1. 1 Depression Diagnosis, epidemiology and etiology Nicole Vogelzangs Department of Psychiatry / EMGO+ Institute VU University Medical Center GGZ inGeest n.vogelzangs@ggzingeest.nl

2. 2 Topics Classification en diagnostics Prevalence of depressive disorders Public mental health Etiology of depression Biological factors and somatic comorbidity

3. 3 Psychiatric disorder Condition characterized by disturbed mental functioning causing distress and/or impaired social functioning Mental functioning: becoming aware of information from the environment, appreciating this information, weighing and testing this by previous experiences, leading to automatic muscle movements and acting on the environment

4. 4 Most psychiatric disorders: Pathologic-anatomical of pathophysiological disease process unknown  Diagnosis is based on pattern of complaints and symptoms  Emphasis on diagnosing based on subjective disease perception, social dysfunctioning and need for care Psychiatric disorder

5. 5 Classification and Diagnostics <1968: Categories and dimensions without clear definition; different “schools” 1968: ICD-8 - Categories with glossary 1980: DSM-III - Categories with explicit inclusion- and exclusion criteria (currently DSM-IV) 1980: Semi-structured and fully structured interviews – for example CIDI psychiatric interview

6. 6 Diagnosing is counting symptoms!

7. 7 1Depressed mood 2Lack of interest 3Sleep disorders 4Appetite/weight changes 5Low energy 6 Concentration problems 7 Retardation or agitation 8Guilt or worthlessness 9Suicidal ideation Depression

8. 8 Major Depressive Disorder ≥ 5 of the 9 key DSM depression criteria present for at least 2 weeks, most of the day limiting daily functioning Dysthymia depressed mood, not always as severe present very chronic: > 2 years Subthreshold depression (minor depression) different definitions: DSM-criteria or screening questionnaire (CES-D, BDI, IDS) prevalence depending on definition Depressive Disorders

9. 9 Melancholy No energy Atypical Nervous Manic Depression = container concept

10. 10 Measuring in a research setting? Psychiatric interview - symptom questionnaire Self-report - observation Problems Overlap between normal and pathology Overlap between disorders Heterogeneity within disorders Little specificity (biological) markers

11. 11 Topics Classification en diagnostics Prevalence of depressive disorders Public mental health Etiology of depression Biological factors and somatic comorbidity

12. 12 The ‘soul’ in numbers: world wide in 2001 Depression 121 million Alcohol use disorder 70 million Alzheimer’s disease 37 million Schizophrenia 24 million =>Lifetime psychiatric disorder: 25% of world population World Health Report, WHO 2001

13. 13 Prevalence of psychiatric disorders per year Netherlands (NEMESIS study, n > 7000) depression anxiety alcohol drug schizo- eating depend. depend. phrenia disorder Bijl et al. Soc Psychiatry Psychiatr Epidemiol 1998 % 2 6 4

14. 14 Lifetime prevalence across gender (NEMESIS)

15. 15 Country% depres. disorder Country% depres. disorder Belgium6.2Libanon6.6 France8.5Nigeria0.8 Germany3.6Japan3.1 Italy3.8Beijing2.5 Netherlands6.9Shanghai1.7 Spain4.9Colombia6.8 Ukraine9.1Mexico4.8 USA9.6 Depressive disorder in last year 15 countries Demytteenaere K et al. JAMA 2004;291:2581-2590

16. 16 WHO 2001 “psychiatric illnesses are not present in selected areas or groups: they are everywhere!”

17. 17 Life time prev. 1-year prev. Prevalence of depression in the Netherlands (NEMESIS study: 18-64 years) men women Bijl et al. Soc Psychiatry Psychiatr Epidemiol 1998 major depression dysthymia %

18. 18 Major depression by age and sex % * * * * p<.05 Results from the Longitudinal Aging Study Amsterdam

19. 19 Subthreshold depressive symptoms by age and sex % * * * p<.05 Results from the Longitudinal Aging Study Amsterdam *

20. 20 Comorbidity of depression & anxiety disorders Comorbid anxiety Comorbid depression Comorbid total Current* depressive disorder 59%23%63% Current* anxiety disorder 31%59%65% * last 6 months N=2981

21. 21 1992 2003 % Kessler et al. JAMA 2003; NEJM 2005 Prevalence of depression across time (NCS en NCS-R studies, n>18,000)

22. 22 36-50% of serious cases in developed countries and 76-85% of serious cases in less-developed countries DO NOT RECEIVE TREATMENT Demyttenaere K et al. JAMA 2004;291:2581-2590

23. 23 Filter model of Goldberg & Huxley Depression in general population (1-MP: N=250.000) Depression in general practice (search for care) (1-MP: 80%  N=200.000) Recognition depression by GP (recognition) (1-MP: 50-70%  120.000) Referral to ambulant GGZ (referral) (1-MP: 7-9%  8.500) Intramural GGZ (referral) (1-MP: 1%  1.000)

24. 24 Topics Classification en diagnostics Prevalence of depressive disorders Public mental health Etiology of depression Biological factors and somatic comorbidity

25. 25 Rank 2030Disease% DALYs 1Depression9.6% 2Heart disease5.9% 3Alzheimer, dementia5.8% 4Alcohol problems4.7% 5Diabetes4.5% 6Stroke4.5% 7Hearing loss4.1% 8Cancer3.0% 9Arthritis2.9% 10Lung disease2.5% Worldwide disease burden* in disability-adjusted life years (DALYs)= lost life years + loss of quality of life, Western countries WHO : Mathers; Plos Medicine 2006

26. 26 ‘Dutch’ top ten diseases with largest disease burden 1Coronary heart disease 2Anxiety disorders 3Stroke 4Depression 5COPD 6Diabetes Mellitus 7Lung cancer 8Alcohol dependency 9Arthritis 10Dementia Assessed in healthy life expectancy Source: RIVM, Nationaal Kompas Volksgezondheid

27. 27 Why high disease burden of depression? High prevalence Chronic disease: high relapse rate and chronicity Episodes cause substantial loss of quality of life Onset at relatively young age – on average between 25-30 years of age

28. 28 Course of depression is very variable disease time sub-clinical normal symptoms

29. 29 Course of depression Various studies: After 1-3 years: 50% still depressed “ Single episodes are extremely rare if the period of observation is significantly extended “ Angst et al. Psychiatr Neurol Neurochir 1973

30. 30 Costs of depression €132 million per million adults About the same costs in minor depression About twice as much in dysthymia  Total costs about € 600 million per million adults Smit et al. Journal of Mental Health Policy and Economics, 2006 Cuijpers et al. Acta Psychiatrica Scandinavica, 2007

31. 31 So why is prevention necessary? Because of high Prevalence Incidence Costs Burden of disease Limited possibilities of treatment

32. 32 Epidemiology of depression in the Netherlands Influx 357.000 Prevalence 738.000 recovery Mortality relapse Prevention Cure

33. 33 Topics Classification en diagnostics Prevalence of depressive disorders Public mental health Etiology of depression Biological factors and somatic comorbidity

34. 34 depression: complex disease

35. 35 ….depression manifests in many ways….

36. 36 Depression is a complex disorder: many interacting contributing mechanisms Identified contributing factors include stressors as well as vulnerabilities: - Genetic factors - Psychosocial factors - Behavioral factors - Somatic health factors - Biological factors

37. 37 Vulnerability - Stress Model Grouping of most mentioned etiological factors VulnerabilityStressors Environment lack of social support deprivation Personal vulnerability genetic load vulnerable personality childhood experiences previous depression Recent life events / loss (lasting) conflicts adverse conditions Physical unhealthiness diseases medication disability or handicap Depression adapted from Brown & Harris, 1978; Beekman & Ormel, 1999

38. 38 Overview of genome wide linkage studies Genetic factors Twin studies: heritability = 30 – 40%

39. 39 Psychosocial risk factors for depression Psychological Personality (esp. neuroticism) Locus of control / mastery Cognitive vulnerability (rumination, irritability, etc) Social Childhood trauma and life events Social network and support Work (circumstances)

40. 40 Behavioral (lifestyle) factors associated with depression Smoking Depressed persons: smoke more often + less likely to quit + inhale more + smoke more of cigarette NHANES: Anda et al. JAMA 1990 Alcohol use Depressed persons are more often excessive drinkers. Reversed causality is likely: - Alcohol use causes depression – ‘consequence theory’ - Depression causes alcohol use - ‘medicating theory’ - Third factors underlie both

41. 41 Physical activity Depressed persons are more sedentary Physical exercise interventions improve mood Nutrition Vitamin B12 + folate deficiency may increase depression Metabolic syndrome (e.g. cholesterol) & obesity may increase depression N-3 fatty acids  some – not consistent - evidence Behavioral (lifestyle) factors associated with depression

42. 42 Unhealthy lifestyle Controls n=524 Remitted MDD n=774 Current MDD n=1075 p Physical activity -low -moderate -high 12.8% 37.2% 50.0% 15.2% 37.3% 47.5% 21.1% 36.3% 42.6%.001 Alcohol dependence1.4%5.2%9.1%<.001 Smoking26.5%39.5%45.2%<.001 Body Mass Index25.125.625.9.01

43. 43 Topics Classification en diagnostics Prevalence of depressive disorders Public mental health Etiology of depression Biological factors and somatic comorbidity

44. 44 Somatic health risk factors for depression Heart disease / diabetes / stroke Pain / migraine / arthritis Physical disability / frailty Vision and hearing impairment Cognitive impairment

45. 45 Somatic comorbidity of depression Evidence from systematic reviews ReviewNo. of studiesEvidence MortalityWulsin 1999 Cuijpers 2002 n=21 n=25 +, RR=1.9 +, RR=1.8 Heart diseaseRugulies 2002 Wulsin 2003 Nicholson 2006 Van der Kooy 2007 n=11 n=10 n=21 n=28+, RR=1.6 +, RR=1.8 +, RR=1.6 DiabetesKnol 2006n=9+, RR=1.4 Stroke-n=7+ Hypertension-n=7+/- Cancer-n=4-, -/+

46. 46 Possible explanations Life style Diminished self care First signs of disease ( ‘ reverse causality ’ ) Pathophysiological

47. 47 Depression Cardiovascular disease Metabolic disturbances, obesity & atherosclerosis HPA-axis Autonomic nervous system Inflammation

48. 48 Meta-analyses: inflammation in depression Howren et al., Psychosomatic Medicine, 2009 Dowlati et al., Biological Psychiatry, 2010 Marker # studies Effect size / MD p CRP490.15.001 IL-6610.25<.001 IL-1140.35.03 TNF133.97 pg/ml<.001

49. 49 Netherlands Study of Depression and Anxiety www.nesda.nl Funded through the mental health program of the Netherlands Organization of Health Research (ZonMW) and matching funds from participating institutes

50. 50 Naturalistic cohort study Baseline assessment and after 1, 2, 4, 6, 8 years Depression: - Major depression - Dysthymia - Minor depression Anxiety: - Generalized anxiety disorder - Social phobia - Panic disorder NESDA design

51. 51 Persons with depression/anxiety from the general population (NEMESIS) Adults with parents with depression/anxiety (ARIADNE) Primary care: 3-step screening in 65 general practices depression/anxiety patients ‘healthy’ controls Depression/anxiety patients from secondary care New cases at 17 GGZ locations with (primary) anxiety and/or depression NESDA design

52. 52 2981 persons 1979 women (66%), 1002 men (34%) 18-65 year, mean age = 41.9 ± 13.0 year Mean education = 12.1 ± 3.3 year 97% has Dutch nationality 92% born in the Nederlands NESDA population

53. 53 NESDA baseline measurement At home: questionnaire 1 (a.o. severity, functioning, lifestyle) Informed consent Blood draw Breakfast Interview part 1 (demography, CIDI-diagnoses) Medical interview (a.o. blood pressure, heart rate, muscle strength) Interview part 2 (a.o. diseases, functioning, use of care) Psychological computer task Interview part 3 (mental history) At clinic or at home: questionnaire 2 (psychological characteristics) At home: salivary swaps for cortisol 3.5 - 4 hours

54. 54 Depression Status and Inflammation Sex, age, education adjusted model nCRPIL-6TNF-α P sex interaction ***ns MEN Controls193Ref Remitted DD238.089*.061-.017 Current DD369.158**.111**.009 WOMEN Controls301Ref Remitted DD551-.017-.043-.012 Current DD763.003-.016.018 ** p<.01, p<.05 Fully adjusted model CRPIL-6TNF-α ***ns Ref.036-.004-.019.106**.106*-.002 Ref -.017-.043-.012.003-.016.018

55. 55 Adjusted mean CRP levels across age of onset p=.001 p=.002 p=.04 CRP, mg/l n=489 n=890 n=381 n=196 n=129 n=58 Controls < 20 20-29 30-39 40-49 50-65 Age of disorder onset p=.10

56. 56 Depression and Cortisol Increased HPA-as activity Caroll (1976), Holsboer (1984), Nemeroff (1984), Gold (1986), Young (1994), Bhagwagar (2005) Decreased HPA-as activity Chrousos en Gold (1992), Asnis (1995), McGinn (1996), Levitan (2002), Stetler en Miller (2005) No association Schlechte (1986), Strickland (1998), Anisman (1999), Posener (2000), Young (2002)

57. 57 Saliva cortisol collection Saliva sampling at home 73% of samples returned Cortisol awakening response: T1: at awakening T2: +30 minutes T3: +45 minutes T4: +60 minutes

58. 58 Cortisol Awakening Rise in MDD Current MDD Remitted MDD Control Cortisol (nmol/l) Remitted MDD vs controlsp=.03 Current MDD vs controls p=.005 * Adjusted for sociodemographics, sampling factors, health indicators Vreeburg et al., Arch Gen Psychiatry 2009

59. 59 Meta-analysis: depression and heart reate variability 13 studies, n depressed = 312, n control = 374, overall effect size d=0.332 Depression is associated with overall reduction in HRV. This effect is of small-to-medium size. J. Rottenberg in Biological Psychology (2007)

60. 60 Measurement of autonomic nervous system activity VU-AMS (Ambulatory Monitoring System) Continuous registration of a.o.: - Heart Rate - Heart Rate Variability registration during NESDA interview (~ 80 minutes)  available for 98% of respondents

61. 61 Heart rate variability per depression group p<.001 Effect size d= 0.22 adjusted for age, sex, education, BMI, physical activity, smoking, alcohol use, heart diseases, heart medication, chronic disease Licht et al, Arch Gen Psychiatry 2008

62. 62 Heart rate variability according to medication IDS 5.6 15.9 35.9 34.3 34.4 34.8 37.0 N 515 585 433 67 435 134 63 p<.001 p=.05 p=.12 Licht et al, Arch Gen Psychiatry 2008

63. 63 Depression Cardiovascular disease Metabolic disturbances, obesity & atherosclerosis HPA-axis Autonomic nervous system Inflammation

64. 64 Metabolic syndrome ≥ 3 of the following 5: Waist circumference > 102 cm (men) > 88 cm (women) Triglycerides ≥ 150 mg/dl HDL cholesterol < 40 mg/dl (men) < 50 mg/dl (women) Blood pressure≥ 130/85 mmHg or medication Fasting glucose ≥ 110 mg/dl or medication

65. 65 InChianti study Prospective cohort study in general population 1155 men and women, 65 year and older 867 included in these analyses Depression (CES-D ≥ 20): 20% Metabolic syndrome: 25% Methods

66. 66 Metabolic syndrome across depression and cortisol groups % Depressed mood No depressed mood High (> 110 μg) Middle (76-110 μg) Low (< 76 μg) p =.008 Cortisol tertiles Vogelzangs et al., Psychoneuroendocrinology, 2007

67. 67 Health, Aging, and Body Composition (ABC) study Prospective cohort study in general population 3075 well functioning black (41%) and white (59%) older persons, 70-79 year Depressive symptoms (CES-D; 20 items, 0-60) mean (SD) = 4.7 (5.3) Metabolic syndrome: 39% Methods

68. 68 cm 2 No depressive symptoms Depressive symptoms Visceral fat - 7.1 BMI 0.23 - 0.04 9.4 Depressive symptoms and 5-year change in visceral fat and BMI p =.001 p =.18 Vogelzangs et al., Arch Gen Psychiatry 2008

69. 69 Visceral fat and onset of depressive symptoms over 5 years years of research % with new depression 012345 0 10 20 30 Men, normal visceral fat Men, high visceral fat (≥194 cm2) Women, normal visceral fat Women, high visceral fat (≥ 168 cm2) Vogelzangs et al., J Clin Psychiatry 2010

70. 70 Metabolic syndrome & course of depression OR95%CIp Metabolic syndrome2.711.00-7.33.05 Waist circumference1.390.95-2.01.09 Triglycerides1.610.90-2.88.11 HDL cholesterol0.720.49-1.06.10 Systolic blood pressure1.210.82-1.80.34 Diastolic blood pressure1.310.90-1.92.16 Glucose1.020.63-1.66.93 Number of metabolic syndrome components 1.661.16-2.38.005 a Adjusted for sociodemografics, life style and disease Vogelzangs et al., J Clin Psychiatry 2011

71. 71 Depression = heterogeneous disorder Etiology Clinical presentation Defining subgroups of depression based on link between etiology, genetic vulnerability, clinical characteristics and course e.g. metabolic depression….. Conclusion

72. 72 Questions….? The end….