Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines.

Beta-thalassemia major patients are treated with repeated blood transfusions, which may cause iron overload, which in turn may induce immune aberrations, and show an increased risk of depression. The aim of the present study is to examine whether repeated blood transfusions, iron overload, and immune-inflammatory responses are associated with depression in children (6-12 years) with transfusion-dependent thalassemia (TDT). The Children's Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%), and serum levels of CCL11, IL-1ß, IL-10, and TNF-α were measured in TDT with (n = 54) and without (n = 57) a major depression-like episode (MDLE) and in healthy children (n = 55). The results show that MDLE due to TDT is associated with a greater number of blood transfusions and increased iron overload and IL-1ß levels. Partial least squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, iron overload, and increased levels of IL-1ß and TNF-α. The latter two cytokines partly mediate the effects of iron overload on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by iron overload and the path from iron overload to immune activation. Iron overload is also associated with increased IL-10 and lower CCL11 levels, but these alterations are not significantly associated with depression. In conclusion, blood transfusions may be causally related to MDLE in TDT children and their effects are in part mediated by increased iron overload and the consequent immune-inflammatory response. The results suggest that effects of iron overload and its consequences including inflammation and oxidative stress toxicity may cause MDLE. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate iron overload and immune-inflammatory responses and to prevent MDLE in children with TDT.

Effectiveness of depression interventions for people living with HIV in Sub-Saharan Africa: A systematic review & meta-analysis of psychological & immunological outcomes.

This meta-analytic review evaluated the effectiveness of depression interventions on the psychological and immunological outcomes of people living with HIV in sub-Saharan Africa. 14 studies, yielding 932 participants were eligible. A random-effects models indicated that depression interventions were followed by large reductions in depression scores (effect size = 1.86, 95% CI = 1.71, 2.01, p < 0.01). No significant effect on immune outcome was observed, however there was a trend toward immune improvement of medium effect size (effect size on CD4 count and/or viral suppression = 0.57, 95% CI = -0.06, 1.20, p = 0.08). Pharmacological interventions appeared to have a significantly larger improvement in depression scores than psychological interventions. The greatest improvement in immune status was demonstrated in psychological treatments which incorporated a component to enhance HIV medication adherence, however these results did not reach significance. Small sample sizes and highly heterogeneous analysis necessitate caution in interpretation. The results of this meta-analysis should thus be treated as preliminary evidence and used to encourage further studies of immunopsychiatry in HIV in sub-Saharan Africa.

The Psychoneuroimmunological Role of Omega-3 Polyunsaturated Fatty Acids in Major Depressive Disorder and Bipolar Disorder.

Context • Psychoneuroimmunology is the interdisciplinary study that links behavioral health with the neuroendocrinal system and investigates that link's bidirectional impact on the human immune system. Mechanistic studies have shown how omega-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, can modulate key pathways involved in inflammation, sympathetic activity, oxidative stress, transcription factors, and inflammatory cytokine production. Objective • The research team intended to investigate the effects that PUFAs have on the brain and the immune system, including the effects of proinflammatory cytokines and oxidative stress, and their therapeutic benefits in major depressive disorder (MDD) and bipolar disorder, either as an alternative monotherapy or a complementary adjunct treatment. Design • A literature search was conducted through PubMed and Google Scholar, with no restrictions on the publication dates or geographically. Setting • The research occurred at research facilities in Washington, DC, and Davis, California. Results • Well-described links between inflammation and MDD and bipolar disorder have been established. Similarly, a highly inflammatory state is a contributing factor to many significant health complications, and omega-3 PUFAs can help treat those issues. Conclusions • The research team concluded that omega-3 fatty acids have therapeutic benefits in the treatment of both MDD and bipolar disorder and are effective as a monotherapy and, particularly, as an adjunct therapy. The efficacy of omega-3 supplementation is clearly useful in promoting better health overall and supplementation should be encouraged in the primary care setting. A meta-analysis exploring an adjunct treatment of supplemental eicosapentaenoic acid or docosahexaenoic acid is likely to yield the greatest benefits to psychiatric conditions and provide an answer to proper dosing regimens. The team also created a chart of the supplements' salient features, demonstrating the overall health benefits of omega-3 fatty acids.

Immunological aspects of the treatment of depression and schizophrenia.

Schizophrenia and major depression (MD) have been associated with immune system dysfunction. One example of this is the altered level of cytokines-important inflammatory mediators-in blood, and a proinflammatory immune state has been described in some subgroups of patients. A knock to the immune system in early life might trigger a life-long increased immune reactivity, and infections and autoimmune disorders are now known to be risk factors for development of schizophrenia and MD. Pro- and anti-inflammatory cytokines mediate indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenin in the central nervous system and degrades serotonin. Alterations of serotonergic, noradrenergic, and glutamatergic neurotransmission have been associated with low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic benefit in MD and schizophrenia, as shown in meta-analyses. Moreover, antidepressants and antipsychotics have intrinsic immunomodulatory effects. With evidence pointing to the role inflammatory processes play in the pathogenesis of major psychiatric disorders, this review will look at various immunological aspects of treatment of such disorders.

La esquizofrenia y la depresión mayor (DM) se han asociado con una disfunción del sistema inmune, como lo demuestra la alteración en el nivel sanguíneo de citoquinas - importantes mediadores inflamatorios - y un estado inmune proinflamatorio descrito en algunos subgrupos de pacientes. Una agresión al sistema inmune en edades precoces puede gatillar un aumento de la reactividad inmune a lo largo de la vida. Hoy se sabe que las infecciones y los trastornos inmunes constituyen factores de riesgo para el desarrollo de la esquizofrenia y la DM. Las citoquinas pro y anti-inflamatorias median la actividad de la indolamina 2,3 dioxigenasa, enzima que estimula el metabolismo del triptófano y la quinurenina en el sistema nervioso central y que degrada la serotonina. Los resultados de meta-análisis han asociado la alteración de la neurotransmisión serotoninérgica, noradrenérgica y glutamatérgica con bajos niveles de neuroinflamación, y el beneficio terapéutico de los compuestos antiinflamatorios en la DM y en la esquizofrenia. Además, los antidepresivos y los antipsicóticos tienen efectos inmunomoduladores intrínsecos. Este artículo revisa varios aspectos inmunológicos del tratamiento de importantes trastornos psiquiátricos, de acuerdo con la evidencia que apunta al papel que juegan los procesos inflamatorios en la patogénesis de estos trastornos.

Schizophrénie et dépression caractérisée sont associées à une dysfonction du système immunitaire comme le montrent l'altération du taux de cytokines (médiateurs inflammatoires importants) dans le sang et l'état immunitaire pro-inflammatoire décrit chez certains sous-groupes de patients. Une atteinte précoce du système immunitaire peut déclencher une augmentation de la réactivité immunitaire tout au long de la vie, les infections et les troubles auto-immuns étant connus aujourd'hui pour être des facteurs de risque de développement de schizophrénie et de dépression caractérisée. Les cytokines pro- et anti-inflammatoires sont les médiateurs de l'activité de l'indoléamine 2,3-dioxygénase, enzyme qui stimule le métabolisme du tryptophane et de la kynurénine dans le système nerveux central et qui dégrade la sérotonine. Il existe une association entre des modifications de la neurotransmission sérotoninergique, noradrénergique et glutamatergique et une neuro-inflammation de faible niveau ; de plus, des méta-analyses montrent un bénéfice thérapeutique des anti-inflammatoires dans la schizophrénie et la dépression caractérisée. D'autre part, les antidépresseurs et les antipsychotiques ont des effets immunomodulateurs intrinsèques. Cet article s'intéresse aux différents aspects immunologiques du traitement des troubles psychiatriques caractérisés en soulignant les données en faveur du rôle joué par les processus inflammatoires dans leur pathogenèse.

Alteration of immune markers in a group of melancholic depressed patients and their response to electroconvulsive therapy.

BACKGROUND: Immune system dysfunction is implicated in the pathophysiology of major depression, and is hypothesized to normalize with successful treatment. We aimed to investigate immune dysfunction in melancholic depression and its response to ECT. METHODS: 55 melancholic depressed patients and 26 controls participated. 33 patients (60%) were referred for ECT. Blood samples were taken at baseline, one hour after the first ECT session, and 48h after ECT series completion. RESULTS: At baseline, melancholic depressed patients had significantly higher levels of the pro-inflammatory cytokine IL-6, and lower levels of the regulatory cytokine TGF-ß than controls. A significant surge in IL-6 levels was observed one hour after the first ECT session, but neither IL-6 nor TGF-ß levels normalized after completion of ECT series. Seventy per cent (n=23) of ECT recipients showed clinical response and 42% (n=10) reached remission. Neither IL-6 nor TGF-ß changes correlated with clinical improvement following ECT. No significant changes in IL-10, TNF-α and CRP levels were found in relation to melancholia or response to ECT. LIMITATIONS: As a naturalistic study, some potential confounders could not be eliminated or controlled, including medication use. CONCLUSIONS: Melancholic depressed patients demonstrated a peripheral increase in IL-6 and reduction in TGF-ß, which did not normalize despite clinical response to ECT. These findings may be consistent with emerging hypotheses of the role of inflammation in mediating neurotrophin expression. The implications of chronic inflammation in the melancholic depressed population for future medical health, particularly cardiovascular risk, are largely unknown and warrant further investigation.

Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway.

AIM: Major depressive disorder (MDD) is a debilitating mental disorder associated with dysfunction of the neurotransmitter-neuroendocrine system and neuroinflammatory responses. Salvianolic acid B (SalB) has shown a variety of pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects. In this study, we examined whether SalB produced antidepressant-like actions in a chronic mild stress (CMS) mouse model, and explored the mechanisms underlying the antidepressant-like actions of SalB. METHODS: Mice were subjected to a CMS paradigm for 6 weeks. In the last 3 weeks the mice were daily administered SalB (20 mg·kg(-1)·d(-1), ip) or a positive control drug imipramine (20 mg·kg(-1)·d(-1), ip). The depressant-like behaviors were evaluated using the sucrose preference test, the forced swimming test (FST), and the tail suspension test (TST). The gene expression of cytokines in the hippocampus and cortex was analyzed with RT-PCR. Plasma corticosterone (CORT) and cerebral cytokines levels were assayed with an ELISA kit. Neural apoptosis and microglial activation in brain tissues were detected using immunofluorescence staining. RESULTS: Administration of SalB or imipramine reversed the reduced sucrose preference ratio of CMS-treated mice, and significantly decreased their immobility time in the FST and TST. Administration of SalB significantly decreased the expression of pro-inflammatory cytokines IL-1ß and TNF-α, and markedly increased the expression of anti-inflammatory cytokines IL-10 and TGF-ß in the hippocampus and cortex of CMS-treated mice, and normalized their elevated plasma CORT levels, whereas administration of imipramine did not significantly affect the imbalance between pro- and anti-inflammatory cytokines in the hippocampus and cortex of CMS-treated mice. Finally, administration of SalB significantly decreased CMS-induced apoptosis and microglia activation in the hippocampus and cortex, whereas administration of imipramine had no significant effect on CMS-induced apoptosis and microglia activation in the hippocampus and cortex. CONCLUSION: SalB exerts potent antidepressant-like effects in CMS-induced mouse model of depression, which is associated with the inhibiting microglia-related apoptosis in the hippocampus and the cortex.

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

Inflammation: depression fans the flames and feasts on the heat.

Depression and inflammation fuel one another. Inflammation plays a key role in depression's pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of how (pathways) and for whom (predispositions) these links exist, which are the focus of this article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further, unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood in individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional links between depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.

An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes.

Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better understanding of both the neuro- degenerative and -regenerative repair functions as present within the neuroimmune network during depression. Furthermore T cells may be important players in restoration of normal behaviour and immune cell homeostasis in depression.

Anti-neuropeptide Y plasma immunoglobulins in relation to mood and appetite in depressive disorder.

Depression and eating disorders are frequently associated, but the molecular pathways responsible for co-occurrence of altered mood, appetite and body weight are not yet fully understood. Neuropeptide Y (NPY) has potent antidepressant and orexigenic properties and low central NPY levels have been reported in major depression. In the present study, we hypothesized that in patients with major depression alteration of mood, appetite and body weight may be related to NPY-reactive autoantibodies (autoAbs). To test this hypothesis, we compared plasma levels and affinities of NPY-reactive autoAbs between patients with major depression and healthy controls. Then, to evaluate if changes of NPY autoAb properties can be causally related to altered mood and appetite, we developed central and peripheral passive transfer models of human autoAbs in mice and studied depressive-like behavior in forced-swim test and food intake. We found that plasma levels of NPY IgG autoAbs were lower in patients with moderate but not with mild depression correlating negatively with the Montgomery-Åsberg Depression Rating Scale scores and with immobility time of the forced-swim test in mice after peripheral injection of autoAbs. No significant differences in NPY IgG autoAb affinities between patients with depression and controls were found, but higher affinity of IgG autoAbs for NPY was associated with lower body mass index and prevented NPY-induced orexigenic response in mice after their central injection. These data suggest that changes of plasma levels of anti-NPY autoAbs are relevant to altered mood, while changes of their affinity may participate in altered appetite and body weight in patients with depressive disorder.

Sleep and inflammation: psychoneuroimmunology in the context of cardiovascular disease.

BACKGROUND: Poor sleep is prospectively linked to all-cause and cardiovascular mortality. Inflammatory processes may be an important biological mechanism linking poor sleep to cardiovascular disease. Such processes involve active participation of signaling molecules called cytokines in development of atherosclerotic plaques. PURPOSE: I review evidence from experimental sleep deprivation and clinical observational studies suggesting a bidirectional relationship between sleep and inflammatory cytokines. RESULTS: Findings from sleep deprivation studies indicate that sleep loss is associated with increases in these cytokines. Similarly, studies in clinical populations with sleep problems, such as primary insomnia patients and those diagnosed with major depression, also show elevations in these same cytokines. CONCLUSIONS: Bidirectional communication between the brain and the immune system is carried out through a complex network of autonomic nerves, endocrine hormones, and cytokines. Disturbed sleep appears to perturb the functioning of this network and therefore contribute to elevations in inflammatory mediators linked to cardiovascular disease.

Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment.

BACKGROUND: An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines. METHODS: 95 outpatients with major depressive disorder were treated for 6 weeks with EA, fluoxetine or placebo. Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI) were used to assess severity and therapeutic effects. 30 volunteers served as controls. Serum cytokine concentrations were measured by ELISA. RESULTS: Increased proinflammatory cytokine interleukin (IL)-1beta and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contract, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients. The ratio of IFN/IL-4 was also increased. Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1beta concentrations in responders. However, only acupuncture attenuated TNF-alpha concentration and INF-gamma/IL-4 ratio towards the control level. DISCUSSION: These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-gamma or TNF-alpha and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1beta. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-alpha and decreasing IL-4.

Investigating the inflammatory phenotype of major depression: focus on cytokines and polyunsaturated fatty acids.

There is evidence that increased inflammatory activity contributes to treatment non-response in depression and studies suggest that omega-3 fatty acid supplementation is effective in antidepressant non-responders. We tested the hypotheses that in major depression (1) the plasma omega-6:omega-3 fatty acid ratio is greater in antidepressant non-responders than responders and (2) higher omega-6:omega-3 ratios are associated with a pro-inflammatory cytokine profile. Twenty DSM-IV major depressives who had failed a six week course of an SSRI, 14 subjects who responded to a six week course of an SSRI and were currently euthymic and 24 healthy comparison subjects took part in the study. Six millilitres of whole blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes for determination of fatty acids together with IL-6 and TNF-alpha. Arachidonic acid (AA) levels were elevated in both the responders and the non-responders. IL-6 was elevated in a similar manner but differences in TNF-alpha did not reach statistical significance. The eicosapentaenoic acid (EPA):AA ratio in the three groups was as follows: controls 0.08+/-0.01; responders 0.08+/-0.01; non-responders 0.04+/-0.01. These differences are significant (p<0.001). AA and IL-6 were highly correlated in both responders and non-responders but not in healthy volunteers. The findings of this study provide further support for the view that major depression is associated with a pro-inflammatory phenotype which at least partially persists when patients become normothymic.

A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders.

The Kraepelinian classification of psychiatric disorders, in particular the dichotomy of dementia praecox and manic-depressive psychosis is under discussion since a long time. In recent years, not only new research in the fields of psychopathology and clinical outcome, but also findings of biological markers in the areas of neurophysiology, neuroendocrinology, psychoneuroimmunology, genetics, or psychopharmacology show a big overlap between both groups of disorders. This overlap of symptoms and markers of both disorders intensified the discussion and the proposals for new criteria for the classification of psychiatric disorders. By means of findings from the field of psychoneuroimmunology and inflammation it will be shown that different pathological mechanisms in depression and schizophrenia may lead to the same final common pathway of inflammation. These mechanisms include the immunological balance between type-1 and type-2 immune activation which influences the tryptophan-degradating enzyme indoleamine 2,3-dioxygenase (IDO) in the CNS in opposite ways, leading to an altered availability of tryptophan and serotonin, and a disturbance of the kynurenine metabolism with an imbalance in favor of the production of the NMDA-receptor agonist quinolinic acid in depression and of the NMDA-receptor antagonist kynurenic acid in schizophrenia. In both disorders, however, an increased production of prostaglandin E2 and increased expression of cyclo-oxygenase-2 reflect a slight inflammatory process taking place probably in different regions of the CNS. Albeit this common inflammatory pathway--inflammation is a general pathway of the body as answer to a lot of different noxae and pathogens--the Kraepelinian dichotomy is important with respect to pathological mechanisms and therapeutic approaches, not only for further research in understanding the exact pathological mechanisms but also for the development of preventive strategies in high risk individuals and in patients. Opposite pathways regarding the immune activation, the neurotoxic versus neuroprotective kynurenine metabolites and the agonistic versus antagonistic effects on the NMDA receptor and the glutamatergic neurotransmission show despite a possible therapeutic advantage of anti-inflammatory therapy in both disorders that the Kraepelinian dichotomy still has a significant value from a biologic-psychiatric point of view.

Depression and immunity: inflammation and depressive symptoms in multiple sclerosis.

There is strong evidence that depression involves alterations in multiple aspects of immunity that may contribute to the development or exacerbation of a number of medical disorders and also may play a role in the pathophysiology of depressive symptoms. Accordingly, aggressive management of depressive disorders in medically ill populations or individuals at risk for disease may improve disease outcome or prevent disease development. On the other hand, in light of data suggesting that immune processes may interact with the pathophysiologic pathways known to contribute to depression, novel approaches to the treatment of depression may target relevant aspects of the immune response. Taken together, the data provide compelling evidence that a psychoimmunologic frame of reference may have profound implications regarding the consequences and treatment of depression. In addition, this approach may be used to investigate the possibility that peripheral and central production of cytokines may account for neuropsychiatric symptoms in inflammatory diseases. This article summarizes evidence for a cytokine-mediated pathogenesis of depression and fatigue in MS. The effects of central inflammatory processes may account for some of the behavioral symptoms seen in patients who have MS that cannot be explained by psychosocial factors or CNS damage. This immune-mediated hypothesis is supported by indirect evidence from experimental and clinical studies of the effect of cytokines on behavior, which have found that both peripheral and central cytokines may cause depressive symptoms. Emerging clinical data from patients who have MS support an association of central inflammation (as measured by MRI) and inflammatory markers with depressive symptoms and fatigue. Based on the literature reviewed in this article, subtypes of MS fatigue and depression may exist that are caused by different pathogenetic mechanisms, including inflammation and CNS damage as well as psychosocial factors or predisposition. The existence of these subtypes could have important clinical implications. For example, an inflammatory depression may require different therapeutic approaches than a reactive depression in MS. Future research should aim to characterize these subtypes better with the goal of optimizing treatment.

Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.

BACKGROUND: Major depression has been associated cross-sectionally with increased cell-mediated immune activation but causality has been difficult to establish. This study prospectively investigated the hypothesis that baseline level of immune activation predicts the development of depression during interferon-alpha (IFN-alpha) treatment. METHODS: Sixteen hepatitis C patients without psychiatric disorder underwent IFN-alpha treatment. Proinflammatory and anti-inflammatory cytokines were determined before starting treatment. Presence of a major depressive disorder (MDD) was assessed at baseline and several times during treatment. RESULTS: Baseline soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations were significantly increased in the five subjects that developed MDD during treatment compared with those that did not, with standardized effect sizes of 1.08, 1.16, and 1.25, respectively, controlling for marijuana use, cigarette smoking, and baseline level of depressive symptoms. CONCLUSIONS: Results suggest that increased immune activation, rather than an epiphenomenon, is a causal risk factor for the development of MDD.

Cytokines and major depression.

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Evidence-informed assessment and treatment of depression in HCV and interferon-treated patients.

More than 4 million people are currently infected with Hepatitis C an RNA virus that may ultimately result in complete hepatic failure and is often a silent infection until late in the course of disease. Hepatitis C patients have increased rates of major depression (as well as substance abuse) and treatment of hepatitis with interferon, the current standard treatment, provokes episodes of depression in as many as a third of patients treated. Immune-dysfunction mediated mechanisms for the depression in these patients have been proposed and have increasing experimental support. The resulting depression has interfered with treatment for many patients, but several standard treatments for depression have been shown to be effective in patients with interferon-associated depression, suggesting that this should not be a barrier to effective treatment. In this paper, we review the evidence for associations between depression and Hepatitis C and interferon treatment, as well as the evidence supporting an immune mechanism for the association, and finally the data showing effective treatment and recommendations for prophylactic use of anti-depressants.

Lymphocyte subsets and lymphokine production in patients with melancholic versus nonmelancholic depression.

Several studies have reported immune changes during depression, but the results have not been fully consistent. Some of these changes could be related to the presence of melancholic features. A total of 42 depressed patients (melancholic [MEL] and nonmelancholic [non-MEL]) and 20 healthy controls participated in the study. We detected a higher CD4+ lymphocyte subset in MEL patients than in controls during the depressive state, which disappeared after clinical remission. We also found an increase in interleukin-2 (IL-2) production both in MEL and non-MEL patients, but these values did not differ from control values after clinical remission. Some of these changes may be related to the melancholic characteristics of depression.