Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D2 receptors... more Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D2 receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT2A receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for 5-HT2A receptors as cyamemazine, whereas its D2 receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2–3):142–147, 2008). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT2A receptors. Objectives The objective of this study is to measure steady-state plasma levels of N-desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D2 and serotonin 5-HT2A receptor occupancies (RO) assessed by positron emission tomography (PET). Methods Eight patients received Tercian® 37.5, 75, 150, or 300 mg/day according to their symptoms. Dopamine D2 and serotonin 5-HT2A RO were assessed at steady-state cyamemazine plasma levels using [11C]raclopride and [11C]N-methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant (K i) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. Results After 6 days of cyamemazine administration, plasma N-desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377–384, 2005). Plasma levels of N-desmethyl cyamemazine were closely related to striatal D2 RO (r 2 = 0.942) and extrastriatal 5-HT2A RO (r 2 = 0.901). The estimated K i(app) value of N-desmethyl cyamemazine for striatal D2 receptors was about fivefold higher than that for extrastriatal 5-HT2A receptors (48.7 vs. 10.6 nM). Striatal D2 RO increased with the plasma levels of N-desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N-desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT2A and D2 receptor occupancy. Conclusions In patients orally given cyamemazine, N-desmethyl cyamemazine, but not cyamemazine sulfoxide, should significantly contribute to in vivo frontal 5-HT2A and striatal D2 receptor occupancy. The higher in vivo affinity of cyamemazine and its desmethyl metabolite for serotonin 5-HT2A receptors compared with dopamine D2 receptors should explain the low incidence of extrapyramidal adverse effects.
Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux... more Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux (SPCD), la perte de poids, les troubles de la mobilité et la perte d’autonomie fonctionnelle, sont responsables d’une altération de la qualité de vie du patient. Les SPCD représentent la principale complication de la maladie. Il est important de les dépister, de les prévenir et de les traiter précocement. Leur prise en charge doit comprendre, en première intention, les mesures non pharmacologiques associées ou non aux mesures pharmacologiques. La perte de poids, quant à elle, est associée à une augmentation du risque d’hospitalisation et d’entrée en institution. Elle pourra être surveillée par le suivi de la courbe pondérale et le MNA. Les troubles de la mobilité, responsables de chutes et les symptômes moteurs sont également les complications fréquemment rencontrées. Enfin, l’épuisement de l’aidant doit évidemment être considéré comme une conséquence de la maladie et un élément important de sa prise en charge. Ces complications et leur conséquences doivent être identifiées et, dans la mesure du possible, évitées grâce à un plan de soin d’aide et de suivi spécifique. Complications in Alzheimer’s disease such as functional decline, weight loss, gait and balance disturbances and behavioral and psychological symptoms in dementia (BPSD) have a negative impact on quality of life. It is therefore important to identify these complications at an early stage. BPSD are major features of Alzheimer’s disease and related disorders. They represent half of admissions to special care units with, in order of frequency, agitation and agressivity. The non pharmacological approach must be implemented first and linked to a pharmacological approach. Weight loss is of complex physiopathology. It can be monitored by observation of the weight curve and use of the Mini Nutritional Assessment (MNA). Weight loss may be responsible for an increased risk of institutionalization and mortality. Gait and balance disturbances are also a prevalent complication of the illness and lead to an increased risk of falls and injuries. Neurological complications take the form of seizures and motor symptoms. Amongst these complications the burden of the caregiver must also be assessed. These complications and their consequences must be identified and, wherever possible, prevented with a specific care plan.
The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably between individuals... more The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably between individuals, with some subjects showing substantial deterioration and others showing little or no change over the course of the disease. These wide variations support the relatively new concept of Rapid Cognitive Decline (RCD). Patients with an accelerated rate of cognitive decline have showed to present a worse evolution in terms of mortality, loss of autonomy and institutionalisation. The conclusions from RCD studies conducted in the past years remain very heterogeneous and sometimes contradictory. This is possibly due to methodological differences, mainly the different “a priori” definitions of RCD used to identify rapid decliners. Consequently of this, there is considerable variation in reported frequency of patients with RCD which may vary from 9.5% to 54%. The lack of both consensus definition and consensual clinical assessment tools is one of the major barriers for establishing an appropriated management of rapid decliners in clinical practice. Presently, management of rapid decliners in AD remains to be a challenge waiting to better know predictive factors of a RCD. To date no specific guidelines exist to follow-up or to treat patients with this condition. This consensus paper proposes the loss of 3 points or greater in Mini-Mental State Examination (MMSE) during six months as an empirical definition of rapid cognitive decline to be used in routine medical practice and to be relevant for clinical-decision making in patients with mild to moderately-severe AD.
Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux... more Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux (SPCD), la perte de poids, les troubles de la mobilité et la perte d’autonomie fonctionnelle, sont responsables d’une altération de la qualité de vie du patient. Les SPCD représentent la principale complication de la maladie. Il est important de les dépister, de les prévenir et de les traiter précocement. Leur prise en charge doit comprendre, en première intention, les mesures non pharmacologiques associées ou non aux mesures pharmacologiques. La perte de poids, quant à elle, est associée à une augmentation du risque d’hospitalisation et d’entrée en institution. Elle pourra être surveillée par le suivi de la courbe pondérale et le MNA. Les troubles de la mobilité, responsables de chutes et les symptômes moteurs sont également les complications fréquemment rencontrées. Enfin, l’épuisement de l’aidant doit évidemment être considéré comme une conséquence de la maladie et un élément important de sa prise en charge. Ces complications et leur conséquences doivent être identifiées et, dans la mesure du possible, évitées grâce à un plan de soin d’aide et de suivi spécifique. Complications in Alzheimer’s disease such as functional decline, weight loss, gait and balance disturbances and behavioral and psychological symptoms in dementia (BPSD) have a negative impact on quality of life. It is therefore important to identify these complications at an early stage. BPSD are major features of Alzheimer’s disease and related disorders. They represent half of admissions to special care units with, in order of frequency, agitation and agressivity. The non pharmacological approach must be implemented first and linked to a pharmacological approach. Weight loss is of complex physiopathology. It can be monitored by observation of the weight curve and use of the Mini Nutritional Assessment (MNA). Weight loss may be responsible for an increased risk of institutionalization and mortality. Gait and balance disturbances are also a prevalent complication of the illness and lead to an increased risk of falls and injuries. Neurological complications take the form of seizures and motor symptoms. Amongst these complications the burden of the caregiver must also be assessed. These complications and their consequences must be identified and, wherever possible, prevented with a specific care plan.
Contexte Chez les sujets âgés, les troubles du sommeil sont très variés. On peut répartir les suj... more Contexte Chez les sujets âgés, les troubles du sommeil sont très variés. On peut répartir les sujets âgés en trois groupes: en bonne santé, dépendants, fragiles. Le concept de fragilité est récent et correspond à des personnes avec une morbimortalité plus grande. Objectifs Le but de cette revue de consensus est de décrire les troubles du sommeil observés chez les sujets âgés dans ces trois groupes et de discuter les potentiels troubles du sommeil et leurs conséquences chez les sujets âgés fragiles. Méthodes Un groupe de travail incluant des neurologues, des gériatres, des psychiatres et des spécialistes du sommeil a été créé pour étudier les troubles du sommeil dans ces trois groupes de sujets âgés. Toutes les études publiées sur le sommeil des sujets âgés sur Ovid Medline ont été revues, et 106 ont été retenues. Résultats De nombreux sujets âgés en bonne santé se plaignent de la qualité de leur sommeil. Ils rapportent des difficultés à s’endormir, de multiples éveils nocturnes, un réveil de mauvaise qualité et trop précoce et une somnolence diurne. L’architecture du sommeil est modifiée par l’âge, avec une augmentation du temps passé en stade 1 et une diminution du temps passé en stades 3 et 4. L’insomnie est fréquente chez le sujet âgé. Parmi ses causes, on retrouve les pathologies douloureuses, le stress psychologique, la diminution de l’activité physique et les effets indésirables des médicaments. La somnolence diurne des sujets âgés est souvent d’origine médicamenteuse. La prévalence des troubles primaires du sommeil, tels le syndrome des jambes sans repos (SJSR), les mouvements périodiques de jambes (MPJ) et les troubles ventilatoires du sommeil, augmente avec l’âge. Ces troubles ont des conséquences sur la mortalité, les atteintes neurologiques et cardiovasculaires des sujets âgés. La cause la plus fréquente de dépendance est la maladie d’Alzheimer. Les patients atteints de cette maladie ont un sommeil perturbé. Les modifications du sommeil chez ces patients sont du même type que chez les sujets âgés non déments, mais sont plus sévères. Les plaintes principales sont des troubles du maintien du sommeil et une somnolence diurne. Ces troubles sont la conséquence de modifications du rythme veille/sommeil, de facteurs environnementaux, psychologiques et iatrogènes. Ils peuvent être majorés par d’autres troubles du sommeil comme les troubles ventilatoires du sommeil. Le sommeil des sujets âgés fragiles n’a jamais été formellement étudié, mais quatre axes d’investigations devraient être explorés: 1) les anomalies de l’architecture du sommeil; 2) l’insomnie; 3) le SJSR; 4) les troubles ventilatoires du sommeil. Conclusion Les connaissances dans le domaine du sommeil du sujet âgé se sont développées ces dernières années. Mais cette population très hétérogène devrait être étudiée en fonction de son état de santé. Context There are many kinds of sleep disorders amongst the elderly population, a group that can be divided into three subgroups, namely: the healthy, the dependent and the fragile. This new concept of fragility refers to people with higher morbidity-mortality rates. Objectives This consensus review aims to describe sleep disorders observed in these three groups and discuss potential sleep disorders and their possible effects on the more fragile. Method: A working group consisting of neurologists, gerontologists, psychiatrists and sleep specialists was established, in order to study sleep disorders in the three subgroups of elderly people. All studies that had been published so far on Ovid Medline relating to sleep problems in the elderly were reviewed, and 106 were used for the survey. Results Many healthy elderly individuals complain about the quality of their sleep. They find it difficult to get to sleep, wake frequently, wake up too early and then feel sleepy during the day. Sleep architecture alters with age, with more time being spent in stage 1 and less in stages 3 and 4. The elderly often suffer from insomnia, which has a range of causes: painful conditions, psychological stress, reduced physical activity, side effects of medicines. Daytime somnolence is often caused by medication. Primary sleeping problems such as restless legs syndrome and breathing difficulties increase with age. Such disorders in the elderly can impact on mortality, as well as causing neurological and cardiovascular problems. The most common cause of dependence is Alzheimer’s disease. Patients suffering from this illness have disturbed sleep patterns, which are similar to, but more severe than those of elderly individuals not affected by dementia. The main complaints are the inability to stay asleep and daytime somnolence. These disturbances are caused by alterations to the waking/sleeping rhythm, as well as by environmental, psychological, and iatrogenic factors. They can be exacerbated by other sleep problems, such as breathing difficulties. The sleeping patterns of fragile, elderly populations have not yet been studied formally, but there are four clear directions worthy of investigation: 1) anomalies in sleep architecture; 2) insomnia; 3) restless legs syndrome; 4) breathing difficulties during sleep. Conclusion Our knowledge of sleeping patterns in the elderly has increased over the past few years, but this very diverse population should be studied in subgroups, determined by state of general health.
Given the poorer prognosis of Alzheimer&a... more Given the poorer prognosis of Alzheimer's disease (AD) patients with rapid cognitive decline (RCD), there is a need for a clinical assessment tool to detect these patients. To investigate if there is a Mini Mental State Examination (MMSE) threshold of decline during 6 months of follow-up which predicts a worse disease progression at the 2-year follow-up. Then, to propose a feasible definition of RCD for routine clinical practice. Data from 565 community-dwelling AD patients recruited in a multi-centre prospective observational study were assessed. All patients had MMSE scores between 10 and 26 at inclusion and were followed up 6-monthly using a standardised clinical assessment. Patients were classified as rapid and non-rapid decliners according to 2 MMSE decline thresholds tested: >or=3 points and >or=4 points for decline over the first 6 months of the study. Worse disease outcome was defined as attainment of 1 of 4 clinical end points 18 months later: institutionalisation, death, increased physical dependence or worsening of behavioural and psychological symptoms. 135 patients (23.9%) lost >or=3 points during the first 6 months of follow-up in the MMSE score and 77 patients (13.6%) lost >or=4 points. Patients with moderate disease and a loss of >or=4 points showed a significantly increased risk of mortality (HR = 5.6, 95% CI 2.0-15.9) and institutionalisation (HR = 3.8, 95% CI 1.8-8.1) at the 2-year follow-up. The same MMSE threshold was associated with a higher risk of physical decline (HR = 1.6, 95% CI 1.2-2.3). The loss of >or=4 points in MMSE during the first 6 months of follow-up seems to be a predictor of worse clinical course, and thus it could be used to define the category of AD patients presenting a RCD.
Intravenous (iv) administration of an antidepressant is a common practice in some European countr... more Intravenous (iv) administration of an antidepressant is a common practice in some European countries, particularly in France, Spain, and Italy in the initial treatment phase of hospitalised, severe depressed patients. After a beneficial response is observed, patients are switched to an oral formulation. The approved treatment period of the iv form of citalopram is limited to 8-10 days. The high bioavailability of citalopram permits the use of identical iv and oral doses. Citalopram is a racemate, consisting of a 1:1 mixture of the S- and R-enantiomers. The therapeutically active component is the S-enantiomer (escitalopram). Pharmacokinetic single dose administration studies in healthy subjects have demonstrated that daily oral administration of 20 mg of escitalopram or 40 mg citalopram results in similar plasma concentrations of the S-enantiomer of citalopram. This open-label multicentre French prospective study investigated the tolerability and efficacy of oral escitalopram 10 and 20 mg/day, administered for a 6-week period as continuation treatment of citalopram (20 mg or 40 mg daily) intravenous (iv), in patients with Major Depressive Disorder. A total of 171 patients were enrolled, of whom 147 (85%) completed the study. The mean MADRS score at inclusion (last citalopram dose) was 31.6 +/- 9.9. The total MADRS score decreased after 3 days of oral treatment with escitalopram. Escitalopram demonstrated a continuous effect in treating depressive symptoms throughout the study. The decrease in MADRS mean total score from baseline was statistically significant to each visit (day 3, 15; p < 0.0001). At final visit (J42), the decrease was - 18.9 +/- 11.7 (p < 0.0001) and the MADRS mean total score was 12.7 +/- 9.3. There were no differences seen in the patient response comparing gender, age, and the single or recurrent episodes. The changes of Clinical Global Impression scores (CGI-S, CGI-I, PGE-Patient Global Evaluation) were also indicative of an improvement of the patients' depression. The CGI-I and PGE scores were significantly correlated indicating good agreement between investigator and patient in rating the degree of improvement. At the end of the study, 67% of patients were classified as responders (decrease of MADRS score from baseline > or = 50%), and the majority of them were considered remitters (final MADRS score < or = 12). Overall, the switch from intravenous citalopram to oral escitalopram was well tolerated in the study population. In all, 57 patients (33%) reported at least one adverse event (AE) during the study (21 patients in the 10 mg group and 36 patients in the 20 mg group); of these, 7 patients (4%) withdrew from the study. The most frequently reported AEs were suggestive of residual symptoms of depression (anxiety, 9%; insomnia, 5% of patients). In conclusion, in this study oral escitalopram (10 mg or 20 mg) was well tolerated as continuation treatment after switching from intravenous citalopram (20 mg or 40 mg). From the efficacy and safety data of this study, it can be concluded that the switch from citalopram iv to oral escitalopram (10 and 20 mg/day) is effective in decreasing depressive symptoms, and could be safely proposed in patients with major depressive disorder.
Background Sleep disorders differ widely in the heterogeneous older adult population. Older adult... more Background Sleep disorders differ widely in the heterogeneous older adult population. Older adults can be classified into three groups based upon their overall level of disability: healthy, dependent, and frail. Frailty is an emerging concept that denotes older persons at increased risk for poor outcomes. Objective The aim of this consensus review is to describe the sleep disorders observed in healthy and dependent older adults and to discuss the potential sleep disorders associated with frailty as well as their potential consequences on this weakened population. Methods A review task force was created including neurologists, geriatricians, sleep specialists and geriatric psychiatrists to discuss age related sleep disorders depending on the three categories of older adults. All published studies on sleep in older adults on Ovid Medline were reviewed and 106 articles were selected for the purpose of this consensus. Results Many healthy older adults have complains about their sleep such as waking not rested and too early, trouble falling asleep, daytime napping, and multiple nocturnal awakenings. Sleep architecture is modified by age with an increased percentage of time spent in stage one and a decreased percentage spent in stages three and four. Insomnia is frequent and its mechanisms include painful medical conditions, psychological distress, loss of physical activity and iatrogenic influences. Treatments are also involved in older adults’ somnolence. The prevalence of primary sleep disorders such as restless legs syndrome, periodic limb movements and sleep disordered breathing increases with age. Potential outcomes relevant to these sleep disorders in old age include mortality, cardiovascular and neurobehavioral co-morbidities. Sleep in dependent older adults such as patients with Alzheimer Disease (AD) is disturbed. The sleep patterns observed in these patients are often similar to those observed in non-demented elderly but alterations are more severe. Nocturnal sleep disruption and daytime sleepiness are the main problems. They are the results of Sleep/wake circadian rhythm disorders, environmental, psychological and iatrogenic factors. They are worsened by other sleep disorders such as sleep disordered breathing. Sleep in frail older adults per se has not yet been formally studied but four axes of investigation should be considered: i) sleep architecture abnormalities, ii) insomnia iii) restless legs syndrome (RLS), iv) sleep disordered breathing. Conclusion Our knowledge in the field of sleep disorders in older adults has increased in recent years, yet some groups within this heterogeneous population, such as frail older adults, remain to be more thoroughly studied and characterized.
Background Many patients develop psychiatric and behavioral disturbances in the course of Alzheim... more Background Many patients develop psychiatric and behavioral disturbances in the course of Alzheimer’s disease (AD). Among these disturbances, depressive symptoms are frequent and affect nearly 40% of patients. The natural history and course of such symptoms in AD, and in particular the predictive factors, are little known. We studied the incidence and risk factors for the development of the first depressive symptoms in AD. Design Multicenter prospective study. Participants Three hundred twelve AD patients from the French Network on AD (REAL.FR) without depression and without antidepressant treatment at baseline were followed up and assessed every 6 months for 4 years. During follow-up, all events occurring between two visits were carefully recorded. Measurements We used the Neuropsychiatric Inventory (NPI) for comprehensive evaluation of behavioral and psychological symptoms and depressive symptoms in particular. A multivariate analysis was performed using a backward stepwise Cox proportional hazards model. Results The incidence of depressive symptoms was 17.45% person/years, 95%CI (13.88–21.02). Among non-time dependent variables, duration of disease (RR=0.51; 95%CI: 0.30–0.85, p=0.0102) and the number of comorbid conditions (RR=0.45; 95%CI: 0.24–0.83, p=0.0115) were protective factors against the development of depressive symptoms. Agitation/aggression (RR=1.96; 95%CI: 1.19–3.23, p=0.0078) and sleep disturbances (RR=2.65; 95%CI: 1.40–5.00, p=0.0026) were time-dependent variables predictive of depressive symptoms. Conclusion Better knowledge of predictive factors of mood disturbances in AD will enable clinicians to set up appropriate management of their patients. As published longitudinal studies are few, further works should be carried out to improve knowledge of the pattern and course of depression and depressive symptoms in AD.
Psychotropic medication is widely prescribed in clinical practice for the management of behaviora... more Psychotropic medication is widely prescribed in clinical practice for the management of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). However, there have been few pharmaco-epidemiological studies or studies conducted in a natural setting on the real use of antidepressants in AD. The aim of this survey was to assess the prevalence of antidepressant use in AD and to identify the clinical factors associated with antidepressant prescription. REAL.FR is a four-year, prospective, multi-center study. Baseline data including demographic characteristics, clinical variables and drug intake were obtained. Depressive symptoms were determined using the Neuropsychiatric Inventory (NPI). A total of 686 AD patients were included. Antidepressant treatment was prescribed for 34.8% of patients. Clinically significant depressive symptoms (NPI >or= 4) were observed in 20.5% of the total population. Although depressed subjects were significantly more likely to be treated with antidepressants than non-depressed subjects (p<0.0001), only 60% of depressed subjects overall were prescribed an antidepressant. In multivariate analysis, clinically significant depressive symptoms were associated with antidepressant prescription although this result was only observed in subjects without a previous history of depression. The available data on antidepressant efficacy in BPSD other than depression (in particular, agitation, aggression and, occasionally, psychotic symptoms) do not influence prescription choices. Depressive symptoms may be taken more seriously in the absence of a previous history of depression, leading to increased antidepressant prescription rates in individuals presenting with depression for the first time.
Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D2 receptors... more Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D2 receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT2A receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for 5-HT2A receptors as cyamemazine, whereas its D2 receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2–3):142–147, 2008). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT2A receptors. Objectives The objective of this study is to measure steady-state plasma levels of N-desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D2 and serotonin 5-HT2A receptor occupancies (RO) assessed by positron emission tomography (PET). Methods Eight patients received Tercian® 37.5, 75, 150, or 300 mg/day according to their symptoms. Dopamine D2 and serotonin 5-HT2A RO were assessed at steady-state cyamemazine plasma levels using [11C]raclopride and [11C]N-methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant (K i) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. Results After 6 days of cyamemazine administration, plasma N-desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377–384, 2005). Plasma levels of N-desmethyl cyamemazine were closely related to striatal D2 RO (r 2 = 0.942) and extrastriatal 5-HT2A RO (r 2 = 0.901). The estimated K i(app) value of N-desmethyl cyamemazine for striatal D2 receptors was about fivefold higher than that for extrastriatal 5-HT2A receptors (48.7 vs. 10.6 nM). Striatal D2 RO increased with the plasma levels of N-desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N-desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT2A and D2 receptor occupancy. Conclusions In patients orally given cyamemazine, N-desmethyl cyamemazine, but not cyamemazine sulfoxide, should significantly contribute to in vivo frontal 5-HT2A and striatal D2 receptor occupancy. The higher in vivo affinity of cyamemazine and its desmethyl metabolite for serotonin 5-HT2A receptors compared with dopamine D2 receptors should explain the low incidence of extrapyramidal adverse effects.
Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux... more Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux (SPCD), la perte de poids, les troubles de la mobilité et la perte d’autonomie fonctionnelle, sont responsables d’une altération de la qualité de vie du patient. Les SPCD représentent la principale complication de la maladie. Il est important de les dépister, de les prévenir et de les traiter précocement. Leur prise en charge doit comprendre, en première intention, les mesures non pharmacologiques associées ou non aux mesures pharmacologiques. La perte de poids, quant à elle, est associée à une augmentation du risque d’hospitalisation et d’entrée en institution. Elle pourra être surveillée par le suivi de la courbe pondérale et le MNA. Les troubles de la mobilité, responsables de chutes et les symptômes moteurs sont également les complications fréquemment rencontrées. Enfin, l’épuisement de l’aidant doit évidemment être considéré comme une conséquence de la maladie et un élément important de sa prise en charge. Ces complications et leur conséquences doivent être identifiées et, dans la mesure du possible, évitées grâce à un plan de soin d’aide et de suivi spécifique. Complications in Alzheimer’s disease such as functional decline, weight loss, gait and balance disturbances and behavioral and psychological symptoms in dementia (BPSD) have a negative impact on quality of life. It is therefore important to identify these complications at an early stage. BPSD are major features of Alzheimer’s disease and related disorders. They represent half of admissions to special care units with, in order of frequency, agitation and agressivity. The non pharmacological approach must be implemented first and linked to a pharmacological approach. Weight loss is of complex physiopathology. It can be monitored by observation of the weight curve and use of the Mini Nutritional Assessment (MNA). Weight loss may be responsible for an increased risk of institutionalization and mortality. Gait and balance disturbances are also a prevalent complication of the illness and lead to an increased risk of falls and injuries. Neurological complications take the form of seizures and motor symptoms. Amongst these complications the burden of the caregiver must also be assessed. These complications and their consequences must be identified and, wherever possible, prevented with a specific care plan.
The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably between individuals... more The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably between individuals, with some subjects showing substantial deterioration and others showing little or no change over the course of the disease. These wide variations support the relatively new concept of Rapid Cognitive Decline (RCD). Patients with an accelerated rate of cognitive decline have showed to present a worse evolution in terms of mortality, loss of autonomy and institutionalisation. The conclusions from RCD studies conducted in the past years remain very heterogeneous and sometimes contradictory. This is possibly due to methodological differences, mainly the different “a priori” definitions of RCD used to identify rapid decliners. Consequently of this, there is considerable variation in reported frequency of patients with RCD which may vary from 9.5% to 54%. The lack of both consensus definition and consensual clinical assessment tools is one of the major barriers for establishing an appropriated management of rapid decliners in clinical practice. Presently, management of rapid decliners in AD remains to be a challenge waiting to better know predictive factors of a RCD. To date no specific guidelines exist to follow-up or to treat patients with this condition. This consensus paper proposes the loss of 3 points or greater in Mini-Mental State Examination (MMSE) during six months as an empirical definition of rapid cognitive decline to be used in routine medical practice and to be relevant for clinical-decision making in patients with mild to moderately-severe AD.
Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux... more Les complications de la maladie d’Alzheimer, parmi lesquelles les symptômes psychocomportementaux (SPCD), la perte de poids, les troubles de la mobilité et la perte d’autonomie fonctionnelle, sont responsables d’une altération de la qualité de vie du patient. Les SPCD représentent la principale complication de la maladie. Il est important de les dépister, de les prévenir et de les traiter précocement. Leur prise en charge doit comprendre, en première intention, les mesures non pharmacologiques associées ou non aux mesures pharmacologiques. La perte de poids, quant à elle, est associée à une augmentation du risque d’hospitalisation et d’entrée en institution. Elle pourra être surveillée par le suivi de la courbe pondérale et le MNA. Les troubles de la mobilité, responsables de chutes et les symptômes moteurs sont également les complications fréquemment rencontrées. Enfin, l’épuisement de l’aidant doit évidemment être considéré comme une conséquence de la maladie et un élément important de sa prise en charge. Ces complications et leur conséquences doivent être identifiées et, dans la mesure du possible, évitées grâce à un plan de soin d’aide et de suivi spécifique. Complications in Alzheimer’s disease such as functional decline, weight loss, gait and balance disturbances and behavioral and psychological symptoms in dementia (BPSD) have a negative impact on quality of life. It is therefore important to identify these complications at an early stage. BPSD are major features of Alzheimer’s disease and related disorders. They represent half of admissions to special care units with, in order of frequency, agitation and agressivity. The non pharmacological approach must be implemented first and linked to a pharmacological approach. Weight loss is of complex physiopathology. It can be monitored by observation of the weight curve and use of the Mini Nutritional Assessment (MNA). Weight loss may be responsible for an increased risk of institutionalization and mortality. Gait and balance disturbances are also a prevalent complication of the illness and lead to an increased risk of falls and injuries. Neurological complications take the form of seizures and motor symptoms. Amongst these complications the burden of the caregiver must also be assessed. These complications and their consequences must be identified and, wherever possible, prevented with a specific care plan.
Contexte Chez les sujets âgés, les troubles du sommeil sont très variés. On peut répartir les suj... more Contexte Chez les sujets âgés, les troubles du sommeil sont très variés. On peut répartir les sujets âgés en trois groupes: en bonne santé, dépendants, fragiles. Le concept de fragilité est récent et correspond à des personnes avec une morbimortalité plus grande. Objectifs Le but de cette revue de consensus est de décrire les troubles du sommeil observés chez les sujets âgés dans ces trois groupes et de discuter les potentiels troubles du sommeil et leurs conséquences chez les sujets âgés fragiles. Méthodes Un groupe de travail incluant des neurologues, des gériatres, des psychiatres et des spécialistes du sommeil a été créé pour étudier les troubles du sommeil dans ces trois groupes de sujets âgés. Toutes les études publiées sur le sommeil des sujets âgés sur Ovid Medline ont été revues, et 106 ont été retenues. Résultats De nombreux sujets âgés en bonne santé se plaignent de la qualité de leur sommeil. Ils rapportent des difficultés à s’endormir, de multiples éveils nocturnes, un réveil de mauvaise qualité et trop précoce et une somnolence diurne. L’architecture du sommeil est modifiée par l’âge, avec une augmentation du temps passé en stade 1 et une diminution du temps passé en stades 3 et 4. L’insomnie est fréquente chez le sujet âgé. Parmi ses causes, on retrouve les pathologies douloureuses, le stress psychologique, la diminution de l’activité physique et les effets indésirables des médicaments. La somnolence diurne des sujets âgés est souvent d’origine médicamenteuse. La prévalence des troubles primaires du sommeil, tels le syndrome des jambes sans repos (SJSR), les mouvements périodiques de jambes (MPJ) et les troubles ventilatoires du sommeil, augmente avec l’âge. Ces troubles ont des conséquences sur la mortalité, les atteintes neurologiques et cardiovasculaires des sujets âgés. La cause la plus fréquente de dépendance est la maladie d’Alzheimer. Les patients atteints de cette maladie ont un sommeil perturbé. Les modifications du sommeil chez ces patients sont du même type que chez les sujets âgés non déments, mais sont plus sévères. Les plaintes principales sont des troubles du maintien du sommeil et une somnolence diurne. Ces troubles sont la conséquence de modifications du rythme veille/sommeil, de facteurs environnementaux, psychologiques et iatrogènes. Ils peuvent être majorés par d’autres troubles du sommeil comme les troubles ventilatoires du sommeil. Le sommeil des sujets âgés fragiles n’a jamais été formellement étudié, mais quatre axes d’investigations devraient être explorés: 1) les anomalies de l’architecture du sommeil; 2) l’insomnie; 3) le SJSR; 4) les troubles ventilatoires du sommeil. Conclusion Les connaissances dans le domaine du sommeil du sujet âgé se sont développées ces dernières années. Mais cette population très hétérogène devrait être étudiée en fonction de son état de santé. Context There are many kinds of sleep disorders amongst the elderly population, a group that can be divided into three subgroups, namely: the healthy, the dependent and the fragile. This new concept of fragility refers to people with higher morbidity-mortality rates. Objectives This consensus review aims to describe sleep disorders observed in these three groups and discuss potential sleep disorders and their possible effects on the more fragile. Method: A working group consisting of neurologists, gerontologists, psychiatrists and sleep specialists was established, in order to study sleep disorders in the three subgroups of elderly people. All studies that had been published so far on Ovid Medline relating to sleep problems in the elderly were reviewed, and 106 were used for the survey. Results Many healthy elderly individuals complain about the quality of their sleep. They find it difficult to get to sleep, wake frequently, wake up too early and then feel sleepy during the day. Sleep architecture alters with age, with more time being spent in stage 1 and less in stages 3 and 4. The elderly often suffer from insomnia, which has a range of causes: painful conditions, psychological stress, reduced physical activity, side effects of medicines. Daytime somnolence is often caused by medication. Primary sleeping problems such as restless legs syndrome and breathing difficulties increase with age. Such disorders in the elderly can impact on mortality, as well as causing neurological and cardiovascular problems. The most common cause of dependence is Alzheimer’s disease. Patients suffering from this illness have disturbed sleep patterns, which are similar to, but more severe than those of elderly individuals not affected by dementia. The main complaints are the inability to stay asleep and daytime somnolence. These disturbances are caused by alterations to the waking/sleeping rhythm, as well as by environmental, psychological, and iatrogenic factors. They can be exacerbated by other sleep problems, such as breathing difficulties. The sleeping patterns of fragile, elderly populations have not yet been studied formally, but there are four clear directions worthy of investigation: 1) anomalies in sleep architecture; 2) insomnia; 3) restless legs syndrome; 4) breathing difficulties during sleep. Conclusion Our knowledge of sleeping patterns in the elderly has increased over the past few years, but this very diverse population should be studied in subgroups, determined by state of general health.
Given the poorer prognosis of Alzheimer&a... more Given the poorer prognosis of Alzheimer's disease (AD) patients with rapid cognitive decline (RCD), there is a need for a clinical assessment tool to detect these patients. To investigate if there is a Mini Mental State Examination (MMSE) threshold of decline during 6 months of follow-up which predicts a worse disease progression at the 2-year follow-up. Then, to propose a feasible definition of RCD for routine clinical practice. Data from 565 community-dwelling AD patients recruited in a multi-centre prospective observational study were assessed. All patients had MMSE scores between 10 and 26 at inclusion and were followed up 6-monthly using a standardised clinical assessment. Patients were classified as rapid and non-rapid decliners according to 2 MMSE decline thresholds tested: >or=3 points and >or=4 points for decline over the first 6 months of the study. Worse disease outcome was defined as attainment of 1 of 4 clinical end points 18 months later: institutionalisation, death, increased physical dependence or worsening of behavioural and psychological symptoms. 135 patients (23.9%) lost >or=3 points during the first 6 months of follow-up in the MMSE score and 77 patients (13.6%) lost >or=4 points. Patients with moderate disease and a loss of >or=4 points showed a significantly increased risk of mortality (HR = 5.6, 95% CI 2.0-15.9) and institutionalisation (HR = 3.8, 95% CI 1.8-8.1) at the 2-year follow-up. The same MMSE threshold was associated with a higher risk of physical decline (HR = 1.6, 95% CI 1.2-2.3). The loss of >or=4 points in MMSE during the first 6 months of follow-up seems to be a predictor of worse clinical course, and thus it could be used to define the category of AD patients presenting a RCD.
Intravenous (iv) administration of an antidepressant is a common practice in some European countr... more Intravenous (iv) administration of an antidepressant is a common practice in some European countries, particularly in France, Spain, and Italy in the initial treatment phase of hospitalised, severe depressed patients. After a beneficial response is observed, patients are switched to an oral formulation. The approved treatment period of the iv form of citalopram is limited to 8-10 days. The high bioavailability of citalopram permits the use of identical iv and oral doses. Citalopram is a racemate, consisting of a 1:1 mixture of the S- and R-enantiomers. The therapeutically active component is the S-enantiomer (escitalopram). Pharmacokinetic single dose administration studies in healthy subjects have demonstrated that daily oral administration of 20 mg of escitalopram or 40 mg citalopram results in similar plasma concentrations of the S-enantiomer of citalopram. This open-label multicentre French prospective study investigated the tolerability and efficacy of oral escitalopram 10 and 20 mg/day, administered for a 6-week period as continuation treatment of citalopram (20 mg or 40 mg daily) intravenous (iv), in patients with Major Depressive Disorder. A total of 171 patients were enrolled, of whom 147 (85%) completed the study. The mean MADRS score at inclusion (last citalopram dose) was 31.6 +/- 9.9. The total MADRS score decreased after 3 days of oral treatment with escitalopram. Escitalopram demonstrated a continuous effect in treating depressive symptoms throughout the study. The decrease in MADRS mean total score from baseline was statistically significant to each visit (day 3, 15; p < 0.0001). At final visit (J42), the decrease was - 18.9 +/- 11.7 (p < 0.0001) and the MADRS mean total score was 12.7 +/- 9.3. There were no differences seen in the patient response comparing gender, age, and the single or recurrent episodes. The changes of Clinical Global Impression scores (CGI-S, CGI-I, PGE-Patient Global Evaluation) were also indicative of an improvement of the patients' depression. The CGI-I and PGE scores were significantly correlated indicating good agreement between investigator and patient in rating the degree of improvement. At the end of the study, 67% of patients were classified as responders (decrease of MADRS score from baseline > or = 50%), and the majority of them were considered remitters (final MADRS score < or = 12). Overall, the switch from intravenous citalopram to oral escitalopram was well tolerated in the study population. In all, 57 patients (33%) reported at least one adverse event (AE) during the study (21 patients in the 10 mg group and 36 patients in the 20 mg group); of these, 7 patients (4%) withdrew from the study. The most frequently reported AEs were suggestive of residual symptoms of depression (anxiety, 9%; insomnia, 5% of patients). In conclusion, in this study oral escitalopram (10 mg or 20 mg) was well tolerated as continuation treatment after switching from intravenous citalopram (20 mg or 40 mg). From the efficacy and safety data of this study, it can be concluded that the switch from citalopram iv to oral escitalopram (10 and 20 mg/day) is effective in decreasing depressive symptoms, and could be safely proposed in patients with major depressive disorder.
Background Sleep disorders differ widely in the heterogeneous older adult population. Older adult... more Background Sleep disorders differ widely in the heterogeneous older adult population. Older adults can be classified into three groups based upon their overall level of disability: healthy, dependent, and frail. Frailty is an emerging concept that denotes older persons at increased risk for poor outcomes. Objective The aim of this consensus review is to describe the sleep disorders observed in healthy and dependent older adults and to discuss the potential sleep disorders associated with frailty as well as their potential consequences on this weakened population. Methods A review task force was created including neurologists, geriatricians, sleep specialists and geriatric psychiatrists to discuss age related sleep disorders depending on the three categories of older adults. All published studies on sleep in older adults on Ovid Medline were reviewed and 106 articles were selected for the purpose of this consensus. Results Many healthy older adults have complains about their sleep such as waking not rested and too early, trouble falling asleep, daytime napping, and multiple nocturnal awakenings. Sleep architecture is modified by age with an increased percentage of time spent in stage one and a decreased percentage spent in stages three and four. Insomnia is frequent and its mechanisms include painful medical conditions, psychological distress, loss of physical activity and iatrogenic influences. Treatments are also involved in older adults’ somnolence. The prevalence of primary sleep disorders such as restless legs syndrome, periodic limb movements and sleep disordered breathing increases with age. Potential outcomes relevant to these sleep disorders in old age include mortality, cardiovascular and neurobehavioral co-morbidities. Sleep in dependent older adults such as patients with Alzheimer Disease (AD) is disturbed. The sleep patterns observed in these patients are often similar to those observed in non-demented elderly but alterations are more severe. Nocturnal sleep disruption and daytime sleepiness are the main problems. They are the results of Sleep/wake circadian rhythm disorders, environmental, psychological and iatrogenic factors. They are worsened by other sleep disorders such as sleep disordered breathing. Sleep in frail older adults per se has not yet been formally studied but four axes of investigation should be considered: i) sleep architecture abnormalities, ii) insomnia iii) restless legs syndrome (RLS), iv) sleep disordered breathing. Conclusion Our knowledge in the field of sleep disorders in older adults has increased in recent years, yet some groups within this heterogeneous population, such as frail older adults, remain to be more thoroughly studied and characterized.
Background Many patients develop psychiatric and behavioral disturbances in the course of Alzheim... more Background Many patients develop psychiatric and behavioral disturbances in the course of Alzheimer’s disease (AD). Among these disturbances, depressive symptoms are frequent and affect nearly 40% of patients. The natural history and course of such symptoms in AD, and in particular the predictive factors, are little known. We studied the incidence and risk factors for the development of the first depressive symptoms in AD. Design Multicenter prospective study. Participants Three hundred twelve AD patients from the French Network on AD (REAL.FR) without depression and without antidepressant treatment at baseline were followed up and assessed every 6 months for 4 years. During follow-up, all events occurring between two visits were carefully recorded. Measurements We used the Neuropsychiatric Inventory (NPI) for comprehensive evaluation of behavioral and psychological symptoms and depressive symptoms in particular. A multivariate analysis was performed using a backward stepwise Cox proportional hazards model. Results The incidence of depressive symptoms was 17.45% person/years, 95%CI (13.88–21.02). Among non-time dependent variables, duration of disease (RR=0.51; 95%CI: 0.30–0.85, p=0.0102) and the number of comorbid conditions (RR=0.45; 95%CI: 0.24–0.83, p=0.0115) were protective factors against the development of depressive symptoms. Agitation/aggression (RR=1.96; 95%CI: 1.19–3.23, p=0.0078) and sleep disturbances (RR=2.65; 95%CI: 1.40–5.00, p=0.0026) were time-dependent variables predictive of depressive symptoms. Conclusion Better knowledge of predictive factors of mood disturbances in AD will enable clinicians to set up appropriate management of their patients. As published longitudinal studies are few, further works should be carried out to improve knowledge of the pattern and course of depression and depressive symptoms in AD.
Psychotropic medication is widely prescribed in clinical practice for the management of behaviora... more Psychotropic medication is widely prescribed in clinical practice for the management of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). However, there have been few pharmaco-epidemiological studies or studies conducted in a natural setting on the real use of antidepressants in AD. The aim of this survey was to assess the prevalence of antidepressant use in AD and to identify the clinical factors associated with antidepressant prescription. REAL.FR is a four-year, prospective, multi-center study. Baseline data including demographic characteristics, clinical variables and drug intake were obtained. Depressive symptoms were determined using the Neuropsychiatric Inventory (NPI). A total of 686 AD patients were included. Antidepressant treatment was prescribed for 34.8% of patients. Clinically significant depressive symptoms (NPI >or= 4) were observed in 20.5% of the total population. Although depressed subjects were significantly more likely to be treated with antidepressants than non-depressed subjects (p<0.0001), only 60% of depressed subjects overall were prescribed an antidepressant. In multivariate analysis, clinically significant depressive symptoms were associated with antidepressant prescription although this result was only observed in subjects without a previous history of depression. The available data on antidepressant efficacy in BPSD other than depression (in particular, agitation, aggression and, occasionally, psychotic symptoms) do not influence prescription choices. Depressive symptoms may be taken more seriously in the absence of a previous history of depression, leading to increased antidepressant prescription rates in individuals presenting with depression for the first time.
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Papers by Christophe Arbus