Ellen M. Whyte

Post stroke depression: epidemiology, pathophysiology, and biological treatment

Depression is a common occurrence after stroke and is associated with excess disability, cognitive impairment, and mortality. The authors undertook a systematic review of the English language literature to review several aspects of this illness, including the prevalence of this disorder, the debate on its etiology, and the current understanding of the biological treatment of poststroke depression. Methodological problems encountered in the study of poststroke depression are highlighted throughout the manuscript. The authors conclude that the available evidence supports poststroke depression as being multifactorial in origin and consistent with the biopsychosocial model of mental illness.

A fully automated method for quantifying and localizing white matter hyperintensities on MR images

White matter hyperintensities (WMH), commonly found on T2-weighted FLAIR brain MR images in the elderly, are associated with a number of neuropsychiatric disorders, including vascular dementia, Alzheimers disease, and late-life depression. Previous MRI studies of WMHs have primarily relied on the subjective and global (i.e., full-brain) ratings of WMH grade. In the current study we implement and validate an automated method for quantifying and localizing WMHs. We adapt a fuzzy-connected algorithm to automate the segmentation of WMHs and use a demons-based image registration to automate the anatomic localization of the WMHs using the Johns Hopkins University White Matter Atlas. The method is validated using the brain MR images acquired from eleven elderly subjects with late-onset late-life depression (LLD) and eight elderly controls. This dataset was chosen because LLD subjects are known to have significant WMH burden. The volumes of WMH identified in our automated method are compared with the accepted gold standard (manual ratings). A significant correlation of the automated method and the manual ratings is found (P<0.0001), thus demonstrating similar WMH quantifications of both methods. As has been shown in other studies (e.g. [Taylor, W.D., MacFall, J.R., Steffens, D.C., Payne, M.E., Provenzale, J.M., Krishnan, K.R., 2003. Localization of age-associated white matter hyperintensities in late-life depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 27 (3), 539-544.]), we found there was a significantly greater WMH burden in the LLD subjects versus the controls for both the manual and automated method. The effect size was greater for the automated method, suggesting that it is a more specific measure. Additionally, we describe the anatomic localization of the WMHs in LLD subjects as well as in the control subjects, and detect the regions of interest (ROIs) specific for the WMH burden of LLD patients. Given the emergence of large NeuroImage databases, techniques, such as that described here, will allow for a better understanding of the relationship between WMHs and neuropsychiatric disorders.

Depression After Stroke: A Prospective Epidemiological Study

Objectives: To elucidate the relationship between stroke and depressive symptoms and to determine whether disability or cerebrovascular risk factors mediate that relationship.

Maintenance Treatment of Depression in Old Age: A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy

CONTEXT Cognitive impairment in late-life depression is a core feature of the illness. OBJECTIVE To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment. DESIGN Randomized, double-blind, placebo-controlled maintenance trial. SETTING University clinic. PARTICIPANTS One hundred thirty older adults aged 65 years and older with recently remitted major depression. INTERVENTIONS Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo. MAIN OUTCOME MEASURES Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression. RESULTS Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression. CONCLUSIONS Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177671.

A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression: The Study of Pharmacotherapy of Psychotic Depression (STOP-PD)

CONTEXT Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression (MD) with psychotic features. OBJECTIVES To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy; and to compare response by age. DESIGN Twelve-week, double-blind, randomized, controlled trial. SETTING Clinical services of 4 academic sites. Patients Two hundred fifty-nine subjects with MD with psychotic features randomized by age (<60 or > or =60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants). Intervention Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day. Main Outcome Measure Remission rates of MD with psychotic features. RESULTS Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (chi(2)(1) = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001). CONCLUSIONS Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00056472.

Cognitive and affective predictors of rehabilitation participation after stroke.

OBJECTIVE To examine associations between cognitive and affective impairments and rehabilitation participation during stroke rehabilitation. DESIGN Secondary analyses of stroke patients who received acetylcholinesterase inhibitors during inpatient rehabilitation. SETTING University-affiliated inpatient rehabilitation facilities. PARTICIPANTS Patients (N=44) admitted to inpatient stroke rehabilitation with impairment in attention, memory, or executive functions. INTERVENTIONS Secondary analysis of patients receiving inpatient stroke rehabilitation care plus random assignment to one of two acetylcholinesterase inhibitors or no drug at rehabilitation admission. MAIN OUTCOME MEASURES Correlations between measures of cognitive (Digit Span, Hopkins Verbal Learning Test, Executive Interview) and affective impairments (Hamilton Rating Scale for Depression, Apathy Evaluation Scale) and participation (Pittsburgh Rehabilitation and Participation Scale) were examined. Significant correlates of participation were examined in a linear multiple regression model. RESULTS Executive functions and depressive symptoms were significant correlates of participation. After controlling for baseline disability, executive functions predicted participation, but depressive symptoms did not (F(4,32)=9.35; R(2)=.54, P<.001). CONCLUSIONS These findings are an important first step toward understanding potentially modifiable clinical factors that contribute to rehabilitation participation and overall functional status after rehabilitation. A better understanding of cognitive impairment and rehabilitation participation may be used to develop strategies for improving functional outcomes after stroke.

Onset of Depression in Elderly Persons After Hip Fracture: Implications for Prevention and Early Intervention of Late‐Life Depression

OBJECTIVES: To identify predictors of onset of major depressive disorder (MDD) and of depressive symptoms in subjects who suffered a hip fracture.

Medical burden in late-life bipolar and major depressive disorders.

BACKGROUND Elderly patients with bipolar disorder have been found to have higher mortality than those with major depressive disorder. The authors compare medical burden in elderly patients with bipolar disorder with that in those with major depressive disorder. METHODS Fifty-four patients with bipolar I or II disorder who were 60 years of age and older were equated 1-to-2 to 108 patients with nonpsychotic, major depressive disorder according to age, sex, race, and lifetime duration of mood disorder illness. Variables examined included the following: Cumulative Illness Rating Scale for Geriatrics (CIRS-G) total scores, body mass index (BMI), and CIRS-G subscale scores. RESULTS Compared with patients with major depressive disorder, patients with bipolar disorder had similar levels of general medical comorbidity on the CIRS-G total score and number of systems affected but higher BMI. After controlling for multiple comparisons, the endocrine/metabolic and respiratory subscale scores on the CIRS-G were higher for patients with bipolar disorder. CONCLUSION Although overall medical burden appears comparable in elderly patients with bipolar and those with major depressive disorder, patients with bipolar disorder have higher BMI and greater burden of endocrine/metabolic and respiratory disease.

Time course of response to antidepressants in late-life major depression: Therapeutic implications

In the treatment of depression, there is considerable interest in the time course of response and, in particular, the speed with which individuals recover from depressive episodes. Examination of the time course and speed of response is critical for assessing the usefulness of specific treatments. However, while this issue has received attention in mid-life adult populations, it has received little consideration in the context of late-life major depression. The synthesis of empirical reports indicates that, while older adults with depression seem to respond with the same speed as mid-life adults, several factors have consistently been associated with reduced speed of response to antidepressant treatment, including greater severity of depressive symptoms and co-occurring anxiety symptoms. Limited evidence suggests that sleep impairment and genetic factors (e.g. presence of the s allele of the serotonin transporter gene promoter region) may also be associated with reduced speed of response. Some factors have consistently been found to be unrelated to speed of response (demographic characteristics, nonpsychiatric physical illnesses) whereas other factors have only mixed evidence supporting any effect (psychosocial and other clinical factors). While there is little work available to date, some evidence suggests that time course and speed of response affect longer-term outcomes of depression pharmacotherapy; thus, older adults with more rapid versus slower patterns of response may differ in the types of maintenance treatment needed to avert additional depressive episodes.None of potential strategies for accelerating speed of response have been clearly shown to be effective in late-life depression. Future treatment studies for late-life depression should routinely consider not only overall efficacy of a given pharmacotherapy (i.e. total rate of response), but time course and speed of response. To this end, new investigations must be designed to overcome the methodological limitations of prior studies that have examined time course and they should include a range of potential covariates and outcomes of between-patient differences in speed of response. Better understanding of factors related to such differences may suggest new intervention strategies to accelerate response.

Empirically derived decision trees for the treatment of late-life depression.

OBJECTIVE Several predictors of treatment response in late-life depression have been reported in the literature. The aim of this analysis was to develop a clinically useful algorithm that would allow clinicians to predict which patients will likely respond to treatment and thereby guide clinical decision making. METHOD A total of 461 patients with late-life depression were treated under structured conditions for up to 12 weeks and assessed weekly with the 17-item Hamilton Rating Scale for Depression (HAM-D-17). The authors developed a hierarchy of predictors of treatment response using signal-detection theory. The authors developed two models, one minimizing false predictions of future response and one minimizing false predictions of future nonresponse, to offer clinicians two clinically useful treatment algorithms. RESULTS In the first model, early symptom improvement (defined by the relative change in HAM-D-17 total score from baseline to week 4), lower baseline anxiety, and an older age of onset predict response at 12 weeks. In the second model, early symptom improvement represents the principal guide in tailoring treatment, followed by baseline anxiety level, baseline sleep disturbance, and--for a minority of patients--the adequacy of previous antidepressant treatment. CONCLUSIONS Our two models, developed to help clinicians in different clinical circumstances, illustrate the possibility of tailoring the treatment of late-life depression based on clinical characteristics and confirm the importance of early observed changes in clinical status.