Jean-Jacques Pere

Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up

Objective: To compare the efficacy and safety of clozapine in drug induced psychosis in Parkinson’s disease (PD). Methods: A four week, randomised, double blind, parallel comparison of clozapine and placebo, followed by a 12 week clozapine open period, plus a one month period after drug discontinuation, in 60 patients with PD. The primary efficacy outcome was the “clinical global impression scale” (CGI); the positive subscore of the “positive and negative syndrome scale” (PANSS) was used as the secondary efficacy parameter and the “unified Parkinson’s disease rating scale” (UPDRS) and the “mini mental test examination” (MMSE) as safety outcomes. Results: The mean (SD) dosage of clozapine was 35.8 (12.5–50) mg at the end of the double blind period. The mean (SD) scores on the CGI improved by 1.8 (1.5) for the clozapine group compared with 0.6 (1.1) for the placebo group (p  =  0.001). The mean (SD) positive subscore of PANSS improved by 5.6 (3.9) for the clozapine group (0.8 (2.8) for the placebo group; p < 0.0001). At the end of the open period, 25 patients had completely recovered from delusions and hallucinations, and 19 experienced a relapse within one month after the clozapine washout period. The UPDRS motor and MMSE mean scores did not change significantly in either group. Somnolence was more frequent with clozapine than with placebo. Conclusions: Clozapine at a mean dose lower than 50 mg/day improves drug induced psychosis in PD without significant worsening of motor function, and the effect wears off once the treatment stops.

Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil.

Summary Background: Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimers disease (AD). Donepezil is a specific, reversible inhibitor of AChE, while rivastigmine is a slowly reversible (pseudoirreversible) dual cholinesterase (ChE) inhibitor, with brain-regional specificity for the cerebral cortex and hippocampus. According to the European Marketing Authorisations, the clinical benefit of ChE inhibitors should be reassessed on a regular basis and discontinuation should be considered when evidence of a therapeutic effect is no longer present. However, substantial differences in the pharmacological and pharmacokinetic profiles of the available ChE inhibitors suggest that it may be desirable to switch between ChE inhibitors if patients fail to show efficacy, deteriorate or are unable to tolerate their initially prescribed medication. Design: This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons). Results: At the end of the study, 56.2% of patients were responders to rivastigmine, as assessed using a global function scale (the Clinicians’ Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of patients, respectively. Rivastigmine was generally well tolerated, the most common adverse events being nausea and vomiting, consistent with reports from previous clinical studies. The occurrence of side-effects or lack of efficacy with donepezil treatment was not a predictor of similar problems when treated with rivastigmine. Conclusion: Rivastigmine treatment appears to be beneficial in AD patients who have previously failed to benefit from, or were unable to tolerate treatment with, donepezil.

Fast Cognitive Decline at the Time of Dementia Diagnosis: A Major Prognostic Factor for Survival in the Community

Background/Aims: Current findings suggest the existence of a category of fast cognitive decliners with a poorer prognosis but better treatment response. Our study aimed at confirming the concept of fast decliners at the time of Alzheimer’s disease (AD) diagnosis which best predicts mortality, in an unselected sample. Methods: 245 incident cases of AD were selected from the French longitudinal cohort PAQUID. We investigated a different threshold of cognitive decline [measured by the annual loss of points in the Mini Mental State Examination (MMSE) score] to define when a subject could be considered as a fast decliner. We used Cox proportional hazards models to study the relation between cognitive decline and mortality. Results:The significant threshold of decline associated with a higher mortality rate was a loss of 3 points per year in the MMSE score. Among the 245 AD cases, 83 (33.9%) subjects were considered as fast decliners. Of them, 78.3% died during the follow-up compared with 63.0% of the slow decliners (RR = 1.7, 95% CI 1.2–2.5). Conclusion:These results constitute an empirical validation of the concept of fast decliners in community-based AD patients and justify the cutoff of 3 points for the definition of this condition.

Efficacy and Tolerability of Entacapone as Adjunctive Therapy to Levodopa in Patients with Parkinson’s Disease and End-of-Dose Deterioration in Daily Medical Practice: An Open, Multicenter Study

Entacapone is a potent, reversible and orally active inhibitor of catechol-O-methyltransferase. This open multicenter study evaluated the efficacy, safety and tolerability of entacapone as adjunct therapy to levodopa/dopa decarboxylase inhibitor (≧3 daily doses) in patients with idiopathic Parkinson’s disease and end-of-dose motor fluctuations. The 8-week study included 489 patients under conditions of typical daily medical practice. Patients were treated with a 200-mg fixed dose of entacapone administered with each scheduled dose of levodopa to a maximum of 10 doses per day. Other antiparkinsonian medication should have been stable for at least 1 month. The primary efficacy criteria were: (1) Part II (activities of daily living, ADL) of the Unified Parkinson’s Disease Rating Scale (UPDRS), (2) the reduction of ‘off’ time during the daily waking period as assessed by the percentage of patients improving by at least one category at Item 39 of Part IV of the UPDRS. Secondary outcome measures included: (1) the investigator’s global assessment of change, (2) quality of life (QoL) was assessed using the Parkinson’s Disease Questionnaire (PDQ-39). Adverse events, vital signs and liver enzymes were monitored at weeks 2 and 8. The baseline mean score for ADL was 10.5 (±7.04), which decreased to 8.5 (±6.37) at the end of the study (p < 0.0001). Compared to baseline, 40.8% of patients experienced a reduction in ‘off’ time during the waking period; this improvement was highly significant (p < 0.0001). A reduction in the daily dose of levodopa was observed in 35.8% of patients (mean decrease 209 ± 149 mg). QoL was improved by a mean of 10% in all categories of the PDQ-39 (p < 0.001), except social support and cognition. This improvement was statistically significant (p < 0.001). The dyskinesia score (UPDRS Item 32) was decreased significantly from 2.3 to 2.1 from baseline to end of study (p < 0.001), although 52.7% of patients reported levodopa-induced dyskinesia as an adverse event. There was no case of increased liver enzymes. The study results confirm that the excellent risk/benefit ratio seen in phase III controlled studies can be seen in daily neurological practice. Moreover, the study suggests that the benefits of entacapone are associated with a significant improvement in QoL.

Parkinson's disease dementia can be easily detected in routine clinical practice.

Parkinsons disease (PD) is mainly characterized by its motor manifestations, but it is also frequently associated with dementia. Early diagnosis of PD dementia (PDD) is particularly important because effective cholinesterase inhibitor treatments are available. This study aimed at validating a short procedure for screening for PDD in routine clinical practice and which adopts recently published diagnostic criteria. One hundred eighty‐eight patients with PD participated in the study. The examination procedure comprised three steps: standard clinical examination, a short cognitive function assessment fulfilling the requirements of the Movement Disorders Society (Mini Mental State Examination, five‐word test, word generation task, and impact on daily life, including a questionnaire on compliance with medication) and an extensive evaluation of cognitive functions and behavior. After each step, the suspected presence or absence of dementia was recorded. After the short cognitive function assessment, PDD was suspected in 18.62% of the patients [95% confidence interval (CI): 13.32‐24.93%]. After the extensive assessment, 21.81% (95% CI: 16.13‐28.40%) met the criteria for probable PDD. The short batterys sensitivity and specificity were 65.85% (95% CI = 49.41‐79.92%) and 94.56% (95% CI = 89.56‐97.62%), respectively. A stepwise logistic regression analysis showed that use of a specific cut‐off considerably enhanced the short batterys sensitivity (85.37%, 95% CI = 70.83‐94.43%) without decreasing its specificity (83.67%, 95% CI = 76.69‐89.25%). With an easy‐to‐use, short battery of tests that are commonly used in routine clinical practice, it is possible to diagnose PDD in accordance with reference criteria and with the same sensitivity and specificity as in a more extensive evaluation.

Utility of the Mattis dementia rating scale to assess the efficacy of rivastigmine in dementia associated with Parkinson's disease.

IntroductionThe severe, cortical, cholinergic depletion accompanying Parkinson’s disease (PD) is considered as a highly probable correlate of cognitive and behavioural dysfunction. Recent studies have demonstrated that cholinesterase inhibitors (notably rivastigmine) are beneficial in patients suffering from dementia associated with PD (PDD). However, the primary efficacy variables used in such work came from scales designed for Alzheimer’s disease (AD), even though the cognitive symptoms in PD and AD dementia do not overlap completely. The aim of the present study (a double-blind, placebo-controlled clinical trial) was to determine the utility of the Mattis dementia rating scale - the most commonly used scale in PD patients - to assess the efficacy of a 24-week rivastigmine treatment.MethodsTwenty-eight patients with PD, who constituted a subgroup of patients enrolled to the EXPRESS study (Emre et al, N Engl J Med 2004) participated in this study. They suffered from mild to moderately severe dementia (MMSE scores above 10 and below 24), with an onset of cognitive symptoms occurring at least two years after the diagnosis of PD. Patients were randomly assigned to treatment with rivastigmine (3 to 12 mg per day) or placebo. The Mattis dementia rating scale was administered to patients from six centres in France at the baseline and end-point visits.ResultsCompared with placebo, a 24-week rivastigmine treatment led to a significant improvement in the overall score on the Mattis dementia rating scale (p = 0.031), with a trend towards a significant improvement in the “Attention” subscale score (p = 0.061). Correlation analysis showed that in the rivastigmine group, performance on the Mattis “Attention” and “Initiation” subscales appeared to contribute heavily to the improvement in the overall score. Moreover, the latter was also related to an improvement in activities of daily living and a reduction in behavioural disturbances.DiscussionBy using the Mattis dementia rating scale (which comprises items that are sensitive to executive dysfunction), the present study confirmed that rivastigmine has a beneficial effect on cognitive function in PDD. Despite our study’s small sample size, the Mattis scale was able to detect this improvement and could thus be considered as an interesting outcome measure in further work.

No donepezil discontinuation effect in patients with Alzheimer's disease who were switched to rivastigmine after failing to benefit from donepezil treatment.

In 2002 we published findings from a study that evaluated the efficacy and safety/tolerability of the cholinesterase (ChE) inhibitor, rivastigmine (Exelon, Novartis), in patients with Alzheimer’s disease (AD) who had previously failed to benefit from donepezil (Aricept, Pfizer) treatment. The findings of this study show that more than 50% of patients who fail to receive sustained therapeutic efficacy from donepezil respond positively to subsequent treatment with rivastigmine. Since publication of this article, however, there has been some confusion as to whether the clinical decline seen in patients prior to being switched to rivastigmine was induced due to discontinuation (or ‘washing out’) of donepezil, and we would like to clarify this point here. In total, 382 patients with probable AD participated in this prospective 26-week, open-label study. Patients included were those who had experienced efficacy problems with donepezil (n = 304) and those unable to tolerate donepezil (n = 42). For patients included as efficacy failures, inclusion criteria stipulated a decline of at least two points on the Mini-Mental State Examination (MMSE) scale within a 12-month period while on (and not during discontinuation of) donepezil treatment, or a significant and documented loss of functional autonomy as assessed by their physician. An additional 36 patients included in the study met the inclusion criteria for both efficacy and tolerability problems on donepezil treatment. The efficacy of rivastigmine post-switch was assessed using the Clinicians’ Global Impression of Change (CGIC) scale (primary efficacy parameter), the MMSE and the four Instrumental Activities of Daily Living (4-IADL) scale. In patients fulfilling the entry criteria, treatment with donepezil was discontinued and patients underwent a drug-free period of at least 7 days and up to a maximum of 3 months (median duration – 14 days; 13 days in RESEARCH LETTER

Validation of the Test Your Memory (F-TYM Test) in a French Memory Clinic Population

The Test Your Memory (TYM) test has been proposed for screening dementia. We present a French version and its validation in memory clinics. F-TYM was administered to 201 patients with memory complaints visiting five secondary referral hospital centers. Final diagnosis was dementia in 34%, amnestic mild cognitive impairment (MCI) in 32%, non-amnestic MCI in 11%, absence of cognitive disorder in 23% and F-TYM scores were respectively (M ± SD) 30.9 ± 7.6, 40.5 ± 6.3, 44.3 ± 4.5 and 43.5 ± 6.6 (p < .0001). F-TYM showed high correlation with MMSE (r = .78), excellent internal consistency, no effect of educational level, sex, or mood but a significant effect of age (p = .004). A F-TYM score ≤ 39 had 0.90 sensitivity and 0.70 specificity for diagnosis of dementia. F-TYM was unable to discriminate MCI and patients without cognitive disorders. F-TYM could be proposed for screening of dementia in patients with memory complaints.

Cross-validation of a Shortened Battery for the Assessment of Dysexecutive Disorders in Alzheimer Disease.

The frequency of executive disorders in mild-to-moderate Alzheimer disease (AD) has been demonstrated by the application of a comprehensive battery. The present study analyzed data from 2 recent multicenter studies based on the same executive battery. The objective was to derive a shortened battery by using the GREFEX population as a training dataset and by cross-validating the results in the REFLEX population. A total of 102 AD patients of the GREFEX study (MMSE=23.2±2.9) and 72 patients of the REFLEX study (MMSE=20.8±3.5) were included. Tests were selected and receiver operating characteristic curves were generated relative to the performance of 780 controls from the GREFEX study. Stepwise logistic regression identified 3 cognitive tests (Six Elements Task, categorical fluency and Trail Making Test B error) and behavioral disorders globally referred as global hypoactivity (P=0.0001, all). This shortened battery was as accurate as the entire GREFEX battery in diagnosing dysexecutive disorders in both training group and the validation group. Bootstrap procedure confirmed the stability of AUC. A shortened battery based on 3 cognitive tests and 3 behavioral domains provides a high diagnosis accuracy of executive disorders in mild-to-moderate AD.

Reply: Brief cognitive tests in the screening of dementia in Parkinson's disease†‡

We read with interest the article by Dujardin et al., in which the investigators aimed to design a simple neuropsychological battery able to easily and accurately screen for dementia in Parkinson’s disease (PDD) in routine clinical practice. Brief cognitive tests have been developed in the field of dementias for screening mild Alzheimer’s disease, but few efforts have been done for screening PDD. We would like to note that our group previously published, in Movement Disorders, the validation study of the PDD-Short Screen (PDD-SS), a brief cognitive test that showed high diagnostic accuracy for screening PDD. Although abundant data regarding clinimetrics may bore clinicians looking for a practical neuropsychological instrument, adequate clinimetric development is mandatory for an instrument to be recommended. In this regard, no information on the validity, consistency, reliability, and administration time of the scale was provided, and no single cut-off score for the whole scale was given. The investigators indicated cut-off scores for some of the tests that form the battery, but no detail of the accuracy for each item was provided. Although the scale appears to have excellent specificity (95%) for screening PDD, overall sensitivity (65%) is rather low. Moreover, it was not indicated which cut-off score was obtaining this diagnostic accuracy. Instructions regarding how to add the scores of every item of the scale to obtain the final score should have also been provided. In screening for PDD, and using a cut-off score 11, the PDD-SS showed 89.8% sensitivity, 88.5% specificity, 80.7% positive predictive value, and 93.6% negative predictive value for the diagnosis of PDD. The PDD-SS showed a similar diagnostic accuracy than the Mattis Dementia Rating Scale, with the additional benefit of having a significantly shorter administration time (4–7 vs. 17–25 minutes). In our validation study, the PDD-SS also showed appropriate clinimetric characteristics, with good to excellent construct and discriminative validity, and test-retest and interrater realibility. Also, PDD-SS scores were not influenced by age or education. The robustness in the structure and the ability of the scale to detect neuropsychological differences between individual patients allowed us to set up a short final version with a single cut-off score, which simplifies and allows an easier generalization of the instrument. Although simplicity and briefness are important virtues for a cognitive scale, its applicability as a screening instrument must be supported by appropriate clinimetric investigations that guarantee a correct diagnosis in clinical situations (i.e., diagnosis of dementia) with important individual consequences.