1. 1 Innate immune response in depression and anxiety Nicole Vogelzangs a Johannes H Smit a, Sabine Bahn b, Brenda W Penninx a a Psychiatry & EMGO + Institute VU university medical center & GGZ inGeest Amsterdam n.vogelzangs@vumc.nl n.vogelzangs@ggzingeest.nl b Institute of Biotechnology, University of Cambridge, Cambridge, United Kingdom

2. Meta-analyses: inflammation in depression Howren et al. Psychosomatic Medicine, 2009 Dowlati et al. Biological Psychiatry, 2010 Confirmed by: Hiles et al. Brain, Behavior, and Immunity, 2012 Liu et al. J Affective Disorders, 2012 Marker# studies Effect size / Mean Difference CRP490.15 IL-6610.25 IL-1140.35 TNF-α133.97 pg/ml 2 ISAD Berlin - April 29, 2014

3. Inflammation in anxiety Some studies suggest increased inflammation in anxiety: - anxiety symptoms 1,2 - post traumatic stress disorder 3,4 - panic disorder 5,6 - generalized anxiety disorder 5,7 1. Pitsavos et al. Atherosclerosis, 2006 2. Liukkonen et al., Eur Psychiatry, 2011 3. Gill et al., Perspect Psychiatr Care, 2009 4. Spitzer et al., J Psychiatr Res, 2010 5. Vogelzangs et al., Transl Psychiatry, 2013 6. Hoge et al., Depress Anxiety, 2009 7. Bankier et al., Eur Heart J, 2008 3 ISAD Berlin - April 29, 2014

4. But, … Meta-analyses show large heterogeneity + Basal circulating inflammation levels: - low levels - circadian rhythmicity - high inter-individual variability 4 ISAD Berlin - April 29, 2014 => Stimulate the immune system to assess the maximal production capacity of cytokines = innate immune response - higher levels, less variable - mimics natural environment more closely - under strong genetic control => Take depressive and anxiety characteristics into account

5. Questions Is the innate immune response increased in depression and anxiety? Is innate immune response associated with depressive and anxiety characteristics?  Severity?  Duration?  Ag of onset?  Comorbidity?  Cognitive vs. somatic symptoms? 5 ISAD Berlin - April 29, 2014

6. 6 Design Naturalistic cohort study Assessments at baseline and after 1, 2, 4 and 8 years. Sample 2,981 subjects (1979 F, 1002 M), 18-65 years (mean age: 42y) recruited in community, primary care and specialized mental health care to reflect total range of psychopathology Includes healthy controls and both remitted and current depressed and/or anxiety disorder patients Penninx et al. Int J Meth Psychiatric Res 2008 Netherlands Study of Depression and Anxiety www.nesda.nl ISAD Berlin - April 29, 2014

7. 7 Depressive and anxiety disorders and characteristics Depressive / Anxiety disorder diagnosis Major Depressive Disorder, Dysthymia Generalized anxiety, Social phobia, Panic disorder, Agoraphobia CIDI interview, DSM-IV based, current recency (6 months) Severity Inventory of Depressive Symptoms (IDS) Beck Anxiety Inventory (BAI) Cognitive vs. symptoms taken from IDS and BAI ComorbidityDepression only, anxiety only, depression + anxiety Duration % of time affected in past 4 years, life chart Age of onset in years (derived from CIDI) ISAD Berlin - April 29, 2014

8. Innate immune response Ex vivo whole blood stimulation by addition of lipopolysaccharide (LPS) Multi-analyte profiling of plasma using Human CytokineMAP A v 1.0 (Myriad RBM, Austin, TX) N=1241 with available data on LPS-stimulated cytokines LPS-stimulated cytokines Interferon (IFN)-γ IL-2, IL-4, IL-6, IL-8, IL-10, IL-18 Monocyte chemotactic protein (MCP)-1 Macrophage inflammatory protein (MIP)-1α, MIP-1β Matrix metalloproteinase (MMP)-2 TNF-α, TNF-β LPS-stimulated index: sum of all standardized LPS-stimulated markers 8 ISAD Berlin - April 29, 2014

9. Baseline characteristics 9 ISAD Berlin - April 29, 2014 No dep/anx n=297 Remitted dep/anx n=251 Current dep/anx n=694 p Women, %62.066.9.30 Age (yrs)42.2 (13.9)45.9 (12.2)41.9 (12.1)<.001 Education (yrs)13.1 (3.2)12.8 (3.3)11.7 (3.2)<.001 Current smoker, %23.634.343.9<.001 Alcohol intake, %<.001 None21.221.939.2 Moderate66.765.749.6 Heavy12.112.411.2 Physical activity (MET-min)4.0 (13.1)3.7 (2.8)3.5 (3.1).08 BMI25.2 (4.7)26.2 (4.8)25.7 (5.2).06 # of chronic diseases0.5 (0.7)0.6 (0.8)0.7 (1.0)<.001 Anti-inflammatory med, %2.08.45.3.003

10. Immune response and depression/anxiety disorder 10 ISAD Berlin - April 29, 2014 Remitted disorderCurrent disorder OR95%CIpOR95%CIp LPS index1.080.87-1.34.501.190.99-1.43.06 IL-81.361.13-1.64.0011.351.16-1.59<.001 IL-181.150.95-1.39.151.221.04-1.43.01 Adjusted for sociodemographics Adjusted for lifestyle and health factors Remitted disorderCurrent disorder OR95%CIpOR95%CIp LPS index1.020.82-1.28.861.120.92-1.35.27 IL-81.281.06-1.55.011.251.06-1.48.01 IL-181.150.95-1.39.151.130.96-1.33.14

11. Immune response and depression/anxiety severity Adjusted for sociodemographics 11 ISAD Berlin - April 29, 2014 IDSBAI βpβp IFN-γ-.006.87.047.16 IL-2.017.58.027.38 IL-4.007.81-.024.40 IL-6.054.14.107.003 IL-8.113<.001.115<.001 IL-10.078.03.106.003 IL-18.076.01.098.001 MCP-1.134<.001.140<.001 MIP-1α.039.26.071.04 MIP-1β.073.04.103.003 MMP2.103.001.142<.001 TNF-α-.005.88.034.32 TNF-β.069.03.119<.001 LPS index.091.01.127<.001

12. Immune response and depression/anxiety severity Adjusted for lifestyle and disease 12 ISAD Berlin - April 29, 2014 IDSBAI βpβp IFN-γ IL-2 IL-4 IL-6.077.03 IL-8.069.02.066.03 IL-10.059.10.078.03 IL-18.029.32.053.07 MCP-1.087.008.088.007 MIP-1α.032.35 MIP-1β.028.42.055.11 MMP2.071.02.110<.001 TNF-α TNF-β.042.16.094.002 LPS index.046.18.087.01

13. Cognitive vs. somatic symptoms Duivis, Vogelzangs et al., PNEC, 2013: Basal CRP, IL-6 and TNF-α are associated with somatic symptoms of IDS and BAI, but NOT with cognitive symptoms of IDS and BAI 13 ISAD Berlin - April 29, 2014 LPS indexIDSBAI βpβp Total.091.01.127<.001 Somatic.094.009.131<.001 Cognitive.082.03.102.005 Adjusted for sociodemographics

14. Depressive and anxiety characteristics Within the subsample of current depressive/anxiety patients (N=694) Severity => replication of findings within total sample Duration => no association Age of onset => no association Comorbidity => no differences between pure depression, pure anxiety disorder and comorbid depressive and anxiety disorder 14 ISAD Berlin - April 29, 2014

15. Conclusions Innate immune response is increased in persons with higher levels of depressive and in particular anxiety symptoms, even when taking lifestyle and health factors into account. IL-8 production capacity is increased in both previously and currently depressed an anxious persons => genetic vulnerability? No specific associations with duration, age of onset or comorbidity. Unlike basal inflammation levels, innate immune response is associated with both somatic and cognitive depressive/anxiety symptoms. => Measuring innate immunity provides additional insight in immune functioning in depression and anxiety. 15 ISAD Berlin - April 29, 2014

16. 16 Thank you for your attention! ISAD Berlin - April 29, 2014