Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.

BACKGROUND: Depressive disorders are linked to dysfunction in reward-related behaviors and corticostriatal reward circuitry. Low-grade dysregulation of the immune system, e.g., elevations in plasma interleukin 6 (IL-6) and tumor necrosis factor α, have been thought to affect corticostriatal reward circuitry. Little is presently known about the degree to which these relationships generalize to patients with treatment-resistant depression (TRD) and/or childhood trauma history. METHODS: Resting-state functional connectivity between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) regions and plasma inflammatory marker levels (IL-6, tumor necrosis factor α) were measured in 74 adults with TRD. Regression analyses examined associations of inflammatory markers with VS-vmPFC connectivity and the moderating effects of self-reported childhood trauma on these associations, with exploratory analyses examining trauma subtypes. RESULTS: IL-6 was negatively associated with VS-vmPFC connectivity (specifically for the left VS). Childhood trauma moderated the relationships between tumor necrosis factor α and VS-vmPFC connectivity (specifically for the right VS) such that greater childhood trauma severity (particularly emotional neglect) was associated with stronger cytokine-connectivity associations. CONCLUSIONS: This study independently extends previously reported associations between IL-6 and reductions in corticostriatal connectivity to a high-priority clinical population of treatment-seeking patients with TRD and further suggests that childhood trauma moderates specific associations between cytokines and corticostriatal connectivity. These findings suggest that associations between elevated plasma cytokine levels and reduced corticostriatal connectivity are a potential pathophysiological mechanism generalizable to patients with TRD and that such associations may be affected by trauma severity.

Low plasma serotonin linked to higher nigral iron in Parkinson's disease.

A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson's disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin (p < 0.0001) and higher nigral iron content (SNc: p < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) = - 0.501, p < 0.001). This correlation was significant even in patients newly diagnosed (< 1 year) and stronger in the SNc than any other region examined. This study reveals an early, linear association between low serotonin and higher nigral iron in PD patients, which is absent in controls. This is consistent with a serotonin-iron relationship in the disease process, warranting further studies to determine its cause and directionality.

Associations between estrogen and progesterone, the kynurenine pathway, and inflammation in the post-partum.

BACKGROUND: Depression during and after pregnancy is common, affecting at least 15% of women. Features of depression in pregnancy range from mild symptoms of disrupted mood and interest to severe depression and suicidal behavior. Previous studies suggest hormone- and immune dysregulations might contribute to post-partum depression, but consistent evidence is lacking. METHODS: A total of 163 women were included in the study in the post-partum. Peri-partum depression (PPD) was diagnosed using SCID interviews and depressive symptoms were quantified using the Edinburgh Perinatal Depression Rating Scale (EPDS), retrospectively long-term, as well as acutely. Plasma estrogen, progesterone, pro- and anti-inflammatory cytokines and kynurenine metabolites were measured in the post-partum. RESULTS: Higher estrogen and progesterone in the post-partum were linked to more severe depressive symptoms over pregnancy. In the post-partum, estrogen was positively correlated with the pro-inflammatory cytokine IL-6 and negatively correlated with kynurenine and picolinic acid. Conversely, progesterone was negatively correlated with IL-1ß and several metabolites in the kynurenine pathway, including quinolinic acid. LIMITATIONS: Associative study design, did not attempt to assess causality. Did not adjust hormone levels for medication effects. CONCLUSIONS: Our study suggests that higher sex hormones in the post-partum are linked to depression severity over pregnancy. Estrogen was coupled with a pro-inflammatory profile and neurotoxic kynurenine metabolites, whereas progesterone was linked to an anti-inflammatory profile in the post-partum.

Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise.

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults (n = 10; mean age 64 years), levels of kynurenine increased 1 hour (P = .03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours (P = .02). In contrast, no significant changes after exercise were seen in young adults (n = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.

Vitamin D and inflammation in major depressive disorder.

BACKGROUND: Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects. METHODS: We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score. RESULTS: There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p < 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03). LIMITATIONS: The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI. CONCLUSION: While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state.

Role of the kynurenine pathway and the endocannabinoid system as modulators of inflammation and personality traits.

BACKGROUND: Kynurenine pathway metabolites and endocannabinoids both exert potent regulatory effects on the immune system, but the relationship between these molecules is unknown. The role of these immunobiological mediators in emotionality and personality traits is not previously characterized. METHODS: Interleukin-6 (IL-6), 2-arachidonoylglycerol (2-AG) and picolinic acid (PIC) were measured in the plasma of physically healthy individuals who had history of mood, anxiety, and personality disorders (n = 96) or who had no history of any psychiatric disorder (n = 56) by DSM-5 Criteria. Dimensional assessments of personality were performed using the Eysenck Personality Questionnaire (EPQ) and the Tridimensional Personality Questionnaire (TPQ). RESULTS: Plasma IL-6 levels were significantly associated with plasma 2-AG levels and plasma PIC levels across all subjects. PIC levels were also negatively associated with 2-AG levels across all subjects, independent of IL-6 levels. In our analysis of the biological determinants of personality factors, we identified significant associations between IL-6 and novelty seeking assessment, and between PIC and neuroticism assessment. CONCLUSIONS: These data provide evidence of a biological link between metabolites of the kynurenine pathway, the endocannabinoid system and IL-6 and suggest that these factors may influence personality traits.

Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson's disease.

BACKGROUND: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. METHODS: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. RESULTS: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology, cytokine production and an upregulation in genes involved in the inflammatory response in the LPS-injected mice by RNA sequencing analysis). LPS-injected mice had significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. As expected, RNA sequencing analysis on striatal tissue revealed differential gene expression between LPS and IL-4-injected mice; with the genes upregulated in tissue from mice injected with LPS including several of those involved in an inflammatory response. CONCLUSIONS: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

Six autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters.

Previous findings suggest a link between neuroinflammatory processes and suicidality. Despite several lines of evidence supporting this link, including increased pro-inflammatory markers in blood-, cerebrospinal fluid (CSF)- and in post-mortem brain samples from suicidal individuals, the underlying mechanisms remain poorly understood. In this pilot study, we explored the possibility that autoimmune encephalopathies might be found among suicide attempters. We analysed the presence of six different autoantibodies (N-methyl-D-aspartate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor, the γ-amino-butyric acid B-receptor, the leucine-rich, glioma-inactivated 1, the contactin-associated protein-like 2, and the dipeptidyl-peptidase-like protein-6), all previously associated with psychopathology, in CSF samples from 29 unmedicated suicide attempters. Five of these subjects had high CSF/serum albumin ratio, indicative of increased blood-brain-barrier permeability. We were not able to detect any of these autoantibodies in the CSF samples. These pilot data do not support a role for autoimmune encephalopathies in suicidal behaviour, although the presence of lower levels of these autoantibodies cannot be ruled out in these patients.

Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting Pro-Inflammatory Cytokines.

BACKGROUND: Exendin-4 is a peptide agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently in clinical trials as a potential disease-modifying therapy for Parkinson's disease. In light of this, it is important to understand potential modes of action of exendin-4 in the brain. Exendin-4 is neuroprotective and has been proposed to be directly anti-inflammatory, and that this is one way it reduces neurodegeneration. However, prior studies have focused on animal models involving both neurodegeneration and inflammation, therefore, it is also possible that the observed decreased inflammation is secondary to reduced neurodegeneration. OBJECTIVE: To investigate whether exendin-4 directly reduces inflammation in the brain following an insult that involves neuroinflammation but not neurodegeneration, namely systemic administration of lipopolysaccharide (LPS). METHODS: Rats were administered LPS systemically and were treated with either 0.5 µg/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-α and IL-1ß levels in cerebrospinal fluid and cytokine mRNA expression in striatal, hippocampal and cortical tissues using qPCR. We determined brain monoamines using high-performance liquid chromatography. Finally, we isolated primary brain microglia from rats and measured cytokine production after exendin-4 treatment and LPS stimulation. RESULTS: Exendin-4 treatment did not affect cytokine mRNA expression in brain, cytokine levels in cerebrospinal fluid or cytokine production from cultured microglia, although there was a trend towards increased striatal dopamine. Importantly, exendin-4 significantly prevented depressive-like behavior at 24 hours after LPS injection, indicating that the drug engaged a target in the brain. Depressive-like behavior was associated with altered dopamine turnover in the striatum. CONCLUSION: We did not detect any anti-inflammatory effects of exendin-4. In previous studies exploring the effects of exendin-4 on brain insults involving neurodegeneration, observations of reduced inflammation might have been secondary to mitigation of neuronal death. Our results indicate that the effects of exendin-4 on behavior may be due to effects on dopamine synthesis or metabolism.

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects.

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.

Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood.

BACKGROUND: Low levels of vitamin D may play a role in psychiatric disorders, as cross-sectional studies show an association between vitamin D deficiency and depression, schizophrenia and psychotic symptoms. The underlying mechanisms are not well understood, although vitamin D is known to influence the immune system to promote a T helper (Th)-2 phenotype. At the same time, increased inflammation might be of importance in the pathophysiology of depression and suicide. We therefore hypothesized that suicidal patients would be deficient in vitamin D, which could be responsible for the inflammatory changes observed in these patients. METHODS: We compared vitamin D levels in suicide attempters (n=59), non-suicidal depressed patients (n=17) and healthy controls (n=14). Subjects were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and went through a structured interview by a specialist in psychiatry. 25(OH)D2 and 25(OH)D3 were measured in plasma using liquid-chromatography-mass-spectrometry (LC-MS). We further explored vitamin D's association with plasma IL-1ß, IL-6 and TNF-α. RESULTS: Suicide attempters had significantly lower mean levels of vitamin D than depressed non-suicidal patients and healthy controls. 58 percent of the suicide attempters were vitamin D deficient according to clinical standard. Moreover, there was a significant negative association between vitamin D and pro-inflammatory cytokines in the psychiatric patients. Low vitamin D levels were associated with higher levels of the inflammatory cytokines IL-6 and IL-1ß in the blood. CONCLUSION: The suicide attempters in our study were deficient in vitamin D. Our data also suggest that vitamin D deficiency could be a contributing factor to the elevated pro-inflammatory cytokines previously reported in suicidal patients. We propose that routine clinical testing of vitamin D levels could be beneficial in patients with suicidal symptoms, with subsequent supplementation in patients found to be deficient.

Cerebrospinal fluid inflammatory markers in Parkinson's disease--associations with depression, fatigue, and cognitive impairment.

Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-ß in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.

Connecting inflammation with glutamate agonism in suicidality.

The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (P<0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine.

Non-motor symptoms in patients with Parkinson's disease - correlations with inflammatory cytokines in serum.

BACKGROUND: Parkinson's Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD. METHODS AND MATERIALS: We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in blood samples from PD patients (n=86) and healthy controls (n=40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively. RESULTS: IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for. DISCUSSION: We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.

Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence.

OBJECTIVE: The primary aim was to relate Toxoplasma gondii seropositivity and serointensity to scores on the self-rated Suicide Assessment Scale (SUAS-S). Another aim was to reevaluate the previously reported positive association between T gondii serointensity and a history of nonfatal suicidal self-directed violence. METHOD: This cross-sectional, observational study compared T gondii serointensity and seropositivity in plasma from 54 adult suicide attempters (inpatients at Lund University Hospital, Lund, Sweden) and 30 adult control subjects (randomly selected from the municipal population register in Lund, Sweden) recruited between 2006 and 2010. The potential of patients and controls for self-directed violence was evaluated with the SUAS-S. Psychiatric diagnoses were made according to DSM-IV criteria. Plasma samples were tested for immunoglobulin G antibodies to T gondii, cytomegalovirus, and herpes simplex virus type 1. Data were analyzed using multivariable logistic regression to investigate the association between T gondii serointensity or seropositivity and a history of nonfatal suicidal self-directed violence; multivariable linear regression was used to explore the relationship between T gondii serointensity or seropositivity and the SUAS-S. Both regression models included sex, age, and body mass index as covariates. RESULTS: Seropositivity of T gondii (adjusted odds ratio [OR] = 7.12; 95% CI, 1.66-30.6; P = .008) and serointensity of T gondii (adjusted OR = 2.01; 95% CI, 1.09-3.71; P = .03) were positively associated with a history of nonfatal suicidal self-directed violence. Seropositivity of T gondii was associated with higher SUAS-S scores, a relationship significant for the whole sample (P = .026), but not for suicide attempters only. No significant associations with other pathogens were identified. CONCLUSIONS: These results are consistent with previous reports on the association between T gondii infection and nonfatal suicidal self-directed violence. Confirming these results in future large longitudinal studies and including suicide as an outcome may lead to novel individualized approaches in suicide prevention.

Aldosterone synergizes with peripheral inflammation to induce brain IL-1ß expression and depressive-like effects.

Recent findings have shown that the physiological functions of the hormone aldosterone go far beyond its well-known role in blood-pressure regulation and salt/water homeostasis. Aldosterone is for example involved in the regulation of inflammation, and also binds directly to mineralocorticoid receptors in specific brain regions. Interestingly, depressive symptoms appear to correlate with alterations of the aldosterone system but the underlying mechanisms have not been elucidated. In this study aldosterone (2 µg/100g body weight/day) was continuously administered via osmotic minipumps for 5 days. Lipopolysaccharide (LPS) was administered once a day for 5 days in a dose of 1mg/kg ip. The rats were tested for depressive-like behavior 24h after the last LPS injection. Protein levels of cytokines were measured in serum and cerebrospinal fluid (CSF). mRNA expression of interleukin (IL)-1ß and IL-6 in the prefrontal cortex (PFC) was analyzed using reverse transcriptase qPCR. We found that aldosterone treatment increased LPS-induced IL-1ß mRNA expression in the PFC and CSF. Moreover, there was a positive correlation between IL-1ß in CSF and depressive-like behaviors. These findings suggest that IL-1ß is affected by the renin-aldosterone-angiotensin system (RAAS) activity and connected to symptoms of depression.

Cytokine levels in the blood may distinguish suicide attempters from depressed patients.

Elevated plasma cytokines is a common finding in Major Depressive Disorder (MDD), although not consistent. It is currently not known whether the inflammatory changes are confined to any specific subgroup of depressive patients. We here analyzed three inflammatory markers in suicidal and non-suicidal depressed patients, as well as healthy controls. Plasma interleukin (IL)-2, IL-6 and tumor necrosis factor (TNF)-α were measured in 47 suicide attempters, 17 non-suicidal depressed patients and 16 healthy controls. Study participants were evaluated using the Comprehensive Psychopathological Rating Scale (CPRS) with subscales for anxiety and degree of depression, as well as the Suicide Assessment Scale (SUAS). We found increased levels of IL-6 and TNF-α as well as decreased IL-2 concentrations in suicide attempters compared to non-suicidal depressed patients and healthy controls. The results were adjusted for potential confounders of cytokine expression, such as age, sex, body mass index (BMI), degree of depression, anxiety, personality disturbance, abuse and type of medication. These results demonstrate for the first time that suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients. Thus, our study provides further support for a role of inflammation in the pathophysiology of suicidality.

Exercise-induced release of cytokines in patients with major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) may display elevated plasma levels of pro-inflammatory substances. Although the underlying mechanisms are unknown, inflammation has been proposed to play a direct role in the generation of depressive symptoms. Skeletal muscle is a potent producer of cytokines, and physical exercise has been suggested to alleviate symptoms of depression. In this study we therefore addressed the question of whether MDD patients display altered levels of pro-, anti-inflammatory and regulatory factors in the blood in response to acute exercise. METHODS: Eighteen MDD patients and 18 healthy controls performed a maximal-workload exercise challenge. Blood samples were taken before the test, at sub-maximal and maximal workload, as well as 30 and 60 min after testing. The plasma levels of SAA, TNF-alpha, S-VCAM, S-ICAM, CRP, IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 and IL-13 were assayed using multiplex sandwich ELISA. RESULTS: Exercise-induced significant changes in the plasma levels of inflammatory substances in both MDD patients and controls. IL-8, IL-6 and TNF-alpha increased, and IL-4 decreased during the challenge in both groups. In addition, IFN-gamma decreased in the controls. There was a significant difference in IL-6 reactivity between the groups at the sub-max timepoint. LIMITATIONS: Group sizes are comparably limited. CONCLUSION: Exercise induces changes in the blood levels of cytokines in unmedicated MDD patients. Whether these changes affect symptoms of depression should be evaluated in long-term studies of the anti-depressive effects of exercise.

Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity.

BACKGROUND: Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. METHODS: We measured interleukin-1beta, interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. RESULTS: IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MADRS scores and CSF IL-6 levels in all patients. IL-6 and TNF-alpha correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. CONCLUSIONS: We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.