HPA axis and sleep: identifying subtypes of major depression

It is increasingly acknowledged that the diagnosis of major depression encompasses patients who do not necessarily share the same disease biology. Though the diagnostic criteria allow the specification of different subtypes, e.g. melancholic and atypical features, a consensus still has to be reached with regard to the clinical symptoms that clearly delineate these subtypes. Beside clinical characteristics, biological markers may help to further improve identification of biologically distinct endophenotypes and, ultimately, to devise more specific treatment strategies. Alterations of the hypothalamus-pituitary-adrenal (HPA) axis and sleep architecture are not only commonly observed in patients with major depression, but the nature and extent of these alterations can help to identify distinct subtypes. Thus, a HPA overdrive, due to enhanced secretion of corticotropin-releasing hormone (CRH) and an impaired negative feedback via glucocorticoid receptors, seems to be most consistently observed in patients with melancholic features. These patients also show the clearest sleep-electroencephalogram (EEG) alterations, including disrupted sleep, low amounts of slow wave sleep (SWS), a short rapid eye movement (REM) latency and a high REM density. In contrast, patients with atypical features are characterized by reduced activity of the HPA axis and ascending noradrenergic neurons in the locus coeruleus. Though sleep-EEG alterations have been less thoroughly examined in these patients, there are data to suggest that SWS is not reduced and that REM sleep parameters are not consistently altered. While the atypical and melancholic subtypes of major depression may represent the extremes of a spectrum, the distinct clinical features provide an opportunity to further explore biological markers, as well as environmental factors, contributing to these clinical phenotypes. Moreover, dysregulations of the HPA axis and sleep-EEG alterations can also be induced in rodents, thereby allowing alignment of critical biological aspects of a human disease subtype with an animal model. Such "Translational Research" efforts should help to develop targeted therapies for distinct patient populations.     

Depression and bulimia: the link between depression and bulimic cognitions

This study assessed the link between bulimic and depressive cognitions. Twenty-nine bulimics and 16 controls from the general population were first assessed on levels of depression using the Schedule for Affective Disorders and Schizophrenia-Change Version and the Beck Depression Inventory (BDI). Bulimics were significantly more depressed than controls. Bulimics differed significantly from controls on all cognitive measures associated with depression (Automatic Thoughts Questionnaire, Dysfunctional Attitude Scale, and Attributional Style Questionnaire), but differences on these measures were nonsignificant when depression, as measured by the BDI, was controlled. Bulimics differed from controls regardless of level of depression on the three scales of the Restraint Inventory, the Rationalization and All-or-None scales of the Thoughts About Eating Inventory, and most of the eight scales of the Eating Disorders Inventory. Bulimics showed more maladaptive thinking associated with depression, but these differences likely reflect the levels of depression for each group. The differences on the measures of cognitive and behavioral symptoms of bulimia remained when the level of depression was controlled statistically. This suggests that although depression can be frequently diagnosed in a bulimic sample, specific maladaptive cognitions and behaviors reflect a distinct disorder (bulimia) and are not simply the expression of an affective disorder.     

Circadian activity of the hypothalamic-pituitary-adrenal axis is differentially affected in the rat chronic mild stress model of depression

The altered activity of the hypothalamic-pituitary-adrenal (HPA) axis is often observed in stress-related disorders. According to the literature, about 60% of patients with major depressive disorder elicit high levels of cortisol. It is still unclear why high cortisol levels are not observed in all patients. In this study, we used the chronic mild stress (CMS) rat model of depression, which is based on continuous exposure to unpredictable stressors, to track longitudinal changes in HPA function using fecal corticosterone metabolites (FCM) as a read out. The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Our results show (1) a disturbance in diurnal corticosterone rhythm measured as fluctuations of the diurnal FCM peak, (2) differences in corticosterone levels between stress-susceptible and stress-resilient animals, (3) recovery of diurnal corticosterone rhythm after 8 weeks of CMS, and (4) alterations in sensitivity to dexamethasone in negative feedback regulation of corticosterone secretion during the time course of CMS. Thus, a disruption of HPA axis circadian rhythmicity coincides with the initial state in the development of depression-like behavior. This chronobiological abnormality, as well as the hypersecretion of corticosterone, is state, rather than trait, dependent.     

Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat

Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.     

Enhancement of serotonin uptake by cortisol: a possible link between stress and depression

Stress and depression are characterized by elevation of circulating cortisol, as well as by changes in physiological functions. In this study, we addressed the possibility that elevated cortisol is also associated with the origin and development of depression. We report here that cortisol at the nM-μM concentration range induces a substantial increase in serotonin uptake both in vitro, by human peripheral blood lymphocytes (PBLs) and cortical neuronal cells, and in vivo, by rabbit PBLs, owing to promotion of synthesis of the serotonin transporter. These findings offer a novel molecular mechanism for depression associated with stress. Accordingly, the elevated cortisol induced by stress increases serotonin uptake, under both rest and nerve stimulation, which is overtly expressed in symptoms of depression.     

Gender differences in the link between intimate partner physical violence and depression

Studies show that, in violent relationships, both partners suffer from higher levels of depression than in non-violent relationships. Most of these studies were based on samples of battered women. Very little research has examined the depression levels of women who physically assault a marital or dating partner or men who assault or are victims of female assaults. Moreover, the association between intimate partner physical violence and depression does not provide a theoretical framework or an explanation for the differences in depression levels of male and female perpetrators and victims. This article presents a preliminary, yet empirically grounded, foundation for explaining research findings on depression levels for males and females in three “Dyadic Types” of intimate partner physical violence: Male-Only, Female-Only, and Both Violent. The theoretical framework involves identifying the relation of intimate partner physical violence to be of greater male than female concern with status enhancement and greater female than male concern with risk reduction, and how these play out in each of the Dyadic Types.     

Variation in hypothalamic-pituitary-adrenal axis activity among bullied and non-bullied children

We examined the relationship between being bullied during childhood and activity of the hypothalamic-pituitary-adrenal (HPA) axis as assessed through repeated measures of salivary cortisol. A non-clinical sample of 154 (74 boys) predominantly Caucasian middle-class 12-year-olds each provided detailed information about their experiences with bullying and six saliva samples were standardized across time and day. Children with a history of child maltreatment, diagnosed psychiatric illness, foster care placement, medication use (psychotropic and oral contraception) and aggression directed toward peers and/or family members were excluded. Using multilevel regression and applying orthogonal polynomial contrasts to model the observed circadian pattern in the data, we found that occasional and frequent verbal peer victimization was associated with hyposecretion of cortisol when controlling for sex, pubertal status, age, depression and anxiety. This relation, however, was moderated by sex. For boys, occasional exposure was associated with higher cortisol levels, whereas for girls exposure was associated with lower cortisol levels. The present study highlights the need to consider the plight of peer-victimized children seriously, as it is associated with alterations to the HPA axis that affect males and females differently, and likely diminishes a person's ability to cope with stress, possibly placing them at risk for psychopathology and ill health.     

Recurrence in major depression: a conceptual analysis

Theory and research on major depression have increasingly assumed a recurrent and chronic disease model. Yet not all people who become depressed suffer recurrences, suggesting that depression is also an acute, time-limited condition. However, few if any risk indicators are available to forecast which of the initially depressed will or will not recur. This prognostic impasse may be a result of problems in conceptualizing the nature of recurrence in depression. In the current paper we first provide a conceptual analysis of the assumptions and theoretical systems that presently structure thinking on recurrence. This analysis reveals key concerns that have distorted views about the long-term course of depression. Second, as a consequence of these theoretical problems we suggest that investigative attention has been biased toward recurrent forms of depression and away from acute, time-limited conditions. Third, an analysis of how these theoretical problems have influenced research practices reveals that an essential comparison group has been omitted from research on recurrence: people with a single lifetime episode of depression. We suggest that this startling omission may explain why so few predictors of recurrence have as yet been found. Finally, we examine the reasons for this oversight, document the validity of depression as an acute, time-limited disorder, and provide suggestions for future research with the goal of discovering early risk indicators for recurrent depression.     

A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression

Alteration of tryptophan (TRP) metabolism elicited by proinflammatory cytokines has gained attention as a new concept to explain the etiological and pathophysiological mechanisms of major depression. The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is the main TRP metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression. Furthermore, metabolites of the KYN pathway have neurotoxic/neuroprotective activities; 3-hydroxykynurenine and quinolinic acid are neurotoxic, whereas kynurenic acid is neuroprotective. The hippocampal atrophy that appears in chronic depression may be associated with imbalances in neurotoxic/neuroprotective activities. Because proinflammatory cytokines also activate the hypothalamo-pituitary-adrenal (HPA) axis, these imbalances may inhibit the hippocampal negative feedback system. Thus, changes in the TRP metabolism may also relate to the HPA axis-hyperactivity hypothesis of major depression. In this article, we review the changes in TRP metabolism by proinflammatory cytokines under stress, which is assumed to be a risk factor for major depression, and the relationship between physiological risk factors for major depression and proinflammatory cytokines.     

Resilience and hypothalamic-pituitary-adrenal axis reactivity under acute stress in young men

The present study examined the relationship between resilience (measured using the Resilience Scale for Adults) and hypothalamic-pituitary-adrenal (HPA) axis reactivity. We examined the subjective and cortisol responses of 28 healthy young men to an acute stressor (public speech task). Eight saliva samples were collected in order to obtain the response curve (anticipation, reactivity, recuperation) for each subject. ANOVA indicated that highly resilient individuals tended to display less mood deterioration than less resilient individuals (marginal p(time x group interaction) = 0.075). They also revealed that the former tended to secrete less cortisol overall than the latter during the experiment (marginal p(main group effect) = 0.087) but this effect was not uniform across time (p(time x group interaction) = 0.029). Additional analyses performed to identify the source of this interaction revealed that resilience moderates cortisol secretion in anticipation of the stressor (i.e. highly resilient individuals secreted less cortisol than less resilient ones, p = 0.05) but that it is not conductive to lower HPA reactivity amidst stress (i.e. there was no difference between groups in the increase in cortisol secretion from baseline to peak). The recovery slopes were likewise not statistically different. The implications of these findings regarding health are discussed.     

Investigating the link between liking versus wanting self-esteem and depression in a nationally representative sample of american adults

The self‐esteem movement has been around since the 1970s, and may have influenced how much value people place on self‐esteem. We predicted a negative relationship between age and the amount of value placed on self‐esteem boosts. We also investigated the correlates of liking versus wanting self‐esteem boosts (and other pleasant rewards) on depression. A nationally representative sample of American adults (N = 867) indicated how much they liked and wanted several pleasant rewards (i.e., sex, food, alcohol, money, friendship, self‐esteem boost). They also completed a standardized measure of depressive symptoms. As expected, there was a negative relationship between age and valuing self‐esteem boosts, sex, and alcohol. People with depressive symptoms wanted self‐esteem boosts, even though they did not like them very much. Similar effects were obtained for depressive symptoms and alcohol and friendship. This is the first research to show that self‐esteem boosts are more valued among a nationally representative sample of younger American adults. It also is the first research to explore the association between depression and the motivation to boost self‐esteem. People with depressive symptoms want self‐esteem, and may pursue it, but this pursuit may feel unrewarding because they do not derive pleasure from it.     

Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.     

Comparison of DSM-III-R chronic major depression and major depression superimposed on dysthymia (double depression): validity of the distinction

The nosology of chronic depression has become increasingly complex since the publication of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; American Psychiatric Association, 1987), but there are few data available to evaluate the validity of the distinctions between the subtypes of chronic depression. The validity of the distinction between DSM-III-R chronic major depression (CMD) and major depression superimposed on dysthymia (double depression, DD) was examined. Participants were 635 patients with chronic depression in a 12-week trial of antidepressant medications. Patients with CMD, DD, and a 3rd group with a chronic major depressive episode superimposed on dysthymia (DD/CMD) were compared on demographic and clinical characteristics, family history, and response to treatment. Few differences were evident, although the depression of patients with DD/CMD tended to be more severe.     

MMPI-2 clinical scale differences between dysthymia and major depression

Though dysthymia is considered less severe and more chronic than major depressive disorder, it is unclear whether the two disorders are truly different. In this study, MMPI-2 scales of 21 patients with dysthymia and 30 patients with major depressive disorder were compared. The average scores on Scales 2, 4, 6, 7, and 8 were in the clinical range for both groups. However, sizable differences between the two groups were found for Scale 1 and Scale 3. Smaller but reliable differences were found for Scale 2 and mean clinical scale T score with major depressives scoring higher on all of these measures. Results indicate that not only is major depressive disorder more severe than dysthymia, but also contains more physical/somatic symptoms than dysthymia.     

Revealing negative thinking in recovered major depression: a preliminary investigation

Previous research suggests that formerly dysphoric individuals engage in effortful strategies (e.g., thought suppression) that may mask underlying depressive thinking. The addition of a cognitive load, such as recalling a 6-digit number, which interferes with effortful mental control, reveals depressive thinking in formerly dysphoric individuals. This preliminary study tested whether this effect of cognitive load on revealing negative thinking generalizes to formerly clinically depressed patients. Currently depressed patients, recovered depressed patients and never-depressed patients unscrambled sentences that could form either positive or negative statements, after random allocation to either cognitive load or no cognitive load conditions. The number of negative statements unscrambled was used as an index of negative thinking. Without a load, recovered depressed patients did not differ from never-depressed controls: both groups completed fewer negative statements than currently depressed patients. However, the cognitive load increased negative statements in the recovered depressed group, making them resemble the currently depressed group more than the never-depressed group. These preliminary findings extend previous demonstrations of cognitive load unmasking negative thinking in dysphoric students to a clinical population, suggesting that formerly depressed patients utilize effortful strategies to minimize the report of negative thinking, which is undermined by the addition of a cognitive load.     

Cognitive vulnerability to depression: a comparison of the weakest link, keystone and additive models

Multiple theories of cognitive vulnerability to depression have been proposed, each focusing on different aspects of negative cognition and utilising different measures of risk. Various methods of integrating such multiple indices of risk have been examined in the literature, and each demonstrates some promise. Yet little is known about the interrelations among these methods, or their incremental validity in predicting changes in depression. The present study compared three integrative models of cognitive vulnerability: the additive, weakest link, and keystone models. Support was found for each model as predictive of depression over time, but only the weakest link model demonstrated incremental utility in predicting changes in depression over the other models. We also explore the correlation between these models and each model's unique contribution to predicting onset of depressive symptoms.     

Rumination and attention in major depression

Up until recently, it had been assumed that attentional biases for negative information do not exist in depression. However studies using post-conscious exposure durations have produced contradictory results. The limitations of common attentional tasks, suitability of stimulus materials and differences in stimulus duration times may have contributed to these inconsistencies. We aimed to address many of these issues and examine attentional responses in major depression at two post-conscious exposure times. We also investigated possible roles for rumination and distraction in increasing and lessening attentional biases for negative information. We used a fully controlled experimental design to test the effects of both induced and trait rumination and distraction on attention in patients with major depression and healthy controls. Attention was assessed using the dot-probe task. The findings revealed an attentional bias for negative information in depressed patients only at the longer post-conscious exposure duration. Furthermore although this bias was not influenced by either induced or trait distraction, it was related to trait rumination. Overall, the results showed that depression is associated with a strategic attentional bias towards negative information and that this bias is stronger in individuals who habitually ruminate.     

Defense mechanisms and morality: a link between isolation and moralization

The relationship between morality and perceptual defense mechanisms was studied. Three new scales were constructed to measure different aspects of morality: moralism (the tendency to evaluate everything in terms of right and wrong), conscience (strength of feelings of right and wrong) and reparation (inclination to repair the damage one has caused). Perceptual defense mechanisms were measured with Kragh's Defense Mechanism Test (DMT). Three hypotheses about relationships between morality and defense mechanisms, derived from psychoanalytical literature, were tested on 54 male University students. Results show positive correlations between the defense mechanism isolation of affect and moralism, and between identification with the aggressor and reparation. Total amount of perceptual defense correlated positively with moralism. It is argued that the psychological study of morality should take unconscious processes into consideration.     

Perceptual asymmetry differences between major depression with or without a comorbid anxiety disorder: a dichotic listening study.

Predictions that anxious and nonanxious depression would differ in perceptual asymmetry (PA), as well as in sensitivity for perceiving emotional words, were evaluated using dichotic listening tasks. A total of 149 patients having a major depressive disorder (51 with and 98 without an anxiety disorder) and 57 healthy controls were tested on fused-word and complex tone tasks. The anxious and nonanxious depression groups showed a consistent difference in PA across tasks; that is, the anxious group had a larger left-ear advantage for tones and a smaller right-ear advantage for words when compared with the nonanxious group. There was no group difference in sensitivity for perceiving emotional words. Patients having an anxious depression appear to have a greater propensity to activate right than left-hemisphere regions during auditory tasks, whereas those having a nonanxious depression have the opposite hemispheric asymmetry.