Clinical and biochemical manifestations of depression: relation to the neurobiology of stress.

Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching treatment-resistant major depression and potential adverse effects associated with this complex and intricate network are highlighted. The authors used PubMed as the database for this review. Each author extracted relevant data and assessed the methodological quality of each study.

Personality disorders in offspring of mothers with mood disorders: results from a longitudinal family study.

Offspring of mothers with mood disorders are known to be at risk for a range of adverse outcomes, but the prevalence of personality disorders (PDs) in this group is unknown. The goal of this study was to assess risk of PD diagnoses and symptoms in offspring of mothers with and without mood disorders, and to explore contributing factors to this risk. This longitudinal study assessed PDs and symptoms of PDs in offspring of mothers with bipolar disorder (O-BD), major depression (O-MDD), and no psychiatric diagnosis (O-WELL) in mid-adolescence and in early adulthood. O-BD were more likely to develop a Cluster B PD than O-MDD or O-WELL in adolescence, and more likely to develop a Cluster B PD then O-WELL in early adulthood. Dimensional analyses revealed that O-BD had elevated symptoms in PDs across all PD clusters at mid-adolescence and young adulthood. O-MDD showed elevated symptoms of antisocial PD at both time points, and of obsessive-compulsive PD at young adulthood. Offspring of mothers with mood disorders, especially O-BD, are at increased risk for PD diagnoses and symptoms in mid-adolescence and early adulthood. Contributing factors to risk of PD symptoms in at-risk offspring are discussed.

CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques.

CONTEXT: Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence. OBJECTIVE: To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques. DESIGN: We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption. SETTING: National Institutes of Health Animal Center. PARTICIPANTS: Rhesus macaques. MAIN OUTCOME MEASURES: Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH -2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance. RESULTS: We show that -2232C>G alters DNA x protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior. CONCLUSION: Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.

Maternal and environmental factors influence the hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone infusion in offspring of mothers with or without mood disorders.

Individuals with melancholic major depression exhibit basal hypercortisolism and an attenuated ACTH response to exogenous corticotropin-releasing hormone (CRH) infusion. Given the greater incidence of depression in children of depressed parents, we examined the ACTH and cortisol responses to ovine CRH (oCRH) infusion in 63 adolescent offspring of mothers with major depression, bipolar illness, or no psychiatric illness. Psychiatric and observational assessments of these families had been conducted over the course of 10 years preceding this study. We examined the children's responses to CRH in relation to maternal characteristics and family environment and found the following: (a) cortisol responses were negatively related to chronic family stress and (b) offspring of depressed mothers with an avoidant personality disorder showed an exaggerated ACTH response. In addition, adolescents in late puberty (Tanner 4 and 5) had lower ACTH and cortisol responses to oCRH infusion than those in early puberty. Further, offspring with early histories of mood problems, and those who developed major depressive disorder as young adults, did not exhibit basal hypercortisolism but did show an attenuated ACTH response to CRH. Our results add to the growing body of literature showing the influence of maternal characteristics and environmental factors on hypothalamic-pituitary-adrenal axis patterns in children.