major Depression 23.7 10.3 1.8Dysthymia 2.6 2.4 2.0Minor Depression without mood disturbance 17.6 16.0 5.6Minor depression with mood disturbance 20.8 34.2 25.5

Wave II

Major Depression

Minor Depressionwith Mood

Disturbance

Minor Depressionwithout Mood Disturbance

Wave I

Broadhead et al., 1993

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 DepressionRisk 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 DepressionRisk 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 Short-Form 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)

0

5

10

15

20

25

Prevalence

55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 80 - 85

Age

MenWomen

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 Long-Term 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

Not marriedFemale genderYounger ageLow SESCognitive impairmentComorbid anxietyInternal locus of controlLonelinessFunctional impairmentBeekman et al., in press

Perceived poor healthFunctional limitationsLonelinessInternal locus on controlNot/no longer marriedHistory of major depressionCognitive impairmentFunctional impairmentStressful life events(Beekman et al., in press Blazer et al., 1991

No gender differenceStressful life eventsComorbid disorders less commonDevenand et al., 1994

Major Depression Minor Depression Dysthymia

Proportion of Elderly Community Sample followed for 10 Years Taking Different

Categories of Antidepressant Medications

1986 1989 1992 1996

SSRIs

0 0.4 0.5 4.8

TCAs 3.4 4.3 4.9 4.5

Total 3.8 5.5 6.4 11.0

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 so-called 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 inControlled Analyses

CES-D Score 9+ 0.94

CES-D Score 6-8 0.63 *

Age 1.05 ***

Chronic Health 1.93 ***

Katz 1.61 **

Rosow-Breslau 2.21 ***

Small BMI 1.61 ***

Cognitive Impairment 1.45 *

Low Income 1.52 **

Hx of Smoking 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.