Abnormal personality and the mood and anxiety disorders: implications for structural models of anxiety and depression

Substantial overlap exists between the mood and anxiety disorders. Previous research has suggested that their comorbidity can be explained by a shared factor (negative emotionality), but that they may also be distinguished by other unique components. The current study explicated these relations using an abnormal personality framework. Current diagnoses of major depression and several anxiety disorders were assessed in 563 Gulf War veterans. Participants also completed the schedule for nonadaptive and adaptive personality (SNAP) to determine how these disorders relate to abnormal personality traits. Analyses of individual diagnoses indicated that depression, generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD) were more strongly related to personality than were other anxiety disorders. The Self-Harm Scale distinguished major depression from all other disorders, highlighting its significance for future structural models. Our results add to a growing body of evidence suggesting that GAD and PTSD have more in common with major depression than with their anxiety disorder counterparts.     

Role of hippocampal neurogenesis in mnemonic segregation: implications for human mood disorders

Abstract

Objectives. Although hippocampal neurogenesis has been implicated in mood disorders, the precise role new neurons play in mood regulation is not fully elucidated. Here we examine whether neurogenesis improves mood by facilitating segregation of novel experiences that conflict with older maladaptive memories. Methods. Study 1: Four groups (N = 9 each) of adult male rats (exposed to stress or control conditions plus antidepressant or placebo) underwent active training on the place-avoidance task (PAT) on week 0; tested on recalling the “Initial PAT” on weeks 4 and 8; learning a subtly “Altered PAT” on week 8; and euthanazed on week 9. Study-2: Two groups (N = 12 each) rats tested either on the Initial-PAT or Altered-PAT 3 days post-training and immediately euthanized. Results. Stressed subjects treated with placebo were slower in learning the week 8 Altered Task and had lower neurogenesis rates than non-stressed animals and Stressed subjects given drug (Study 1). Synaptic activation of mature hippocampal neurons inversely correlated with Altered-PAT performance and with neurogenesis rates (Study 2). Conclusions. Increasing neurogenesis enhances acquisition of novel experiences possibly by suppressing activation of mature hippocampal neurons that mediate established, conflicting memories. Therefore, antidepressants may improve mood by stimulating new hippocampal neurogenesis that facilitate detection of positive experiences while suppressing interference from recurring depressogenic thought patterns.     

Interferon-alpha, cytokines and possible implications for mood disorders

Schaefer M, Schmidt F, Neumer R, Scholler G, Schwarz M. Interferon-alpha, cytokines and possible implications for mood disorders. Bipolar Disord 2002: 4(Suppl. 1): 111–113. © Blackwell Munksgaard, 2002     

d-serine levels in Alzheimer's disease: implications for novel biomarker development

Alzheimer''s disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.     

Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders

Over the last ten years, there has been increased interest in the evolutionary origins of depressive phenomena. The current article provides a review of the major schools of thought that have emerged in this area. First, we consider important Darwinian explanations of depressed mood, including an integrative social risk hypothesis recently proposed by the authors. According to the social risk hypothesis, depression represents an adaptive response to the perceived threat of exclusion from important social relationships that, over the course of evolution, have been critical to maintaining an individual's fitness prospects. We argue, moreover, that in the ancestral environment, depression minimized the likelihood of exclusion by inducing: (i) cognitive hypersensitivity to indicators of social risk/threat; (ii) signaling behaviours that reduce social threat and elicit social support; and (iii) a generalized reduction in an individual's propensity to engage in risky, appetitive behaviours. Neurobiological support for this argument is also provided. Finally, we review three models that endeavour to explain the relationship between the adaptations that underlie depressed mood and clinically significant, depressed states, followed by a consideration of the merits of each.     

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.     

Subtyping of psychiatric disorders: implications for drug development

Psychiatric diagnosis suffers from being based on phenomenology and not on pathophysiology. Data are presented showing that psychiatric patients reveal consistent quantitative electroencephalographic abnormalities, such that they can be separated from normals and from each other. Clustering these pathophysiological groupings reveals an underlying variability, which permits useful subtyping. Data are presented relating subtyping to pharmacological treatment.     

Distribution of serotonin transporter labeled fibers in amygdaloid subregions: implications for mood disorders.

BACKGROUND: The serotonin transporter 5-HTT mediates responses to serotonin reuptake inhibitors (SSRIs), a mainstay treatment in mood disorders. The amygdala, a key emotional processing center, has functional abnormalities in mood disorders, which resolve following successful SSRI treatment. To better understand the effects of SSRIs in mood disorders, we examined the distribution of 5-HTT labeled fibers relative to specific nuclear groups in the amygdala. METHODS: Immunocytochemical techniques were used to chart 5-HTT labeled fibers in the amygdala in coronal sections through the brain of six adult Macaques. Nissl staining was used to define nuclear groups in the amygdala. RESULTS: The serotonin transporter 5-HTT is distributed heterogeneously in the primate amygdala, with the lateral subdivision of the central nucleus, intercalated cell islands, amygdalohippocampal area, and the paralaminar nucleus showing the heaviest concentrations. CONCLUSIONS: 5HTT-labeled fibers are very densely concentrated in output regions of the amygdala. High concentrations of 5-HTT-positive fibers in the central nucleus indicate that tight regulation of serotonin is critical in modulating fear responses mediated by this nucleus. High concentrations of 5-HTT-labeled fibers in the intercalated islands and parvicellular basal nucleus/paralaminar nucleus, which contain immature -appearing neurons, suggest a potential trophic role for serotonin in these subregions.     

The implications of genetics studies of major mood disorders for clinical practice

BACKGROUND: This article is a selective review and synthesis of relevant research findings from genetic studies of major mood disorders and the application of these to clinical practice. METHOD: The article discusses the application of genetic research findings in major mood disorders, including epidemiologic and family study risk estimates, risk modifiers, and the concepts of etiologic and phenotypic heterogeneity, to 3 clinical domains: risk counseling, diagnosis, and treatment prediction. RESULTS: Epidemiologic and family studies have provided general risk estimates useful in counseling mood-disordered patients and their relatives. A complete and accurate family pedigree provides more individualized risk estimates for specific cases and is useful in identifying the phenotypic spectrum of the disorder being transmitted in the family. Both proband course parameters and familial loading for psychiatric illnesses may be relevant for the prediction of treatment response. However, the hypothesis of inherited pharmacologic selectivity remains to be proven. CONCLUSION: Genetic studies of mood disorders have not yet provided conclusive evidence of specific susceptibility genes or their pattern of inheritance. However, they have generated information that is useful to clinical practice.     

Brain development and the onset of mood disorders

Research in mood disorder pathophysiology has stimulated considerable interest in clinical and biologic aspects of mood disorders among children and adolescents. From the clinical perspective, developmental aspects of psychiatric disorders have crystallized in the relatively new theoretical school known as developmental psychopathology. This school attempts to understand the nature of developmental changes in behavior, with the goal of differentiating normal from abnormal stage-related behavior. This perspective has exerted major impact on conceptualizations of psychiatric disorders. From the basic science perspective, biologic findings in emotion have stimulated an integration of basic and clinical approaches to mood disorders. The term emotion is often used to refer to brain states elicited by stimuli for which an organism will extend effort to obtain (rewards) or avoid (punishments). Imaging studies suggest that brain regions engaged by rewarding and punishing stimuli in lower mammals are also implicated in mood disorders. Other studies suggest that environmental factors exert profound effects on the development of these brain regions. The impact of 4 areas of research on our understanding of depression pathophysiology is reviewed: (1) mood disorder onset, (2) structural magnetic resonance imaging (MRI), (3) behavioral or cognitive correlates of major depression, and (4) functional MRI of brain regions engaged across development. This is a US government work. There are no restrictions on its use.     

Volumetric asymmetries in late-onset mood disorders: an attenuation of frontal asymmetry with depression severity

The purpose of the study was to examine global and regional volumetric asymmetries in patients with late-onset mood disorders and non-depressed control subjects. Our sample comprised 34 patients with late-onset major depression, 18 patients diagnosed with late-onset minor depression and 30 control subjects. All subjects were scanned using a 1.5 Tesla GE Scanner, and quantitative estimates of global and focal brain volumes were obtained. Control subjects and patients displayed significant right-left volumetric differences across several regions, with right-sided regions being larger than the left. In the frontal lobes, the asymmetry differed significantly in the three groups (P=0.02). It was most pronounced in the control group and decreased significantly in the minor and major depression groups. There was a significant trend (P=0.005) in the magnitude of frontal asymmetry across groups, with the frontal asymmetry decreasing with increasing severity of depression. Hemispheric and temporal asymmetries were comparable in all three groups. These data suggest that an attenuation of the 'normal' volumetric asymmetry in the frontal regions may provide a structural basis to late-onset mood disorders     

Two-year longitudinal study of post-stroke mood disorders: comparison of acute-onset with delayed-onset depression

Patients who developed post-stroke depression 3 to 24 months after hospital discharge (N = 21) were compared with patients who developed depression during hospitalization (N = 26) and patients who never developed depression over 24 months of follow-up (N = 15). During the acute hospitalization and at follow-up, the three groups were not significantly different in their demographic characteristics, neurological impairment, intellectual impairment, or quality of social support. The acute depression group, however, showed an increased correlation between impairment and depression from hospitalization to follow-up. Findings suggest that impairment does not produce depression, but, once depression occurs, it may interact with impairment to influence post-stroke recovery.     

Review of pharmacological treatment in mood disorders and future directions for drug development

After a series of serendipitous discoveries of pharmacological treatments for mania and depression several decades ago, relatively little progress has been made for novel hypothesis-driven drug development in mood disorders. Multifactorial etiologies of, and lack of a full understanding of, the core neurobiology of these conditions clearly have contributed to these development challenges. There are, however, relatively novel targets that have raised opportunities for progress in the field, such as glutamate and cholinergic receptor modulators, circadian regulators, and enzyme inhibitors, for alternative treatment. This review will discuss these promising new treatments in mood disorders, the underlying mechanisms of action, and critical issues of their clinical application. For these new treatments to be successful in clinical practice, it is also important to design innovative clinical trials that identify the specific actions of new drugs, and, ideally, to develop biomarkers for monitoring individualized treatment response. It is predicted that future drug development will identify new agents targeting the molecular mechanisms involved in the pathophysiology of mood disorders.     

Brain‐derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain‐derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant‐naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant‐naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.     

Facial expression recognition in adolescents with mood and anxiety disorders

OBJECTIVE: The authors examined facial expression recognition in adolescents with mood and anxiety disorders. METHOD: Standard facial emotion identification tests were given to youth with bipolar disorder (N=11) or DSM-IV anxiety disorders (N=10) and a group of healthy comparison subjects (N=25). RESULTS: Relative to the anxiety disorder and healthy comparison groups, the subjects with bipolar disorder made more emotion recognition errors when presented with faces of children. Unlike the anxious and comparison subjects, bipolar disorder youth were prone to misidentify faces as angry. No differences in emotion recognition errors were seen when the adolescents were presented with adult faces. CONCLUSIONS: A bias to misinterpret the facial expressions of peers as angry may characterize youth with bipolar disorder but not youth with anxiety disorders. This bias may relate to social impairment in youth with bipolar disorder.