Schizophrenia and Bipolar Disorders II: Analytic Epidemiology and the Search for Etiologic Clues. William Eaton, PhD Johns Hopkins University

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2 Schizophrenia and Bipolar Disorders II: Analytic Epidemiology and the Search for Etiologic Clues William Eaton, PhD Johns Hopkins University

3 Risk Factors for Schizophrenia Genes Season of birth Obstetric complications Modernization Urbanicity Ethnic status Drug use Infections Autoimmune disorders 3

4 Prevalence Correlates for Schizophrenia Marital status Socioeconomic status 4

5 Marital Status and Schizophrenia Reasons Given for Switching to Injection Drug Use Author/Date Place Male Female Odegaard, 1946 Norway Odegaard, 1953 Norway Norris, 1956 England Thomas, 1963 New York Thomas, 1963 Ohio Stein, 1970 England Adapted from Eaton, Acta Psychiatr Scand.,

6 Marital Status and Psychoses Mental Hospitals in Canada, First Admissions per 1,000 Population Single/ Married Ratio Never Married Married Widowed Divorced Schizophrenia Male Female Bipolar disorder Male Female Adapted from: Gregorv, Can Psychiatr Assoc J.,

7 Schizophrenia and Being Single First-admission and re-admission Adapted from: Agerbo et al, Arch Gen Psychiatry, 2004; National Centre for Register-based Research, Aarhus, Denmark 7

8 Socioeconomic Status and Schizophrenia "Incidence" studies since 1975 Finland 1979 Northern Ireland 1982 Netherlands 1983 Ireland, rural 1987 Ireland, urban 1987 Finland Relative Risk for Lower versus Upper Class 8

9 Taiwan Studies of Schizophrenia Prevalence per 1,000 Social Class Upper Middle Lower Adapted from: Warner, Schizophr Bull.,1995; from work of Lin T., Psychiatry 1953; and Lin et al, in Cardell, W; T Lui, Mental Health Research in Asia and the Pacific. Honolulu: East-West Center Press;

10 SES and Marital Status: Conclusions Single persons have high risk Low SES persons have high risk Both associations could be entirely due to insidious onset The chain of causation is complex 10

11 Genetics Genetics 11

12 Family Studies of DSM-III Schizophrenia Family Studies of DSM-III Schizophrenia Author Date Cases/ First-Degree Controls Relatives Morbid Risk Baron Kendler , Frangos Adapted from: Kendler, 1988, Handbook of Schizophrenia; Studies of DSM-III with controls, personal interviews with relatives, and blind diagnoses 12

13 Twin Studies of Schizophrenia Author Date Country MZ DZ Heritability Luxenburger 1928 Germany 14/22 0/13 ** Rosanoff 1934 USA 25/41 7/ Essen-Moller 1941 Sweden 7/11 4/ Kallman 1946 USA 191/245 59/ Slater 1953 England 28/41 11/ Inouye 1963 Japan 33/55 2/ Kringlen 1967 Norway 31/69 14/ Fischer 1973 Denmark 14/23 12/ Gottesman 1972 England 15/26 4/ Tienari 1975 Finland 7/21 6/ Kendler 1983 USA 60/194 18/ Data from: Kendler, 1988, Handbook of Schizophrenia; DZ are same sex; not age corrected 13

14 Danish Adoption Study Method Adoption Register Psychiatric Register (Case Notes) Folkeregister ****Research Design**** Sample 5483 Adoptees Index Cases sex === 34 Controls 247 Relatives ses 265 Relatives Mortality/ Refusal 173 Biologic 74 Adoptive 174 Biologic 91 Adoptive Psychiatric Interview 118 Schizophrenic: 11 Spectrum 26 Normal 81 Adapted from: Kety, Rosenthal, Wender, Schulsinger, Jacobsen, ****Results**** Frequencies

15 Genomic Scan in Schizophrenia Results for part of chromosome 6 Locus Prior H P in Stage I P in Stage II No 0.77 D6S274 Yes D6S285 Yes 0.66 D6S299 No 0.38 D6S306 No 0.42 D6S276 No 0.3 D6S273 No 0.04 D6S291 No D6S271 No

16 Genome Scan Meta-Analysis of Schizophrenia Adapted from: Lewis et al, Am J Hum Genet 2003, Table 2 16

17 Genome Scan Meta-Analysis of BPD Model 1: BP-I or BP-I & SAB Adapted from: Segurado et al., Am J Hum Genet 2003, Table 3 17

18 Genetics: Conclusion Schizophrenia and bipolar disorder are inherited The degree of inheritance is stronger than for most psychiatric disorders It is unlikely to be a Mendelian pattern Inheritance pattern is different for schizophrenia and bipolar disorder 18

19 Environmental Risk Factors: Conditions of Birth Environmental Risk Factors Conditions of Birth 19

20 Season of Birth and Schizophrenia Investigator Year Sample Northern Hemisphere Tramer Petersen de Sauvage Nolting Huntington Laestadius de Sauvage Nolting Norris and Chowning Hare and Price Dalen Hare et al Odegard Videbech et al Parker and Balza Shimura et al Torrey et al O Hare et al Watson et al Kendell and Kemp Hafner et al Adapted from: Eaton and Chen, 2004 Continued 20

21 Season of Birth and Schizophrenia Investigator Year Sample Bourgeois et al Torrey et al Rodrigo et al Torrey et al Aschauer et al Kim et al Tam and Sewell Chen et al Torrey et al Mortensen Southern Hemisphere Dalen and Roche Parker and Neilson McGrath et al Adapted from: Eaton and Chen,

22 Season of Birth in Denmark Adapted from: Videbech et al, Acta Osychiatr Scand. 1974, Figure 1. 22

23 Obstetric Complications and Schizophrenia Odds Ratios and 95% Confidence Intervals in 9 Studies Author Date Sample Woerner McNeil Jacobsen Eagles O'Callaghan Kinney Gunther-Genta Done Buka Adapted from: Geddes and Lawrie, BJP, 1995; Studies of obstetric records only; Done estimate from original BMJ

24 Brain Structure, Genetic and Obstetric Risk 6.5 Danish High Risk Sample Standardized CSF-Brain Ratio Low Risk High Risk Very High Risk 4.5 No Complications Delivery Complications Complications Adapted from: Cannon et al, Arch Gen Psychiatry,

25 SOB and OCs: Conclusions Season of birth (SOB) is a consistent but weak risk factor for schizophrenia but not BPD Season of birth expresses a cause that is not genetic Obstetric complications are a consistent risk factor of moderate strength for schizophrenia but not BPD SOB and OCs interact with genetic risk in some as-yetunknown way There are intriguing specific complications that involve high risk Infection is probably part of the causal picture 25

26 Urban Residence Urban Residence 26

27 Urban Areas Continued 27

28 Urban Areas 28

29 Manic-Depressive Insanity 29

30 Schizophrenia Rates 30

31 Schizophrenia 31

32 Place of Residence and Schizophrenia First Hospitalization in Maryland, Center City Annual Rate per Metro-urban Rural Data from: Eaton, J Health Soc Behav., 1974 Age at First Hospitalization 32

33 Place of Upbringing and Schizophrenia Swedish Conscripts Cities Large Towns Small Towns Rural Cases Others 10,311 4,970 14,583 19,059 Incidence/1000/year Crude Odds Ratio Adjusted Odds Ratio Data from: Lewis et al, Lancet,

34 Urbanization and Risk for Psychosis in Denmark 7 Relative Risks and 95% Confidence Intervals Schizophrenia 2 Non-Affective Psychosis 1 (Reference) Affective Psychosis 0 Rural Small Cities Large Cities Suburbs Copenhagen 34

35 Is Schizophrenia a Modern Disease? Is Schizophrenia a Modern Disease? 35

36 Hieronymus Bosch, The Cure of Folly, 16th Century 36

37 Hieronymus Bosch, Ship of Fools,

38 Pieter Breughel, Dulle Griet ( Mad Meg ), 16th Century 38

39 39

40 40

41 She speaks much of her father; says she hears there s tricks in the world, and hems, and beats her heart, spurns enviously at straws, speaks things in doubt that carry but half sense. Her speech is nothing, yet the unshaped use of it doth move the hearers to collection. They aim at it and botch the words up fit to their own thoughts; which, as her winks and nods and gestures yield them, indeed would make one think there would be thought, though nothing sure, yet much unhappily. Shakespeare, Hamlet; Act 4, Scene 5, describing Ophelia 41

42 Insanity in England and Wales Data from: Torrey and Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present,

43 Asylum Admission Rates: England and Wales Year of Admission 43 Annual Rate per 1000

44 Insanity in the United States 4 Insanity in the United States United States Insane Persons per 1000 Population Year 44 Data from: Torrey and Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present, 2001.

45 Insanity in Atlantic Canada 4.5 Insanity in Atlantic Canada Insane Persons per 1000 Population Year 45 Data from: Torrey and Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present, 2001.

46 Insanity in Ireland Insanity in Ireland Insane persons per 1000 Population Year 46 Data from: Torrey and Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present, 2001.

47 Insanity in Four Countries Insanity in Four Countries Insane Persons per 1000 Population Year England and Wales Ireland Atlantic Canada United States Data from: Torrey and Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present,

48 Admissions to Aarhus Hospital 800 Admissions to Aarhus Hospital Number of Persons Year of Admission 48 Source: Redrawn from Stromgen, Br J Psychiatry, 1987

49 Insanity in the United States Insane Persons per 1000 Population Insanity in the United States United States Masschusetts United States Year Data from: United States, , Torrey and Miller, 2001; Massachusetts, , Goldhamer and Marshall in Eaton, 2001; United States, , Witkin et al,

50 Explanations for Rise in Schizophrenia, New Virus (Hare) Cephalopelvic disproportion (Warner) Life planning (Eaton and Harrison) New toxin New contact with vector (Torrey and Yolken) N. B.: genetics is not a good explanation 50

51 Modern, Urban Life: Conclusions Schizophrenia may have emerged in the past 500 years Bipolar disorder is ancient Urban life raises risk for schizophrenia Urban life is not associated with risk for bipolar disorder Explanations for the urban risk include social and biological causes 51

52 Ethnicity Ethnicity 52

53 Ethnic Disadvantage and Schizophrenia Studies in the U.K. and Holland Data from: Eaton and Chen,

54 Ethnic Disadvantage: Conclusions In certain settings, disadvantaged ethnic status is a consistent and strong risk factor for schizophrenia The differential risk is not explained by genetic differences in ethnic groups For bipolar disorder, ethnic differences may possibly be genetic in origin 54

55 Drug Use and Schizophrenia Prospective Studies Location Relative Risk Sweden 2.3 Netherlands 2.8 New Zealand 6.6 Data from: Witton et al, Cannibis as a causal factor for psychosis a review of the evidence. In Gattaz, W.G., and Hafner, H., Search for the Causes of Schizophrenia, Volume V, Darmstadt, Steinkopf, 2004, pages

56 Infection and Autoimmune Hypotheses Infection and Autoimmune Hypotheses 56

57 Findings That Link Infections and Schizophrenia Cohort studies of flu epidemics and high rates Case control studies of antibodies Toxoplasma Herpes simplex virus Prenatal rubella 57

58 Recent Studies of Toxoplasma and Schizophrenia Data from: Torrey & Yolkem, Emerg Infect Dis.,

59 IgG Antibodies IgG Antibodies* in Maternal Sera at Birth of CPP Offspring 27 Adult Psychotics 54 Controls Toxoplasma gondii Human parvovirus Rubella virus Cytomegalovirus Herpes simplex virus Herpes simples virus ** 0.24 *Optical density units via immunoassay **Significantly different from controls at p <

60 Prenatal Rubella Exposure and Nonaffective Psychosis (a) Unexposed (Saratoga study) Total Non-NAP NAP Relative risk (b) Unexposed (ECA study) Rubella exposed (a) 5.2 ( ) (b) 16.3 ( ) Modified from text in Comparison of Diagnostic Outcomes. Source: Brown et al., Am J Psychiatry,

61 Arthritis and Schizophrenia Odds Ratios and 95% Confidence Intervals in 6 studies Author Date Sample Ross et al Pilkington Baldwin Mohamed et al Allebeck et al Oken & Schulzer Oken & Schulzer Mors et al Data from: Eaton and Chen,

62 Prevalence of Celiac Disease in Cases of Schizophrenia Data from linked Danish National Case Registers Prevalence/1,000 Relative Risk* Cases Controls Univariate Adjusted Celiac ( ) Chrons Disease ( ) Ulcerative Colitis ( ) Data from: Eaton et al, BMJ,

63 Mary Mary Munoz: What What do do * * refer refer to? to? Schizophrenia: Autoimmune Disease? Findings that suggest Schizophrenia might be some sort of autoimmune disease Relapsing course with unpredictable episodes; autoantibodies can produce psychosis (SLE)** Immunologic abnormalities (Ganguli et al) Decreased IL 2** Increased IL 2 receptors* Increased IL 6* Autoimmune disorders are associated with schizophrenia Thyroid disorders are more common** Rheumatoid Arthritis is less common** Celiac disease is more common** 63

64 Prenatal Autoimmune Schizophrenia involves heterozygous advantage Relatives of schizophrenics are protected from viral but not bacterial infections Winter birth of schizophrenics suggests influenza Second trimester influenza infection is most risky Maternal antibodies cross the placenta Antibodies to influenza cross-react with brain tissue Source; Wright and Murray, Ann Med., 1993; Wright et al, Schizophr Res.,

65 Population Attributable Risk for Three Risk Factors Risk Factor PAR in Percent Schizophrenia in sibling or parent 5.5 Season of birth 10.5 Place of birth 34.6 Data from: Mortensen et al, NEJM,