Biomedical subjects

Meryl A Butters

Publications and source records attributed to Meryl A Butters.

18 recordsLinked to original sources

PubMed2006

Maintenance treatment of major depression in old age.

BACKGROUND: Elderly patients with major depression, including those having a first episode, are at high risk for recurrence of depression, disability, and death. METHODS: We tested the efficacy of maintenance paroxetine and monthly interpersonal psychotherapy in patients 70 years of age or older who had depression (55 percent of whom were having a first episode) in a 2-by-2, randomized, double-blind, placebo-controlled trial. Among patients with a response to treatment with paroxetine and psychotherapy, 116 were randomly assigned to one of four maintenance-treatment programs (either paroxetine or placebo combined with either monthly psychotherapy or clinical-management sessions) for two years or until the recurrence of major depression. Clinical-management sessions, conducted by the same nurses, social workers, and psychologists who provided psychotherapy, involved discussion of symptoms. RESULTS: Major depression recurred within two years in 35 percent of the patients receiving paroxetine and psychotherapy, 37 percent of those receiving paroxetine and clinical-management sessions, 68 percent of those receiving placebo and psychotherapy, and 58 percent of those receiving placebo and clinical-management sessions (P=0.02). After adjustment for the effect of psychotherapy, the relative risk of recurrence among those receiving placebo was 2.4 times (95 percent confidence interval, 1.4 to 4.2) that among those receiving paroxetine. The number of patients needed to be treated with paroxetine to prevent one recurrence was 4 (95 percent confidence interval, 2.3 to 10.9). Patients with fewer and less severe coexisting medical conditions (such as hypertension or cardiac disease) received greater benefit from paroxetine (P=0.03 for the interaction between treatment with paroxetine and baseline severity of medical illness). CONCLUSIONS: Patients 70 years of age or older with major depression who had a response to initial treatment with paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine. Monthly maintenance psychotherapy did not prevent recurrent depression. (ClinicalTrials.gov number, NCT00178100.).

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PubMed2006

Perspectives on depression, mild cognitive impairment, and cognitive decline.

CONTEXT: The public health implications of depression and cognitive impairment in late life are enormous. Cognitive impairment and late-life depression are associated with increased risk for subsequent dementia; however, investigations of these phenomena appear to be proceeding along separate tracks. OBJECTIVES AND DATA SOURCE: The National Institute of Mental Health organized the conference "Perspectives on Depression, Mild Cognitive Impairment, and Cognitive Decline" to consider how the varied perspectives might be better integrated to examine the associations among depression, mild cognitive impairment, and cognitive decline and to illuminate the common or distinct mechanisms involved in these associations. DATA SYNTHESIS: The following 2 broad questions were addressed: (1) What gaps in our knowledge have the greatest public health significance? (2) Can we more efficiently use our research dollars and participant resources to fill these gaps? Meeting participants included grantees from the National Institute of Mental Health and the National Institute on Aging and program staff from the National Institute of Mental Health, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke. CONCLUSIONS: One of the most important recommendations to emerge from the meeting discussions is for increased collaboration among clinical and epidemiological investigators whose work focuses in the area of depression with those working primarily in the area of memory disorders. Directions for future research were identified.

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PubMed2005

Prefrontal and striatal activation during sequence learning in geriatric depression.

BACKGROUND: Frontostriatal dysfunction is a primary hypothesis for the neurocognitive changes of depression in late life. The aim of the present study was to test this hypothesis with the use of functional magnetic resonance imaging (fMRI) tasks that are known to engage the prefrontal and neostriatal cognitive circuits. METHODS: Twenty-three elderly subjects (mean age, 69.9 years) participated: 11 subjects with a current major depressive episode and 12 nondepressed elderly control subjects. Subjects underwent fMRI while performing a concurrent implicit and explicit sequence learning task. Region of interest (ROI)-based analyses were conducted, focusing on the dorsal anterior cingulate cortex, the dorsolateral prefrontal cortex, and the neostriatum. RESULTS: As expected, both the control and depressed subjects learned the sequence during both implicit and explicit conditions. During explicit learning, decreased prefrontal activation was found in the depressed subjects, along with increased striatal activation. The increased striatal activity in the depressed subjects was due to increased activity on the trials that violated the sequence. During implicit learning, no significant differences were found between the groups in the identified ROIs. CONCLUSIONS: The increased striatal activation on trials that violated the sequence demonstrates a greater response to negative feedback for depressed compared with control subjects. Our observations of significant differences in both prefrontal and striatal regions in the depressed elderly subjects relative to elderly control subjects supports the frontostriatal dysfunction hypothesis of late-life depression.

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PubMed2005

Prefrontal and striatal activation in elderly subjects during concurrent implicit and explicit sequence learning.

Decreased function in the prefrontal cortex (PFC) is regarded as a primary mechanism of cognitive aging. However, despite a strong association between the prefrontal cortex and the neostriatum, the role of the neostriatum in cognitive aging is less certain. In the current study, event-related functional MRI was used to distinguish the cognitive contributions of neostriatal and prefrontal function in elderly versus young subjects. Twenty healthy subjects, 9 elderly (mean age 67.6 years), and 11 young (mean age 22 years) performed a concurrent implicit and explicit sequence learning task while undergoing functional MR imaging. Both groups showed learning in both the implicit and explicit task conditions. Relative to the young subjects, the elderly subjects showed decreased activation in the left PFC during both implicit and explicit learning, decreased activation in the right putamen during implicit learning, and increased activation in the right PFC during explicit learning. Our results support the theory that changes in a network of brain regions, including the dorsolateral prefrontal cortex and the striatum, are related to cognitive aging. Moreover, these changes are observed during an implicit task, and thus do not seem to be mediated by awareness.

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PubMed2005

Does education moderate neuropsychological impairment in late-life depression?

OBJECTIVE: The increased resistance of better-educated individuals to the cognitive effects of neuropathology has been conceptualized as reflecting brain reserve. This study examined whether educational level influences the degree of neuropsychological impairment associated with late-life depression. METHODS: The neuropsychological performances of 115 older depressed patients and of 44 comparison subjects of similar age and education were compared as a function of educational level. RESULTS: While depressed patients performed worse than comparison subjects on all the measures, the severity of this impairment (with respect to comparison subjects) did not differ with the educational level of the patients. CONCLUSIONS: Brain reserve, as indexed by the patients' level of education, does not mitigate the cognitive decrements associated with late-life depression.

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PubMed2005

Late-onset major depression: clinical and treatment-response variability.

OBJECTIVE: To explore clinical and treatment-response variability in late-onset vs early-onset non-bipolar, non-psychotic major depression. METHODS: We grouped patients from a late-life depression treatment study according to illness-course characteristics: those with early-onset, recurrent depression (n = 59), late-onset, recurrent depression (n = 27), and late-onset, single-episode depression (n = 95). Early-onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late-onset was defined as having a first episode of major depression at age 60 or later. We characterized the three groups of patients with respect to baseline demographic, neuropsychological, and clinical characteristics, use of augmentation pharmacotherapy to achieve response, and treatment outcomes. RESULTS: Rates of response, remission, relapse, and termination were similar in all three groups; however, patients with late-onset, recurrent major depression took longer to respond to treatment than those with late-onset, single-episode depression (12 weeks vs 8 weeks) and had more cognitive and functional impairment. Additionally, patients with recurrent depression (whether early or late) were more likely to require pharmacotherapy augmentation to achieve response than patients with a single lifetime episode. CONCLUSION: Late-onset, recurrent depression takes longer to respond to treatment than late-onset single-episode depression and is more strongly associated with cognitive and functional impairment. Further study of biological, neuropsychologic, and psychosocial correlates of late-onset, recurrent depression is needed.

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PubMed2005

Comorbid anxiety disorder in late life depression: association with memory decline over four years.

OBJECTIVE: In elderly persons with Major Depressive Disorder (MDD), coexisting Generalized Anxiety Disorder (GAD) or Panic Disorder (PD) is associated with more severe symptoms and poorer short-term treatment outcomes. The purpose of this study was to determine whether comorbid GAD or PD was associated with poorer long-term outcomes of late-life MDD, in terms of symptoms, functional disability, and cognitive status. METHODS: Seventy-nine older subjects with major depressive disorder who had responded to initial treatment in clinical trials were followed at yearly intervals for up to four years with assessment of their symptoms, cognitive status, and functional disability. For this analysis, subjects were divided into two groups, anxious and non-anxious, based on presence (n = 37) or absence (n = 42) of a lifetime diagnosis of GAD and/or PD. RESULTS: The anxious group showed a greater decline in memory, but not in other cognitive measures or measures of functional status. Depression recurrence was similar in the anxious and non-anxious groups. Among those in the anxious group, a later age of onset (> 55) of the anxiety disorder was associated with worse overall cognition at baseline, but a similar rate of decline in cognition over time, compared with early-onset anxiety disorder. CONCLUSION: We found evidence that comorbid GAD or PD is associated with a greater decline in memory in late-life MDD. The data also suggest that anxiety disorders with an onset later in life may be associated with cognitive impairment, although further study is needed to confirm this finding.

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PubMed2004

The nature and determinants of neuropsychological functioning in late-life depression.

CONTEXT: Cognitive impairment in late-life depression (LLD) is highly prevalent, disabling, poorly understood, and likely related to long-term outcome. OBJECTIVES: To determine the characteristics and determinants of neuropsychological functioning LLD. DESIGN: Cross-sectional study of groups of LLD patients and control subjects. SETTING: Outpatient, university-based depression research clinic. PARTICIPANTS: One hundred patients without dementia 60 years and older who met DSM-IV criteria for current episode of unipolar major depression (nonpsychotic) and 40 nondepressed, age- and education-equated control subjects. MAIN OUTCOME MEASURES: A comprehensive neuropsychological battery. RESULTS: Relative to control subjects, LLD patients performed poorer in all cognitive domains. More than half exhibited significant impairment (performance below the 10th percentile of the control group). Information processing speed and visuospatial and executive abilities were the most broadly and frequently impaired. The neuropsychological impairments were mediated almost entirely by slowed information processing (beta =.45-.80). Education (beta =.32) and ventricular atrophy (beta =.28) made additional modest contributions to variance in measures of language ability. Medical and vascular disease burden, apolipoprotein E genotype, and serum anticholinergicity did not contribute to variance in any cognitive domain. CONCLUSIONS: Late-life depression is characterized by slowed information processing, which affects all realms of cognition. This supports the concept that frontostriatal dysfunction plays a key role in LLD. The putative role of some risk factors was validated (eg, advanced age, low education, depression severity), whereas others were not (eg, medical burden, age at onset of first depressive episode). Further studies of neuropsychological functioning in remitted LLD patients are needed to parse episode-related and persistent factors and to relate them to underlying neural dysfunction.

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PubMed2004

Neuropathologic correlates of late-onset major depression.

Late life major depression (LLMD) is frequently associated with cognitive impairment, and increases the risk for subsequent dementia. Cerebrovascular disease, Alzheimer's disease (AD), and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, though prospective studies have yet to examine these hypotheses with autopsy confirmation of the clinical diagnoses. The aim of this study is to examine the rates of cerebrovascular, AD, and DLB pathology among the first 10 participants in an LLMD brain tissue donation program. Subjects' psychiatric diagnoses and cognitive status were prospectively determined during their participation in clinical research protocols of the Intervention Research Center for Late Life Mood Disorders. After death, final clinical diagnoses were made using all clinical information, while blind to neuropathologic diagnoses. Neuropathologic assessments were conducted blind to final clinical diagnoses. Rates of neuropathology were compared with those in a cohort of subjects with dementia, without a history of LLMD, participating in an Alzheimer Disease Research Center. Seven (70%) subjects had evidence of onset of a dementia prior to death. LLMD with dementia was significantly associated with a neuropathologic diagnosis of AD. Cerebrovascular disease and DLB pathology were also frequent in the LLMD subjects with dementia, and were found in an LLMD subject without dementia. Rates of AD, DLB, and cerebrovascular disease were similar to those in the comparison subjects. These preliminary findings suggest that AD is the predominant neuropathologic condition in LLMD subjects with dementia. Further assessment of the role of comorbid cerebrovascular disease and comorbid DLB is needed.

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PubMed2004

Serotonin 1A receptor binding and treatment response in late-life depression.

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

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PubMed2004

The BOLD hemodynamic response in healthy aging.

Several previous studies have compared the blood oxygen level-dependent (BOLD) hemodynamic response (HDR) in healthy elderly subjects to the HDR in young subjects. Some studies have found a relative decreased amplitude in the elderly in the visual cortex, whereas other studies have found the elderly HDR amplitude in the visual cortex to be nearly identical to that in young subjects. A possible explanation for the different findings is that the peak voxel HDR is similar between the groups, but that the HDR in the group-averaged region-of-interest (ROI) is "washed out" by the inclusion of less significant voxels (due to a smaller extent of activation in the elderly) or by the inclusion of negative-peaking voxels. We tested this hypothesis using event-related functional magnetic resonance imaging (fMRI ). While undergoing fMRI, subjects performed a simple visual and motor task, pressing with their index fingers in response to visual presentation of the word tap. Data from 18 subjects, 8 young and 10 elderly, were analyzed. For each subject, a visual and a motor ROI was selected by choosing the most significant positive voxels within the anatomically defined ROI. This individual subject approach excluded both low-significance and negative-peaking voxels. Similar peaks were found for the elderly and the young subjects in both motor and visual regions and a more sustained BOLD response was found for the elderly in both regions. Additionally, as predicted, a greater percentage of voxels with a negative HDR was found for the elderly in the visual region; this finding was also replicated in our reanalysis of an independent fMRI and aging study from the fMRI Data Center. Functional neuroimaging observations of negative HDRs in visual areas have been interpreted as the effect of unconstrained processing during rest. Our results suggest that the elderly may have more unconstrained visual processing during the rest condition in the scanner. The observation that the group differences in the BOLD response are sensitive to voxel selection (e.g., inclusion of low-significance and/or negative voxels) underscores the importance of ROI selection criteria in the interpretation of fMRI studies using elderly populations.

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PubMed2004

Cognitive functioning in late-life bipolar disorder.

OBJECTIVE: This study characterized cognitive functioning in elderly patients with bipolar disorder. METHOD: The cognitive functioning of 18 euthymic patients with a history of bipolar disorder I or II, ages 60 years and older, was tested with the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale, and the Executive Interview. Cognitive functioning in these subjects was compared with that of an age- and education-matched group of 45 comparison subjects without mood disorders. RESULTS: Approximately half of the bipolar subjects scored one or more standard deviations below the mean of the comparison subjects on the MMSE (N=8, 44%) and the Mattis Dementia Rating Scale total (N=10, 56%). On the Executive Interview, three subjects (17%) scored between one and two standard deviations below the mean of the comparison subjects. CONCLUSIONS: A significant proportion of older bipolar subjects exhibited neuropsychological deficits when they were clinically euthymic.

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PubMed2003

APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression.

OBJECTIVE: There is a recognized but poorly understood relationship between late-life depression (LLD) and progressive dementia. Both cognitive impairment co-occurring with LLD and a late age-of-onset of first lifetime depressive episode appear to be associated with subsequent progressive dementia. A history of major depression, especially when the first onset occurs in late-life, has been identified as a risk factor for Alzheimer's disease (AD). The major genetic risk factor for sporadic AD is carrying one or more apolipoprotein E4 (APOE4) alleles. We hypothesized that the association between LLD and dementia risk would be mediated by APOE4, specifically that APOE4 allele frequency would be associated with cognitive impairment and later age-of-depression-onset. We also predicted that APOE4 allele frequency would be increased among subjects with LLD. METHODS: We compared the distribution of APOE2, APOE3, and APOE4 alleles in groups of LLD (n=160), AD (n=568) and elderly control (EC; n=156) subjects. RESULTS: The allele distribution of the cognitively impaired LLD subgroup was not different from either the cognitively normal subgroup or the EC group but was different from the AD group. However, mean age-of-onset of depression in APOE4 carriers (51.4+/-20.7) was significantly lower than non-carriers (58.8+/-16.8). The allele distribution in LLD overall was significantly different from the AD but not the EC group. CONCLUSIONS: The finding that neither LLD, accompanying cognitive impairment, nor late age-of-onset was associated with an increased APOE4 allele frequency suggests that LLD acts as a risk factor for developing AD as well as non-AD dementia through mechanisms independent of APOE4. The unexpected finding that age-of-onset of LLD was significantly reduced in APOE4 carriers is similar to the association between APOE4 and age-of-onset in AD. Replication of the association of APOE4 with earlier age-of-depression-onset is indicated.

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PubMed2003

Apathy and executive function in depressed elderly.

Apathy and executive cognitive dysfunction (ECD) are important though conceptually different aspects of late-life depression. The primary objective of this study was to evaluate the relationship of apathy to ECD. The authors also evaluated the relationship of apathy and ECD to global cognitive impairment and word generation. Fifty-two elderly subjects with major depression and MMSE scores of 15 or greater were evaluated with apathy-related items from the Hamilton rating scale for depression (ApHRSD), the Executive Interview (EXIT), the Dementia Rating Scale (DRS), and the Controlled Oral Word Association test (COWA). ApHRSD scores were not significantly correlated with any of these variables. EXIT scores were correlated significantly with DRS and COWA. The results suggest that apathy and ECD may be independent of each other in some samples of elderly with late-life depression. Correlations may have been reduced by low variance for the variables of interest and by psychometric limitations of the ApHRSD.

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PubMed2002

Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration.

OBJECTIVE: The authors' goal was to compare regional brain volumes in depressed elderly subjects with those of nondepressed elderly subjects by using voxel-based morphometry. METHOD: They used statistical parametric mapping to analyze magnetic resonance imaging scans from 30 depressed patients 59 to 78 years old and 47 nondepressed comparison subjects 55 to 81 years old. RESULTS: Depressed patients had smaller right hippocampal volume than comparison subjects. The volume of the hippocampal-entorhinal cortex was inversely associated with the number of years since the first lifetime episode of depression. CONCLUSIONS: These data provide further evidence of structural brain abnormalities in geriatric depression, particularly in patients with a longer course of illness.

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PubMedDate not supplied

Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine.

Cognitive dysfunction is common in older persons suffering from a major depression. However, the degree to which this dysfunction is reversible with successful treatment of the depression remains uncertain. The present study examined the effects that treatment (randomized double-blind design) with either an SSRI (paroxetine) or a tricyclic antidepressant (nortriptyline) had on cognition in older depressed patients. The patients' performance was compared to that of a group of normal controls of similar age and education. Patients and controls were administered measures of working memory, information-processing speed, episodic memory and attention five times over the course of a 12 week trial. At baseline, the patients performed more poorly than the elderly controls on all cognitive measures. While the patients' performance did improve over the course of their treatment, the magnitude of this improvement did not exceed that produced in the elderly controls by practice alone. The same pattern of results was evident in both intent-to-treat and responder analyses. Thus, there was no evidence that the depressed patients' cognitive performance normalized after response to antidepressant therapy. Neither the patients' age at onset nor their baseline level of cognitive functioning influenced the amount by which their performance improved over the 12 week trial. There was no difference between paroxetine and nortriptyline in the amount of cognitive change associated with treatment. The present results suggest that cognitive dysfunction persists in older depressed patients even after their mood disorder has responded to antidepressant medications.

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PubMedDate not supplied

Executive functioning, illness course, and relapse/recurrence in continuation and maintenance treatment of late-life depression: is there a relationship?

OBJECTIVE: The authors tested the hypothesis that impaired executive functioning leads to high rates of relapse and recurrence in late-life depression. METHODS: They analyzed data from subjects participating in two independent intervention trials. Study I included 53 elderly depressed patients who participated in an open trial comparing the efficacy of paroxetine and nortriptyline and recurrence prevention over 18 months. Study II focused on 146 elderly depressed patients who received open treatment with paroxetine in a relapse-prevention study over 4 months of continuation treatment. They examined the effect of cognitive functioning, in general, and executive functioning, in particular, on time-to-relapse/recurrence, using baseline and post-treatment measures of neuropsychological functioning. RESULTS: The associations between cognitive measures and both probability of, and time-to-relapse/recurrence were small and statistically nonsignificant. CONCLUSION: Data failed to support the hypothesis that cognitive impairment, in general, or executive dysfunction, in particular, predicts relapse or recurrence of major depression in late life. Authors recommend future testing of the hypothesis with detailed, comprehensive measures over longer periods of observation during maintenance trials.

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PubMedDate not supplied

Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia.

Vitamin B12 deficiency is common in elderly persons, yet its role in dementia and psychiatric illness is unclear. The authors examined the relationship between vitamin B12 serum levels and cognitive and neuropsychiatric symptoms in dementia. Community-dwelling elderly subjects (N=643) meeting NINCDS-ADRDA criteria for probable or possible Alzheimer disease (AD) underwent comprehensive neuropsychiatric evaluation and measurement of vitamin B12 serum levels. Thirty-seven subjects (5.7%) had low B12 serum levels (200 pcg/ml or less). Subjects with low B12 levels were significantly older and had significantly lower scores on the Mini-Mental State Exam and higher scores on the Blessed Dementia Scale, but not a different pattern of cognitive or behavior disturbances compared with the normal-B12 subjects. In AD, the prevalence of low vitamin B12 serum levels is consistent with that found in community-dwelling elderly persons in general but is associated with greater overall cognitive impairment.

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