Translational Research in Late-Life Mood Disorders: Implications for Future Intervention and Prevention Research

PET Centre, Centre for Addiction and Mental Health, Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Neuropsychopharmacology (Impact Factor: 7.05). 10/2007; 32(9):1857-75. DOI: 10.1038/sj.npp.1301333
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Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.

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Available from: Warren Taylor, Mar 24, 2014
    • "Furthermore, as loss of system xc-protects against nigrostriatal dopaminergic neurodegeneration (Massie et al., 2011), this strategy could be of interest in treating age-related neurodegenerative disorders such as Parkinson's disease that have important co-occurrence of anxiety and depression (Chaudhuri and Schapira, 2009). Finally, changes in affective behavior in aged system xc-deficient mice occur in absence of impairment in either spatial reference memory or working memory (De Bundel et al., 2011), which might favor such interventions in late-life psychiatric disorders that are strongly associated with dementia and cognitive impairment (Laks and Engelhardt, 2010; Smith et al., 2007). Astrocytic glutamate release via system xc-can activate extrasynaptic NMDA receptors, as well as group I and group II metabotropic glutamate receptors (Bridges et al., 2012). "
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    ABSTRACT: There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.010 · 3.69 Impact Factor
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    • "The most consistent cognitive deficits observed in non-demented, geriatric depressed patients include slowed speed of processing and deficits in executive function, verbal fluency, confrontation naming, explicit sequence learning, verbal and spatial memory, and visual-spatial function (Kramer-Ginsberg et al., 1999; Butters et al., 2000; Lockwood et al., 2000, 2002; de Asis et al., 2001; Nebes et al., 2003; Aizenstein et al., 2005; Alexopoulos et al., 2005). An understanding of the mechanisms underlying treatment resistance, of affective and cognitive symptoms, is among the central priorities in geriatric depression research (Smith et al., 2007). "
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    ABSTRACT: Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. This study evaluated the cerebral glucose metabolic effects of citalopram treatment and applied multivariate, functional connectivity analyses to identify brain networks associated with improvements in affective symptoms and cognitive function. Sixteen geriatric depressed patients underwent resting positron emission tomography (PET) studies of cerebral glucose metabolism and assessment of affective symptoms and cognitive function before and after 8 weeks of selective serotonin reuptake inhibitor treatment (citalopram). Voxel-wise analyses of the normalized glucose metabolic data showed decreased cerebral metabolism during citalopram treatment in the anterior cingulate gyrus, middle temporal gyrus, precuneus, amygdala, and parahippocampal gyrus. Increased metabolism was observed in the putamen, occipital cortex, and cerebellum. Functional connectivity analyses revealed two networks which were uniquely associated with improvement of affective symptoms and cognitive function during treatment. A subcortical-limbic-frontal network was associated with improvement in affect (depression and anxiety), while a medial temporal-parietal-frontal network was associated with improvement in cognition (immediate verbal learning/memory and verbal fluency). The regions that comprise the cognitive network overlap with the regions that are affected in Alzheimer's dementia. Thus, alterations in specific brain networks associated with improvement of affective symptoms and cognitive function are observed during citalopram treatment in geriatric depression.
    Human Brain Mapping 10/2011; 32(10):1677-91. DOI:10.1002/hbm.21135 · 5.97 Impact Factor
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    • "Geriatric depression is a clinically and neurobiologically heterogeneous disorder.1,2 The treatment of depression in the elderly is complicated by age-related changes in cognition, brain structure, function, and neurochemistry ,and by comorbid medical illnesses and the contribution of neurodegenerative and cerebrovascular disease processes. "
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    ABSTRACT: Since the renewed emphasis on the heterogeneity of geriatric depression and the impact on treatment response variability over a decade ago,1 neuroimaging methods have been increasingly applied to understand the underlying neurobiology of treatment response variability in geriatric depression.2 The application of neuroimaging methods has resulted in fundamental observations with respect to the neural circuitry and the role of the serotonin system. The observations that some patients remain symptomatic after adequate treatment with a selective serotonin uptake inhibitor (SSRI) ami that despite remission of mood symptoms, residual cognitive and other behavioral deficits persist, suggest that other neurochemical mechanisms may be involved. This review will focus on neurochemical imaging research in geriatric depression that has led to an initial understanding of the neurobiological mechanisms underlying remission of depression in late life. Future research directions to investigate the mechanisms underlying treatment resistance of mood and cognitive aspects of the illness will be discussed.
    Dialogues in clinical neuroscience 12/2008; 10(4).
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