David J. Moser

Escitalopram and Problem-Solving Therapy for Prevention of Poststroke Depression: A Randomized Controlled Trial

CONTEXT Depression occurs in more than half of patients who have experienced a stroke. Poststroke depression has been shown in numerous studies to be associated with both impaired recovery in activities of daily living and increased mortality. Prevention of depression thus represents a potentially important goal. OBJECTIVE To determine whether treatment with escitalopram or problem-solving therapy over the first year following acute stroke will decrease the number of depression cases that develop compared with placebo medication. DESIGN, SETTING, AND PARTICIPANTS A multisite randomized controlled trial for prevention of depression among 176 nondepressed patients was conducted within 3 months following acute stroke from July 9, 2003, to October 1, 2007. The 12-month trial included 3 groups: a double-blind placebo-controlled comparison of escitalopram (n = 59) with placebo (n = 58), and a nonblinded problem-solving therapy group (n = 59). MAIN OUTCOME MEASURES The main outcome measure was the development of major or minor poststroke depression based on symptoms elicited by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) and the diagnostic criteria from DSM-IV for depression due to stroke with major depressive-like episode or minor depression (ie, research criteria). RESULTS Patients who received placebo were significantly more likely to develop depression than individuals who received escitalopram (11 major and 2 minor cases of depression [22.4%] vs 3 major and 2 minor cases of depression [8.5%], adjusted hazard ratio [HR], 4.5; 95% confidence interval [CI], 2.4-8.2; P < .001) and also more likely than individuals who received problem-solving therapy (5 major and 2 minor cases of depression [11.9%], adjusted HR, 2.2; 95% CI, 1.4-3.5; P < .001). These results were adjusted for history of mood disorders and remained significant after considering possible confounders such as age, sex, treatment site, and severity of impairment in the model. Using an intention-to-treat conservative method of analyzing the data, which assumed that all 27 patients who did not start randomized treatment would have developed depression, and controlling for prior history of mood disorders, escitalopram was superior to placebo (23.1% vs 34.5%; adjusted HR, 2.2; 95% CI, 1.2-3.9; P = .007), while problem-solving therapy was not significantly better than placebo (30.5% vs 34.5%; adjusted HR, 1.1; 95% CI, 0.8-1.5; P = .51). Adverse events, including all-cause hospitalizations, nausea, and adverse effects associated with escitalopram were not significantly different between the 3 groups. CONCLUSIONS In this study of nondepressed patients with recent stroke, the use of escitalopram or problem-solving therapy resulted in a significantly lower incidence of depression over 12 months of treatment compared with placebo, but problem-solving therapy did not achieve significant results over placebo using the intention-to-treat conservative method of analysis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00071643.

Impairments of attention after cingulotomy

Background: Outcome studies have generally not indicated significant cognitive disturbances after cingulotomy. There is now considerable evidence that the cingulate may play an important role in emotional behavior and attention. Objective: To characterize impairments of attention associated with bilateral lesions of the anterior cingulate cortex produced by cingulotomy. Methods: Twelve patients who underwent cingulotomy for treatment of intractable pain were administered tests of attention, executive functions, response intention and production, and a broad range of other neurocognitive functions before surgery and again 3 and 12 months after surgery. Data from this within-subjects repeated-measures design were analyzed by multivariate analysis of variance procedures. Results: After cingulotomy, patients initially had executive and attentional impairments. By 12 months, these had resolved into more circumscribed deficits, with greatest impairments on tasks requiring intention and spontaneous response production, and milder impairments of focused and sustained attention. Other aspects of attention and other cognitive functions were generally unaffected. Conclusion: The anterior cingulate cortex modulates response intention and focused attention.

Repetitive Transcranial Magnetic Stimulation as treatment of poststroke depression: A preliminary study

BACKGROUND Depression has a significant impact on poststroke recovery and mortality. There are a proportion of patients with poststroke depression (PSD) who do not respond to antidepressants. Repetitive Transcranial Magnetic Stimulation (rTMS) might be a safe and effective alternative in these refractory cases. METHODS We conducted a randomized, parallel, double-blind study of active versus sham left prefrontal rTMS in patients with refractory PSD. After discontinuing antidepressants, patients were randomly assigned to receive 10 sessions of active (10 Hz, 110% of the motor threshold, 20 trains of 5 seconds duration) or sham left prefrontal rTMS. Efficacy measures included HAM-D scores, response and remission rates. Patients completed a neuropsychological battery at baseline and after completing the protocol. RESULTS When compared with sham stimulation, 10 sessions of active rTMS of the left dorsolateral prefrontal cortex were associated with a significant reduction of depressive symptoms. This reduction was not influenced by patients age, type or location of stroke, volume of left frontal leukoaraiosis or by the distance of the stimulating coil to the prefrontal cortex. However, there was a significant positive correlation between the percentage of reduction of Ham-D scores and frontal gray and white matter volumes. There were no significant changes in cognitive functioning between the active and the sham stimulation groups. In addition, there were few and mild adverse effects that were equally distributed among groups. CONCLUSIONS Taken together, these preliminary findings suggest that rTMS may be an effective and safe treatment alternative for patients with refractory depression and stroke.

Treatment of Vascular Depression Using Repetitive Transcranial Magnetic Stimulation

CONTEXT The term vascular depression (VD) has been used to describe late-life depressive disorders in patients with clinical evidence of cerebrovascular disease. Preliminary data on poststroke depression suggest that repetitive transcranial magnetic stimulation (rTMS) might also be effective among patients with VD. OBJECTIVE To examine the efficacy and safety of rTMS to treat VD. DESIGN Prospective, randomized, sham-controlled study. SETTING University hospital. METHODS After discontinuation of antidepressant therapy, 92 patients with clinically defined VD were randomly assigned to receive active or sham rTMS of the left dorsolateral prefrontal cortex. Approximately half of the patients met criteria for magnetic resonance imaging-defined VD. In experiment 1, we administered a total cumulative dose (TCD) of 12 000 pulses (TCD-12K); in experiment 2, 18,000 pulses (TCD-18K). Sham stimulation was performed using a sham coil. RESULTS In experiment 1, the sham group showed a 13.6% decrease in the 17-item Hamilton Depression Rating Scale (HAMD-17) scores compared with a 33.1% decrease in the TCD-12K group (P = .04). Response rates were 6.7% in the sham group and 33.3% in the active-stimulation group (P = .08); remission rates were 6.7% and 13.3%, respectively (P = .50). In experiment 2, the sham group showed a 17.5% decrease in the 17-item Hamilton Depression Rating Scale scores compared with a 42.4% decrease observed in the TCD-18K group (P < .001). Response rates were 6.9% in the sham group and 39.4% in the active-stimulation group (P = .003); remission rates were 3.5% and 27.3%, respectively (P = .01). Response rates to rTMS were negatively correlated with age and positively correlated with higher frontal gray matter volumes. CONCLUSIONS To our knowledge, this is the first controlled trial that demonstrates the efficacy of rTMS among geriatric patients with VD. Older age and smaller frontal gray matter volumes were associated with a poorer response to rTMS.

Escitalopram and Enhancement of Cognitive Recovery Following Stroke

CONTEXT Adjunctive restorative therapies administered during the first few months after stroke, the period with the greatest degree of spontaneous recovery, reduce the number of stroke patients with significant disability. OBJECTIVE To examine the effect of escitalopram on cognitive outcome. We hypothesized that patients who received escitalopram would show improved performance in neuropsychological tests assessing memory and executive functions than patients who received placebo or underwent Problem Solving Therapy. DESIGN Randomized trial. SETTING Stroke center. PARTICIPANTS One hundred twenty-nine patients were treated within 3 months following stroke. The 12-month trial included 3 arms: a double-blind placebo-controlled comparison of escitalopram (n = 43) with placebo (n = 45), and a nonblinded arm of Problem Solving Therapy (n = 41). OUTCOME MEASURES Change in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail-Making, Controlled Oral Word Association, Wechsler Adult Intelligence Scale-III Similarities, and Stroop tests. RESULTS We found a difference among the 3 treatment groups in change in RBANS total score (P < .01) and RBANS delayed memory score (P < .01). After adjusting for possible confounders, there was a significant effect of escitalopram treatment on the change in RBANS total score (P < .01, adjusted mean change in score: escitalopram group, 10.0; nonescitalopram group, 3.1) and the change in RBANS delayed memory score (P < .01, adjusted mean change in score: escitalopram group, 11.3; nonescitalopram group, 2.5). We did not observe treatment effects in other neuropsychological measures. CONCLUSIONS When compared with patients who received placebo or underwent Problem Solving Therapy, stroke patients who received escitalopram showed improvement in global cognitive functioning, specifically in verbal and visual memory functions. This beneficial effect of escitalopram was independent of its effect on depression. The utility of antidepressants in the process of poststroke recovery should be further investigated. Trial Registration clinicaltrials.gov Identifier: NCT00071643.

Improved executive functioning following repetitive transcranial magnetic stimulation.

Abstract—The cognitive effects of active and sham repetitive transcranial magnetic stimulation (rTMS) were examined in 19 middle-aged and elderly patients with refractory depression. Patients received either active (n = 9) or sham (n = 10) rTMS targeted at the anterior portion of the left middle frontal gyrus. Patients in the active rTMS group improved significantly on a test of cognitive flexibility and conceptual tracking (Trail Making Test–B).

Endothelial function and white matter hyperintensities in older adults with cardiovascular disease.

Background and Purpose— The presence of white matter hyperintensities on brain MRI is common among elderly individuals. Previous research suggests that cardiovascular risk factors are associated with increased white matter hyperintensities. Examining the role of direct physiological measures of vascular function will help to clarify the vascular mechanisms related to white matter hyperintensities. The aim of the present study was to examine the association between endothelial-dependent and endothelial-independent vasodilatation and white matter hyperintensity volume. Methods— Twenty-five older adults with a range of cardiovascular diseases underwent brain MRI and completed assessments of blood vessel integrity using endothelial-dependent and independent flow-mediated dilation of the brachial artery. A semi-automated pixel-based method was used to quantify total brain volume and white matter hyperintensity volume, with white matter hyperintensity volume corrected for total brain volume. The association between measures of flow-mediated dilation and log-transformed white matter hyperintensities was examined. Results— Correlation analysis revealed that endothelial-dependent vasodilatation was significantly and inversely associated with white matter hyperintensity volume. In contrast, endothelial-independent vasodilatation was not associated with white matter hyperintensities. Neither endothelial-dependent nor endothelial-independent vasodilatation was associated with total brain volume. Conclusions— These data provide preliminary evidence that the integrity of the vascular endothelium is associated with white matter hyperintensities in older adults with cardiovascular disease. Impaired vascular function may be one mechanism that contributes to the development of white matter hyperintensities in the brain. Additional longitudinal research combining measures of vessel function, neuroimaging and cognition will be helpful in clarifying this potential mechanism.

Neurocognitive functioning and improvement in quality of life following participation in cardiac rehabilitation

We investigated the relationship between neurocognitive functioning and quality of life/self-perceived health status (QOL) among cardiac rehabilitation (CR) patients to determine whether level of neurocognitive functioning is related to baseline QOL and improvement following CR. CR patients (n = 35) were given a neurocognitive screening before participation in CR, and also completed a behavioral inventory (SF-36) before and after CR to measure QOL associated with medical illness. At baseline, CR patients obtained relatively low SF-36 scores compared with published norms, and as reported previously, demonstrated inferior neurocognitive performance compared with healthy controls. Furthermore, neurocognitive performance was strongly positively correlated to SF-36 scores. Significant improvements were evident on many of the SF-36 subscales following rehabilitation. These improvements were relatively greater among SF-36 indexes of physical health status compared with SF-36 indexes of mental health status. Baseline neurocognitive performance also correlated strongly to the degree of improvement in SF-36 scores following rehabilitation. These findings indicate a strong relationship between baseline neurocognitive functioning and QOL before CR, and the degree to which QOL improves following this intervention.

Patients with Huntington's disease have impaired awareness of cognitive, emotional, and functional abilities

The clinical literature in Huntingtons disease (HD) suggests that unawareness of deficits is prevalent among HD patients. However, few studies have characterized unawareness of different types of impairment within this neuropsychiatric disorder. The purpose of the current study was to examine self-awareness of functioning across symptom domains in HD patients and to explore the association between impaired awareness and cognitive dysfunction. A total of 66 pairs of HD patients and collaterals of the patients completed symptom-rating measures regarding both the patients’ and the collaterals’ behavior. A subset of 19 patients also underwent neurological and neuropsychological assessments. The results indicated that patients lacked awareness across symptom domains (i.e., behavioral control, emotional control, activities of daily living), which was significantly greater for their perception of their own behavior than for their perception of their collaterals behavior. Exploratory analyses revealed associations between impaired self-awareness, global cognition, and deficits in executive functioning and memory. The current findings underscore the importance of examining different types of impaired awareness including both over- and underreporting of abilities. Future studies will benefit also from examining the association between awareness and cognition in larger samples.

Neuropsychological characteristics and personality traits in pathological gambling.

INTRODUCTION Pathological gambling disorder (PG) has been associated with fronto-temporal dysfunction and maladaptive personality traits, such as impulsivity and novelty seeking. The purpose of this study was to examine the predictive variance of neuropsychological and personality characteristics in PG. METHODS Persons with PG (n=25) and a comparison group (n=34) were administered a battery of neuropsychological tests, the Temperament and Character Inventory, and the Barratt Impulsiveness Scale. Subjects with PG had evidence of fronto-temporal dysfunction as assessed by the Stroop, Wisconsin Card Sorting Test-64, Wechsler Adult Intelligence Scale Letter-Number Sequencing, Controlled Oral Word Association Test, and Boston Diagnostic Aphasia Examination Animal Naming Test. RESULTS Subjects with PG also had impaired decision making on the Iowa Gambling Task. PG subjects had elevated levels of impulsivity, novelty seeking, and harm avoidance, and lower levels of self-directedness and cooperativeness. Logistic regression analyses indicated that neuropsychological variables did not add significant incremental variance over personality traits in predicting PG (Block chi-square=5.19, P=.074), while personality variables added significant incremental variance over neuropsychological traits in predicting PG (Block chi-square=25.13, P<.001). CONCLUSION These results suggest that personality traits are better predictors than neuropsychological characteristics of whether someone has PG.