Antenatal depression programs cortisol stress reactivity in offspring through increased maternal inflammation and cortisol in pregnancy: The Psychiatry Research and Motherhood - Depression (PRAM-D) Study.

INTRODUCTION: Antenatal depression is associated with a broad range of suboptimal outcomes in offspring, although the underlying mechanisms are not yet understood. Animal studies propose inflammation and glucocorticoids as mediators of the developmental programming effect of prenatal stress on offspring stress responses, but studies in humans are not yet at this stage. Indeed, to date no single study has examined the effects of a rigorously defined, clinically significant Major Depressive Disorder (MDD) in pregnancy on maternal antenatal inflammatory biomarkers and hypothalamic-pituitary (HPA) axis, as well as on offspring HPA axis, behavior and developmental outcomes in the first postnatal year. METHODS: A prospective longitudinal design was used in 106 women (49 cases vs. 57 healthy controls) to study the effect of MDD in pregnancy and associated antenatal biology (inflammatory and cortisol biomarkers), on offspring stress response (cortisol response to immunization, at 8 weeks and 12 months), early neurobehavior (Neonatal Behavioral Assessment Scale, NBAS, at day 6), and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development at 12 months). RESULTS: Compared with healthy controls, women with MDD in pregnancy had raised interleukin (IL) IL-6 (effect size (δ) = 0.53, p = 0.031), IL-10 (δ = 0.53, p = 0.043), tumor necrosis factor alpha (δ = 0.90, p = 0.003) and vascular endothelial growth factor (δ = 0.56, p = 0.008), together with raised diurnal cortisol secretion (δ = 0.89, p = 0.006), raised evening cortisol (δ = 0.64, p = 0.004), and blunted cortisol awakening response (δ = 0.70, p = 0.020), and an 8-day shorter length of gestation (δ = 0.70, p = 0.005). Furthermore, they had neonates with suboptimal neurobehavioral function in four out of five NBAS clusters measured (range of δ = 0.45-1.22 and p = 0.049-<0.001) and increased cortisol response to stress at one year of age (δ = 0.87, p < 0.001). Lastly, maternal inflammatory biomarkers and cortisol levels were correlated with infant stress response, suggesting a mechanistic link. CONCLUSION: This study confirms and extends the notion that depression in pregnancy is associated with altered offspring behavior and biological stress response, and demonstrates that changes in maternal antenatal stress-related biology are associated with these infant outcomes.

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders.

Historically, only cells of the adaptive immune system have been considered capable of retaining memory for infectious challenges. Recently, however, cells of the innate immune system have been shown to be capable of displaying long-term functional memory following a single immunostimulatory challenge, leading to enhanced production of proinflammatory molecules upon other subsequent, and temporally distant, immunostimulatory challenges. This effect has been termed 'trained innate immunity', and is underwritten by stable epigenetic changes in immune and metabolic pathways. Importantly, the long-term training of innate immune cells can occur as a result of infectious as well as and non-infectious challenges, including stress. Given the role that both stress and an activated immune system have in neuropathology, innate immune training has important implications for our understanding and treatment of neuropsychiatric disorders. This review focuses on the evidence for trained innate immunity and highlights some insights into its relevance for psychiatric diseases.

Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice induces behavioural and biological changes relevant to depression.

Numerous studies have examined links between postnatal neurogenesis and depression using a range of experimental methods to deplete neurogenesis. The antimitotic drug temozolomide (TMZ) has previously been used successfully as an experimental tool in animals to deplete adult neurogenesis and is used regularly on human patients as a standard chemotherapy for brain cancer. In this study, we wanted to evaluate whether TMZ as a model for chemotherapy treatment could affect parameters related to depression in an animal model. Prevalence rates of depression in patients is thought to be highly underdiagnosed, with some studies reporting rates as high as 90%. Results from this study in mice, treated with a regimen of TMZ similar to humans, exhibited behavioural and biochemical changes that have relevance to the development of depression. In particular, behavioural results demonstrated robust deficits in processing novelty and a significant increase in the corticosterone response. Quantification of neurogenesis using a novel sectioning method, which clearly evaluates dorsal and ventral neurogenesis separately, showed a significant correlation between the level of ventral neurogenesis and the corticosterone response. Depression is a complex disorder with discoveries regarding its neurobiology and how it relates to behaviour being only in their infancy. The findings presented in this study demonstrate that chemotherapy-induced decreases in neurogenesis results in previously unreported behavioural and biochemical consequences. These results, we argue, are indicative of a biological mechanism, which may contribute to the development of depression in patients being treated with chemotherapy and is separate from the mental distress resulting from a cancer diagnosis.

Animal models to improve our understanding and treatment of suicidal behavior.

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

Perinatal hypothalamic-pituitary-adrenal axis regulation among women with eating disorders and their infants.

BACKGROUND: Psychiatric illness is associated with heightened hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy which may have long term effects on infant stress regulation. HPA axis regulation has not previously been investigated in women with eating disorders (ED) or their infants during the perinatal period. METHODS: Women were recruited to a prospective longitudinal study in three groups: 1) current or active ED (C-ED=31), 2) past ED (P-ED=29) and healthy control (HC=57). Maternal psychopathology, diurnal cortisol levels, corticotropin-releasing hormone (CRH) and CRH binding protein (CRH-BP) were measured during the third trimester of pregnancy. At eight weeks postpartum infant cortisol was obtained before and after routine immunisations to determine infant hormonal response to a stressful situation. RESULTS: Women with current ED had a significantly lower cortisol decline throughout the day compared to HC, in both adjusted and unadjusted analyses. Lower cortisol decline among women with a current ED were associated with higher levels of psychopathology during pregnancy. Women's cortisol awakening response, CRH and CRH-BP levels did not differ across the three groups. Infants' stress response was also significantly higher among those in the C-ED group, although this effect was attenuated after controlling for confounders. CONCLUSIONS: During pregnancy women with ED have lower cortisol declines, suggestive of blunted diurnal cortisol rhythms. Postnatally, their infants also have a heightened response to stress. This is the first study to identify HPA axis dysfunction in pregnancy in women with ED, and to show an intergenerational effect. Since dysfunctions in HPA activity during childhood may represent a risk factor for psychological and physical health problems later in life, further investigation of the potential long-term implications of these findings is crucial.

Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study.

Animal studies and a handful of prospective human studies have demonstrated that young offspring exposed to maternal prenatal stress show abnormalities in immune parameters and hypothalamic-pituitary-adrenal (HPA) axis function. No study has examined the effect of maternal prenatal depression on offspring inflammation and HPA axis activity in adulthood, nor the putative role of child maltreatment in inducing these abnormalities. High-sensitivity C-reactive protein (hs-CRP) and awakening cortisol were measured at age 25 in 103 young-adult offspring of the South London Child Development Study (SLCDS), a prospective longitudinal birth cohort of mother-offspring dyads recruited in pregnancy in 1986. Maternal prenatal depression was assessed in pregnancy at 20 and 36 weeks; offspring child maltreatment (birth 17 years) was assessed at offspring ages 11, 16 and 25; and offspring adulthood depression (18-25 years) was assessed at age 25. Exposure to maternal prenatal depression predicted significantly elevated offspring hs-CRP at age 25 (odds ratio=11.8, 95% confidence interval (CI) (1.1, 127.0), P=0.041), independently of child maltreatment and adulthood depression, known risk factors for adulthood inflammation. In contrast, maternal prenatal depression did not predict changes in offspring adulthood cortisol; however, offspring exposure to child maltreatment did, and was associated with elevated awakening cortisol levels (B=161.9, 95% CI (45.4, 278.4), P=0.007). Fetal exposure to maternal depression during pregnancy has effects on immune function that persist for up to a quarter of a century after birth. Findings are consistent with the developmental origins of health and disease (DOHaD) hypothesis for the biological embedding of gestational psychosocial adversity into vulnerability for future physical and mental illness.

Inflammatory insults and mental health consequences: does timing matter when it comes to depression?

It has become widely accepted that the immune system, and specifically increased levels of inflammation, play a role in the development of depression. However, not everyone with increased inflammation develops depression, and as with all other diseases, there are risk factors that may contribute to an increased vulnerability in certain individuals. One such risk factor could be the timing of an inflammatory exposure. Here, using a combination of PubMed, EMBASE, Ovid Medline and PsycINFO, we systematically reviewed whether exposure to medically related inflammation in utero, in childhood, and in adolescence, increases the risk for depression in adulthood. Moreover, we tried to determine whether there was sufficient evidence to identify a particular time point during the developmental trajectory in which an immune insult could be more damaging. While animal research shows that early life exposure to inflammation increases susceptibility to anxiety- and depressive-like behaviour, human studies surprisingly find little evidence to support the notion that medically related inflammation in utero and in adolescence contributes to an increased risk of developing depression in later life. However, we did find an association between childhood inflammation and later life depression, with most studies reporting a significantly increased risk of depression in adults who were exposed to inflammation as children. More robust clinical research, measuring direct markers of inflammation throughout the life course, is greatly needed to expand on, and definitively address, the important research questions raised in this review.

Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties.

Major depressive disorder is an extremely debilitating condition affecting millions of people worldwide. Nevertheless, currently available antidepressant medications still have important limitations, such as a low response rate and a time lag for treatment response that represent a significant problem when dealing with individuals who are vulnerable and prone to self-harm. Recent clinical trials have shown that the N-methyl-D-aspartate receptor antagonist, ketamine, can induce an antidepressant response within hours, which lasts up to 2 weeks, and is effective even in treatment-resistant patients. Nonetheless, its use is limited due to its psychotomimetic and addictive properties. Understanding the molecular pathways through which ketamine exerts its antidepressant effects would help in the developing of novel antidepressant agents that do not evoke the same negative side effects of this drug. This review focuses specifically on the effects of ketamine on three molecular mechanisms that are relevant to depression: synaptogenesis, immunomodulation and regulation of glycogen synthase kinase-3 activity.

Glucocorticoids and inflammation: a double-headed sword in depression? How do neuroendocrine and inflammatory pathways interact during stress to contribute to the pathogenesis of depression?

Both glucocorticoids and inflammation have been implicated in the pathogenesis of depression. There is a large body of literature indicating that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) dysfunction are present in a significant proportion of depressed patients. There is also evidence of increased inflammatory processes in depressed populations, with higher levels of cytokines being a prominent finding - including raised levels of IL-6, and IL-1. These findings appear difficult to reconcile given the well-recognised property of glucocorticoids as prominent anti-inflammatory molecules. There are three potential solutions posed to this dilemma. Firstly, it has been argued that the glucocorticoid system and the inflammatory system exist in balance with one another and chronic stress can disrupt this balance in favour of inflammatory processes at the expense of glucocorticoid signalling. It has also been suggested that glucocorticoids have more complex actions than typically thought, and, in low levels can actually be pro-inflammatory, rather than universally anti-inflammatory. Lastly, it is possible that inflammation and glucocorticoid signalling may act on the same processes and structures without direct interaction to give rise to cumulative damage. Improved understanding of this interaction will allow further progress in determining targets for treatment.

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) and p57(Kip2). In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.

Structural analysis of foot-and-mouth disease virus 3C protease: a viable target for antiviral drugs?

Foot-and-mouth disease virus causes a major global agricultural problem that is difficult to control with existing vaccines. Structural analyses of the viral 3C protease not only have provided fresh insights into the catalytic mechanism of an unusual class of chymotrypsin-like cysteine proteases, but also are generating valuable information to drive the quest for effective antiviral therapies.

Locating high-affinity fatty acid-binding sites on albumin by x-ray crystallography and NMR spectroscopy.

Human serum albumin (HSA) is a versatile transport protein for endogenous compounds and drugs. To evaluate physiologically relevant interactions between ligands for the protein, it is necessary to determine the locations and relative affinities of different ligands for their binding site(s). We present a site-specific investigation of the relative affinities of binding sites on HSA for fatty acids (FA), the primary physiological ligand for the protein. Titration of HSA with [(13)C]carboxyl-labeled FA was used initially to identify three NMR chemical shifts that are associated with high-affinity binding pockets on the protein. To correlate these peaks with FA-binding sites identified from the crystal structures of FA-HSA complexes, HSA mutants were engineered with substitutions of amino acids involved in coordination of the bound FA carboxyl. Titration of [(13)C]palmitate into solutions of HSA mutants for either FA site four (R410A/Y411A) or site five (K525A) within domain III of HSA each revealed loss of a specific NMR peak that was present in spectra of wild-type protein. Because these peaks are among the first three to be observed on titration of HSA with palmitate, sites four and five represent two of the three high-affinity long-chain FA-binding sites on HSA. These assignments were confirmed by titration of [(13)C]palmitate into recombinant domain III of HSA, which contains only sites four and five. These results establish a protocol for direct probing of the relative affinities of FA-binding sites, one that may be extended to examine competition between FA and other ligands for specific binding sites.

Differential expression of CD25 and HC2 antigens on subtypes of acute myeloid leukemias.

The presence of CD25 and HC2 antigens in 66 different patients with acute myeloid leukemia (AML) was investigated. The expression of both antigens was observed in 32% of AML cells. Dual fluorescence staining experiments performed in 5 AML patient cells showed that CD25 and HC2 antigens were simultaneously expressed in a single cell. The expression of both antigens was mainly observed in the M4 and M5 subtypes of AML. Although immunopurified IL-2 was able to block the binding of anti-CD25 monoclonal antibody to the AML cells, the IL-2 receptor did not appear to be functional.

Mitogenic activation of the human lymphocytes induce the release of proenkephalin derived peptides.

Several reports indicate that enkephalins participate in lymphocyte proliferation and several events of the immune response. It has been proposed that peptides involved in these processes may originate in the nervous system or endocrine glands. We have found that human peripheral blood lymphocytes (PBL) activated with a mitogenic agent contain and release proenkephalin derived peptides. The kinetics of met-enkephalin and cryptic products of proenkephalin in PBL activated with phytohemaglutinin (PHA) were studied. Peptides were released to the supernatant of stimulated PBL, reaching the highest values after 18 to 24 hours. The material secreted corresponds to high, intermediate and low molecular weight peptides derived from proenkephalin, displaying met-enkephalin and synenkephalin (proenkephalin 1-70) immunoreactivity. Therefore, an intrinsic lymphocytic proenkephalin system is induced by PHA and may play an important role in the regulation of the immune response.