Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The authors evaluated the potential of methylphenidate to improve antidepressant response to citalopram, as assessed by clinical and cognitive outcomes, in elderly depressed patients. METHOD: The authors conducted a 16-week randomized double-blind placebo-controlled trial for geriatric depression in 143 older outpatients diagnosed with major depression comparing treatment response in three treatment groups: methylphenidate plus placebo (N=48), citalopram plus placebo (N=48), and citalopram plus methylphenidate (N=47). The primary outcome measure was change in depression severity. Remission was defined as a score of 6 or less on the Hamilton Depression Rating Scale. Secondary outcomes included measures of anxiety, apathy, quality of life, and cognition. RESULTS: Daily doses ranged from 20 mg to 60 mg for citalopram (mean=32 mg) and from 5 mg to 40 mg for methylphenidate (mean=16 mg). All groups showed significant improvement in depression severity and in cognitive performance. However, the improvement in depression severity and the Clinical Global Impressions improvement score was more prominent in the citalopram plus methylphenidate group compared with the other two groups. Additionally, the rate of improvement in the citalopram plus methylphenidate group was significantly higher than that in the citalopram plus placebo group in the first 4 weeks of the trial. The groups did not differ in cognitive improvement or number of side effects. CONCLUSIONS: Combined treatment with citalopram and methylphenidate demonstrated an enhanced clinical response profile in mood and well-being, as well as a higher rate of remission, compared with either drug alone. All treatments led to an improvement in cognitive functioning, although augmentation with methylphenidate did not offer additional benefits.

Antidepressant treatment of melancholia in older adults.

OBJECTIVE: This is the first prospective trial in an outpatient sample comparing the effect of nortriptyline with sertraline in the treatment of depression with and without melancholia. We hypothesized that patients with melancholia would respond better to nortriptyline than sertraline, whereas among patients without melancholia, nortriptyline and sertraline would have equal efficacy. METHODS: We conducted a randomized 12-week trial comparing sertraline with nortriptyline in the treatment of patients with nonpsychotic, unipolar major depression stratified by the presence of melancholia. One hundred ten unipolar depressed patients with and without melancholia comprised our intent-to-treat sample. Seventy-two were nonmelancholic depressed and randomly assigned to treatment with sertraline (N = 40) or nortriptyline (N = 32). Thirty-eight were melancholic depressed and randomly assigned to treatment with sertraline (N = 18) or nortriptyline (N = 20). RESULTS: The test of the interaction of medication group and melancholia status on response was not statistically significant. Among patients with melancholia, response rates were 47% to sertraline and 75% to nortriptyline, whereas among patients without melancholia, response rates were 51% to sertraline and 42% to nortriptyline. The odds of response for patients with melancholia treated with nortriptyline compared with sertraline was 3.46. The odds of response for patients without melancholia treated with sertraline compared with nortriptyline was 0.69. Similar findings were obtained in the remission and continuous outcome analyses. CONCLUSION: This study did not find a significant difference between sertraline and nortriptyline in the treatment of depressed older adults with melancholia.

The patterns of cognitive and functional impairment in amnestic and non-amnestic mild cognitive impairment in geriatric depression.

OBJECTIVES: Depressed older adults are at risk for the development of mild cognitive impairment (MCI), but few studies have characterized MCI subtypes in geriatric depression. The objective of this study was to identify the clinical patterns of MCI in late-life depression. DESIGN: Baseline demographic, clinical, and neuropsychological test data collected as part of a randomized antidepressant trial for geriatric depression. SETTING: UCLA-based outpatient clinic. PARTICIPANTS: One hundred thirty-eight older adults with major depression. MEASUREMENTS: A neuropsychological test battery and comprehensive evaluations of depression, apathy, quality of life, medical burden, and vascular risk factors. RESULTS: Seventy-one participants (51%) had MCI and 67 (49%) were cognitively normal. Of subjects with MCI, 14 (20%) had amnestic MCI and 57 (80%) had non-amnestic MCI. Overall, patients with MCI had greater depression severity, poorer quality of life, and worse performance on the Mini-Mental State Exam than patients without MCI. Patients with non-amnestic MCI had significantly greater depression severity than patients without MCI. Across all subjects, depression severity correlated with impaired performance in language and visuospatial functioning. CONCLUSION: Our findings suggest that MCI is associated with greater severity of depression, poorer quality of life, and worse global cognitive function. Overall, subtypes of MCI in geriatric depression differ in the patterns of functional impairment, which may require different therapeutic approaches.

Vascular depression: overrepresented among African Americans?

OBJECTIVE: Our primary aim was to compare the rate of vascular depression among a clinical sample of African American and Caucasian depressed older adults. Secondary aims included characterizing the clinical and neuropsychological profile of vascular depression and comparing antidepressant response rates between patients with vascular and nonvascular depression. METHODS: This was a two-site, multi-ethnic, open 8-week trial of antidepressant medication in older adults with depression. Men and women 50 years or older meeting DSM-IV criteria for nonpsychotic unipolar depression participated in this trial. Each participant underwent a comprehensive psychiatric and neuropsychological evaluation and a brain MRI, which were performed at baseline. RESULTS: Forty-six patients met inclusion and exclusion criteria. Forty-two of those patients received an MRI at baseline. Sixteen patients met criteria for vascular depression. Patients with vascular depression were significantly more likely to be African American and have a higher likelihood of being female, a higher rate of hypertension and psychomotor retardation, a lower rate of family history of affective illness, and frontal systems dysfunction on neuropsychological testing. The difference in response rates between patients with vascular and nonvascular depression did not reach statistical significance. CONCLUSIONS: This is the first study to document high rates of vascular depression in a clinical sample of African Americans and Caucasians. Our findings suggest that vascular depression may be overrepresented among African Americans, which is consistent with the high rates of cardiovascular disease, hypertension, and stroke in this population.

The external validity of MRI-defined vascular depression.

OBJECTIVE: Multiple diagnostic criteria have been used to define vascular depression (VD). As a result, there are discrepancies in the clinical characteristics that have been established for the illness. The aim of this study was twofold. First, we used empirically established diagnostic criteria to determine the clinical characteristics of magnetic resonance imaging (MRI)-defined VD. Second, we assessed the agreement between a quantitative and qualitative method for identifying the illness. METHOD: We examined the baseline clinical and neuropsychological profile of 38 patients from a larger, double-blind, randomized, 12-week clinical trial comparing nortriptyline with sertraline in depressed older adults. Ten patients met quantitative criteria for MRI-defined VD based on the highest quartile of deep white matter hyperintensity (DWMH) volume. Fourteen patients met qualitative criteria for MRI-defined VD based on a DWMH score of 2 or higher on the Fazekas' modified Coffey rating scale. RESULTS: Age, gender, cumulative illness rating scale-geriatric (CIRS-G) score, two measures of psychomotor retardation [the psychomotor retardation item of the Hamilton Rating Scale for Depression (HRSD) as well as performance on the Purdue Pegboard], and performance on the Stroop Color/Word test (a measure of the response inhibition component of executive functioning) were significantly different between those with VD and non-VD. CONCLUSIONS: Patients with VD have a distinct clinical and neuropsychological profile that is mostly consistent across different methods for identifying the illness. These findings support the notion that MRI-defined VD represents a unique and valid subtype of late-life depression.

Change in cognitive functioning in depressed older adults following treatment with sertraline or nortriptyline.

OBJECTIVE: The aim of this study was to compare the impact of nortriptyline to sertraline on change in cognitive functioning in depressed older adults. METHODS: We used pre-post neuropsychological data collected as part of a 12-week medication trial comparing sertraline to nortriptyline in the treatment of older adults with non-psychotic, unipolar major depression to examine change in cognitive functioning. Neuropsychological assessments included mental status (Mini-Mental Status Exam), psychomotor speed (Purdue Pegboard), attention (Continuous Performance Test, Trail Making Test A), executive functioning (Stroop Color/word Test, Trail Making Test B), and memory (Buschke Selective Reminding Test). RESULTS: Within treatment groups, patients treated with sertraline improved only on verbal learning. This change did not depend on responder status. Between treatment groups, patients treated with sertraline improved more in verbal learning compared with patients treated with nortriptyline. Looking at change in cognition as a function of medication condition and responder status revealed that sertraline responders improved more in verbal learning compared with nortriptyline responders but not more than sertraline non-responders or nortriptyline non-responders. Nortriptyline responders were the only treatment by responder status group to show no improvement in verbal learning from baseline to endpoint. CONCLUSIONS: Unexpectedly, nortriptyline responders showed no improvement in verbal learning as compared with patients treated with sertraline or nortriptyline non-responders. However, given the small sample sizes and number of statistical tests (potential for type 1 error), replication is warranted.

Executive dysfunction and treatment response in late-life depression.

OBJECTIVES: Executive dysfunction in geriatric depression has been shown to predict poor response to antidepressant medication. The purpose of this review is to clarify which aspects of executive functioning predict poor antidepressant treatment response. METHODS: Literature review. RESULTS: From our review, the aspects of executive functioning that appear to be associated with antidepressant response rates are verbal fluency and response inhibition. There is some indication that the semantic strategy component may account for the effects of verbal fluency, although evidence comes from one study and needs replication. Processing speed has been proposed as a substrate that may underlie the effects of executive dysfunction on treatment response. Although processing speed does not appear to account for the relationship between response inhibition and treatment outcome, this issue has yet to be assessed with respect to verbal fluency. CONCLUSIONS: Verbal fluency and response inhibition are specific aspects of executive dysfunction that appear to impact antidepressant response rates. Disruption of the frontostriatal limbic circuit (particularly the anterior cingulate and dorsolateral prefrontal cortex) may explain the relation between these two mechanisms.

MRI signal hyperintensities and failure to remit following antidepressant treatment.

BACKGROUND: MRI signal hyperintensities predict poor remission to antidepressant treatment. Previous studies using volumetrics in outpatient samples have relied on total lesion volume. The purpose of this study was to test whether remission from geriatric depression depends on lesion volume by region of interest (ROI). METHOD: Thirty-eight patients received baseline MRIs as part of a larger 12-week, randomized clinical trial comparing sertraline and nortriptyline in the treatment of late-life depression. MRIcro was used to quantify MRI-hyperintensity volume into total hyperintensity, deep white matter hyperintensity (DWMH), and periventricular hyperintensity (PVH) volumes. High versus low total, DWMH, and PVH volumes were defined based on the highest quartile of their respective distributions. Remission from depression was defined as a 24-item Hamilton Rating Scale for Depression score ≤ 7 for two consecutive weeks. RESULTS: Patients classified as having high DWMH were 7.14 times more likely not to remit following antidepressant treatment compared to patients classified as having low DWMH (p=0.02). Similar odds ratios were obtained for PVH (OR=4.17, p=0.16) and total volumes (OR=5.00, p=0.05). Importantly, adjusting for age did not change the magnitude of these effects. LIMITATIONS: A small and predominantly White sample. CONCLUSIONS: This is the first study to test whether remission from geriatric depression depends on lesion volume by ROI in an outpatient sample. The pattern of remission rates and odds ratios was similar when patients were classified as having high DWMH, PVH or total volume suggesting that lesion location may not be critical.

MRI-defined vascular depression: a review of the construct.

OBJECTIVE: To review the construct of MRI-defined vascular depression and to examine the substantive and methodological issues that bear on its validity as a distinct subtype of depression in late life. DESIGN: Literature review. RESULTS: We identified three areas that are critical to establishing the validity of MRI-defined vascular depression: (1) understanding and delineating the relationship between MRI hyperintensities, executive dysfunction, and antidepressant treatment outcome; (2) understanding the relationship between, and establishing the validity of, qualitative and quantitative approaches to the measurement of MRI hyperintensities (the primary feature of the proposed subtype); (3) establishing the clinical presentation and course of the subtype in the context of other late-life disorders. CONCLUSIONS: Despite considerable data supporting the validity of MRI-defined vascular depression, there are a number of critical issues that remain, including establishing a causal relationship between cerebrovascular disease and late-life depression, establishing consistent diagnostic criteria, determining the importance of lesion type and location, and understanding the course of the disorder.