Diagnosis of Alzheimer's disease patients with rapid cognitive decline in clinical practice: interest of the Deco questionnaire.

BACKGROUND: Patients with Alzheimer's disease (AD) who deteriorate rapidly are likely to have a poorer prognosis. There is a clear need for a clinical assessment tool to detect such a decline in newly diagnosed patients. OBJECTIVE: To identify the predictive factors of rapid cognitive decline (RCD) in a cohort of patients with mild to moderate AD ; and to validate a self-questionnaire for caregivers as a diagnostic tool for rapid decline. DESIGN AND ANALYSIS: An open-label, observational, 12-month, multicenter, French study. Physicians were asked to record data of three eligible rivastigmine naïve (or on rivastigmine for < 1 year) AD patients. Risk factors of RCD and the detection power of the Détérioration Cognitive Observée scale (Deco), a 19 item self-questionnaire for caregivers, were assessed at endpoint using regression analyses. RESULTS: Out of the 361 patients enrolled in the study, 91 (25.2%) were excluded due to loss of follow-up. Among subjects using cholinesterase inhibitors or memantine, 161 (59.6%) experienced a stabilization (29.2%) or an improvement (30.4%) in global functioning as measured by the CGI-C. Sixty of the remaining 204 patients retained for analysis (29.6%, CI 95% [23.4; 35.8]) lost three or more points on the MMSE score between the inclusion and one of the follow-up visit. In the multivariate logistic regression analysis, institutionalization, higher level of education and the loss of 3 points or more on the MMSE were found to be significant predictors of a rapid cognitive loss in this population. The threshold which maximizes the predictive values of the Deco score as a diagnostic tool of rapid cognitive decline was significantly different according to the age of the patient (below or over 75 years old). A score below 16 for patients < 75 years old and below 14 for patients ≥ 75 years old consistently predicted a RCD within the next year. CONCLUSION: The Deco test appears to be a simple tool to alert the physician to the possibility of an aggressive course of the disease which warrants particular management.

Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment.

We investigated the efficacy and safety of rivastigmine alone and combined with memantine in Alzheimer's disease patients previously failing on donepezil or galantamine. This was a prospective, open-label, multicentre study. After stopping donepezil or galantamine, patients received rivastigmine 3-12 mg/day for 16 weeks. Non-responders to rivastigmine monotherapy at week 16 received memantine 5-20 mg/day plus rivastigmine for 12 weeks. The primary efficacy parameter was response (Mini-Mental State Examination equal or better than at week 16) to dual therapy at week 28. Secondary criteria were changes on cognitive and behavioural scales. Two hundred and two patients were included. Ninety-three (46.3%) patients responded to rivastigmine monotherapy. Of 86 patients receiving additional memantine for another 12 weeks, 67 (77.9%) responded. Combination therapy caused no apparent safety concerns. When patients fail on donepezil or galantamine, switching to rivastigmine may improve cognition and behaviour. Should they continue to deteriorate, the addition of memantine may be beneficial.

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.

[Leponex, 10 years after -- a clinical review]. / Leponex, 10 ans après -- Une revue clinique.

Clozapine was one of the major advances in the treatment of schizophrenia since the introduction of the classic antipsychotic agent chlorpromazine in the 1950s. Over the past 10 years, clozapine has become the reference compound for the development of new antipsychotics, and new drugs have been developed which have also claimed atypical status. The indications of clozapine were recently extended to Psychosis in Parkinson's disease and harmonized in the European Union. This provides the opportunity to update the data on clozapine in the treatment of schizophrenia. In this article we review current clinical evidence in schizophrenia to address the following issues: 1) Efficacy in refractory/positive symptoms: a systematic and critical analysis of 14 double-blind clinical trials in comparison with both standard and novel antipsychotics show consistent findings in favour of clozapine, with all but three of the reports demonstrating superiority. The review of studies allow us to say little about the predictors of treatment response, time to clozapine response and about the impact of clozapine on the quality of patients'life and longer-term outcome. Treatment options for clozapine non-responders are reviewed. 2) Risk of EPS: clozapine is considered to have a minimal risk of EPS and in all studies where a valid methodology was used, a clear superiority over the other neuroleptics is demonstrated. It is pointed out that, if the prevalence and incidence of EPS with clozapine is low, it is not zero. All the studies assessing clozapine treatment for TD have major methodological limitations, so no final conclusion can be drawn. 3) Efficacy for primary and secondary negative symptoms and neurocognitive effects: the data of clinical studies where negative symptoms scales were used favour clozapine in terms of improvement. However most of the studies were carried out in populations with predominantly positive symptoms. With regard to the need to distinguish primary and secondary symptoms, data are conflicting regarding the benefit of clozapine. Due to the lack of studies with a valid methodology, no definitive conclusion can be drawn about the efficacy on clozapine on the deficit syndrome and on neurocognitive disorders. 4) Impact on suicide risk: 4 out of 6 retrospective studies provide evidence for the ability of clozapine therapy to reduce suicidal behaviour. The results of a recent randomized, parallel-group study designed to compare clozapine versus olanzapine in preventing suicide attempts seems to confirm this hypothesis. We also address the tolerability and safety data, especially haematologic, comitial, cardiovascular and metabolic side-effects. The effectiveness of blood monitoring for the management of neutropenia and agranulocytosis demands that the recommendations are strictly followed. The use of clozapine at doses higher than 600 mg daily should follow published recommendations, in order to minimize the risk of seizures; these include anticonvulsant regimens based on blood levels. With regard to the cardiovascular mortality, if clozapine therapy has negligible effects on QT interval, its association with potential fatal myocarditis cannot be excluded in young patients who should be investigated if they develop cardiac symptoms in the first weeks of treatment. Available data support the notion that the frequency of bodyweight gain is high with several new antipsychotics, including clozapine. Potential long term effects of bodyweight gain on mortality and morbidity have to be taken into consideration. The pharmacological mechanisms underlying the "unique clozapine profile" is discussed. Clozapine remains the only antipsychotic with efficacy at relatively low D2 receptor occupancy. The pharmacogenetic and pharmacokinetic aspects are also reviewed. Finally, the place of clozapine in the current treatment of schizophrenia is highlighted to inform the development of guidelines for clinical management.

Efficacy and tolerability of entacapone in patients with Parkinson's disease treated with levodopa plus a dopamine agonist and experiencing wearing-off motor fluctuations. A randomized, double-blind, multicentre study.

The efficacy and tolerability of entacapone was investigated in a randomized, double-blind, placebo-controlled, 3-month study of 162 patients with Parkinson's disease (PD) treated with levodopa and a dopamine agonist and experiencing wearing-off motor fluctuations. Patients were randomized in a 3 : 2 ratio to entacapone 200 mg or placebo, administered with each dose of levodopa. Efficacy was judged on the improvement of "on" and "off" time while awake (Patient Diary and UPDRS part IV Item 39), Investigators' Global Assessment, the SF-36 Health Survey, and changes in levodopa dosages. Patients were monitored for adverse events, laboratory safety and vital signs throughout the study. Improvements in "on" time as assessed using patient diary data showed a trend in favour of entacapone, however these did not reach statistical significance. "Off" time while awake (UPDRS part IV Item 39) showed an improvement of at least one category in 36% of entacapone-treated patients, compared with 22% in the control group (p = 0.0038). The proportion of patients showing an improvement at the Investigators' Global Assessment was significantly higher (p = 0.0006) in the entacapone-treated group of patients. Also, the proportion of patients with a reduction in their daily levodopa dose was significantly higher (p = 0.02) in the entacapone group (28%) compared with placebo (13%). As expected, the most frequent adverse events were dopamine-mediated (dyskinesia: entacapone 31% versus placebo 13%), and harmless urinary discoloration. The modest increase in dyskinesias could be readily managed by levodopa down-adjustment, and, at study end there was no significant difference for the UPDRS "overall dyskinesia score" between entacapone and placebo. In conclusion, although the primary efficacy variable did not reach statistical significance, the present results demonstrate that entacapone provides additional antiparkinsonian benefits to levodopa therapy and is well tolerated in levodopa-treated PD patients experiencing wearing-off motor fluctuations despite adjunct dopamine agonist therapy.

[Rivastigmine in current clinical practice in patients with mild to moderate Alzheimer's disease]. / Utilisation de la rivastigmine en pratique médicale courante chez des patients ambulatoires présentant une maladie d'Alzheimer.

Six hundred and sixty nine out patients with mild to moderate Alzheimer's disease were enrolled by 193 French neurologists, psychiatrists and gerontologists. The patients, 38p.cent males and 62p.cent females with a mean age of 75 years were progressively titrated from 3 to 12mg by day of rivastigmine, Exelon((R)), a day, and treated for 6 months. Mean Mini-Mental State (MMS) at baseline was 18.6. Concomitant pathologies and treatments were present in 89p.cent of the patients. Safety was good though 86p.cent reported an adverse event which was mild in most of the cases. The premature drop out rate was 29p.cent. Seventy-five patients showed no change or an improvement in their 4 Instrumental Activities of Daily Living (IADL) score with no change in the MMS at the end of treatment (18.8). Four items of the Neuro-Psychiatric Inventory (NPI): delusions, anxiety, apathy, and irritability were significantly improved at week 12 and the improvement in anxiety was still significant at the end of treatment. The total score frequency X severity showed a tendency to improvement. The correlations between the sum of the 4 IADL, MMS and NPI scores were strongly significant.

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

BACKGROUND: Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimer's 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.

A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.

OBJECTIVE: This prospective, double-blind, multicenter, parallel-group study compared the efficacy and safety of therapeutic doses of clozapine and risperidone in patients with severe chronic schizophrenia and poor previous treatment response. METHOD: Male or female patients aged 18-65 years who met DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response (N=273) were randomly assigned to double-blind treatment with either clozapine or risperidone administered over 12 weeks in increasing increments. The primary efficacy measures were the magnitude of improvement in Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. Adverse events were recorded throughout the study. RESULTS: The magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group. Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures (Positive and Negative Syndrome Scale, Calgary Depression Scale, Psychotic Depression Scale, and Psychotic Anxiety Scale). The adverse event profile was similar for both treatment groups, with a lower risk of extrapyramidal symptoms in the clozapine group. CONCLUSIONS: Clozapine showed superior efficacy over risperidone in this patient population. Both treatments were equally well tolerated as demonstrated through their adverse event profiles, although as expected clozapine was associated with a lower risk of extrapyramidal symptoms than risperidone.

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 (> or = 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.

[Clinical psychopharmacology: the example of clozapine (Leponex)]. / Psychopharmacologie clinique: l'exemple de la clozapine (Leponex).

Ever since clozapine was discovered, researchers have been attempted to answer the question of what makes it different and how to relate its many pharmacological actions to its clinical features. Its clinical profile conflicts with the hypothesis that antipsychotic effect is due entirely to D2 dopamine receptor blockade. Clozapine is known to interact with many neurotransmitters systems. To date, four main hypothesis have been proposed in an attempt to explain some or all for clozapine's atypical properties: selective blockade of mesolimbic dopamine function; D1, D2, D3 and D4 receptor blockade; 5-HT2 and D2 receptor blockade; Potent alpha 1 adrenergic blockade. These hypothesis are reviewed in relation to the clozapine clinical profile. No hypothesis fully accounts for clozapine's spectrum of neurotransmitter interactions. Such a multiplicity of action would preclude a unified mechanism.

[Therapeutic trials in Alzheimer disease. Selection--recruitment and stratification]. / Essais thérapeutiques dans la maladie d'Alzheimer. Sélection--recrutement et stratification.

Therapeutic trials conducted in Alzheimer's disease have benefited from the standardization of diagnostic criteria based on internationally recognized scales (DSM III-R, NINCDS-ADRDA) which ensure more valid inclusions. Well specified exclusion criteria are also of the utmost importance, in particular depression, vascular dementia and concomitant psychotropic drugs. Cognitive and/or functional scales allow an appreciation of the severity of the disease. Due to the heterogeneity of Alzheimer's disease stratification methods on identified prognostic factors i.e. aphasia, extrapyramidal symptoms should be performed. Selection of responders during an enrichment phase has still to be discussed. Multicentric studies become imperative because of the large number of patients required and the difficulties in selecting the adequate patients. These raise the issues of investigators' experience, coordination and between center variability.

[Clozapine (Leponex) in France]. / La clozapine (Leponex) en France.

Leponex (clozapine) is an atypical neuroleptic indicated in severe schizophrenia, launched in France in December 1991. The safety and efficacy data pertaining to 1,062 patients treated on a compassionate needs basis between May 1989 and December 1991 constitute the first French experience on the drug. The results of an interim analysis pertaining to 602 patients, i.e. available data on 03-15-1992, generally collected on a retrospective basis, by means of a specific questionnaire are reviewed. The population included patients with severe and long-standing schizophrenia i.e. 15.71 +/- 9.3 years, resistant to usual neuroleptic therapy (90.86% of cases), and rarely with a history of intolerance to this class (2.49%). The indication was in the majority of the cases a paranoid schizophrenia (67.2%). The mean maintenance daily dose was 419 mg/d (+/- 152). Overall, with respect to associated drugs, neuroleptics were recorded in 16.4%, another psychotropic drug in 44.7% and symptomatic treatments for extrapyramidal disorders in 21.3% of patients. Of interest is the fact that, for those patients started on Leponex more recently, the drug is more often prescribed on a single basis. Leponex was stopped in 24.3% for the following reasons: adverse events 10.6%, lack of efficacy 6%, non compliance 3.8%, other reasons 3.8%. The adverse event profile is consistent with the literature data, taking into account the fact that certain adverse events were more commonly described: fatigue of lower limbs 11.8%, leucocytosis 19.8% and eosinophilia 4.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clozapine and resistant schizophrenia]. / Clozapine et schizophrénie résistante.

Clozapine is an atypical antipsychotic drug, with distinguishing features from neuroleptics which are believed to exert their therapeutic effect by blocking dopamine receptors in the limbic system. Clozapine is both chemically and pharmacologically distinct from neuroleptics such as chlorpromazine and haloperidol. This tricyclic dibenzodiazepine derivative is moderately active on the dopaminergic pathways, blocking D1 and D2 receptors to the same extent; and chronic treatment with clozapine does not lead to a compensatory increase in the number of striatal D2 receptors in rats. Pharmacological studies showed that clozapine produces psychomotor inhibition but without catalepsy and other typical effects of dopamine receptor blockade. The drug also has adrenergic (alpha 1), histamine (H1), and serotonin (5-HT2) blocking activity and is a potent muscarinic antagonist. The efficacy and side-effect profile of clozapine are unique. Treatment-resistant patients are much more likely to respond to clozapine than to haloperidol or chlorpromazine. In double-blind trials, clozapine has improved both positive and negative psychotic symptoms in schizophrenic patients who were refractory to conventional neuroleptics. Extrapyramidal side-effects are exceptional during therapy and tardive dyskinesia never demonstrated in relationship to clozapine. There is an increased risk of agranulocytosis with clozapine use estimated to be up to 20 cases of agranulocytosis per thousand patients treated during one year. Accordingly, a careful patient selection and regular blood monitoring are mandatory over the treatment period (blood testing to be performed weekly and immediately at the first sign of infection). Generally, this agranulocytosis is reversible with early detection and prompt drug discontinuation.

Reliability of clinical criteria for the diagnosis of dementia. A longitudinal multicenter study.

The reliability of the clinical diagnosis of dementia was estimated by comparing the diagnosis made at 1-year intervals on 55 consecutive subjects with suspected cognitive impairment seen at three different centers by neurologists and gerontologists. The diagnosis was based on history and clinical examination, the criteria of the Diagnostic and Statistical Manual of Mental Disorders (revised ed 3), the Modified Ischemic Score, and a computed tomographic scan. Fifty-two of 55 subjects were given the same diagnosis a year later indicating a reliability of 95%. The study shows that a diagnosis of dementia established by simple clinical criteria comparable to the NINCDS/ADRDA criteria affords sufficient reliability to allow the comparability of groups at different centers for purposes of research, including research on the evaluation of the efficacy of pharmacologic treatment.

Predictors of non-bedridden survival in dementia.

The present study examined non-bedridden survival in 105 patients diagnosed as demented (Alzheimer's disease, multi-infarct dementia, mixed dementia) in a neurological ward. Follow-up observations were made. During the first year, the cumulative mortality rate was 69% compared to a rate of 44% in the second year. The initial disability stage, as assessed by the Dementia Disability Scale, was found to be the only significant predictor of non-bedridden survival. The type of dementia, age, type of diagnosis, and post-hospitalization placement in an institution have not been found to be significant predictors of this evolution.

[Development of a neurological score for the clinical evaluation of sylvian infarctions]. / Mise au point d'un score neurologique pour l'évaluation clinique des infarctus sylviens.

Among the main methodological problems raised by clinical trials in cerebral vascular accidents, one of the most serious is the lack of well-established and widely accepted criteria to evaluate the course of the disease. On the basis of published scores and of several trials carried on by us in three different centres during the last few years, we have developed a neurological score devised to reflect, as accurately as possible, deficits due to infarctions in the Sylvian territory, yet rapid and simple enough to provide an objective and reproducible rating. We report here the results of a prospective study concerning the inter-rater variations of the score from one centre to the other (inter-centre study) and within each centre (intra-centre study). These results have led us to withdraw three items with insufficient response rate and poor agreement, viz, "mental confusion", "visual field" and "sensory disorders". With the remaining 10 items the mean agreement between individual items varied from 85% to 90% and the global score agreement exceeded 90%. A study comparing our score with the Barthel index showed close correlation up to the autonomy threshold (Barthel index = 60) and divergent results beyond that point. The good agreement observed between inter-rater variations suggests that the score is reliable but does not inform on its sensitivity. In view of their relative independence, the neurological and the functional score should be regarded as complementary and should be used together as criteria of clinical assessment.

[Methodology of a controlled trial of dihydroergotoxine in acquired intellectual impairment in the adult]. / Méthodologie d'un essai contrôlé de la dihydroergotoxine dans les détériorations intellectuelles acquises de l'adulte.

The aim of the trial was to compare the clinical efficacy of dihydroergotoxin with a placebo, and to define its indications in the treatment of acquired dementia of abiotrophic origin (degeneration by primary cerebral atrophy) or arteriopathic (deterioration as the result of multiple cerebral infarcts) origin. It was a single centre, double-blind, randomized, controlled, experimental clinical trial. The trial involved 3 groups, each corresponding to a stage of increasing severity. Each group was randomized separately. The separation between the abiotrophic dementia group and the arteriopathic dementia group was made after the trial, on the basis of clinical criteria (Hachinski ischemic score), and a scan when applicable. The number of subjects necessary was fixed at 100 (33 per group). The duration of the trial was 6 months per patient.