Evidence suggests several causes for depression, including traumatic life events, disease, poison, and nutritional deficiencies. Many of these causes are associated with elevated levels of inflammatory biomarkers in the blood, which may in turn lead to inflammatory changes in the brain. Our authors examine what the latest research reveals about the link between inflammation in the brain and depression, and how a better understanding of that link can play a critical first step in the personalization of care.
A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.
Background: Factors promoting cardiovascular health in the face of high risk, ie, resilience, are unknown and may identify novel areas of intervention for reducing racial health disparities. We examined neighborhood perceptions and psychological attributes of blacks living in high and low cardiovascular–risk neighborhoods, as potential characteristics of resilience promoting cardiovascular health. Methods and Results: We identified 1433 blacks residing in census tracts of Atlanta, GA, with higher-than-expected (“high” risk) or lower-than-expected (“low” risk) rates of cardiovascular mortality, hospitalizations, and emergency department visits during 2010–2014. Domains of psychosocial well-being and neighborhood quality were assessed via telephone survey between August 2016 and October 2016. Using multilevel logistic regression, odds of reporting better resilient characteristics were compared between individuals living in low- versus high-risk neighborhoods. Those from low-risk (versus high-risk) neighborhoods reported better neighborhood aesthetic quality (odds ratio [OR], 1.84), healthy food access (OR, 1.69), and absence of violence (OR, 0.67). Individuals from low-risk neighborhoods reported greater optimism (OR, 1.38), purpose in life (OR, 1.42), and fewer depressive symptoms (OR, 0.69). After full adjustment, these associations remained significant for neighborhood factors (aesthetic quality, healthy food access, violence) and psychosocial well-being (purpose in life). We found no evidence of differences in self-reported cardiovascular risk factors or disease history between low- versus high-risk neighborhoods. Conclusions: Positive neighborhood environments and psychological characteristics are associated with low cardiovascular–risk neighborhoods, despite similar prevalence of cardiovascular risk factors, in the census tracts studied. These factors may confer cardiovascular resilience among blacks.
Glucocorticoids play an essential role in the response to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine and immune reactions. A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids (glucocorticoid resistance), which is believed to be related in part to impaired functioning of the glucocorticoid receptor (GR). Glucocorticoid resistance, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. Recent data indicate that glucocorticoid resistance may be a result of impaired GR function secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress. Indeed, inflammatory cytokines and their signaling pathways including mitogen-activated protein kinases, nuclear factor-kB, signal transducers and activators of transcription, and cyclooxygenase have been found to inhibit GR function. Mechanisms include disruption of GR translocation and/or GR-DNA binding through protein-protein interactions of inflammatory mediators with the GR itself or relevant steroid receptor cofactors as well as alterations in GR phosphorylation status. Interestingly, cAMP signal transduction pathways can enhance GR function and inhibit cytokine signaling. Certain antidepressants have similar effects. Thus, further understanding the effects of cytokines on GR signaling and the mechanisms involved may reveal novel therapeutic targets for reversal of glucocorticoid resistance and restoration of glucocorticoid-mediated inhibition of relevant bodily/immune responses during stress and immune challenge.
Studies consistently report that groups of individuals with major depressive disorder (MDD) demonstrate increased levels of a variety of peripheral inflammatory biomarkers when compared with groups of nondepressed individuals. These findings are often interpreted as meaning that MDD, even in medically healthy individuals, may be an inflammatory condition. In this article, we examine evidence for and against this idea by looking more closely into what the actual patterns of inflammatory findings indicate in terms of the relationship between MDD and the immune system. Data are presented in support of the idea that inflammation only contributes to depression in a subset of patients versus the possibility that the depressogenic effect of inflammatory activation is more widespread and varies depending on the degree of vulnerability any given individual evinces in interconnected physiologic systems known to be implicated in the etiology of MDD. Finally, the treatment implications of these various possibilities are discussed.
Cytokine-induced stimulation of p38 mitogen activated protein kinase (MAPK) has been shown to influence behaviorally-relevant pathophysiologic pathways including monoamine neurotransmission and neuroendocrine function and thus may contribute to behavioral changes that occur during chronic administration of the innate immune cytokine, interferon (IFN)-alpha. Accordingly, in the current study, phosphorylation (activation) of intracellular p38 MAPK in peripheral blood lymphocytes was analyzed by flow cytometry every 2 hours for 12 hours following the initial injection of IFN-alpha in eleven patients with chronic hepatitis C. Hourly assessments of plasma concentrations of adrenocorticotropic hormone, cortisol and interleukin-6 were also obtained. Symptoms of depression and fatigue were measured at baseline and after 4 and 12 weeks of IFN-alpha treatment. Acute administration of IFN-alpha significantly increased the percentage of lymphocytes staining positive for intracellular phosphorylated p38 (p-p38). IFN-alpha-induced increases in p-p38 were significantly greater in patients that developed clinically significant depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS) score ≥15] during the first 12 weeks of IFN-alpha treatment. Increases in the percentage of p-p38-positive lymphocytes following the first IFN-alpha injection also highly correlated with depression severity at weeks 4 (r=0.85, p=0.001) and 12 (r=0.70, p=0.018). Similar relationships were observed for fatigue. Examination of relationships between p-p38 induction and factors previously reported to predict IFN-alpha-induced depressive symptoms revealed strong associations of p-p38 with baseline MADRS (r=0.82, p=0.002) and cortisol responses to the initial injection of IFN-alpha (r=0.91, p=0.000). Taken together, these findings indicate that sensitivity of p38 MAPK signaling pathways to immune stimulation is associated with depressive symptoms during chronic IFN-alpha treatment.
Sir—Celecoxib is a widely used nonsteroidal anti-inflammatory agent that acts through selective inhibition of COX-2. Here we demonstrate that celecoxib also significantly increases nuclear localization of the glucocorticoid receptor (GR), increases GR binding to its DNA responsive element and enhances GR-mediated gene transcription in association with inhibition of p38 MAP kinase. These results expand the intracellular targets of COX-2 inhibitors while widening their potential clinical application to multiple disorders associated with impaired GR function including major depression.
Background
Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a non-human primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys.
Methods
Eight rhesus monkeys were administered recombinant human (rHu)-IFN-alpha (20 MIU/m2) or saline for 4 weeks in counterbalanced fashion, and videotaped behavior, as well as plasma and cerebrospinal fluid (CSF), were obtained at regular intervals to assess behavioral, neuroendocrine, immune and neurotransmitter parameters. Additionally, expression and activity of IFN-alpha/beta receptors in monkey peripheral blood mononuclear cells (PBMCs) were assessed.
Results
Compared to saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. In addition, IFN-alpha induced significant increases in plasma concentrations of ACTH, cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in 3 animals, depressive-like, huddling behavior was observed. Monkeys that displayed huddling behavior exhibited significantly higher plasma concentrations of ACTH and lower CSF concentrations of the dopamine metabolite, homovanillic acid. Rhesus monkey PBMCs were found to express mRNA and protein for the IFN-alpha/beta receptor. Moreover, treatment of PBMCs with rHu-IFN-alpha led to induction of STAT1, one of the primary IFN-alpha-induced signaling molecules.
Conclusions
IFN-alpha evoked behavioral, neuroendocrine and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.
Interferon (IFN)-alpha is an innate immune cytokine that induces significant depressive symptoms in clinical populations. A number of mechanisms have been considered regarding the relationship between IFN-alpha and depression, including the effects of IFN-alpha on the hypothalamic-pituitary-adrenal (HPA) axis. Here, we examined the impact of mouse interferon (mIFN)-alpha and its signaling pathways on the functioning of the glucocorticoid receptor (GR), which plays a key role in HPA axis regulation. mIFN-alpha treatment (100–1000 IU/ml) of HT22 mouse hippocampal cells for 24 hours was found to significantly inhibit dexamethasone (DEX)-induced GR-mediated MMTV-luciferase activity and significantly decrease DEX-induced GR-binding to its DNA response element. Of note, mIFN-alpha treatment for 24 hours had no effect on DEX-induced GR translocation or GR protein expression. Inhibition of DEX-induced GR function by mIFN-alpha was significantly reversed by pharmacological inhibition of janus kinase/signal transducer and activator of transcription (Jak-STAT) signaling pathways, but not by inhibition of p38 mitogen-activated protein kinase. Moreover, pretreatment of cells with siRNA targeted to STAT5, but not STAT1 or STAT2, significantly attenuated IFN-alpha inhibition of DEX-induced MMTV-luciferase activity. Immunoprecipitation experiments revealed nuclear co-immunoprecipitation of activated STAT5 and GR following IFN-alpha plus DEX treatment. Taken together, these results indicate that negative regulation of GR function by IFN-alpha in hippocampal HT22 cells is mediated by activation of Jak/STAT signaling pathways leading to nuclear STAT5-GR protein-protein interactions. Given the role of GR in depressive disorders, IFN-alpha effects on GR function in cells of hippocampal origin may contribute to HPA axis alterations and depressive symptoms in IFN-alpha-treated patients.
Antipsychotic polypharmacy (APP) is a common strategy despite guidelines advising against this practice. This article seeks to quantify the prevalence and correlates of APP using Medicaid Analytic eXtract files from 2003 to 2004. Nineteen percent of Medicaid recipients who received an antipsychotic were treated with APP. Individuals who received APP were more likely to be white, male, disabled, between the ages of 18–29, diagnosed with a psychotic disorder, and diagnosed with a higher number of psychiatric conditions. Geographic variation in APP rates was also observed. Quality improvement initiatives may help reduce APP for medically vulnerable patients.