Infections and autoimmunity as risk factors for mental disorders
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1 Common threads New York March 2018 Infections and autoimmunity as risk factors for mental disorders - Danish nationwide register and biobank studies M.D., Ph.D.
2 The Danish Registers Prescription Database All redeemed prescriptions since 1995 CPR-number Register Hospital Registers - Psychiatry since Somatic since 1977
3 SCHIZOPHRENIA OR RELATED PSYCHOSIS (F20-29) Autoimmune diseases and infections as risk factors for schizophrenia ( ) (N=3,56 million; Schizophrenia cases=39,076) Benros et al. 2011, American Journal of Psychiatry
4 SCHIZOPHRENIA OR RELATED PSYCHOSIS (F20-29) Autoimmune diseases and infections as risk factors for schizophrenia ( ) (N=3,56 million; Schizophrenia cases=39,076) Benros et al. 2011, American Journal of Psychiatry
5 SCHIZOPHRENIA OR RELATED PSYCHOSIS (F20-29) Autoimmune diseases and schizophrenia risk
6 SCHIZOPHRENIA OR RELATED PSYCHOSIS (F20-29) Localization of the infection and schizophrenia risk
7 SCHIZOPHRENIA (F20) Risk of schizophrenia (F20) and association with type of first infection (N=843,390 born , Schizophrenia cases=3,409) Type of infection IRR 95% CI Cases Bacterial infection only Viral infection only Different types No infections 1.00 (reference) 1,860 Nielsen PR, Benros ME, Mortensen PB. Schizophr Bull. 2014
8 DEPRESSION (F30-39) Autoimmune diseases and infections as risk factor for mood disorders ( ; N=3,56 millioner; F30-F39=91,637) Benros et al. JAMA Psychiatry. 2013
9 MOOD DISORDERS (F30-39) Autoimmune diseases and infections as risk factors for mood disorders ( ) (N=3,56 million; Mood disorder cases=91,637) Benros et al. 2013, JAMA Psychiatry
10 MOOD DISORDERS (F30-39) Autoimmune diseases and risk of mood disorders
11 MOOD DISORDERS (F30-39) Localization of the infection and risk of mood disorders
12 SUICIDE Infections and risk of suicide (N=7.2 millions; Suicides=32.683) Incidence Rate Ratio Referenc e Number 2 of 3 Different 4 Infections Helene, Benros ME, et al. JAMA Psych. 2016
13 Schizophrenia Affective disorders 4 Schizophrenia-spectrumNo. of cases HRR 1 No. of cases HRR 1 Series1 Anti-infective agent: (%) Schizophrenia (95%-CI) spectrum (%) Affective disorders (95%-CI) Total No. of cases HRR Time Affective since disorders last antiinfective agent 251 (4.4) 1.00 (Ref.) 414 (3.2) 1.00 (Ref.) 5,759 (100) 1 13,044 No. of cases (100) HRR 1 3 (%) (95%-CI) (%) (95%-CI) No anti-infective prescription 12,630 (96.8) 1.64 ( ) DOSE-RESPONSE Total 5,759 (100) 13,044 (100) Any anti-infective No agent 5, (95.6) (4.4) (Ref.) 414 (3.2) 1.00 (Ref.) 2 prescription ( ) Anti-infective 0-3 months 875 (15.2) 1.43 (1.28; 1.59) 10,196 2,486 (19.1) (78.2) 1.95 (1.81; 2.11) 3-6 months 464 (8.1) 1.33 (1.18; 1.50) 1,229 (9.4) 1.73 (1.58; 1.88) prescription but no 4,496 (78.1) months 686 (11.9) 1.35 (1.19; 1.51) 1,713 (13.1) 1.74 (1.60; 1.89) 1 hospitalization 1-2 years with 847 (14.7) ( ) 1.27 (1.13; 1.42) 2,124 (16.3) 1.51 (1.39; 1.64) infection 2-5 years 1,384 (24.0) 1.21 (1.08; 1.35) 2,813 (21.6) 1.32 (1.21; 1.43) 5-10 years 964 (16.7) 1.13 (0.99; 1.29) 1,808 (13.9) 1.13 (1.02; 1.24) Anti-infective 0 10 years 288 (5.0) 1.52 (1.20; 1.93) 457 (3.5) 1.22 (0.99; 1.50) prescription 0 anti-infective agents and a 2-4 anti-infective agents anti-infective agents hospitalization with infection ANTI-INFECTIVE PRESCRIPTIONS Anti-infective agent prescriptions and the risk of schizophrenia and mood disorders 1,012 (17.4) 2.05 ( ) 1.56 ( ) 2,434 (18.7) 2.59 ( )
14 ANTI-INFECTIVE PRESCRIPTIONS Type of anti-infectives and risk of schizophrenia and mood disorders Anti-infective agent: Schizophrenia spectrum No. of cases HRR (%) (95%-CI) Affective disorders No. of cases (%) HRR (95%-CI) Total 5,759 (100) 13,044 (100) No anti-infective agents 251 (4.4) 1.00 (Ref.) 414 (3.2) 1.00 (Ref.) Any anti-infective agent 5,508 (95.6) 1.37 ( ) 12,630 (96.8) 1.64 ( ) Antibiotics Broad spectrum Moderate spectrum Narrow spectrum Topical 5,418 (94.1) 1,746 (30.3) 1,654 (28.7) 4,053 (70.4) 2,051 (35.6) 1.44 ( ) 1.53 ( ) 1.50 ( ) 1.40 ( ) 1.36 ( ) 12,479 (95.7) 4,858 (37.2) 4,615 (35.4) 9,472 (72.6) 5,306 (40.7) 1.65 ( ) 1.61 ( ) 1.50 ( ) 1.30 ( ) 1.54 ( ) Antivirals 609 (10.6) 1.25 ( ) 1,759 (13.5) 1.20 ( ) Antimycotics 2,175 (37.8) 1.27 ( ) 5,498 (42.2) 1.07 ( ) Antiparasitic 1,336 (23.2) 0.94 ( ) 3,586 (27.5) 1.24 ( )
15 ANTI-INFECTIVE PRESCRIPTIONS Dose-response association (p<0.001) 4 3 Schizophrenia-spectrum Series1 Affective disorders Number of prescriptions Köhler 0, Petersen L, Gasse C, Yolken R, Mortensen PB, Benros M Acta Psychiatr Scand
16 STREPTOCOCCAL INFECTION Streptococcal infection (n=349,982) and risk of mental disorders ( ) (N=1,07 million children; Mental disorders=15,408) Any mental Disorder No. IRR (95%CI) Positive streptococcal infection 15, ( ) No test 13, (ref) OCD Positive streptococcal infection ( ) No test (ref) Tic Disorders Positive streptococcal infection ( ) No test (ref) Orlovska, Vestergaard, Bech, Nordentoft, Vestergaard, Benros. 2017, American JAMA Psychiatry
17 STREPTOCOCCAL INFECTION Streptococcal infection (n=349,982) and risk of mental disorders ( ) (N=1,07 million children; Mental disorders=15,408) Orlovska, Vestergaard, Bech, Nordentoft, Vestergaard, Benros. 2017, American JAMA Psychiatry
18 STREPTOCOCCAL INFECTION Time since the last Streptococcal infection and risk of mental disorders (N=1,07 million children; Mental disorders=15,408) Orlovska, Vestergaard, Bech, Nordentoft, Vestergaard, Benros. 2017, American JAMA Psychiatry
19 STREPTOCOCCAL INFECTION Age at the first Streptococcal infection and risk of mental disorders (N=1,07 million children; Mental disorders=15,408) Orlovska, Vestergaard, Bech, Nordentoft, Vestergaard, Benros. 2017, American JAMA Psychiatry
20 META-ANALYSIS Meta-analysis of exacerbations linked to GABHS (82 children with PANDAS and 97 control children) Nielsen, Köhler-Forsberg, Hjorthøj, Benros et al. 2018, Submitted
21 META-ANALYSIS Meta-analysis Rate of GABHS infection in children diagnosed with PANDAS Nielsen, Köhler-Forsberg, Hjorthøj, Benros et al. 2018, Submitted
22 META-ANALYSIS Meta-analysis Rate of neuropsychiatric exacerbations in children diagnosed with PANDAS Nielsen, Köhler-Forsberg, Hjorthøj, Benros et al. 2018, Submitted
23 Prevalence of the potential risk factors A previous hospital contact for infections had occurred in 23% of people with schizophrenia and in 32% of mood disorders 96% had prior infections treated with antibiotics before the schizophrenia or mood disorder diagnosis A total of 6% of people with schizophrenia have a hospital contact with an autoimmune disease 5% of people with mood disorders had a previous hospital contact with autoimmune diseases
24 C-reactive protein (CRP) and leucocyte levels in schizophrenia and mood disorders (n=3034) Highest CRP levels in bipolar disorder (3.5 mg/l) (particularly during manic states, 3.9 mg/l), followed by schizophrenia (3.1 mg/l), and depression (2.8 mg/l), - (normal CRP<1mg/L) CRP differed significantly between the mental disorders at baseline (P=0.01) Elevated CRP levels were associated with increased allcause mortality: by HR=1.56 (95%CI= ) for CRP levels 3 10 mg/l and HR=2.07 (95%CI= ) for CRP levels >10 mg/l. Baseline leucocyte level did not differ (median 7.1x10 9 /L). Horsdal HT, Köhler 0, Benros M, Gasse C European Psychiatry
25 CSF studies Systematic review and meta-analysis 109 CSF studies between , out of which 33 studies included healthy controls, but only few investigated the same parameters Increased permeability of the blood-brain barrier in both schizophrenia (54 patients; SMD: 0.62; 95%CI: ) and mood disorders (302 patients; SMD=0.43; 95%CI= ), compared to healthy controls Elevated CSF cytokine s: IL-6, IL-8 (all p<0.05) Orlovska S, Köhler 0, Brix S, Nordentoft N, Kondziella D, Krogh J, Benros M. Under preparation
26 POLYGENIC RISK SCORE Polygenic risk score for schizophrenia Based on the latest PGC sample (34,241 cases and 45,604 controls) Danish Replication sample: 1,697 cases and 1,725 controls Number of SNPs: 102,366 Basic adjustment Additional adjustment for family history with infections and psychiatric family history Additional adjustment for the polygenic score 1 Cases RR (95%CI) RR (95%CI) RR (95%CI) Infection ( ) 1.42 ( ) 1.41 ( ) No infection (ref) 1.00 (ref) 1.00 (ref) Benros ME, Trabjerg B, Meier S, Mortensen PB, Nordentoft M, Agerbo E. Biol Psychiatry 2016
27 POLYGENIC RISK SCORE Risk of schizophrenia dependent on Polygenic risk score in quartiles stratified for infections No infections Infections ce Rate Ratio Polygenic score quartiles
28 IMMUNO-GENETICS GWAS of infections (n=65.545) Infection is mostly environment with a small polygenic contribution (PRS predicted infection status among cases with mental disorders) SNP Heritability of infection was only 4% Significant genetic correlation between infections and mental disorders with a rg of 0.5 (P = , SE = 0.058) PRS for schizophrenia did not predict the risk of acquiring infections (RR=1.00; 95%CI= )
29 Anti-inflammatory treatment: Meta-analysis Depression vs. Depressive symptoms Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar R, Mors O, Krogh J. JAMA Psych 2015
30 Anti-inflammatory treatment: Meta-analysis NSAIDs vs. Cytokine-inhibitors Köhler O, Benros ME, et al. JAMA Psychiatry. 2014
31 Ongoing studies Psych-Flame Identifying immune-related subgroups
32 Take home messages Autoimmune diseases and particularly infections increases the risk of schizophrenia and mood disorders in a dose-response relationship At diagnosis there are increased levels of peripheral inflammation, increased BBB permeability and increased CSF cytokine levels Some of the psychiatric symptoms could be caused by inflammation or brain-reactive antibodies RCT s with anti-inflammatory treatment has a moderate effect on depression and depressive symptoms but RCT s based on immune-related biomarkers is needed!
33 Thank you for your attention! Thanks to my collaboraters: Mental Health Center Copenhagen, Copenhagen University Merete Nordentoft, Ole Köhler, Sonja Orlovska, Jesper Krogh Centre for Register-based Research, Aarhus University Preben Mortensen, Philip Nielsen, Marianne Pedersen, Berit Waltoft, Carsten Pedersen, Liselotte Petersen, Betina Trabjerg, Sandra Meier, Manuel Mattheisen and Esben Agerbo Institute of Biological Psychiatry, Mental Health Center St. Hans, Copenhagen University Wes Thompson, Thomas Werge, Roni Nudel, Yunpeng Wang The State Serum Institute: Niels Heegaard, Bent Nørgaard-Pedersen, and David Hougaard Johns Hopkins University, USA: William Eaton, Robert Yolken Financial support: Lundbeck Foundation Stanley Medical Research Institute ERC advanced grant
Infections and autoimmunity as risk factors for mental disorders
C O M M O N T h r e a d s N e w Yo r k M a r c h 2 0 1 8 Infections and autoimmunity as risk factors for mental disorders - Danish nationwide register and biobank studies M.D., Ph.D. Copenhagen University
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