The Fuzzy World of Subsyndromal Depression: And Epidemiologic Challenge

1. The Fuzzy World of Subsyndromal Depression: And Epidemiologic Challenge Dan G. Blazer MD, PHD JP Gibbons Professor of Psychiatry and Behavioral Sciences

2. 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.

3. 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

4. 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.

5. 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

6. 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

7. The “Case” for Subsyndromal or Minor Depression

8. 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

9. The Case for Subsyndromal Depression - Prevalence Studies Mean CES-D Scores (modified) by Age in the Duke EPESE sample in 1986-87Blazer et al, 1991

10. 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

11. The Case for Subsyndromal Depression Outcome Studies Wave I Minor Depression with Mood Disturbance Minor Depression without Mood Disturbance Major Depression Wave II Asymptomatic 35.4 37.2 65.1 Major Depression 23.7 10.3 1.8 Dysthymia 2.6 2.4 2.0 Minor Depression without mood disturbance17.6 16.0 5.6 Minor depression with mood disturbance 20.8 34.2 25.5 Broadhead et al., 1993

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. The Emergence of Subsyndromal Depression

19. 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

20. 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)

21. Prevalence (%) of Minor Depression by Age and Gender(Beekman et al, 1995)

22. 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.

23. Prevalence in Outpatient Settings 20.2% using RDC (Oxmam et al, 1990)

24. 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.

25. Risk Factors for Major Depression, Minor Depression, and Dysthymia in Late Life Major Depression Minor Depression Dysthymia Not married Female gender Younger age Low SES Cognitive impairment Comorbid anxiety Internal locus of control Loneliness Functional impairment Beekman et al., in press 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 No gender difference Stressful life events Comorbid disorders less common Devenand et al., 1994

26. Proportion of Elderly Community Sample followed for 10 Years Taking Different Categories of Antidepressant Medications Blazer et al, 2000

27. Conclusion Subsyndromal or minor Depression has been reified by clinicians as an entity. Therefore

28. 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

29. Has the research agenda therefore been set in stone for subsyndromal or minor depression?

30. The Case Against Subsyndromal Depression as an Entity (a thing)

31. 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 increasedrisk of comorbid medical illness and clinical depression.’…[on the other hand], a depressive reaction to life

32. 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)

33. What is a Case of Subsyndromal Depression?

34. 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

35. 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

36. 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)

37. Snaith Criteria (1987) Snaith proposes a biogenic from of mild depression. Anhedonia is the central and reliable symptm of “hypomelancholia” (or mild biogenic depression

38. 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)

39. 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.

40. What is the Frequency and Distribution of Subsyndromal Depression?

41. 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)

42. 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.

43. What are the Risk Factors for Subsyndromal Depression? All the risk factors for major depression “and more”.

44. What is the Outcome of Subsyndromal Depression?

45. 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

46. 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 * CognitiveImpairment 1.45 Low Income 1.52 ** ** Hx of Smoking 1.48 Odds of Mortality in Females in Controlled Analyses Hybels et al, in preparation

47. 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?

48. Are we asking the wrong questions? Are we looking in the wrong place?

49. A Brief History of the Diagnosis of Depression

50. 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)