Values of Cytokines and Tryptophan Metabolites over a 12 Weeks Time Course in Patients with Depression and Somatoform Disorder.

OBJECTIVE: Previous studies have suggested alterations in the kynurenine pathway as a major link between cytokine and neurotransmitter abnormalities in psychiatric disorders. Most of these studies used a cross-sectional case-control study design. However, knowledge is still lacking regarding the stability over time of kynurenine pathway metabolites and the functionally related cytokines. Therefore, we studied the stability of cytokines and tryptophan (TRP) parameters over a period of 12 weeks. METHODS: A total of 117 participants-39 with major depression, 27 with somatoform disorder, and 51 healthy controls were enrolled. Four evaluations, including blood withdrawal and psychometric testing, were performed over a period of 12 weeks. We used ELISA to measure interleukin (IL)-6, IL-1 receptor antagonist (RA) and tumor necrosis factor α (TNF α). High-performance liquid chromatography was used to analyze neurotransmitter variables, i.e. TRP, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), 3-OH-kynurenine (3-HK), and kynurenic acid (KYNA). RESULTS: We found no significant fluctuations of TRP, its metabolites (5-HIAA, KYN, KYNA, and 3-HK), or the cytokines (IL-1RA, IL-6, and TNF α) in any of the groups over the 12 weeks. CONCLUSION: To our knowledge, this is the first longitudinal study performed in psychiatric patients to verify the stability and consequently the reliability of the biological parameters we investigated. Our data indicate that TRP metabolites and cytokines are reliable biological parameters in psychiatric research because they do not fluctuate significantly over time.

Stability of Cellular Immune Parameters over 12 Weeks in Patients with Major Depression or Somatoform Disorder and in Healthy Controls.

OBJECTIVE: Cellular immune status in major depression (MD) patients differs from that in somatoform disorder (SFD) patients and healthy controls (HC). It is still questionable whether the patterns of immune parameters remain stable over time. Therefore, we studied lymphocyte and monocyte cell counts and neopterin levels in peripheral blood of MD and SFD patients and HC over 12 weeks and tested for correlations between biochemical and psychometric parameters. METHODS: Thirty-nine patients with MD, 27 with SFD, and 51 HC were recruited. Peripheral blood was drawn at four visits, at 4-week intervals. We assessed the total cell count of B lymphocytes, natural killer (NK) cells, T lymphocyte subpopu-lations, and monocytes by flow cytometry, and neopterin serum levels by ELISA. Psychometric parameters were measured with questionnaires. RESULTS: Counts of lymphocytes, monocytes, and neopterin were stable in the SFD and HC groups. In the MD group, total CD3+, CD3+CD8+, NK cells, and CD3+CD25+ T cells showed inhomogeneous variances in Friedman tests, particularly in females. Neopterin correlated with depressed mood in MD patients, and with body mass index in HC. CONCLUSIONS: Cellular immune parameters are stable in HC and SFD. Our results may indicate influences of MD and gender on some cellular immune parameters. This may need to be considered in future immunological studies.

Blunted exercise-induced mobilization of monocytes in somatization syndromes and major depression.

BACKGROUND: Previous research indicates that physical activity may alter the number of immune cells. We examined whether increasing or decreasing the level of physical activity affects circulating lymphocyte and monocyte counts in patients with somatization syndromes and patients with major depression. METHODS: Thirty-eight participants with major depression, 26 participants with somatization syndromes and 47 healthy controls participated in the study. Using an experimental within-subject design, participants were involved in 1 week of increased physical activity (daily exercise sessions) and 1 week of reduced physical activity. Counts of total lymphocytes, lymphocyte subsets and monocytes were determined before and after each trial. Linear mixed models adjusted for sex, body mass index, age, fitness status and the order of trials were used for longitudinal data analysis. RESULTS: One week of exercise increases the number of monocytes in healthy controls (p<.05), but not in patients with somatization syndromes or patients with major depression. In addition, after 1 week of exercise, depressive symptoms were reduced in patients with major depression (p<.05) while somatoform symptoms were reduced (p<.05) in both clinical groups. Baseline comparisons and mixed models indicated reduced T helper cell counts in patients with somatization syndromes. LIMITATIONS: Relatively small sample size. The time of physical activity was relatively short and restricted to low-graded exercise. CONCLUSIONS: This study demonstrates a blunted mobilization of monocytes by exercise in both patients with somatization syndromes and patients with major depression. In addition, even one week of exercise reduces somatoform and depressive symptoms.

The predictive value of somatic and cognitive depressive symptoms for cytokine changes in patients with major depression.

CONTEXT: Elevated concentrations of proinflammatory cytokines have been hypothesized as an important factor in the pathophysiology of depression. Depression itself is considered to be a heterogeneous disorder. Current findings suggest that "cognitive" and "somatic" symptom dimensions are related to immune function in different ways. So far, little research has been done on the longitudinal aspects of inflammation in patients with major depression, especially with respect to different symptom dimensions of depression. Therefore, we investigated which aspects of depression may predict changes in tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 over 4 weeks. METHODS: Forty-one patients with major depression diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and 45 healthy controls were enrolled. Serum measurements of TNF-alpha and IL-6 were conducted at baseline and 4 weeks later. Psychometric measures included the assessment of cognitive-affective depressive symptoms and somatic symptoms during the last 7 days as well as somatic symptoms during the last 2 years. RESULTS: Patients with depression showed increased levels of TNF-alpha (P<0.05) compared to healthy controls. Hierarchical regression analyses indicated that neither depressive nor somatic symptoms predict changes in proinflammatory cytokines in the whole sample of depressed patients. Moderation analyses and subsequent sex-stratified regression analyses indicated that higher somatoform symptoms during the last 2 years significantly predict an increase in TNF-alpha in women with major depression (P<0.05) but not in men. Exploratory analyses indicated that the stability of TNF-alpha and IL-6 (as indicated by intraclass correlation coefficients) over 4 weeks was high for TNF-alpha but lower for IL-6. CONCLUSION: The present study demonstrated that a history of somatoform symptoms may be important for predicting future changes in TNF-alpha in women with major depression.

Exercise affects symptom severity but not biological measures in depression and somatization - results on IL-6, neopterin, tryptophan, kynurenine and 5-HIAA.

Exercise leads to symptom reduction in affective disorders and functional somatic syndromes. Biological hypotheses of underlying mechanisms include serotonergic and immunological pathways. We aimed to investigate biological features in persons with major depression and somatoform syndromes, and to analyze effects of short-term graded exercise on these parameters. Baseline values for depressive and somatoform symptoms, tryptophan, kynurenine, 5-hydroxyindoleacetic acid, neopterin and interleukin-6 were compared with those after one week of increased and one week of reduced physical activity. Thirty-eight persons with major depression, 27 persons with a minimum of 6-8 somatoform symptoms, and 48 healthy controls participated in the study. Depressive and somatoform symptoms were reduced after the active week, and an interaction pointed towards group-specific reduction of psychopathology. Participants with major depression had lower levels of kynurenine compared to controls, with intermediate concentrations in somatoform patients. There were no systematic associations of symptom improvement with biological changes. A possible limitation of the design is that a control condition with low physical activity, but no placebo condition was included. People with multiple somatoform symptoms and major depression benefit from a short and low-graded exercise intervention. These effects do not seem to be mediated by changes in serotonergic and inflammatory parameters.

The influence of physical activity on pain thresholds in patients with depression and multiple somatoform symptoms.

OBJECTIVES: Pain is a common symptom with high occurrence in somatoform syndromes and depressive disorders. Research in this area often focuses on experimental induction of pain and subsequent assessment of pain thresholds, ensuring repeatable stimuli of defined quality. Results on sensitivity to experimental pain in major depression are inconclusive, and data on pain thresholds in multiple somatoform symptoms are scarce. The goals of the present study were to differentiate between groups regarding the pressure pain thresholds, and to investigate the possible influence of physical activity on the pain thresholds in these groups. We postulate that physical fitness and physical activity influence pain thresholds in depression and persons with multiple somatoform symptoms. METHODS: Thirty-eight persons with major depression, 26 persons with a minimum of 6 to 8 somatoform symptoms (somatoform symptom index 8, SSI-8), and 47 healthy participants participated in the study. Baseline values of pressure pain thresholds assessed at different sites of the body were compared with those after 1 week of increased and 1 week of reduced physical activity. RESULTS: We used repeated measurement design (MANCOVA) and partial correlations for data analysis. Depressed participants reported lower pain thresholds compared with controls, and persons with SSI-8 showed intermediate thresholds. After 1 week of physical activity, participants reported higher pain thresholds. Men had higher pain thresholds following activity as compared with women. Participants who reported higher general fitness also showed higher pain thresholds. Sensitivity to pressure pain is associated with depression, but not with multiple somatoform symptoms. DISCUSSION: Short low-graded exercise can have reducing effects on perception of pressure pain. Physical activity level is a relevant covariate when using pressure pain assessment. Reduced general fitness can partially account for lower pain thresholds in depression.

Psychobiological aspects of somatization syndromes: contributions of inflammatory cytokines and neopterin.

Previous research suggests a dysregulation of immune-to-brain communication in the pathophysiology of somatization syndromes (multiple somatoform symptoms). We compared blood levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6) and neopterin between 23 patients with somatization syndromes (Somatoform Symptom Index-8, SSI-8), 23 age- and sex-matched healthy controls and 23 patients with major depression. No group differences were found for IL-1ra and IL-6. While TNF-α was increased in both clinical groups, neopterin was only increased in somatization syndromes. Correlational analyses revealed that neopterin tended to be related to somatoform pain complaints in patients with somatization syndromes. This study is the first to demonstrate increased levels of TNF-α and neopterin in patients with somatization syndromes without a diagnosis of depression, which may support a role of immune alterations in somatization syndromes. Neopterin is a reliable indicator for interferon-γ (IFN-γ) which was identified as the only cytokine that induces significant production of neopterin. Considering recent research indicating that IFN-γ can lead to increased neuronal responsiveness and body perceptions by reducing inhibitory tone in the dorsal horn, the observed association between somatization syndromes and neopterin might support the idea of central sensitization in the pathogenesis of somatoform symptoms.

Depression, cytokines and experimental pain: evidence for sex-related association patterns.

BACKGROUND: There is robust evidence that altered neural-immune interactions including increased levels of proinflammatory cytokines are involved in both the pathogenesis of depression and altered pain processing. Proinflammatory cytokines induce sickness behavior, a constellation of symptoms that bears a strong similarity to those of depression. A feature of sickness behavior is enhanced pain sensitivity and it has been suggested that proinflammatory cytokines interact with pain processing directly and via several neurobiological pathways. Previous research indicates that depression and pain are closely related. We investigated the association between proinflammatory cytokines and experimental pain in major depression. METHODS: Psychopathological variables, pressure pain thresholds (PPT) and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured in 37 outpatients with major depression and 48 healthy controls. RESULTS: Compared with controls, depressed patients exhibited significantly higher levels of TNF-α and significantly decreased PPT indicating enhanced pain sensitivity. The group differences were robust when adjusting for sex and body mass index, although sex was significantly related to PPT. No group difference was observed in IL-6. PPT correlated significantly with TNF-α in women but not in men. LIMITATIONS: Because of the cross-sectional design, causality of the relation between TNF-α and pain cannot be determined. Results should be considered preliminary given the small sample size. CONCLUSION: The present findings suggest that increased pain sensitivity in depression may be linked to increased TNF-α concentration. The absence of this association in men is discussed in terms of pain-related psychobiological sex differences.

Psychobiological differences between depression and somatization.

BACKGROUND: Comorbidity studies have shown that depression and somatization (multiple somatoform symptoms) often overlap. Therefore it has been suggested to classify at least some patients with somatization syndromes under the category of depressive disorders. We wanted to investigate whether psychobiological investigations confirm the lumping of somatization and depression, or whether psychobiological pathways favor distinguishing these disorders. METHOD: An overview is presented summarizing psychobiological studies including patients with depression and/or somatization-associated syndromes. We focus on the following topics: heritability, polymorphisms in special candidate genes, immune activation, hypothalamic-pituitary-adrenal (HPA) axis reactivity, serotonergic pathways, monoamino acids, and fatty acid concentrations. RESULTS: Immunological activation seems to be associated with specific features of somatoform disorders, namely, sickness behavior and pain thresholds. Genetic factors can also contribute to somatic complaints, e.g., via serotonergic pathways, HPA-axis response, immune activation, and other biological systems that contribute to the self-description of not being healthy. Some results indicate that psychobiological aspects of depression and somatization overlap in part (e.g., the relevance of serotonergic pathways), but there is clearly more evidence for discrepancies of psychobiological pathways in depression and somatization (e.g., the relevance of proinflammatory immune processes; HPA-axis activity; monoamino acid availability; omega-3-concentration; the role of triallelic subtypes of 5-HTTLPR). CONCLUSION: Many psychobiological pathways act differently in depression and somatization. These differences in psychobiology favor the distinction of these syndromes in classification approaches.

Lowered omega-3 PUFAs are related to major depression, but not to somatization syndrome.

BACKGROUND: Studies indicated a depletion of omega-3 fatty acid levels and an imbalance between omega-3 and omega-6 PUFAs in depressive patients. Depletion of omega-3 PUFAs may be related to the immune and serotonergic pathophysiologies of depression by alterations in membrane fluidity and modulation of membrane receptors, enzyme activities and carriers. Previous studies also found serotonergic and immunological disturbances in subjects with somatoform symptoms. Based on these findings we aimed to investigate PUFA concentrations and its relations to other biological systems in depressed patients and in patients with somatoform symptoms. METHODS: We examined 150 subjects divided in 4 groups, i.e. somatization syndrome; depression; depression and somatization syndrome; controls. Blood samples were analyzed for fatty acids, markers of the serotonergic system and the immune system. RESULTS: The study was able to replicate earlier findings in patients with depression (lowered omega-3 PUFAs, increased omega-6/omega-3 ratios in serum cholesteryl esters). The somatization syndrome group showed no abnormalities in the mentioned fatty acid levels. Only depressive patients revealed associations between fatty acids with serotonergic and immunological markers. LIMITATIONS: We used current state diagnoses, and the consideration of lifetime diagnoses and longitudinal studies could highlight further aspects of the reported results. CONCLUSIONS: The findings are further confirming that the concepts of depression and somatoform disorders should not be merged indiscriminately together, even though they often occur together. We conclude that in depression and somatoform syndrome different biological mechanisms seem to be involved.