Research advances in geriatric depression

Depression is a leading cause of disability worldwide 1. It results in more years lived with disability (YLDs) than any other disease, and ranks fourth in terms of disability-adjusted life years (DALYs). Additionally, depression is associated with a greater decline in overall health due to multiple illnesses than angina, arthritis, asthma, and diabetes. Geriatric depression in particular not only causes suffering and involves suicide risk; it also increases medical comorbity and disability among elderly individuals. Although depression may be less common in old than in young adults, as younger birth cohorts mature and the elderly population grows in size, an unprecedented number of elderly depressed people will need psychiatric attention. Although the biological causes of depression remain unknown, clinical and biological observations provide the rationale for studying new psychosocial and somatic treatments, or existing treatments applied to new indications. Studies of community-residing older adults show a decline in the overall prevalence of depression compared with middle-aged adults 2. However, medically ill, disabled older adults have a high prevalence of depression. In particular, 10–12% of medical inpatients and 12–14% of nursing home residents have major depression, and larger numbers experience less severe depressive syndromes. A large number of older adults develop depression for the first time in their lives, often in the context of increased medical disease burden or neurologic stigmata. It has been suggested that late-onset depression may include a group of patients with neurologic disorders that are not clinically evident when the depression first appears 3. Although some studies have not supported this view, most have shown that late-onset depression relative to early-onset depression is associated with higher medical morbidity and mortality 4,5, greater disability 6, and more neuropsychological 7,8 and neuroradiological abnormalities 9–11. Cerebrovascular disease frequently occurs 2 to 3 years prior to hospital admission for severe depression 12,13. Depression is common after stroke 14–19, affecting more than 30% of stroke survivors 20. Heart disease 21. 22 and broadly defined cerebrovascular disease are prevalent in elderly patients with depression, with an increase in relative risk of up to 4.5-fold 23,24. The relationship between vascular diseases and depression is likely bidirectional, as pre-existing vascular disease predicts the onset of depression and pre-existing depression predicts the onset of cardiovascular disease and stroke 24. Late-life depression frequently differs from early-life depression in its clinical characteristics, particularly if it is late in onset or accompanied by signs of executive dysfunction or vascular disease. Late-life depression is often associated with executive dysfunction 25,29, a neuropsychological expression of frontal system impairment, with a clinical presentation of depression resembling medial frontal lobe syndromes 25. Depression affects cognitive function in all age groups, but the executive tasks of response inhibition and sustained effort are more frequently impaired in geriatric depression 30. Executive dysfunction generally subsides as depression improves, but tends to persist after remission of depression 31–36. When depressed elderly patients have executive dysfunction, they are more likely to have reduced interest in activities, more profound psychomotor retardation 25, and poor and unstable response to anti-depressants 35,37–39. The clinical presentation of late-onset geriatric depression with comorbid vascular disease is similar to that of geriatric depression with executive dysfunction. Compared to elderly patients with early-onset depression and no vascular risk factors, patients with late-onset major depression and vascular risk factors have shown greater impairment in frontal functions, poorer insight, more psycho-motor retardation, less agitation and guilt, and more disability 40,41. A comparison of magnetic resonance imaging (MRI)-defined vascular and non-vascular depression showed that the vascular group had significantly greater age, age of onset, anhedonia, and disability, but less psychosis. Despite some negative findings 42–44, much past and recent evidence indicates that vascular depression predicts poorer response to antidepressants 10,38,43,45–49. Family history of depression is less common in patients with late-onset depression than in elderly patients with early-onset recurrent depression 50,51; and less common in “vascular depression” than in non-vascular depression 52,53. In a recent, large Swedish twin-pair study, history of early-onset depression in one member of a twin pair was associated with high lifetime risk of depression in the other member. In contrast, late-onset depression was associated with high cotwin risk of vascular disease 54. Finding genes predisposing to depression has been a formidable task. Depression has polygenic inheritance, thus making it difficult to identify the contribution of individual genes. To overcome this obstacle, research increasingly focuses on genes related to specific behavioral or biological functions (endophenotypes) related to depression. Genetic studies of the serotonin transporter exemplify this work. The serotonin transporter is the site of action for serotonin re-uptake inhibitors (SSRIs). A polymorphism of the serotonin transporter gene promoter region (5-HTTLPR) involves a 44-base pair insertion (L allele) or deletion (S allele). The S allele has been shown to reduce gene expression, thus reducing serotonin reuptake 55. In addition to studies relating the S allele to risk for depression 56–58, a number of studies have found an association between the S allele and increased risk of vascular disease. Elevated blood cholesterol and triglycerides, heart disease, and myocardial infarction have been more common among S allele carriers than L allele homozygotes 59; and after acute myocardial infarction, depressive symptoms and negative cardiac outcomes including cardiac death were more common in S-carriers than L-homozygotes 60. In one of our own recent late-life depression studies, we found that, compared with L-homozygotes, S-carriers had microstructural white matter abnormalities (lower fractional anisotropy, to be explained below) in frontolimbic brain regions as well as a lower remission rate of depression 61. Neuroradiological and histopathological studies have found associations among depression, executive dysfunction, and brain abnormalities, most notably those affecting the structural integrity of frontostriatal circuits, which include subcortical regions. Executive dysfunction and depression are hypothesized to be related to fronto-striato-limbic network abnormalities 3. Five such frontostriatal circuits have been described 62,63. Glutamate, enkephalins, and gamma-aminobutyric acid (GABA) are important neurotransmitters in these circuits, with acetylcholine and dopamine serving a modulating role. Because these circuits appear to mediate positive affect-guided anticipation, damage to them, resulting in failure to anticipate incentives, is hypothesized to be a mechanism leading to depression 40. Macroscopic and microscopic changes to brain regions have been associated with mood disorders in histopathological and neuro-imaging studies. In post-mortem studies of depressed patients, glia reduction has been observed in the subgenual prelimbic anterior cingulate gyrus 64. Bipolar and unipolar depression studies have reported neuron abnormalities in the dorsolateral prefrontal cortex 65. Radiological studies have shown low orbitofrontal 66,67, anterior cingulate 68, and hippocampal volumes 69,70 in depressed elderly patients compared to healthy elderly controls, while reports of amygdala volumes have differed 71. Studies of white matter integrity in normal aging have shown a greater tendency for decline in prefrontal white matter with advancing age compared with other areas of the brain 72. Prefrontal white matter microstructural abnormalities have correlated with poorer performance on tasks of executive function, and have been hypothesized to reflect a disconnection state that can increase the risk of geriatric depression 73. Depression has been associated with cerebral infarcts, even when no obvious neurological symptoms are present. In a Dutch study, such “silent” infarcts occurred five times more frequently than cerebral infarcts with peripheral neurologic signs 74. In a large US study, 28% of elderly subjects with no previous history of transient ischemic attack or stroke had evidence of previous infarcts. Eighty-one percent of these had lacunes only, and as a group they showed more cognitive dysfunction than those without any brain infarcts 75. In a Japanese study of 63 patients with late-onset depression, 59 (94%) had silent cerebral infarcts 76. Finally, in a study of infarcts in the thalamus and basal ganglia, such lesions were found in 14 of 35 depressed elderly patients without neurologic history, but in only 1 of 22 normal elderly volunteers 77. Depression has been also associated with white matter abnormalities, including white matter hyperintensities (WMHs; areas of increased intensity on T2-weighted MR images) or microstructural abnormalities demonstrated as reduced fractional anisotropy in diffusion tensor imaging. WMHs have been more common in depressed older patients than healthy older adults 10,67,77–81, especially in frontal and temporal regions 82. A post-mortem study has shown that deep WMHs of depressed elderly patients are more likely to be ischemic in nature than deep WMHs of elderly controls 83. WMHs are associated with cerebrovascular disease 84, cardiac disease 85, smoking 86, hypertension 53,84,86, reduced cerebral blood flow 85, executive dysfunction 73,87,88, and disability 52,89. Based on these findings, the “vascular depression” hypothesis has been proposed, which postulates that cerebrovascular disease predisposes, precipitates, and perpetuates a late-life depression syndrome 3. Vascular disease might lead to depression through damage to specific brain circuits or less directly through inflammation. Proinflammatory cytokines, such as interleukins 1 and 6 (IL1 and IL6) and tissue necrosis factor alpha (TNF-α), are released after damage of the vascular endothelium 90. A post-mortem study found elevated levels of intercellular adhesion molecule-1 (ICAM-1), a marker of ischemia-induced inflammation, in the dorsolateral prefrontal cortex of depressed subjects compared with controls 91. The incidence of depression after treatment with the inflammatory cytokine interferon-alpha (IFN-α) ranges from 30 to 50% 92; and depression has been associated with increases in chemokines, cellular adhesion molecules, acute phase proteins, and proinflammatory cytokines 93,94. Given that proinflammatory cytokines have been associated with atherosclerosis and cardiovascular disease 90, it seems possible that inflammation predisposes to both depression and vascular disease simultaneously; or that inflammation might be involved in a vicious cycle of depression leading to inflammation, which leads to vascular disease, which leads to more inflammation and increased risk for depression. Beyond inflammation, other factors may set forward a vicious cycle perpetuating depression and worsening vascular disease. These include sedentary lifestyle, overeating, diabetes, smoking, nonadherence with medical recommendations, hypertension, hyper-homocysteinemia, nervous system activation, hypothalamic-pituitary-adrenocortical axis activation and other physiological stress responses, cardiac rhythm disturbances, and hypercoagulability 90,94,95. The relationship between depression and hypercoagulability may in turn be mediated by physical inactivity, smoking, or increased platelet activity 96. Therefore, even in cases where vascular disease predisposes to depression, once depression sets in, a vicious cycle may occur that worsens both vascular disease and depression. The “vascular depression” hypothesis has served as the conceptual background for further subclassification of geriatric depression. One group of investigators further described a “vascular depression” subtype, subcortical ischemic depression (SID), and defined it as major depression with MRI evidence of subcortical lesions. Unlike most psychiatric disorders, which are described in purely phenomenological terms, subcortical ischemic depression involves a measurable biological abnormality. The association of late-life depression with executive dysfunction led another group of investigators to describe the depression-executive dysfunction syndrome (DED). Although many patients with DED also meet criteria for SID or other “vascular depression syndromes”, DED's focus on a functional abnormality rather than an anatomical one extends it beyond the vascular depression concept. Advances in late-life depression research include novel or improved treatments, personalization of treatments according to depression type or characteristics of the individual, and strategies to improve access to and delivery of care. The reader is referred else-where for guidelines to treatment of geriatric depression 30,40,97. Here we focus on new developments and trends. Brain research is facilitated by a variety of MRI-based neuroimaging techniques 98,99. Many of these can be performed together in a single MRI scanning session. T1-weighted MRI images allow comparison of brain structure sizes in volumetric brain studies, in addition to classic lesion studies. Brain WMHs can be studied with T2-weighted images, while newer methods allow an examination of white matter tract integrity. Diffusion tensor imaging (DTI) indicates the direction of water diffusion. Fiber tractography uses DTI information to map out putative white matter fiber tracts. Fractional anisotropy (FA) is a DTI measure of the tendency of water to move in a single direction. Low FA can be a sign of compromised white matter integrity. Another method that reflects white matter integrity, but from a different perspective, is magnetization transfer imaging (MTI), which indicates the amount of water bound to macromolecules such as myelin. Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) involves collection of a series of brain images over time, typically 2 seconds apart, so that changes in blood flow reflecting activity throughout the brain can be monitored over time. If a task is performed by the subject in the scanner, usually the goal of the experiment is to identify regions of the brain that are activated in response to the experimental paradigm. Some techniques allow for analysis of the even in the of a experimental such as is the in where subjects are not any task to without methods map out brain activity time is correlated with a or region in the analysis a of the the as if it were the of that are of brain regions in with the to be a of different from different of brain regions and out the In has results to those with a of the experimental time Some findings these techniques have poor treatment response of late-life depression. 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