Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Psychological characteristics of individuals who put forth inadequate cognitive effort in a secondary gain context.

The current study sought to characterize the psychological architecture of individuals who put forth inadequate effort. The Minnesota Multiphasic Personality Inventory, 2nd Edition-Restructured Form was used to identify dimensions of psychological functioning in a mixed outpatient sample of U.S. Veterans referred for neuropsychological evaluation as part of their clinical care. After accounting for external financial incentive and symptom overreporting, results showed that the inadequate effort group (n = 23, mean age = 42.48) scored higher than the adequate effort group (n = 29, mean age = 44.31) on neurologic complaints (NUC) and lower on behavioral/externalizing dysfunction (BXD), antisocial behaviors (RC4), and disconstraint (DISC-r). Lower scores on BXD, RC4, and DISC-r could indicate higher behavioral constraint-a psychological characteristic that has been linked to the pursuit of high-value future rewards. Alternatively, lower scores on these scales could have reflected a self-presentation strategy aimed at minimizing externalizing and RC4 in order to appear more psychological healthy. Implications of each of these interpretations are discussed.

A pilot trial of neuropsychological evaluations conducted via telemedicine in the Veterans Health Administration.

INTRODUCTION: Many veterans live in rural areas distant from Veterans Affairs Medical Centers (VAMCs) and receive primary medical care from community-based outpatient clinics (CBOCs). These veterans often must travel great distances to the nearest VAMC for neuropsychological evaluations, resulting in poor access to care, travel reimbursement costs, fee-basis evaluations of uncontrolled quality, and driving safety concerns. Return trips for feedback compound complications. Accordingly, we initiated a pilot trial of neuropsychological evaluation and feedback via telemedicine (i.e., clinical videoconferencing). SUBJECTS AND METHODS: Participants were veterans referred for neuropsychological evaluation from a rural CBOC 115 miles from the regional VAMC. All veterans were given the choice to undergo evaluation at the CBOC via telemedicine or in-person at the VAMC. Telemedicine equipment allowed presentation of digitized material with simultaneous patient observation. Testing materials were organized in numbered folders and given to veterans by CBOC clerks immediately prior to evaluation. Clerks returned completed materials via facsimile. RESULTS: Fifteen veterans from the rural CBOC were seen for neuropsychological evaluation. Eight chose telemedicine evaluation. Groups based on evaluation modality appeared similar on demographics, referral basis, resulting neuropsychiatric diagnoses, and follow-through on recommendations. No significant technical or clinical difficulties were encountered, and veterans reported satisfaction with telemedicine. All veterans requested feedback via telemedicine. CONCLUSIONS: Neuropsychological evaluation via telemedicine is feasible and appears comparable to in-person evaluation. Experiences are encouraging and consistent with the broader literature on the acceptance of and satisfaction with clinical videoconferencing. Future studies will assess possible psychometric issues in clinical populations.

Pre-existing health conditions and repeat traumatic brain injury.

OBJECTIVE: To assess and compare the effect of Pre-existing epilepsy/seizure disorder and drug/alcohol problem on the hazard of repeat traumatic brain injury (TBI) in persons with TBI who participated in a follow-up study. DESIGN: Retrospective cohort. SETTING: Acute care hospitals in South Carolina. PARTICIPANTS: Participants were from the South Carolina Traumatic Brain Injury Follow-up Registry cohort of persons (N=2118) who were discharged from an acute care hospital in South Carolina and who participated in a year-1 follow-up interview. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Repeat TBI was defined by 2 isolated events of TBI in the same person at least 72 hours apart and recorded in hospital discharge or emergency department records from 1999 through 2005. RESULTS: A Cox proportional hazards model was used to assess the associations of Pre-existing epilepsy/seizure disorder and drug/alcohol problem with time to repeat TBI, controlling for other confounding factors. There were 2099 persons with information on both Pre-existing conditions. There were 147 (7%) persons who sustained repeat TBI after recruitment to the follow-up study, and 82 (3.9%) had a previous TBI before recruitment for which they were seen in the hospital discharge or emergency department since 1996. The hazard of repeat TBI for persons with Pre-existing epilepsy/seizure disorder was 2.3 times the hazard for those without (hazard ratio, 2.3; 95% confidence interval, 1.2-4.4; P=.011). Pre-existing drug/alcohol problem was not associated with repeat TBI. Other variables significantly associated with repeat TBI were having a prior TBI, being insured under Medicaid, and having no insurance. CONCLUSIONS: Pre-existing epilepsy/seizure disorder predisposes to repeat TBI. Appropriate management of seizure control may be an important strategy to allay the occurrence of repeat TBI.

Predictors of psychological symptoms 1 year after traumatic brain injury: a population-based, epidemiological study.

OBJECTIVE: To examine self-reported psychological symptoms 1 year after traumatic brain injury (TBI) in a population-based sample. PARTICIPANTS: There were 1560 adults who had sustained TBI. DESIGN: A telephone survey with questions about recent mood and anxiety symptoms, and diagnoses since TBI. Polychotomous logistic regression with 3 response levels (probable, possible, and no mood or anxiety symptoms) identified predictors of psychological symptoms. RESULTS: Overall, 40% of participants had clinically significant mood or anxiety symptoms-12.6% with probable symptoms and 27.5% with possible symptoms. Main risk factors for probable symptoms included younger age, poor physical functioning, inadequate social support, and being a white woman. Other risk factors included being retired or unemployed, and pre-TBI psychiatric disorder or multiple concussions. CONCLUSIONS: These findings suggest the need for careful screening of persons with TBI who are at particular risk of developing psychological symptoms, and persons who have recently sustained TBI and their families to be educated about the possibility of developing such symptoms.

Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia.

RATIONALE: Cognitive deficits are of particular importance in schizophrenia since they are strongly associated with poor prognosis. We investigated the relationship between prefrontal cortical atrophy as measured by MRI and the neuropsychological performance of participants diagnosed with DSM-IV-TR schizophrenia. METHODS: Fourteen unmedicated adult patients and thirteen matched controls were studied. Subjects underwent MRI yielding 1 mm isotropic T1-weighted images. Voxel based morphometry was applied to all images using SPM5. The mean gray level of Brodmann area (BA) 9 was also extracted and evaluated using simple regression along with relative score differences on patients neuropsychological tests compared to controls. RESULTS: Patients exhibited a poorer performance on the Controlled Word Association Task (COWAT), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Patients also presented a greater level of apathy as indexed by the Apathy Evaluation Scale (AES). There was a significant decrease in gray matter volume in patients with schizophrenia in left supplementary motor area, bilateral superior frontal gyrus, left middle frontal gyrus, right opercular area, left angular gyrus, left superior temporal gyrus and left cerebellar hemisphere. Within the schizophrenia group, decreased BA9 gray matter volume was correlated with poorer performance on the WCST and TMT-B. CONCLUSION: Prefrontal gray matter abnormalities in schizophrenia patients may be associated with some symptoms including difficulties with set-shifting and decreased mental flexibility. Further studies evaluating prefrontal connectivity may clarify if such impairment results from abnormalities of the frontal area alone, or are a result of altered networks involving the frontal and extra-frontal areas.

Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study.

Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia.

Self-reported psychosocial health among adults with traumatic brain injury.

OBJECTIVE: To measure the subjective psychosocial health of a population-based sample of adults with traumatic brain injury (TBI). DESIGN: Retrospective, cohort study involving a 1-year postinjury interview. SETTING: Sixty-two acute care, nonfederal hospitals in South Carolina. PARTICIPANTS: Persons (> or =15y) hospitalized with TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The psychosocial health scales of the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: Of the 7612 participants, 29% reported poor psychosocial health. Factors associated with poor psychosocial well-being included younger age, female sex, Medicaid coverage, no health insurance, inadequate or moderate social support, comorbidities (eg, a preinjury substance abuse problem), cognitive complaints, and some or a lot of limitation with activities of daily living. Only 36% of participants who reported poor psychosocial health reported receiving any mental health services. CONCLUSIONS: A substantial proportion of persons hospitalized with TBI reported poor psychosocial health at 1 year postinjury. To optimize recovery, clinicians need to ensure that patients' psychosocial health needs are addressed during the postacute period.

Donepezil effects on mood in patients with schizophrenia and schizoaffective disorder.

Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients.

Decreased cortical response to verbal working memory following sleep deprivation.

STUDY OBJECTIVE: To investigate the cerebral hemodynamic response to verbal working memory following sleep deprivation. DESIGN: Subjects were scheduled for 3 functional magnetic resonance imaging scanning visits: an initial screening day (screening state), after a normal night of sleep (rested state), and after 30 hours of sleep deprivation (sleep-deprivation state). Subjects performed the Sternberg working memory task alternated with a control task during an approximate 13-minute functional magnetic resonance imaging scan. SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Results from 33 men (mean age, 28.6 +/- 6.6 years) were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Subjects performed the same Sternberg working memory task at the 3 states within the magnetic resonance imaging scanner. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca's area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 hours of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Task performance also decreased. A repeated-measures analysis of variance revealed that subjects at the screening and rested states had similar activation patterns, with each having significantly more activation than during the sleep-deprivation state. CONCLUSIONS: These results suggest that human sleep-deprivation deficits are not caused solely or even predominantly by prefrontal cortex dysfunction and that the paretal cortex, in particular, and other brain regions involved in verbal working memory exhibit significant sleep-deprivation vulnerability.

Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

Substance abuse treatment outcomes for cognitively impaired and intact outpatients.

The purpose of this research was to examine the effects of cognitive impairment on the efficacy of substance abuse treatment outcome. Alcohol, drug, medical, legal, psychological, employment, and family functioning related treatment outcomes were examined for 26 cognitively impaired and 68 cognitively intact abusing outpatients. Subjects were enrolled in an intensive, 3-week, outpatient program for the treatment of their substance abuse. Subjects were administered a battery of neuropsychological tests prior to treatment onset, and outcome data were obtained at 1, 3, 6, and 12 months posttreatment entry. No significant between-group differences were found on any of the outcome measures, and significant treatment gains were observed across all problem domains in both groups. Subjects' largest improvements were made in the first month of treatment for alcohol, drug, legal, family, and psychological problems. Improvements for employment and medical problems were not observed until 6 months posttreatment. Success across domains was maintained through 12 months follow-up, with the exception of psychological problems; 12-month data indicated a return to thelevel observed at 30 days posttreatment for psychological problems, a level that reflected significant improvement from baseline functioning. A greater proportion of treatment dropouts (i.e., no follow-up data obtained after 30 days) were cognitively impaired as compared to treatment completers. These results suggest that this method of intensive substance abuse outpatient treatment is effective for cognitively impaired patients, an important finding given that research evaluating the efficacy of interventions for such patients is limited. Additionally, neuropsychological evaluation may be important in reducing treatment dropouts, as the present findings indicated that greater cognitive impairment was related to an increased likelihood of treatment dropout.