The inflammatory underpinning of depression: An historical perspective.

Over the last thirty years, substantial evidence has accumulated in support of the hypothesis that dysregulation of inflammatory processes plays a critical role in the pathophysiology of depression. This review traces the evolution of research supporting this link, discussing key findings from several major investigative fronts: Alterations in inflammatory markers associated with depression; Mood changes following the exogenous administration of inflammatory challenges; The anti-inflammatory properties of traditional antidepressants and the promising antidepressant effects of anti-inflammatory drugs. Additionally, it explores how inflammatory processes interact with specific brain regions and neurochemical systems to drive depressive pathology. A thorough analysis of the 100 most-cited experimental studies on the topic ensures a comprehensive, transparent and unbiased collection of references. This methodological approach offers a panoramic view of the inflammation-depression nexus, shedding light on the complexity of its mechanisms and their connections to psychiatric categorizations, symptoms, demographics, and life events. Synthesizing insights from this extensive research, the review presents an integrative model of the biological foundations of inflammation-associated depression. It posits that we have reached a critical juncture where the translation of this knowledge into personalized immunomodulatory treatments for depression is not just possible, but imperative.

The Role of Inflammation in Depression and Beyond: A Primer for Clinicians.

PURPOSE OF REVIEW: We evaluate available evidence for the role of inflammation in depression. We reappraise literature involving systemic inflammation, neuroinflammation and neurotransmission and their association with depression. We review the connection between depression, autoimmunity and infectious diseases. We revise anti-inflammatory treatments used in depression. RECENT FINDINGS: Peripheral inflammatory markers are present in a subset of patients with depression and can alter common neurotransmitters in this population but there is no clear causality between depression and systemic inflammation. Infectious conditions and autoimmune illnesses do not have a clear correlation with depression. Certain medications have positive evidence as adjunctive treatments in depression but studies are heterogenic, hence they are sparsely used in clinical settings. The current evidence does not fully support inflammation, infections or autoimmunity as possible etiologies of depression. The available studies have numerous confounders that obscure the findings. Anti-inflammatory agents may have potential for treatment of depression, but further research is needed to clarify their usefulness in routine clinical practice.

Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome.

Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is one of the key risk factors for depression. In addition, a growing body of data implicates chronic inflammation as a major player in depression pathogenesis. More recently, the gut microbiota has emerged as an important regulator of brain and behavior and also has been linked to depression. However, how this holy trinity of risk factors interact to maintain physiological homeostasis in the brain and body is not fully understood. In this review, we integrate the available data from animal and human studies on these three factors in the etiology and progression of depression. We also focus on the processes by which this microbiota-immune-stress matrix may influence centrally mediated events and on possible therapeutic interventions to correct imbalances in this triune.

Comparing underlying mechanisms of depression in multiple sclerosis and rheumatoid arthritis.

Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are common, chronic, autoimmune diseases affecting many people worldwide. While clinically very different in their phenotype, both diseases are thought to have an autoimmune-mediated origin. MS and RA share genetic similarities, and in both diseases, antibodies against host antigens can be found. Aside from the well-known somatic symptoms, many RA patients also show signs and symptoms of psychiatric illnesses, of which depression is the most common diagnosis. In this commentary, both diseases will be introduced and briefly characterized individually and then compared. Depression will be introduced as one of the most frequent psychiatric diseases in the general population. This paper focuses on presenting the possible causes, including psychosocial factors, genetics, and immunologic mechanisms. Hypotheses aimed to explain the higher incidence of depression in these two seemingly different autoimmune diseases will be discussed.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Correlation of Antibodies to Neurotransmitters in the Sera of Women with Alcohol Dependence and Depressive Disorders.

Comparative analysis of blood sera from women with alcohol dependence and depressive disorders or from conditionally healthy women revealed reduced level of antibodies to dopamine, norepinephrine, serotonin, glutamate, and GABA in blood serum in women with dysthymic disorder and a depressive episode and their increased content in women with alcohol dependence in combination with depressive disorders.

A comparison study of metabolic profiles, immunity, and brain gray matter volumes between patients with bipolar disorder and depressive disorder.

BACKGROUND: Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD. METHODS: In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed. RESULTS: Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels. CONCLUSIONS: Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.

Correlation between immune response and self-reported depression during convalescence from COVID-19.

Self-reported depression has been observed in coronavirus disease-2019 (COVID-19) patients, infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during discharge from the hospital. However, the cause of this self-reported depression during the convalescent period remains unclear. Here, we report the mental health status of 96 convalescent COVID-19 patients who were surveyed using an online questionnaire at the Shenzhen Samii Medical Center from March 2 to March 12, 2020 in Shenzhen, China. After obtaining their informed consent, we retrospectively analyzed the clinical characteristics of patients, including routine blood and biochemical data. The results suggested that patients with self-reported depression exhibited increased immune response, as indicated by increased white blood cell and neutrophil counts, as well as neutrophil-to-lymphocyte ratio. However, the mechanism linking self-reported depression to these cellular changes needs further study. In conclusion, self-reported depression occurred at an early stage in convalescent COVID-19 patients, and changes in immune function were apparent during short-term follow-up of these patients after discharge. Appropriate psychological interventions are necessary, and changes in immune function should be emphasized during long-term follow up of these patients.

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors.

Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.

Gut Microbiome Dysbiosis and Depression: a Comprehensive Review.

PURPOSE OF REVIEW: The human gut microbiome is involved in a bi-directional communication pathway with the central nervous system (CNS), termed the microbiota-gut-brain axis. The microbiota-gut-brain axis is believed to mediate or modulate various central processes through the vagus nerve. The microbiota-gut-brain axis is involved with the production of microbial metabolites and immune mediators which trigger changes in neurotransmission, neuroinflammation, and behavior. Little is understood about the utilization of microbiome manipulation to treat disease. RECENT FINDINGS: Though studies exploring the role of the microbiome in various disease processes have shown promise, mechanisms remain unclear and evidence-based treatments for most illnesses have not yet been developed. The animal studies reviewed in the present investigation include an array of basic science studies that clarify mechanisms by which the microbiome may affect mental health. More evidence is needed, particularly as it relates to translating this work to humans. The studies presented in this review demonstrate encouraging results in the treatment of depression. Limitations include small sample sizes and heterogeneous methodology. The exact mechanism by which the gut microbiota causes or alters neuropsychiatric disease states is not fully understood. In this review, we focus on recent studies investigating the relationship between gut microbiome dysbiosis and the pathogenesis of depression.

Sex differences in how inflammation affects behavior: What we can learn from experimental inflammatory models in humans.

Human models demonstrate that experimental activation of the innate immune system has profound effects on brain activation and behavior, inducing fatigue, worsened mood and pain sensitivity. It has been proposed that inflammation is a mechanism involved in the etiology and maintenance of depression, chronic pain and long-term fatigue. These diseases show a strong female overrepresentation, suggesting that a better understanding of sex differences in how inflammation drives behavior could help the development of individualized treatment interventions. For this purpose, we here review sex differences in studies using experimental inflammatory models to investigate changes in brain activity and behavior. We suggest a model in which inflammation accentuates sex differences in brain networks and pre-existing vulnerability factors. This effect could render women more vulnerable to the detrimental effects of immune-to-brain communication over time. We call for systematic and large scale investigations of vulnerability factors for women in the behavioral response to inflammation.

Depressive symptoms and immune transcriptional profiles in late adolescents.

BACKGROUND: Rates of depression increase and peak during late adolescence and alterations in immune processes are thought to be both a risk factor and outcome of depression. However, few studies have examined depression-immune dynamics among adolescents. Using a functional genomics approach, the current study examined whether depressive symptoms were associated with activation of a gene expression profile, characterized by upregulated expression of pro-inflammatory-related genes and downregulated expression of antiviral-related genes in a sample of older adolescents (Mage = 18.37, SD = 0.51). METHOD: Participants (n = 87) reported on their depressive symptoms during the past week using the CES-D, and provided blood samples for genome-wide transcriptional profiling of mRNA. RESULTS: Adolescents with clinically-significant levels of depressive symptoms (CES-D ≥ 16) exhibited upregulated expression of inflammation-related genes and downregulated expression of antiviral-related genes compared to their peers with lower levels of depressive symptoms (CES-D < 16). Bioinformatics analyses suggested that this pattern of differential gene expression was mediated by greater activity of the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB), and reduced activity of glucocorticoid receptors (GRs) and interferon response factors (IRFs). Additional analyses implicated monocytes, B cells, and dendritic cells as primary cellular sources of the observed gene expression patterns associated with depressive symptoms. CONCLUSION: Results are consistent with past work demonstrating links between depression and altered immunity. They provide a molecular basis for these associations and suggest that the underlying molecular signature may emerge as early as late adolescence when rates of depression tend to increase.

Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study.

BACKGROUND: The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. METHODS: In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. RESULTS: The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. CONCLUSIONS: The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.

Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort.

BACKGROUND: Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. METHODS: In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. RESULTS: Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13-2.69) for diurnal mood variation, 1.50 (95% CI, 1.11-2.02) for concentration difficulties, 1.31 (95% CI, 1.12-1.54) for fatigue, and 1.24 (95% CI, 1.01-1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (ß = 0.059, SE = 0.024, P = 0.013) and psychological (ß = 0.056, SE = 0.023, P = 0.016) scores. CONCLUSIONS: Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression.

Systemic low-grade inflammation and subsequent depressive symptoms: Is there a mediating role of physical activity?

OBJECTIVE: Systemic low-grade inflammation has been associated with the onset of depression, but the exact mechanisms underlying this relationship remain elusive. This study examined whether physical activity (PA) explained the association between elevated serum levels of inflammatory markers and subsequent depressive symptoms. DESIGN: Prospective cohort design. METHOD: The sample consisted of 3809 non-depressed men and women (aged 50+) recruited from the English Longitudinal Study of Ageing (ELSA). Serum levels of inflammatory markers (C-reactive protein (CRP), fibrinogen) and covariates (age, sex, education, wealth, body mass index, smoking, cholesterol, triglycerides) were measured at baseline (wave 4, 2008/09). Self-reported weekly moderate/vigorous (high) PA versus no weekly moderate/vigorous (low) PA was examined at a four-year follow-up (wave 6, 2012/13), using a single-item question. Depressive symptoms were assessed at baseline, four years (wave 6, 2012/13) and six years post baseline (wave 7, 2014/15), using the 8-item version of the Centre for Epidemiological Studies Depression Scale (CES-D). RESULTS: Participants with higher baseline concentrations of inflammatory markers were significantly more likely to report low PA levels four years later (CRP: OR: 1.25; 95% CI, 1.05-1.48; fibrinogen: OR: 1.18; 95% CI, 1.05-1.39). Moreover, low PA was associated with higher odds of elevated depressive symptoms at follow-up (OR: 1.59; 95% CI, 1.15-2.19). Mediation analyses revealed that low PA explained a total of 36.71% of the relationship between high CRP and elevated depressive symptoms, and 33.26% between higher levels of fibrinogen and elevated depressive symptoms six years later. No direct association was found between systemic low-grade inflammation and future depressive symptoms. CONCLUSION: These results suggest that low PA is a significant partial mediator of the relationship between systemic low-grade inflammation and subsequent elevated depressive symptoms in a nationally representative cohort of older adults.

Persistent central inflammation and region specific cellular activation accompany depression- and anxiety-like behaviours during the resolution phase of experimental colitis.

Depression and anxiety-related psychological symptoms are increasingly recognised as important co-morbidities in patients with inflammatory bowel disease (IBD). Dextran sulfate sodium (DSS) -induced colitis is an animal model of IBD in which afferent activation of the gut-brain axis can be assessed and explored as a source of behavioural change. Exposure of adult male Wistar rats to DSS (5%) in drinking water induced distal colitis. In parallel to local inflammatory responses in the gut wall, increased expression of IL-6 and iNOS was found in the cerebral cortex and an increase in ventricular volume. Immunoreactivity of immediate early gene FosB/ΔFosB activation was measured as an index of cellular activation and was increased in the nucleus accumbens and dorsal raphe nucleus in acutely colitic animals. Following resolution of the acute colitic response, sustained anhedonia in the saccharin preference test, immobility in the forced swim test, reduced burying behaviour in the marble burying test, and mild signs of anxiety in the elevated plus maze and light/dark box were observed. Central increases in iNOS expression persisted during the recovery phase and mapped to reactive microglia, particularly those found in the parenchyma surrounding circumventricular regions. Evidence of associated nitration was also found. Sustained increases in ventricular volume and reduced T2 magnetic resonance relaxometry time in cortical regions were observed during the recovery period. FosB/ΔFosB activation was evident in the dorsal raphe during recovery. Persistent central inflammation and cellular activation may underpin the emergence of symptoms of depression and anxiety in experimental colitis.

Inflammation associated with coronary heart disease predicts onset of depression in a three-year prospective follow-up: A preliminary study.

Depression frequently co-occurs with coronary heart disease (CHD), worsening clinical outcomes of both, and inflammation has been proposed as a biological link between these two disorders. The aim of the present study was to investigate the role of inflammation in the development of depression in CHD patients during a 3-year follow-up. We examined the inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), measured at baseline, as a potential predictor of later onset of depression. We recruited 89 CHD patients, who were assessed at baseline and then every 6 months, for three years. The sample included, at baseline, 25 depressed and 64 non-depressed CHD patients, as confirmed by Clinical Interview Schedule Revised (CIS-R). Depressive symptoms were assessed at baseline and all follow-up points by the Patient Health Questionnaire-9 (PHQ-9). In all CHD patients (n = 89), we found a significant positive correlation between hsCRP levels and the severity of depressive symptoms at baseline (PHQ-9, r = 0.23, p = 0.032). During follow-up, n = 21 patients (of the 64 non-depressed at baseline) developed depression, defined as being PHQ-9 positive (a score ≥ 10) in at least one follow-up assessment. Of these, n = 9 subjects were defined as developing clinically-significant depression, that is, having a positive PHQ-9 in at least 3 of the 6 follow-up assessments, implying a duration of symptoms of at least one year. We found that increased hsCRP values at baseline predicted future onset of depression. Specifically, baseline hsCRP values were higher in patients who later developed clinically-significant depression (mean ±â€¯SD; 6.76 ±â€¯6.52 mg/L) compared with never-depressed (2.77 ±â€¯3.13 mg/L; F(1,48) = 7.29, p = 0.010), even after controlling for baseline PHQ-9 scores. In conclusion, inflammation in CHD patients is associated with future development of clinically-significant depression. HsCRP, a reliable and ready-to-use biological marker of inflammation, may help to identify depression high-risk phenotypes even among CHD patients, who already have high baseline inflammation. Our study conveys important preliminary findings that will require further replication but that have the potential to affect the mental and physical health of a vulnerable group of individuals.

The role of circulatory systemic environment in predicting interferon-alpha-induced depression: The neurogenic process as a potential mechanism.

Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the brain cellular mechanisms underlying these effects are still not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in the blood of depressed versus non-depressed patients. We investigated the in vitro effect of serum from depressed and non-depressed HCV patients (at baseline, before IFN-α; and after four weeks of IFN-α), on the apoptotic and neurogenic processes in a human hippocampal progenitor cells model. Results show that higher apoptosis during proliferation observed upon treatment of cells with baseline serum, and lower neuronal differentiation observed upon treatment with serum after 4 weeks of IFN-α, were predictive of later development of IFN-α-induced depression (odds ratio = 1.26, p = 0.06, and = 0.80, p = 0.01, respectively). While serum after IFN-α increased neurogenesis compared with baseline serum, a lower increase in neurogenesis was also predictive of later development of depression (odds ratio = 0.86; p = 0.006). Our results provide evidence for the fundamental role of the systemic milieu (captured by serum samples) in the regulation of hippocampal neurogenesis by inflammation, a putative mechanism involved in the development of neuropsychiatric conditions.

The fetal origins of mental illness.

The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections-or simply inflammation-may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain.

Cytokine secretion and the risk of depression development in patients with connective tissue diseases.

Research in the past two decades has revolutionized our understanding of depressive illnesses. Proinflammatory cytokines have become a point of interest in the interconnecting areas of neuropsychiatric and autoimmune diseases. The cytokine hypothesis of depression suggests that pro-inflammatory cytokines play a primary role in the mediation of the pathophysiological characteristics of major depression, in which an inflammatory process may be induced by external and internal stressors, such as psychological and inflammatory diseases, respectively. The higher prevalence of depression, particularly in patients with chronic autoimmune connective tissue disorders (CTD), suggests that depression may present a dysfunctional adaptation of cytokine-induced sickness, which could manifest in times of an exacerbated activation of the innate immune system. Inflammation is thought to contribute to the development of clinical depression through its ability to induce sickness behaviors corresponding to the neurovegetative features of depression, through the dysregulation of the hypothalamic-pituitary-adrenal axis, alterations in neurotransmitter synthesis and reuptake, and through its involvement in the neuroprogression pathways. This review explores the complex interrelationships in which inflammatory responses alter neuroendocrine and neuropsychological regulation contributing to depressive symptoms in CTD. The prevalence and characteristics of depression, and its correlation to the levels of inflammatory cytokines and disease activity among different CTD will be reviewed.