Depression trajectories, inflammation, and lifestyle factors in adolescence: The TRacking Adolescents' Individual Lives Survey.

OBJECTIVE: In adults, depression and inflammation are bidirectionally related. This association is less clear in adolescents. Moreover, somatic and cognitive depressive symptoms might be differentially related to inflammation. Lifestyle factors, as in adults, may play an important mediating role in adolescents. For the current study we evaluated trajectories of depressive symptoms in adolescence over a 5-year course and their relation with subsequent high-sensitivity C-reactive protein (hsCRP) levels, and examined lifestyle factors as mediators. METHOD: Participants of the TRacking Adolescents' Individual Lives' Survey (TRAILS; N = 1166) were followed from 2001 until 2008. Three biennial youth self-report (YSR) assessments of depressive symptoms were taken. Demographics, health, and lifestyle factors and levels of hsCRP were assessed at Wave 3. Latent-class analysis was used to determine trajectories of depression and general linear models to determine the association between depression trajectories and hsCRP. Finally, mediation analysis was performed to test mediation of lifestyle factors. RESULTS: Persistently moderate to high depressive symptoms were associated with higher hsCRP levels. Results were unaltered when we adjusted for demographics and health variables. Smoking mediated the association between depressive symptoms total score and hsCRP, in large part. Persistently higher scores on somatic and cognitive symptom subscales were associated with higher levels of hsCRP than persistently low scores. These results were rendered nonsignificant after covariate adjustment. CONCLUSION: Persistent depressive symptoms were associated with subsequent higher levels of hsCRP, with somatic and cognitive symptoms contributing equally. The association was mediated by smoking behavior. These findings suggest that reducing adolescent depression and smoking are important starting points in the prevention of inflammatory diseases.

Association between exposure to HSV1 and cognitive functioning in a general population of adolescents. The TRAILS study.

BACKGROUND: Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population. METHODS: This study was performed in TRAILS, a large prospective general population cohort (N = 1084, 54% female, mean age 16.2 years (SD 0.6)). At age 16, immunoglobulin G antibodies against HSV1, HSV2, CMV and EBV were measured next to high sensitive C-Reactive Protein (hsCRP). Two years later, immediate memory and executive functioning were assessed using the 15 words task and the self ordered pointing task. Multiple linear regression analysis with bootstrapping was performed to study the association between viral infections and cognitive function, adjusting for gender, socioeconomic status, ethnicity, and cannabis use. RESULTS: Presence of HSV1 antibodies was associated with memory function ((B = -0.272, 95% CI = -0.556 to -0.016, p = 0.047)), while the association with executive functioning did not reach statistical significance (B = 0.560, 95% CI is -0.053 to 1.184, p = 0.075). The level of HSV1 antibodies was associated with both memory function (B = -0.160, 95% CI = -0.280 to -0.039, p = 0.014) and executive functioning (B = 0.296, 95% CI = 0.011 to 0.578, p = 0.046). Other herpes viruses and hsCRP were not associated with cognitive functioning. CONCLUSIONS: Both presence and level of HSV1 antibodies are prospectively associated with reduced cognitive performance in a large cohort of adolescents.

Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms?

BACKGROUND: Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association. METHODS: 2812 Participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio [KYN/TRP]. Depressive symptoms were measured with the Inventory of Depressive Symptomatology. RESULTS: Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group (B=-0.032; 95% CI: -0.103 to 0.028) and for the subgroup of patients with current MDD (B=0.059; 95% CI: -0.037 to 0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group (B=-0.023; 95% CI: -0.093 to 0.045) and in the MDD subgroup B=0.052; 95% CI: -0.019 to 0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group (ß=-0.019, p=0.311) nor in the subgroup with MDD (ß=0.025, p=0.424). CONCLUSIONS: We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms.

Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from the Netherlands Study of Depression and Anxiety (NESDA).

OBJECTIVE: Depression and anxiety have been suggested to be associated with systemic inflammation upregulation. However, results are not always consistent, which may be due to symptom heterogeneity of depression and anxiety. There are some indications that associations with inflammation are mainly driven by somatic symptoms of depression and anxiety. We therefore set out to evaluate the differential association of somatic and cognitive symptoms of depression and anxiety with inflammation, while adjusting for demographic, health related, and lifestyle related variables. METHODS: We evaluated baseline data from 2861 participants from the Netherlands Study of Depression and Anxiety (NESDA). The Inventory of Depressive Symptomatology and the Beck Anxiety Inventory were used to assess depressive symptoms and anxiety symptoms. For both scales somatic and cognitive symptoms scales were calculated. Baseline blood samples were collected to determine high sensitivity C-Reactive Protein (CRP), interleukin (IL)-6, and Tumor Necrosis Factor (TNF)-α. We used linear regression to analyze the associations adjusting for demographics and health indicators and markers for an unhealthy lifestyle. RESULTS: After adjustment for sociodemographic and health indicators, depressive symptoms were associated with higher levels of CRP, IL-6 and TNF-α. This association was mainly driven by somatic symptoms. For anxiety, somatic symptoms were associated with higher levels of CRP, IL-6 and TNF-α, whereas cognitive anxiety symptoms were associated with CRP (men only). Markers of an unhealthy lifestyle explained the significant associations. CONCLUSIONS: Especially somatic symptoms of depression and anxiety are associated with inflammation. However, this association was mostly mediated through unhealthy lifestyles among depressed and anxious individuals.

Depressive symptoms and white blood cell count in coronary heart disease patients: prospective findings from the Heart and Soul Study.

BACKGROUND: Depression has been associated with elevated white blood cell (WBC) count - indicative of systemic inflammation - in cross-sectional studies, but no longitudinal study has evaluated whether depressive symptoms predict subsequent WBC count or vice versa. We sought to evaluate the bidirectional association between depressive symptoms and WBC count in patients with coronary heart disease (CHD). METHODS: Depressive symptoms were assessed at baseline and annually during 5 consecutive years of follow-up in 667 outpatients with stable CHD from the Heart and Soul Study. The presence of significant depressive symptoms was defined as a score of ≥10 on the Patient Health Questionnaire (PHQ-9) at one or more assessments. WBC count was measured in blood samples collected at baseline and after 5 years of follow-up. RESULTS: Of the 667 participants, 443 (66%) had no depressive symptoms (PHQ-9<10), 86 (13%) had depressive symptoms (PHQ-9≥10) at 1 assessment, and 138 (21%) had depressive symptoms at 2 or more annual assessments. Across the three groups, participants with recurrent depressive symptoms had higher WBC levels after 5 years of follow-up (p<.001). This relationship was essentially unchanged after adjustment for demographics, traditional cardiovascular risk factors, cardiac disease severity, inflammatory cytokine levels, and health behaviors (p=.009). Baseline WBC count was not associated with subsequent depressive symptoms (p=.18). CONCLUSIONS: Depressive symptoms independently predicted higher subsequent WBC count in patients with stable CHD, but baseline WBC count did not predict subsequent depressive symptoms. These findings support a unidirectional relationship in which depression is a risk-factor for inflammation.

Depressive symptoms, health behaviors, and subsequent inflammation in patients with coronary heart disease: prospective findings from the heart and soul study.

OBJECTIVE: Depression has been associated with inflammation in patients with coronary heart disease. However, it is uncertain whether depressive symptoms lead to inflammation or vice versa. METHOD: The authors evaluated 667 outpatients with established coronary heart disease from the Heart and Soul Study. Depressive symptoms were assessed annually with the 9-item Patient Health Questionnaire. Participants were categorized as having no significant depressive symptoms (score below 10 at all interviews), depressive symptoms (score of 10 or higher) at one interview, or depressive symptoms at two or more interviews. At baseline and 5-year follow-up, fasting blood samples were collected to measure three inflammatory biomarkers: fibrinogen, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP). RESULTS: Of the 667 participants, 443 had no depressive symptoms, 86 had depressive symptoms at one assessment, and 138 had depressive symptoms at two or more annual assessments. Across the three groups, greater depressive symptoms were associated with higher subsequent log-transformed levels of IL-6 and hsCRP, and the association with higher fibrinogen levels approached significance. Baseline inflammation did not predict subsequent depressive symptoms. The association of depressive symptoms with subsequent inflammation levels was eliminated after adjustment for health behaviors associated with depression-physical inactivity, smoking, and higher body mass index. CONCLUSIONS: Depressive symptoms predicted higher IL-6 and hsCRP levels among outpatients with coronary heart disease, but higher inflammation levels did not predict subsequent depressive symptoms. The association between depressive symptoms and inflammation was no longer significant after adjustment for health behaviors, which suggests these behaviors may mediate depressive effects.