Crossroads of corticotropin releasing hormone,corticosteroids and monoamines. About a biological interface between stress and depression

Mental disorders are frequently preceded by stressful events or situations. Depression is a typical case in point. This raises the question, is depression - or possibly better: are certain forms of depression - caused by stress? Can stress be a true pathogenic factor? Phrased differently: can stress destabilize neuronal systems in the central nervous system to such an extent that depressive symptoms are generated? This question is discussed with the corticotrophin releasing hormone (CRH) and MA systems and hypothalamic-pituitary-adrenal (HPA) axis as major foci. The following issues are explored: the effect of antidepressants on corticosteroid receptor gene expression; the behavioral sequellae of CRH administration; CRH disturbances in depression; the impact of early life adversity on the development of the CRH system and on stress reactivity; the interrelationships of stress hormones and monoaminergic (MA ergic) transmission and finally the therapeutic potential of CRH and cortisol antagonists. The available data suggest that CRH overdrive and cortisol overproduction may play a pathogenic role in the occurrence of certain types of depression, directly and/or indirectly, i.e. by induction or exacerbation of disturbances in MA ergic transmission. Stress should, thus, become a major focus of biological depression research.     

Stress and glucocorticoid footprints in the brain-the path from depression to Alzheimer's disease

Increasingly, stress is recognized as a trigger of depressive episodes and recent evidence suggests a causal role of stress in the onset and progression of Alzheimer's disease (AD) pathology. Besides aging, sex is an important determinant of prevalence rates for both AD and mood disorders. In light of a recent meta-analysis indicating that depressed subjects have a higher likelihood of developing AD, a key message in this article will be that both depression and AD are stress-related disorders and may represent a continuum that should receive more attention in future neurobiological studies. Accordingly, this review considers some of the cellular mechanisms that may be involved in regulating this transition threshold. In addition, it highlights the importance of addressing the question of how aging and sex interplay with stress to influence mood and cognition, with a bias towards consideration of neuroplastic events in particular brain regions, as the basis of AD and depressive disorders.     

Predicting the onset of major depressive disorder and dysthymia in older adults with subthreshold depression: a community based study

BACKGROUND: It is well-established that the incidence of major depressive disorder is increased in subjects with subthreshold depression. A new research area focuses on the possibilities of preventing the onset of major depressive disorders in subjects with subthreshold depression. An important research question for this research area is which subjects with subthreshold depression will develop a full-blown depressive disorder and which will not. METHODS: We selected 154 older subjects with subthreshold depression (CES-D>16) but no DSM mood disorder from a longitudinal study among a large population based cohort aged between 55 and 85 years in The Netherlands. Of these subjects, 31 (20.1%) developed a mood disorder (major depression and/or dysthymia) at three-year or six-year follow-up. We examined risk factors and individual symptoms of mood disorder as predictors of onset of mood disorder. RESULTS: Two variables were found to be significant predictors in both bivariate and multivariate analyses: eating problems and sleep problems. The incidence of mood disorders differed strongly for different subpopulations, varying from 9% (for those not having any of the two risk factors) to 57% (for those having both risk factors). CONCLUSIONS: It appears to be possible to predict to a certain degree whether a subject with subthreshold depression will develop a mood disorder during the following years.     

Can stress cause depression?

The central issue raised in this paper is: can stress cause depression? Phrased more precisely: can stress cause brain disturbances thought to underlie (certain forms of) depression or particular components of the depressive syndrome. Focussing on 5-hydroxytryptamine (5-HT) and the stress hormones, this question was answered in the affirmative, based on the following two considerations: changes in the 5-HT and stress hormone systems produced by sustained stress mimic to a substantial extent the disturbances in these systems that may be observed in depression. Substantial evidence indicates that the 5-HT and stress hormone disturbances in depression are of pathophysiological significance and not merely a consequence of the depressed state or a product of stress generated by the depressed state. Furthermore, the question was raised whether a depression type could be identified particularly stress-inducible. This question, too, was answered in the affirmative. The depression type in question was named anxiety/aggression-driven depression and characterized on three levels: psychopathologically, biologically and psychologically. Preferential treatment of this depression type was discussed. In studying stress-inducible depression, biological depression research should shift focus from depression per se to the neurobiological sequelae of stress. Treatment of stress-inducible depressions and particularly its prevention should be geared towards reduction of stress and stress sensitiveness, utilising both biological and psychological means.     

Common genetic factors for depression and cardiovascular disease

There is increasing knowledge regarding the considerable comorbidity between depression and cardiovascular disease, which are two of the most common disorders in developed countries. The associated vulnerability is not unidirectional, as the presence of cardiovascular disease can also influence mood states. Although this may be the result of psychological factors, common biological mechanisms, including genetic ones, are thought to be responsible for this interaction; we can thus question whether variations in genes could be predisposing factors. Regarding the multiple interactions in the mechanisms between depression and cardiovascular system disorders, e.g., dysfunctions in the hypothalamic-pituitary-adrenocortical and sympathoadrenal axis and the response to stress, the importance of the serotonergic and immune systems, or the impact on the renin-angiotensin system, several candidate genes are being investigated. However, despite the interest in unraveling the potential susceptibility genes for both disorders, most available studies have so far dealt with the impact of polymorphisms in relation to either depression or cardiovascular disease. A few recent studies have now examined the effects of gene-gene or gene-environment interactions, and are investigating the impact of "depression-related" variants on cardiac response to stress. The first promising results were obtained with the serotonin transporter, and it may be hypothesized that this polymorphism interacts via the impact of the S allele on depression and via the effect of the L allele on platelet activation. However, the role played by various other candidate genes remains to be determined, especially regarding the question as to whether they are indicative of common pathophysiological mechanisms, or for identifying a subgroup of patients with somatic disorders that are more closely related to psychiatric symptoms.     

Bipolar spectrum: Relevant psychological and biological factors

The bipolar spectrum is a concept which bridges bipolar Ⅰ disorder and unipolar depression. As Kraepelin described, there may be continuity across mood disorders. If this is the case, why should we discriminate for drug choice? For example, it is generally accepted that mood stabilizers should be used for the bipolar spectrum, whereas antidepressants are for unipolar depression. If these disorders are diagnostically continuous, it is possible that the same drug could be effective in treating both bipolar Ⅰ disorder/spectrum and unipolar depression. To resolve this question, I would like to propose my hypothesis that there is an inflexion point which constitutes the boundary between the bipolar spectrum and unipolar depression. It is likely that this inflexion point consists of temperaments as, reportedly, there are many significant differences in the presence of various temperaments between the bipolar spectrum(bipolar Ⅱ, Ⅱ1/2 and Ⅳ) and unipolar depression. These findings suggest that temperaments could draw a boundary between the bipolar spectrum and unipolar depression. Moreover, it has been shown that certain temperaments may be associated with several biological factors and may be associated with drug response. As such, whilst the concept of the bipolar spectrum emphasizes continuity, it is the proposed inflexion point that discriminates drug responses between the bipolar spectrum and unipolar depression. At the moment, although hypothetical, I consider this idea worthy of further research.     

Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders

In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with mood and anxiety disorders. The results of such studies could have significant implications for the development of novel treatments for these disorders. A challenge currently facing the field is to assimilate the large and growing corpus of imaging data to inform a systems-level model of the neural circuitry underlying the disorders. One prominent theoretical perspective highlights the top-down inhibition of amygdala by ventromedial prefrontal cortex (vmPFC) as a crucial neural mechanism that may be defective in certain mood and anxiety disorders, such as major depression and post-traumatic stress disorder. In this article, we provide a critical review of animal and human data related to this model. In particular, we emphasize the considerable body of research that challenges the veracity (or at least completeness) of the predominant model. We propose a framework for constructing a more comprehensive model of vmPFC function, with the goal of fostering further progress in understanding the neuropathophysiological basis of mood and anxiety disorders.     

Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells.

The influence of stress and glucocorticoids on neuronal pathology has been demonstrated in animal and clinical studies. It has been proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals. New evidence implicates the prefrontal cortex (PFC) in addition to the hippocampus as a site of neuropathology in depression. The PFC may be involved in stress-mediated neurotoxicity because stress alters PFC functions and glucocorticoid receptors, the PFC is directly interconnected with the hippocampus, and metabolic alterations are present in the PFC in depressed patients. Postmortem studies in major depression and bipolar disorder provide the first evidence for specific neuronal and glial histopathology in mood disorders. Three patterns of morphometric cellular changes are noted: cell loss (subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal cortex), and increased numbers of cells (hypothalamus, dorsal raphe nucleus). The relevance of cellular changes in mood disorders to stress and prolonged PFC development and a role of neurotrophic/neuroprotective factors are suggested, and a link between cellular changes and the action of therapeutic drugs is discussed. The precise anatomic localization of dysfunctional neurons and glia in mood disorders may reveal cortical targets for novel antidepressants and mood stabilizers.     

Mood state as a predictor of neuropsychological deficits following cardiac surgery

Objectives: mood disorders and neuropsychological deficits are both commonly reported occurrences after cardiac surgery. We examined the relationship between mood state and postoperative cognitive deficits in this population.Methods: assessments of neuropsychological functions and mood state (depression, anxiety, stress scales; DASS) were performed preoperatively and postoperatively on 147 patients undergoing cardiac surgery.Results: the incidence of preoperative depression, anxiety, and stress symptomatology was 16%, 27%, and 16%, respectively. The incidence of postoperative anxiety symptomatology significantly increased to 45% (p<0.001), while the incidence of depression and stress symptomatology remained stable (19% and 15%, respectively; ns). Changes in mood state did not influence changes in neuropsychological performance. Preoperative mood was a strong predictor of postoperative mood, and was related to postoperative deficits on measures of attention and memory.Conclusions: an assessment of preoperative mood is critical in identifying patients at risk of postoperative mood disorders and neuropsychological deficits. Measures assessing somatic manifestations of anxiety may not be suitable for a surgical population.     

Can drugs cause depression? A review of the evidence.

Drug-induced depressive disorders are classified in the DSM-III-R as organic mood syndrome, depressed type. The ability of certain drugs to cause depression is of clinical relevance because organic mood syndrome is a component of the differential diagnosis of depressive symptoms. Consequently, psychiatric textbooks often provide different lists of drugs thought to be capable of causing depression. Strong evidence supporting the existence of causal associations is often lacking. There is no specific drug for which there is definitive evidence of a causal association with depressive symptoms or depressive disorders. Nevertheless, for a number of drugs, the evidence is suggestive, although not conclusively, of a causal association. Despite this, rational decisions about the continuation or discontinuation of drugs can often be made. In this paper, the literature is reviewed and guidelines are suggested for the management of patients with depressive symptoms which may be related to drugs.     

Une approche évolutionniste de la manie dans une perspective transculturelle

IntroductionThe objective of this paper is to verify if traits and symptoms defined as pathological and maladjusted in certain contexts may produce adaptive effects in other contexts, especially if they occur in sub-threshold forms.MethodsA historical examination of how the symptoms of depression have changed in front of great social changes and an analysis of Sardinian migrants’ thymic profiles toward several metropolises.Results and conclusionsMood disorders have been increasing since the “English malady” in the 17th century, and we suppose that some forms of mood disorders might have an adaptive advantage. Otherwise, the increase of such an epidemic would have been self-limited. From a sociobiological point of view, it is highly probable that the environment of a rapidly evolving society can select people who are explorers and able to support accelerated biorhythms and that the condition of social change stimulates psychological and psychopathologic changes. It is also possible that hyperthymic persons modulate and create the new environment. If this model can explain the epidemic of mood disorders, its verification should guide future research.     

Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus

Recent experimental data suggest that mood disorders are related to inflammatory phenomena and have led to the “inflammatory hypothesis of depression”. Given that the hippocampus is one of the most affected areas in these disorders, we used a model of acute stress (the Porsolt test) to evaluate the consequences of forced swimming on two crucial events related to the pathophysiology of major depression: the functional maturation of newborn granule neurons; and the hippocampal inflammatory milieu. Using PSD95:GFP-expressing retroviruses, we found that forced swimming selectively alters the dendritic morphology of newborn neurons and impairs their connectivity by reducing the number and volume of their postsynaptic densities. In addition, acute stress triggered a series of morphological changes in microglial cells, together with an increase in microglial CD68 expression, thus suggesting the functional and morphological activation of this cell population. Furthermore, we observed an intriguing change in the hippocampal inflammatory milieu in response to forced swimming. Importantly, the levels of several molecules affected by acute stress (such as Interleukin-6 and eotaxin) have been described to also be altered in patients with depression and other mood disorders.     

Affective disorders and S-adenosylmethionine: a new hypothesis

S-Adenosyl-L-methionine (AdoMet) is a safe and probably effective antidepressant agent in certain forms of clinical depression. This article presents a new hypothesis to account for the mechanism of action of S-adenosylmethionine in such illnesses, based upon the known biochemistry of this compound, and upon current knowledge of clinical and genetic aspects of affective disorders. Giulio Cantoni, S. Harvey Mudd and V. Andreoli postulate that at least some major mood disorders are due to abnormalities affecting the AdoMet-dependent methylation of a substance in the CNS. For convenience and without prejudging the chemical structure of this substance, they call it 'barinine'. The model requires that barinine be subject to AdoMet-dependent methylation and that methylbarinine be subject to metabolic demethylation to regenerate the original barinine. Methylbarinine should be mood elevating, whereas barinine itself should not be. Depression is a result of abnormalities lowering the normal steady-state concentration of methylbarinine, whereas mania results from an abnormal elevation of methylbarinine.     

Hierarchical structures of affect and psychopathology and their implications for the classification of emotional disorders

The Diagnostic and Statistical Manual of Mental Disorders-IV groups disorders into diagnostic classes on the basis of the subjective criterion of "shared phenomenological features." The current mood and anxiety disorders reflect the logic of older models emphasizing the existence of discrete emotions and, consequently, are based on a fundamental distinction between depressed mood (central to the mood disorders) and anxious mood (a core feature of the anxiety disorders). This distinction, however, ignores subsequent work that has established the existence of a general negative affect dimension that (a) produces strong correlations between anxious and depressed mood and (b) is largely responsible for the substantial comorbidity between the mood and anxiety disorders. More generally, there are now sufficient data to eliminate the current rational system and replace it with an empirically based taxonomy that reflects the actual-not the assumed-similarities among disorders. The existing structural evidence establishes that the mood and anxiety disorders should be collapsed together into an overarching superclass of emotional disorders, which can be decomposed into three subclasses: the distress disorders (major depression, dysthymic disorder, generalized anxiety disorder, posttraumatic stress disorder), the fear disorders (panic disorder, agoraphobia, social phobia, specific phobia), and the bipolar disorders (bipolar I, bipolar II, cyclothymia). An empirically based system of this type will facilitate differential diagnosis and encourage the ultimate development of an etiologically based taxonomy.     

Age-related cognitive decline in patients with mood disorders

BACKGROUND: The relationship between depression and dementia is complex and appreciation of its true nature is evolving. Depression is an early symptom of dementia. Recent research suggests that mood disorders, in general, may be risk factors for the development of dementia. METHOD: This was a cross-sectional study of the effect of aging on cognition in patients with mood disorders compared to normal controls. Patients and controls were tested with a comprehensive neurocognitive test battery, CNS Vital Signs. The question at issue was the rate of aging-related cognitive decline the same or different in mood disorder patients compared to normal controls. SUBJECTS: 455 patients with mood disorders, 336 with major depression and 119 with bipolar affective disorder, age 18-86, and 1003 normal controls, age 35-90. Normal controls were age 18 or older in the CNS Vital Signs normative database. The normal subjects were healthy, on no centrally-active medication, and free of psychiatric and neurological disorders. RESULTS: Cognitive performance in the two groups run in parallel from age 18 to 45; they begin to diverge during the next decade; after age 65, mood disorder patients, as a group, decline more sharply than normal controls. The differential rate of decline was seen in the domains of memory, attention, processing speed and executive function. CONCLUSIONS: There seems to be an acceleration in age-related cognitive decline in patients with depression in particular, and mood disorders in general, compared to age-matched normal controls. It is likely, then, that as people age, the ones who develop depression, or who fail to recover from early episodes of depression, include a substantial number of patients at risk for developing dementia. This is consistent with the fact that late-life depression may be an early manifestation of dementia. The data are also consistent with the idea that mood disorders are a risk factor, albeit a weak one, for the development of dementia. From a slightly different perspective, one might imagine that some pathophysiological event is shared by the mood disorders and dementing conditions.     

Challenging the unipolar–bipolar division: Does mixed depression bridge the gap?

BACKGROUND: Mixed states, i.e., opposite polarity symptoms in the same mood episode, question the categorical splitting of mood disorders in bipolar disorders and unipolar depressive disorders, and may support a continuum between these disorders. Study aim was to find if there were a continuum between hypomania (defining BP-II) and depression (defining MDD), by testing mixed depression as a 'bridge' linking these two disorders. A correlation between intradepressive hypomanic symptoms and depressive symptoms could support such a continuum, but other explanations of a correlation are possible. METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode (MDE) outpatients were interviewed, cross-sectionally, with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (to assess intradepressive hypomanic symptoms) and the Family History Screen, by a mood disorders specialist psychiatrist in a private practice. Patients presented voluntarily for treatment of depression when interviewed drug-free and had many subsequent follow-ups after treatment start. Mixed depression (depressive mixed state) was defined as the combination of MDE (depression) and three or more DSM-IV intradepressive hypomanic symptoms (elevated mood and increased self-esteem were always absent by definition), a definition validated by Akiskal and Benazzi. RESULTS: BP-II, versus MDD, had significantly lower age at onset, more recurrences, atypical and mixed depressions, bipolar family history, MDE symptoms and intradepressive hypomanic symptoms. Mixed depression was present in 64.5% of BP-II and in 32.1% of MDD (p=0.000). There was a significant correlation between number of MDE symptoms and number of intradepressive hypomanic symptoms. A dose-response relationship between frequency of mixed depression and number of MDE symptoms was also found. CONCLUSIONS: Differences on classic diagnostic validators could support a division between BP-II and MDD. Presence of intradepressive hypomanic symptoms by itself, and correlation between intradepressive hypomanic symptoms and depressive symptoms could instead support a continuum. Other explanations of such a correlation are possible. Depending on the method used, a BP-II-MDD continuum could be supported or not.     

The relationship between panic disorder/agoraphobia and personality disorders

This selective review of the relationship between panic disorder/agoraphobia and DSM-III personality disorders points to a preponderance of dependent, avoidant, and histrionic features and reveals a certain degree of covariation between severity of Axis I disorder and personality functioning. However, the link between panic/agoraphobia and Axis II disorders does not appear to be specific because (1) general features such as neuroticism, stress, dysphoric mood, and interpersonal sensitivity, rather than duration and severity of panic attacks and phobias, emerge as unique predictors or determinants of personality disorder; and (2) similar personality profiles are obtained in a heterogenous population of psychiatric outpatients or patients with social phobia, obsessive-compulsive disorder, and major depression.     

Irritable mood in Italian patients with medical disease

Irritability may be a mood state independent of other moods and anxiety disorders, even though it may be symptomatic of several psychiatric disorders, such as major depression. The aims of this exploratory study were to verify the presence of irritable mood in a group of medical outpatients with a variety of clinical conditions (functional gastrointestinal disorders, cardiovascular disorders, endocrine diseases and cancer) and to examine its relationship with major depression. A total of 609 consecutive outpatients recruited from different medical settings were assessed according to DSM-IV and Diagnostic Criteria for Psychosomatic Research using semistructured research interviews. Irritable mood was identified in 163 (27%) patients, while major depression was present in 113 (19%) patients. Even though there was a considerable overlap between the two diagnoses, 76 (67%) patients with major depression were not classified as irritable, and 126 (77%) patients with irritable mood did not satisfy the criteria for major depression. The findings suggest a high prevalence of irritability in the medically ill, which in most cases is independent of mood disorder. Further research may determine whether irritability, alone or in association with major depression, entails prognostic and clinical implications.     

Reevaluating the prevalence and diagnostic subtypes of depressive disorders in epilepsy

ObjectiveDepressive disorders are common among patients with epilepsy (PWE). The aim of this study was to estimate the prevalence of different forms of depressive disorders among PWE treated in the outpatient setting.MethodsA group of consecutive PWE that visited the epilepsy outpatient clinic was invited to participate in the study. Ninety-six patients met inclusion criteria and were examined by a trained psychiatrist using standardized measures.ResultsA diagnosis of a current major depression was established in 21 (22.3%) out of 96 participants. Furthermore, almost 20% of the study group fulfilled criteria for mood disorder categories other than MDD, adding up to over 40% of PWE suffering from any mood disorder category. Older age and later age at seizure onset, as well as unemployment, were associated with an increase in the odds of MDD diagnosis.Study limitationsA number of limitations are to be considered: the sample size is relatively small, and the findings may not be representative of PWE in general because our population represents a sample coming from a single outpatient clinic with a higher ratio of drug-resistant epilepsy.ConclusionsMajor depression as well as other forms of depressive disorders are common among PWE. Unemployment, age, and age at seizure onset are important factors associated with major depression among PWE.     

Long lasting phantosmia treated with venlafaxine

Qualitative olfactory disorders such as parosmia and phantosmia are not well investigated. In particular, the causes and treatment options for phantosmia are largely unknown. We report a case of long lasting phantosmia that disappeared under anti-depressive treatment, raising the question to what extent certain forms of qualitative olfactory disorders are an early symptom of depression.