Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

BACKGROUND: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines. OBJECTIVES: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression. RESULTS: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6. CONCLUSIONS: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokine

Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

Psychological side effects of immune therapies: symptoms and pathomechanism

Immunotherapies revolutionised the treatment of several disorders but show specific side-effect profiles which frequently involve psychological symptoms. Long term interferon-alpha (IFN-alpha) therapy can cause wide-ranging psychiatric side-effects from fatigue, insomnia, anxiety to full-blown depression. This treatment-emergent depression shares several symptoms with major depressive disorder (MDD) with a predominance of somatic/neurovegetative symptoms, and can be treated with antidepressants. However, this experience directed research to inflammatory mechanisms in MDD. MDD has been confirmed as a heterogeneous disorder with a subgroup of patients suffering from low-grade chronic inflammation and frequently resistant to traditional antidepressant treatment. Thus future research should develop strategies to identify those MDD patients who could benefit from drugs acting through inflammatory pathways

Two nomina nova in Malagasy Grewia L. (Malvaceae-Grewioideae)

An account of the current state-of-affairs of the taxonomic study of Grewia L. (Malvaceae-Grewioideae) in Madagascar is presented. Grewia capuronii Mabb. and G. madagascariensis Capuron are new names for the Malagasy endemics, G. lanceolata Bak., non Miq., and G. discolor Baill., non Fresen., respectively

Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms

The prevalence of depressive disorders is growing worldwide, notably due to stagnation in the development of drugs with greater antidepressant efficacy, the continuous large proportion of patients who do not respond to conventional antidepressants, and the increasing rate of chronic medical conditions associated with an increased vulnerability to depressive comorbidities. Accordingly, better knowledge on the pathophysiology of depression and mechanisms underlying depressive comorbidities in chronic medical conditions appears urgently needed, in order to help in the development of targeted therapeutic strategies. In this review, we present evidence pointing to inflammatory processes as key players in the pathophysiology and treatment of depressive symptoms. In particular, we report preclinical and clinical findings showing that inflammation-driven alterations in specific metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, leads to substantial alterations in the metabolism of serotonin, glutamate and dopamine that are likely to contribute to the development of key depressive symptom dimensions. Accordingly, anti-inflammatory interventions targeting kynurenine and BH4 pathways may be effective as novel treatment or as adjuvants of conventional medications rather directed to monoamines, notably when depressive symptomatology and inflammation are comorbid in treated patients. This notion is discussed in the light of recent findings illustrating the tight interactions between known antidepressant drugs and inflammatory processes, as well as their therapeutic implications. Altogether, this review provides valuable findings for moving toward more adapted and personalized therapeutic strategies to treat inflammation-related depressive symptoms

Tratado de las enfermedades de los niños hasta la pubertad

Mode of access: Internet

High S100B Levels Predict Antidepressant Response in Patients With Major Depression Even When Considering Inflammatory and Metabolic Markers

[EN] Background The relationship between antidepressant response and glial, inflammatory, and metabolic markers is poorly understood in depression. This study assessed the ability of biological markers to predict antidepressant response in major depressive disorder (MDD). Methods We included 31 MDD outpatients treated with escitalopram or sertraline for 8 consecutive weeks. The Montgomery-angstrom sberg Depression Rating Scale (MADRS) was administered at baseline and at week 4 and 8 of treatment. Concomitantly, blood samples were collected for the determination of serum S100B, C-reactive protein (CRP), and high-density lipoprotein cholesterol (HDL)-C levels. Treatment response was defined as >= 50% improvement in the MADRS score from baseline to either week 4 or 8. Variables associated with treatment response were included in a linear regression model as predictors of treatment response. Results Twenty-seven patients (87%) completed 8 weeks of treatment; 74% and 63% were responders at week 4 and 8, respectively. High S100B and low HDL-C levels at baseline were associated with better treatment response at both time points. Low CRP levels were correlated with better response at week 4. Multivariate analysis showed that high baseline S100B levels and low baseline HDL-C levels were good predictors of treatment response at week 4 (R(2 = )0.457, P = .001), while S100B was at week 8 (R-2 = 0.239, P = .011). Importantly, baseline S100B and HDL-C levels were not associated with depression severity and did not change over time with clinical improvement. Conclusions Serum S100B levels appear to be a useful biomarker of antidepressant response in MDD even when considering inflammatory and metabolic markersWe thank the consolidated research groups SGR2017/1798 (RMS) and the Centre for Biomedical Research in Mental Health Network (CIBERSAM), Spain for their support. This work was supported by an "Emili Letang Premi Final de Residencia (2017)" grant (G.O.) from Fundacio Clinic, Barcelona, Spain

Association between the indole pathway of tryptophan metabolism and subclinical depressive symptoms in obesity: a preliminary study

12partially_openInternationalInternational coauthor/editorConverging data support the role of chronic low-grade inflammation in depressive symptomatology in obesity. One mechanism likely to be involved relies on the effects of inflammation on tryptophan (TRP) metabolism. While recent data document alterations in the indole pathway of TRP metabolism in obesity, the relevance of this mechanism to obesity-related depressive symptoms has not been investigated. The aim of this preliminary study was to assess the association between plasma levels of TRP and indole metabolites and depressive symptoms in 44 subjects with severe or morbid obesity, free of clinically relevant neuropsychiatric disorders. The interaction effect of inflammation, reflected in serum high-sensitive C-reactive protein (hsCRP) levels, and indoles on depressive symptoms was also determined. Higher serum levels of hsCRP and lower concentrations of TRP and indoles, particularly indole-3-carboxaldehyde (IAld), correlated with more severe depressive symptoms. Interestingly, the effect of high hsCRP levels in predicting greater depressive symptoms was potentiated by low IAld levels. These results comfort the link between inflammation, the indole pathway of TRP metabolism, and obesity-related depressive symptomsmixedDelgado, Inês; Cussotto, Sofia; Anesi, Andrea; Dexpert, Sandra; Aubert, Agnès; Aouizerate, Bruno; Beau, Cédric; Forestier, Damien; Ledaguenel, Patrick; Magne, Eric; Mattivi, Fulvio; Capuron, LucileDelgado, I.; Cussotto, S.; Anesi, A.; Dexpert, S.; Aubert, A.; Aouizerate, B.; Beau, C.; Forestier, D.; Ledaguenel, P.; Magne, E.; Mattivi, F.; Capuron, L