Considering depression characteristics and antidepressants in the inflammation-depression relationship Nicole Vogelzangs Department of Psychiatry / EMGO+ Institute VU University Medical Center Amsterdam, The Netherlands n.vogelzangs@vumc.nl n.vogelzangs@ggzingeest.nl May 29, 2013

Cardiovascular burden 2 Depression Cardiovascular burden May 29, 2013

Meta-analyses: inflammation in depression 3 Marker # studies Effect size / Mean Difference CRP 49 0.15 IL-6 61 0.25 IL-1 14 0.35 TNF-α 13 3.97 pg/ml 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 May 29, 2013

+ But, … All meta-analyses noted large heterogeneity, 4 All meta-analyses noted large heterogeneity, only for a small degree explained by methodological issues + Clinical presentation of depressive disorders is very heterogeneous (which might represent underlying etiological heterogeneity) => Depression subgroups!? Antidepressant use might alter inflammation-depression relationship May 29, 2013

Example: age of onset 5 vascular disease in co-twin major depression in co-twin Kendler et al. Biol Psychiatry 2009 May 29, 2013

Questions Is inflammation mainly present in subgroups? 6 Is inflammation mainly present in subgroups? Only among most severe/chronic cases? Only among those with late onset? Only among those with somatic symptoms? Only among those with atypical or melancholic depression? Effects of antidepressant medication? May 29, 2013

Penninx et al. Int J Meth Psychiatric Res 2008 Netherlands Study of Depression and Anxiety 7 www.nesda.nl 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, depression subjects and anxiety subjects Penninx et al. Int J Meth Psychiatric Res 2008 May 29, 2013

Depressive disorder and characteristics 8 Depression Diagnosis Major Depressive Disorder, Dysthymia (CIDI interview, DSM-IV based) At baseline and 2-year follow-up (=> persistent depression) Severity Inventory of Depressive Symptomatology (IDS), 0-84 Duration % of time affected in past 4 years, life chart Age of disorder onset in years Somatic vs. cognitive items of the IDS Atypical vs. melancholic depression (according to latent class analyses) Antidepressant medication (by drug container observation) Selective serotonin reuptake inhibitor (SSRI), serotonergic noradrenergic reuptake inhibitor (SNRI), tri- and tetracyclic antidepressants (TCA/TeCA) May 29, 2013

Inflammation Inflammatory markers (in plasma) C-reactive protein (CRP) 9 Inflammatory markers (in plasma) C-reactive protein (CRP) Interleukin (IL)-6 Tumor necrosis factor (TNF)-α May 29, 2013

Vogelzangs et al. Translational Psychiatry 2012 Adjusted mean inflammation levels across depressive disorder status and sex 10 N=2415 Controls Remitted Current Mean(se) p Men N=193 N=238 N=369 CRP 1.04(1.08) 1.03(1.07) .96 1.29(1.06) .02 IL-6 0.76(1.07) 0.78(1.06) .72 0.87(1.05) .10 TNF-α 0.88(1.04) 0.83(1.04) .33 0.86(1.03) .69 Women N=301 N=551 N=763 1.45(1.07) 1.38(1.05) .57 1.30(1.04) .16 0.80(1.06) 0.72(1.04) .13 0.73(1.03) .14 0.84(1.04) 0.82(1.03) .70 0.83(1.02) .90 Cohen d = 0.21 Cohen d = 0.15 Based on ANOVA analyses adjusted for sociodemographics, lifestyle & disease factors May 29, 2013 Vogelzangs et al. Translational Psychiatry 2012

Severity and duration among currently depressed 11 N=1132 CRP IL-6 TNF-α Severity β=-.020 p=.47 β=.038 p=.22 β=.040 p=.20 Duration β=-.005 p=.87 β=-.017 p=.58 β=.012 p=.70 * Based on linear regression analyses adjusted for sociodemographics and health factors Vogelzangs et al. Translational Psychiatry 2012 May 29, 2013

Adjusted mean inflammation levels across age of onset in currently depressed men 12 p=.03 p=.03 p=.03 CRP, mg/l TNF-α, pg/ml Age of depressive disorder onset Age of depressive disorder onset n=193 n=96 n=100 n=68 n=62 n=35 n=193 n=96 n=100 n=68 n=62 n=35 Men only Vogelzangs et al. Translational Psychiatry 2012 May 29, 2013

Cognitive versus somatic symptoms 13 N=2861 CRP IL-6 TNF-α Somatic β=.078 p<.001 β=.054 p=.005 β=.045 p=.02 Cognitive β=.021 p=.27 β=.028 p=.13 β=.035 p=.07 * Based on linear regression analyses adjusted for sociodemographics and health factors Duivis, Vogelzangs et al. Psychoneuroendocrinology 2013 May 29, 2013

Atypical versus melancholic depression 14 Adjusted mean (SE) inflammation levels Control Melancholic Atypical p (A vs. C) (A vs. M) Cohen d CRP 1.18 (1.05) 1.05 (1.12) 1.67 (1.12) .004 .003 0.39 IL-6 0.75 (1.04) 0.69 (1.10) 1.00 (1.09) .002 0.40 TNF-α 0.84 (1.03) 0.77 (1.07) 1.02 (1.06) .001 0.42 * Based on ANOVA analyses adjusted for sociodemographics and health Lamers, Vogelzangs et al. Molecular Psychiatry 2013 May 29, 2013

Atypical versus melancholic depression 15 Cortisol awakening curve Melancholic Ref Atypical p=.001 Controls p=.12 * Based on linear mixed model analyses adjusted for sociodemographics and health May 29, 2013 Lamers, Vogelzangs et al. Molecular Psychiatry 2013

Thus… Do specific depression characteristics 16 Do specific depression characteristics further delineate the depressed person with increased inflammation? Severity => No Duration prior to baseline => No Age of disorder onset => Yes, late onset in men Cognitive vs. somatic => Yes, somatic symptoms Atypical vs. melancholic => Yes, atypical depression What about antidepressants? May 29, 2013

Adjusted mean CRP levels across antidepressant use and sex MEN WOMEN d=0.48 d=0.28 ** * d=0.44 ** CRP, mg/l No med SSRI SNRI TCA/TeCA No med SSRI SNRI TCA/TeCA n=154 n=95 n=35 n=27 n=308 n=231 n=47 n=49 IDS: 36.4 35.9 36.5 32.4 36.4 34.5 34.5 36.3 May 29, 2013

Adjusted mean IL-6 levels across antidepressant use and sex MEN WOMEN d=0.49 ** d=-0.32 ** IL-6, pg/ml No med SSRI SNRI TCA/TeCA No med SSRI SNRI TCA/TeCA n=154 n=95 n=35 n=27 n=308 n=231 n=47 n=49 IDS: 36.4 35.9 36.5 32.4 36.4 34.5 34.5 36.3 May 29, 2013

2-year depressive disorder persistence in antidepressant users: 56.2% 19 AD users (N=310) Recently started on AD (N=103) OR 95%CI p Continuous CRP 1.19 0.93-1.51 .16 0.90 0.57-1.41 .64 IL-6 1.56 1.20-2.02 .001 2.22 1.23-3.98 .008 TNF-α 0.99 0.78-1.25 .93 1.12 0.67-1.86 .67 Dichotomous* 1.33 0.83-2.14 .23 1.26 0.51-3.13 .62 2.18 1.35-3.52 2.72 0.97-7.63 .06 0.93 0.58-1.51 .77 1.15 0.44-3.05 Based on logistic regression analyses adjusted for sociodemographics, lifestyle and disease * Above median (CRP ≥ 1.58; IL-6 ≥ 0.95; TNF-α ≥ 0.80) May 29, 2013

Conclusions Taking depression heterogeneity into account is important! 20 Taking depression heterogeneity into account is important! => inflammation is increased in persons (men) with - an older age of onset - somatic symptoms - atypical depression Antidepressants might differ in their effects on inflammation - SSRI: better inflammatory profile? - SNRI/TCA/TeCA: worse inflammatory profile? Inflammation might indicate poor treatment response May 29, 2013

Clinical implications 21 Current antidepressants are only effective in 1/3-1/2 of patients, likely due to heterogeneity of depression => new treatments are needed for depression subtypes Atypical depression subtype with late onset and somatic symptoms? Poorer course because of treatment resistance? High inflammation has been shown to indicate treatment resistance to antidepressants (Lanquillon 2000; Eller 2008) This subgroup needs new antidepressant interventions Anti-inflammatory medication (Muller 2004; 2006) Lifestyle interventions (e.g. exercise; Mead 2009) => Improve metabolic/inflammatory profile and depression!? May 29, 2013

Thank you! Netherlands Study of Depression and Anxiety www.nesda.nl 22 Netherlands Study of Depression and Anxiety www.nesda.nl funded through the mental health program of the Netherlands Organization for Health Research (ZonMW) and matching funds from participating institutes May 29, 2013