Medical and cognitive comorbidities
There has been an exponential growth in studies in the interface between primary care and psychiatry in the past 10 years.27,28 Studies in the medically ill usually report the negative impact of depression on the rates and speed of recovery as well as the overall outcome of the medical illness (coexisting depression produces excess disability and increases the cost of care).29,30 Depression can be successfully managed in medical settings with depression care strategies. Evidence-based practice can be imported into primary care settings to accelerate recovery and reduce the burden of depressive symptoms, suicidal ideation, and caregiver distress.1
Late-life depression is associated with cognitive deficits, but there is some debate over the profile and significance of the deficits. Performance in episodic memory, verbal fluency, information processing, executive function, and visuospatial ability have been reported to be lower in patients who are depressed than in nondepressed volunteers.31,32 The level of executive dysfunction at baseline has been shown to predict outcomes in terms of increased vulnerability to relapse and resistance to treatment.33 After treatment, some of the deficits are resolved, but the level of performance on executive and memory tasks often does not reach the premorbid level, which suggests that the depression and the residual cognitive deficits are expressions of an underlying and related brain dysfunction. Patients with minor depression show functional and cognitive deficits similar to those demonstrated by patients with major depression.34
Several studies have shown that late-life depression and even depressive symptoms are risk factors for mild cognitive impairment and Alzheimer disease.35-37 For example, semantic clustering—an executive strategy for learning a list of words—mediated executive dysfunction in late-life depression.34 These results support the conceptualization of major and nonmajor depression as a gradual continuum that is associated with increasing cognitive deficits but with the degree of difference dependent on the specific domain of cognitive ability.
Etiology and pathogenesis
Depression is a truly multifactorial disorder.38 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 understanding the variability in the course of the illness, as well as the development of prevention and intervention strategies that are most effective.39
The results of association studies in behavioral genetics have been inconsistent. However, genetic studies are adding to our understanding of pathophysiology, risk factors, treatment response, and adverse-effect profile. Findings from a study by Taylor and colleagues24 indicate that Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with cognitive and neuroimaging changes. In a large study of older adults with depression and controls, the depressed subjects were more likely to be Met66 allele carriers than were the comparison subjects (38.8% vs 24.4%). Met66 allele carriers have almost double the odds of having geriatric depression than do Val66 allele homozygotes. Steffens and colleagues40 recently reported that older age, lower Mini-Mental State Examination score, and apolipoprotein E e4 allele were each correlated with gray matter lesion volume in patients with depression. Results from the study by Whyte and colleagues41 showed that platelet activation is increased in elderly depressed patients, especially those with the 5-HTTLPR l/l genotype.
In addition, data from a clinical study of geriatric depression by Lavretsky and colleagues42 showed that dopamine(Drug information on dopamine) transporter genotype, but not serotonin transporter genotype, was associated with executive dysfunction and preferential response to methylphenidate(Drug information on methylphenidate). Lenze and colleagues43 reported that the 5HTR1A (-1019) G allele is associated with increased depressive symptoms after hip fracture, which in turn accounts for poorer functional recovery. Lotrich and colleagues44 reported an interaction between early paroxetine(Drug information on paroxetine) concentration and the 5-HTTLPR genotype on symptomatic improvement over 12 weeks.
Investigations using structural neuroimaging (CT or MRI) continue to document the importance of cerebrovascular disease. Teodorczuk and colleagues45 demonstrated in a pan-European multicenter study of 639 older adults that white matter changes seen on MRI predate and are associated with the development of depressive symptoms. Sheline and colleagues46 recently reported on the differential significance of the localization of white matter hyperintensities in geriatric depression. In a comparison of patients with depression and controls, greater hyperintensities were seen in the following white matter tracts: the superior longitudinal fasciculus, frontooccipital fasciculus, uncinate fasciculus, extreme capsule, and in-ferior longitudinal fasciculus. In depressed patients, but not in controls, volumes of 3 of these regions correlated with executive function; whole brain white matter hyperintensities correlated with executive function; whole brain white matter correlated with episodic memory, processing speed, and executive function; and whole brain gray matter correlated with processing speed.
In support of these findings, Yuan and colleagues47 looked at the first episode of late-life depression and found that fractional anisotropy in white matter was lower in patients than in controls at the right superior frontal gyrus, left inferior frontal gyrus, left middle temporal gyrus, right inferior parietal lobule, right middle occipital gyrus, left lingual gyrus, right putamen, and right caudate. These results suggest that the white matter integrity of the whole brain was disrupted in first-episode remitted geriatric depression.
Alexopoulos and colleagues48 used diffusion tensor imaging to test the hypothesis that older adults with depression who do not attain remission have microstructural white matter abnormalities in corticostriatolimbic networks, which are implicated in geriatric depression. Subjects who did not achieve remission had lower fractional anisotropy in multiple frontal limbic brain areas, including the rostral and dorsal anterior cingulate, dorsolateral prefrontal cortex, genu of the corpus callosum, white matter adjacent to the hippocampus, multiple posterior cingulate cortex regions, and insular white matter, relative to those who achieved remission. In addition, lower fractional anisotropy was detected in the neostriatum and midbrain as well as select temporal and parietal regions.
There have been attempts to use structural neuroimaging to identify correlates of depressive spectrum disorders. Lavretsky and colleagues49 reported that depression was associated with a reduction in gray matter volumes in the orbitofrontal cortex, but a highly prevalent (in the elderly) syndrome of apathy was associated with the reduction in the gray matter volume in right anterior cingulate. Results from another study demonstrate that the lacunar volume in the deep white matter was associated with symptoms of apathy, anergia, anhedonia, and depression in older persons with and without cognitive impairment.50 The findings indicate that patients with minor depression present with specific neuroanatomical abnormalities that are comparable with the major depression group but significantly different from controls.51 Neuroanatomical abnormalities may represent one aspect of a broader neurobiological diathesis to late-life mood disorders.
Functional neuroimaging correlates have been identified for late-life depression and include widespread reductions in glucose metabolism and cerebral blood flow on positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans. Sheline and colleagues52 used PET scans and [18F]altanserin, a ligand with high affinity for the 5-HT2A receptor, to examine the relationship between 5-HT2A receptor density and geriatric depression. Depressed subjects had less hippocampal 5-HT2A receptor binding than controls. Depressed subjects not previously treated for depression had less hippocampal 5-HT2A receptor binding than previously treated subjects. It may be that earlier medication treatment provides a compensatory up-regulation of the 5-HT2A receptor.
Meltzer and colleagues53 explored the role of the serotonin type 1A (5-HT1A) receptor as a regulator of treatment response, particularly the 5-HT1A autoreceptor in the dorsal raphe nucleus. They used [11C]WAY 100635 and PET scans in the dorsal raphe nucleus and prefrontal cortex and observed significantly diminished [11C]WAY 100635 binding in depressed patients compared with controls that was correlated with pretreatment Hamilton Depression Rating Scores in the depressed cohort.
Postmortem tissue can help clarify the pathways to depression, especially if the postmortem data can be integrated with antemortem neuroimaging findings. Autopsies in 6 persons with a clinical diagnosis of late-life depression, in fact, had dementia; the brains were neuropathologically consistent with dementia, primarily of the Alzheimer type.54