Carmine M. Pariante

The HPA axis in major depression: classical theories and new developments

Studies over the last 40 years have demonstrated that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.

Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment

Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.

Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

Childhood maltreatment predicts adult inflammation in a life-course study

Stress in early life has been associated with insufficient glucocorticoid signaling in adulthood, possibly affecting inflammation processes. Childhood maltreatment has been linked to increased risk of adult disease with potential inflammatory origin. However, the impact of early life stress on adult inflammation is not known in humans. We tested the life-course association between childhood maltreatment and adult inflammation in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Regression models were used to estimate the effect of maltreatment on inflammation, adjusting for co-occurring risk factors and potential mediating variables. Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels 20 years later, in adulthood [risk ratio (RR) = 1.80, 95% confidence interval (CI) = 1.26–2.58]. The effect of childhood maltreatment on adult inflammation was independent of the influence of co-occurring early life risks (RR = 1.58, 95% CI = 1.08–2.31), stress in adulthood (RR = 1.64, 95% CI = 1.12–2.39), and adult health and health behavior (RR = 1.76, 95% CI = 1.23–2.51). More than 10% of cases of low-grade inflammation in the population, as indexed by high C-reactive protein, may be attributable to childhood maltreatment. The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count. Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult health.

Adverse Childhood Experiences and Adult Risk Factors for Age-Related Disease Depression, Inflammation, and Clustering of Metabolic Risk Markers

OBJECTIVE To understand why children exposed to adverse psychosocial experiences are at elevated risk for age-related disease, such as cardiovascular disease, by testing whether adverse childhood experiences predict enduring abnormalities in stress-sensitive biological systems, namely, the nervous, immune, and endocrine/metabolic systems. DESIGN A 32-year prospective longitudinal study of a representative birth cohort. SETTING New Zealand. PARTICIPANTS A total of 1037 members of the Dunedin Multidisciplinary Health and Development Study. Main Exposures During their first decade of life, study members were assessed for exposure to 3 adverse psychosocial experiences: socioeconomic disadvantage, maltreatment, and social isolation. MAIN OUTCOME MEASURES At age 32 years, study members were assessed for the presence of 3 age-related-disease risks: major depression, high inflammation levels (high-sensitivity C-reactive protein level >3 mg/L), and the clustering of metabolic risk biomarkers (overweight, high blood pressure, high total cholesterol, low high-density lipoprotein cholesterol, high glycated hemoglobin, and low maximum oxygen consumption levels. RESULTS Children exposed to adverse psychosocial experiences were at elevated risk of depression, high inflammation levels, and clustering of metabolic risk markers. Children who had experienced socioeconomic disadvantage (incidence rate ratio, 1.89; 95% confidence interval, 1.36-2.62), maltreatment (1.81; 1.38-2.38), or social isolation (1.87; 1.38-2.51) had elevated age-related-disease risks in adulthood. The effects of adverse childhood experiences on age-related-disease risks in adulthood were nonredundant, cumulative, and independent of the influence of established developmental and concurrent risk factors. CONCLUSIONS Children exposed to adverse psychosocial experiences have enduring emotional, immune, and metabolic abnormalities that contribute to explaining their elevated risk for age-related disease. The promotion of healthy psychosocial experiences for children is a necessary and potentially cost-effective target for the prevention of age-related disease.

ELEVATED INFLAMMATION LEVELS IN DEPRESSED ADULTS WITH A HISTORY OF CHILDHOOD MALTREATMENT

CONTEXT The association between depression and inflammation is inconsistent across research samples. OBJECTIVE To test whether a history of childhood maltreatment could identify a subgroup of depressed individuals with elevated inflammation levels, thus helping to explain previous inconsistencies. DESIGN Prospective longitudinal cohort study. SETTING New Zealand. PARTICIPANTS A representative birth cohort of 1000 individuals was followed up to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Study members were assessed for history of childhood maltreatment and current depression. MAIN OUTCOME MEASURES Inflammation was assessed using a clinically relevant categorical measure of high-sensitivity C-reactive protein (>3 mg/L) and a dimensional inflammation factor indexing the shared variance of continuous measures of high-sensitivity C-reactive protein, fibrinogen, and white blood cells. RESULTS Although depression was associated with high levels of high-sensitivity C-reactive protein (relative risk,1.45; 95% confidence interval,1.06-1.99), this association was significantly attenuated and no longer significant when the effect of childhood maltreatment was taken into account. Individuals with current depression and a history of childhood maltreatment were more likely to have high levels of high-sensitivity C-reactive protein compared with control subjects (n = 27; relative risk, 2.07; 95% confidence interval, 1.23-3.47). In contrast, individuals with current depression only had a nonsignificant elevation in risk (n = 109; relative risk, 1.40; 95% confidence interval, 0.97-2.01). Results were generalizable to the inflammation factor. The elevated inflammation levels in individuals who were both depressed and maltreated were not explained by correlated risk factors such as depression recurrence, low socioeconomic status in childhood or adulthood, poor health, or smoking. CONCLUSIONS A history of childhood maltreatment contributes to the co-occurrence of depression and inflammation. Information about experiences of childhood maltreatment may help to identify depressed individuals with elevated inflammation levels and, thus, at greater risk of cardiovascular disease.

Glial cell abnormalities in major psychiatric disorders: the evidence and implications

Recent quantitative post-mortem investigations of the cerebral cortex have convincingly demonstrated cortical glial cell loss in subjects with major depression. Evidence is also mounting that glial cell loss may also be a feature of schizophrenia. These findings coincide with a re-evaluation of the importance of glial cells in normal cortical function. In addition to their traditional roles in neuronal migration and inflammatory processes, glia are now accepted to have roles in providing trophic support to neurons, neuronal metabolism, and the formation of synapses and neurotransmission. Consequently, reduced cortical glial cell numbers could be responsible for some of the pathological changes in schizophrenia and depression, including reduced neuronal size, reduced levels of synaptic proteins, and abnormalities of cortical neurotransmission. Additionally, as astrocytes provide the energy requirements of neurons, deficient astrocyte function could account for aspects of the functional magnetic imaging abnormalities found in these disorders. We discuss the possible basis of glial cell loss in these disorders and suggest that elevated levels of glucocorticoids, due to illness-related stress or to hyperactivity of the hypothalamic-pituitary-adrenal may down-regulate glial activity and so predispose to, or exacerbate psychiatric illness through enhanced excitotoxicity. The potential therapeutic impact of agents which up-regulate glial activity or normalise glial cell numbers is also discussed.

Effects of perinatal mental disorders on the fetus and child

Perinatal mental disorders are associated with increased risk of psychological and developmental disturbances in children. However, these disturbances are not inevitable. In this Series paper, we summarise evidence for associations between parental disorders and offspring outcomes from fetal development to adolescence in high-income, middle-income, and low-income countries. We assess evidence for mechanisms underlying transmission of disturbance, the role of mediating variables (underlying links between parent psychopathology and offspring outcomes) and possible moderators (which change the strength of any association), and focus on factors that are potentially modifiable, including parenting quality, social (including partner) and material support, and duration of the parental disorder. We review research of interventions, which are mostly about maternal depression, and emphasise the need to both treat the parents disorder and help with associated caregiving difficulties. We conclude with policy implications and underline the need for early identification of those parents at high risk and for more early interventions and prevention research, especially in socioeconomically disadvantaged populations and low-income countries.

The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and increased levels of glucocorticoid hormones in patients with depression have mostly been ascribed to impaired feedback regulation of the HPA axis, possibly caused by altered function of the receptor for glucocorticoid hormones, the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate many of the neurobiological disturbances in depression, including HPA axis hyperactivity, and thereby alleviate depressive symptoms. There is strong evidence for the notion that antidepressants exert these effects by modulating the GR. Such modulations, however, can be manifold and range from regulation of receptor expression to post-translational modifications, which may result in differences in GR nuclear translocation and GR-dependent gene transcription. The idea that the therapeutic action of antidepressants is mediated, at least in part, by restoring GR function, is consistent with studies showing that decreased GR function contributes to HPA axis hyperactivity and to the development of depressive symptoms. Conversely, excessive glucocorticoid signalling, which requires an active GR, is associated with functional impairments in the depressed brain, especially in the hippocampus, where it results in reduced neurogenesis and impaired neuroplasticity. In this review, we will focus on the GR as a key player in the precipitation, development and resolution of depression. We will discuss potential explanations for the apparent controversy between glucocorticoid resistance and the detrimental effects of excessive glucocorticoid signalling. We will review some of the evidence for modulation of the GR by antidepressants and we will provide further insight into how antidepressants may regulate the GR to overcome depressive symptoms.