Long-term effects of rivastigmine capsules in patients with traumatic brain injury.

OBJECTIVE: To investigate the safety, tolerability and efficacy of rivastigmine capsules (3-12 mg/day) in a 26-week, multi-centre, open-label extension of a double-blind study. METHODS: Patients with traumatic brain injury (TBI) and persistent cognitive impairment who had received rivastigmine (3-6 mg/day) or placebo for 12 weeks could enter the extension study and receive rivastigmine (< or =12 mg/day). Patients were assessed using a range of cognitive tests including the Hopkins Verbal Learning Test (HVLT) and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB RVIP) A' sub-test. Safety measures included monitoring of adverse events. RESULTS: In the extension study (n = 127), the mean duration of rivastigmine treatment was 23.8 weeks and the mean final dosage was 7.9 mg/day. Approximately 40% of patients were responders (> or =1.0 SD improvement from baseline) on CANTAB RVIP A' or HVLT total score at week 38 or endpoint. Statistically significant changes from week 12 at week 38 were observed for CANTAB-RVIP A' and HVLT-total word recall for the sub-group of ex-placebo patients with greater severity of initial impairment. The safety profile of rivastigmine capsules was consistent with the label. CONCLUSIONS: Treatment with rivastigmine for up to 38 weeks was safe in patients with TBI and cognitive impairment.

Safety and efficacy of rivastigmine in patients with Alzheimer's disease not responding adequately to donepezil: an open-label study.

OBJECTIVE: Switching patients with Alzheimer's disease from one cholinesterase inhibitor to another represents a viable option for patients not responding to current therapy. The objective of this large U.S.-based study was to evaluate the safety and efficacy of a treatment switch to rivastigmine in patients not responding adequately to or declining on treatment with donepezil. METHOD: In this 26-week, prospective, open-label, single-arm, multicenter study conducted from April 24, 2003, to June 25, 2004, patients with mild-to-moderate Alzheimer's disease (DSM-IV-TR criteria) who were not responding to donepezil were treated with rivastigmine 3-12 mg/day. Safety and tolerability were measured by the occurrence of adverse events and patient disposition. Treatment effects on global functioning were assessed using the Clinical Global Impression of Change (CGIC) scale. RESULTS: Two hundred seventy patients with a mean age of 78.5 (SD = 7.56) years and a mean duration of dementia of 3.5 (SD = 2.06) years were included in the study. Sixty-nine percent of patients completed the study with 17.8% discontinuing due to adverse events. Eighty-three percent of patients reported at least 1 adverse event, with the most frequently occurring adverse events affecting the gastrointestinal system (54%). The majority of patients were reported to have either improvement or no decline on the CGIC. A limitation of the study is that the interpretation of the results is based on an overall completion rate of 69%. CONCLUSION: Immediately switching patients from donepezil to rivastigmine without a washout period was safe and well tolerated in the current study. Additionally, these results suggest that patients not responding adequately to or declining while taking donepezil may improve or stabilize after switching to rivastigmine.

Long-term safety and tolerability of rivastigmine in patients with Alzheimer's disease switched from donepezil: an open-label extension study.

OBJECTIVES: The objective of this article is to present safety and tolerability data from the long-term extension phase of a core study conducted in patients with Alzheimer's disease (AD) who were immediately switched to rivastigmine. METHOD: This was a 26-week open-label extension (OLE) of a prospective, 26-week, open-label, single-arm, multicenter study conducted in the United States from October 2003 to January 2005. Patients had a diagnosis of Alzheimer's disease according to DSM-IV-TR and National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. Safety and tolerability of rivastigmine were monitored through monthly telephone contacts. At week 52, patients or caregivers were contacted by telephone to evaluate the patient's well-being. RESULTS: 146 patients (approximately 79% of patients who completed the core phase) entered this OLE. Most patients (N = 115, 78.8%) completed the full 26 weeks of the extension phase, during which time they received a mean rivastigmine dosage of 10.5 mg/day. The number of patients reporting newly occurring or worsening adverse events decreased considerably during the OLE (N = 84, 57.5%) compared with the core phase (the first 26 weeks; N = 116, 79.5%). Most patients reported adverse events that were mild or moderate in severity. At the end of the OLE, the majority of patients (128/146; 87.7%) were still receiving treatment with rivastigmine. At week 52, most caregivers expressed satisfaction with rivastigmine treatment (77.4%) and with the changes observed in the patient's behavior during the study (71.9%). CONCLUSIONS: For patients not tolerating or not responding to donepezil, treatment with rivastigmine was safe and well tolerated for at least 52 weeks.

Domain-specific improvement of cognition on memantine in patients with Alzheimer's disease treated with rivastigmine.

OBJECTIVE: Cholinergic therapy is used in mild-to-moderate Alzheimer's disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. METHODS: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3-6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. RESULTS: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. CONCLUSION: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients.

A pilot study evaluating the efficacy and safety of rivastigmine in patients with mixed dementia.

BACKGROUND AND OBJECTIVE: The two most common causes of dementia in the elderly are Alzheimer's disease (AD) and vascular dementia (VaD), which can coexist as mixed dementia. The object of this study was to assess the efficacy and safety of rivastigmine in patients with mixed dementia (AD with VaD). STUDY DESIGN: This 26-week open-label pilot study was conducted at 19 centres in the US. To reduce bias, the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) raters were blinded to all efficacy measures and to patient dosage information. Patients were treated with rivastigmine and titrated to their highest tolerated dose, up to 12 mg/day (6 mg twice daily). The primary efficacy measure was cognitive function assessed by the ADAS-Cog subscale (without the concentration/distractibility item, to be consistent with cognitive outcome measures used in previous rivastigmine trials). RESULTS: Forty-seven percent of patients treated with rivastigmine 6-12 mg/day demonstrated improvement on the ADAS-Cog at 26 weeks, with >25% of patients having a clinically significant improvement of > or =4 points. Treatment with rivastigmine (6-12 mg/day) was well tolerated by the majority of patients. The most common adverse effects occurring in >10% of patients were nausea, vomiting, dizziness and diarrhoea. CONCLUSION: This pilot study suggests that rivastigmine treatment may have beneficial effects in the treatment of patients with mixed dementia.

Adding memantine to rivastigmine therapy in patients with mild-to-moderate alzheimer's disease: results of a 12-week, open-label pilot study.

OBJECTIVE: At present, inhibition of cholines-terase is the treatment of choice for subjects with mild-to-moderate Alzheimer's disease (AD). Memantine, a noncompetitive antagonist at N-methyl-d-aspartate receptors, is currently used to treat subjects with moderate-to-severe AD. The goal of this multicenter, open-label pilot study was to investigate whether combination therapy with memantine added to rivastigmine is safe and beneficial in subjects with mild-to-moderate AD. METHOD: Patients with a DSM-IV diagnosis of dementia of the Alzheimer's type (N = 95), who were treated with rivastigmine (6-12 mg/day) for a maximum duration of 24 weeks prior to baseline, received memantine (5-20 mg/day) in combination with rivastigmine for 12 weeks. The primary efficacy variable was the change in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score at the end of 12 weeks compared with baseline. The study was conducted between September 15, 2003, and May 27, 2004. RESULTS: There was a statistically significant difference between baseline and week 12 for the ADAS-cog total score, showing a positive effect of combination therapy. Combination therapy did not evidence any unexpected safety concerns and was well-tolerated by most patients. CONCLUSION: Memantine in combination with rivastigmine appears to be safe and beneficial in patients with mild-to-moderate AD. Our results need to be confirmed in a large, long-term, randomized, double-blind, placebo-controlled clinical trial.

Long-term effects of rivastigmine treatment on the need for psychotropic medications in nursing home patients with Alzheimer's disease : results of a 52-week open-label study.

BACKGROUND AND OBJECTIVE: Neuropsychiatric symptoms and behavioural disturbances occur in most patients with Alzheimer's disease (AD), are a source of stress for caregivers, and are the primary cause of patient institutionalisation. These symptoms often are treated with psychotropic medications. However, adverse drug interactions, adverse effects and nursing home regulations make reducing the use of psychotropic medications in elderly AD patients an important goal of therapy. Fifty-two-week data including data from a 26-week prospective open-label, multicentre study and its 26-week open-label extension were analysed. PATIENTS AND METHODS: 173 patients with moderate to severe AD residing in nursing homes were treated with rivastigmine 1.5-6mg twice daily. In the study, psychotropic drug use and behavioural symptoms were measured at baseline and at 52 weeks. RESULTS: Results showed that 40% of patients who were receiving psychotropic medications at baseline had discontinued use or reduced their dose of psychotropic medications at week 52. Furthermore, significant improvements were observed from baseline in 10 of the 12 behavioural domains of the Nursing Home version of the Neuropsychiatric Inventory, including delusions (mean change from baseline -2.0; p = 0.002), hallucinations (mean change -3.1; p < 0.001), anxiety (mean change -1.1; p = 0.014), and euphoria (mean change -3.2; p = 0.006). CONCLUSION: These data suggest favourable tolerability, behavioural and pharmacoeconomic outcomes in nursing home residents with AD who are treated with rivastigmine.

Pretreatment neurophysiologic function and ECT response in depression.

OBJECTIVES: Recent brain imaging studies have provided evidence that brain function assessed prior to treatment of depression may be associated with eventual treatment response. The present study tested the hypothesis that brain activity in midline apical quantitative EEG (QEEG) electrodes would be associated with therapeutic response to electroconvulsive therapy (ECT). METHODS: Ten treatment-refractory patients with unipolar or bipolar depression received a Hamilton Rating Scale for Depression (Ham-D) at baseline, during, and following ECT treatment. Resting, eyes-closed, 35-lead QEEG recordings were done 1 day before the initial ECT treatment. Data were analyzed using QEEG power and cordance. RESULTS: The mean of the theta-band pretreatment cordance from the central brain region was strongly associated with percentage decrease in Ham-D score over the course of treatment (r = 0.80, P = 0.005). QEEG cordance from other brain regions and power from all brain regions did not show an association with clinical improvement. CONCLUSIONS: Depressed subjects with higher pretreatment central cordance appear to be more likely to experience therapeutic benefits of ECT. The location of central electrodes over the cingulate cortex may indicate that pretreatment cingulate activity is associated with response to ECT.

Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior.

BACKGROUND: Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome. METHOD: In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001. RESULTS: Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings. CONCLUSION: The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.