International Journal of Psychiatry in Clinical Practice, 2005; 9(1): 45 /51
ORIGINAL ARTICLE
Risperidone in the treatment of behavioural and psychological symptoms of dementia in patients diagnosed with vascular or mixed-type dementia
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´ N2, JESU ´ -ANTONIO BURO ´ S I. DIAGO2 & ALFONSO J. CRUZ-JENTOFT1, JOSE RICARDO GALLEGO2 1
Hospital Ramo´n y Cajal, Servicio de Geriatria, Madrid, Spain and 2Medical Department, Janssen-Cilag, Madrid, Spain
Abstract Objective . Studies have found that the atypical antipsychotic drug, risperidone, reduces non-cognitive symptoms, such as aggression, agitation, and psychosis, in patients with Alzheimer’s disease. This study assessed whether these effects extend to patients with vascular or mixed-type dementia. Methods . In this multicentre, open-label, prospective study, 75 elderly patients with vascular or mixed-type dementia and concomitant behavioural and psychological symptoms were treated with risperidone for up to 6 months. Results . Risperidone decreased the frequency and severity of overall behavioural and psychological symptoms, as determined by the Neuropsychiatric Inventory, to a mean total score of 7.29/0.7 at end-point compared with 21.09/1.5 at baseline (PB/0.001). Risperidone improved functional capacity (Blessed Dementia Rating Scale, Reisberg’s Global Deterioration Scale) and depression (Cornell Scale for Depression in Dementia). A total of four adverse events (5.3%) were spontaneously reported: two cases of hypotension, one of somnolence, and one of paresthesia. Scores on the Udvalg for Kliniske Undersogeler extrapyramidal symptom subscale remained stable from baseline to endpoint. Conclusion . Overall, these findings indicate that risperidone was effective in reducing behavioural and psychological symptoms and was well tolerated, particularly with respect to extrapyramidal symptoms, in this elderly population diagnosed with vascular or mixed-type dementia.
Key Words: BPSD, mixed-type dementia, open-label, risperidone, vascular dementia
Introduction Dementia is a disabling condition of global cognitive decline, often accompanied by non-cognitive behavioural symptoms, such as aggression and agitation, and psychosis. Dementia has many causes, but most cases are due to Alzheimer’s disease or brain damage resulting from lack of vascular perfusion (vascular dementia) [1]. Mixed-type dementia incorporates elements of both these aetiologies. Although deficits in memory, language, visuospatial skills, complex cognition, emotion and personality are the core criteria for dementia, accompanying behavioural symptoms and psychosis of dementia are frequently more problematic. These symptoms include verbal and physical aggression, agitation, delusion, hallucination, anxiety, wandering, apathy and depression [2]. These symptoms have been linked to patient distress, decreased quality of life, caregiver burden and institutionalization [3 /5].
The primary goals for the treatment of patients with dementia are to improve quality of life and maximize functional performance by enhancing cognition, mood and behaviour [6]. Due to the significant effects of non-cognitive symptoms on quality of life, the treatment of these symptoms has become an important component of dementia therapy. Treatments include non-pharmacological strategies (such as emotion- and stimulation-oriented therapies), as well as pharmacological interventions (primarily with antipsychotic medication) [6]. Pharmacotherapy with conventional neuroleptic drugs, such as haloperidol, provides a small benefit in the treatment of dementia patients with behavioural symptoms, with only 18% more patients showing an improvement compared with those who received placebo [7]. Furthermore, the use of these drugs is limited because they are associated with extrapyramidal motor symptoms, especially in the elderly patient. Risperidone was the first
Correspondence: A. J. Cruz-Jentoft, Unidad de Geriatrı´a, Hospital Ramo´n y Cajal, Ctra. Colmenar km 9,100, Madrid, Spain. Tel: 34-913-368172. Fax: 34913-368431. E-mail: [email protected]
(Received 21 June 2004; accepted 5 October 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014729
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atypical antipsychotic shown to be effective at low doses in treating behavioural and psychotic symptoms of dementia, such as aggression, agitation and psychosis, in nursing-home residents, as reported by three large placebo-controlled clinical trials [8/10]. These trials also demonstrated that there were no differences between the severity of extrapyramidal symptoms in patients who received low-dose risperidone (i.e. lower than 1.5 mg) or placebo. In contrast, these symptoms were significantly more severe in patients who received haloperidol [9]. The controlled trials of risperidone have primarily included patients with Alzheimer’s disease [8/10], with a proportion of patients diagnosed with vascular or mixed-type dementia. Although there are several differences between the symptoms of dementia of the Alzheimer type and vascular or mixed dementias, differential diagnosis between these subtypes of dementia is often challenging for the clinician. In a recent post mortem study, a 56.5% incidence of vascular pathology in 173 autopsy-confirmed AD patients was observed, compared to 42.4% control patients [11], revealing that proper accurate diagnosis of these patients can be difficult. They further concluded that brain weight and severity of cognitive decline did not correspond to the degree of vascular pathology. Sultzer et al. observed that patients with vascular dementia had more severe behavioural retardation, depression and anxiety than those with Alzheimer’s disease who were at a similar level of cognitive impairment [12]. Groves et al. found that patients with vascular dementia were more depressed, more functionally impaired and less cognitively impaired than those with Alzheimer’s disease [1]. The diagnostic criteria for vascular dementia are different from those of the Alzheimer type: the former include the presence of cerebrovascular disease, a temporal correlation of dementia with cerebrovascular disease and often a sudden or step-wise deterioration [1,13]. Patients with vascular dementia may show more motor symptoms than those with Alzheimer’s disease [1]. In fact, an expert panel has concluded that focal motor or sensory signs (except fluent aphasia and apraxia) suggest a diagnosis of vascular dementia or mixed-type dementia and Alzheimer’s disease [6]. Given these symptomatological and pathophysiological dissimilarities, it may be that patients with vascular or mixed-type dementia respond differently to pharmacotherapy than those with dementia of the Alzheimer type. Therefore, the present study was undertaken to assess the efficacy and safety of treatment with risperidone in elderly nursing-home residents with behavioural and/or psychological symptoms diagnosed with vascular or mixed-type dementia.
Methods Patients This study included both Spanish institutionalized and community-dwelling patients who were eligible for study participation if they were diagnosed with dementia with a vascular component according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders / 4th edition (DSM-IV) [14] and were deemed to be in treatment with an antipsychotic due to concomitant behavioural and psychological symptoms. Dementia must have been of the vascular or mixed-type according to the Hachinski scale of dementia, with scores ]/4 [15]. No radiological investigations were performed. Patients who were being treated with other antipsychotic drugs were eligible if they were experiencing problems with tolerability, or if efficacy of their current medication was inadequate. Based on the physician’s examination and the patient’s medical history, those with pure Alzheimer’s or Lewy body diseases were excluded, as were those with disorders of consciousness (e.g. delirium) and those whose dementia was attributable to an identifiable organic aetiology (e.g. hypothyroidism, normotensive hydrocephalus). In addition, patients were excluded if they had a history of severe mental illness other than dementia or any other severe concomitant disease that would contraindicate inclusion in the study or had the potential to interfere with the study parameters. Patients who had received risperidone within the last 3 months were not eligible. Patients could be discontinued from the study for lack of efficacy, intolerance of the study medication, the need to maintain concomitant treatment with other antipsychotic or antidepressant drugs for more than 2 weeks, or any other reason that necessitated withdrawal from risperidone. The study was designed according to Spanish regulations applicable over the study period. The local Spanish Health Authority was informed and agreed with the design and characteristics before the start of the study. Patients were treated with risperidone according to doses and regimens determined by their physician. Design and procedures This was a multicentre, open-label, 6-month, prospective study of risperidone for the treatment of behavioural and psychotic symptoms in patients with vascular or mixed-type dementia. Treatment with risperidone was initiated at doses of 0.5 or 1.0 mg/ day, depending on the severity of symptoms, and increased by 0.5 mg/day until optimal doses within the recommended range were reached (0.5 /1 mg twice daily). For patients who were being treated with conventional neuroleptic drugs at entry to the study, these drugs were gradually withdrawn over
Risperidone in vascular or mixed-type dementia 1 week (haloperidol, pimozide) or 1 /2 weeks (thioridazine, levomepromazine) once maintenance doses of risperidone were reached. Data were collected at baseline and at months 1, 3 and 6.
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Outcome measures Efficacy measures included the Neuropsychiatric Inventory (NPI) [16], Clinical Global Impression of Severity (CGI-S) [17], progressive staging using the Global Deterioration Functional Scale (GDS) [18], and the global opinion of the investigator (deficient, normal, good or excellent). Depression was assessed using the Cornell Scale for Depression in Dementia [19], which rates symptoms (grouped into clusters of mood related signs, behavioural disturbances, physical signs, cyclic functions and ideational disturbances) on a scale of 0 /absent to 2/severe. Functional skills were assessed using the Blessed Dementia Functional Rating Scale [20], which consists of 22 items grouped into the subsets of everyday activities, changes in self-care habits and changes in personality, interests and drives. These subsets were assessed individually and then the total score calculated. Tolerability was assessed on the Udvalg for Kliniske Undersogeler (UKU) extrapyramidal symptom subscale [21], the global impression of the investigator (deficient, normal, good or excellent), and by recording adverse reactions that were reported during guided history assessment (extrapyramidal reactions) or spontaneously by patients/ caregivers (other reactions). Only extrapyramidal symptoms were assessed at every visit in a structured way. Adverse reactions were judged for their intensity (mild, moderate, severe) and relationship to treatment (remote, possible, probable, very probable). Use of antiparkinsonian and other medications was also monitored.
(81.3%, Table I). Patients had a mean age of 76.5 years and the genders were equally represented (52.1% female) in the study population. Over the entire study period, a total of 14 patients (18.7%) discontinued treatment prematurely. Two of these patients died (2.7%) during the course of the study: one patient died of bronchoaspiration and one of acute pulmonary oedema, and these deaths were rated by the investigator as not being related to the drug treatment., Two patients (2.7%) were withdrawn because of intolerance of the study medication and another patient (1.3%) stopped treatment due to clinical improvement. Four patients (5.3%) discontinued for other reasons. In addition, five patients (6.7%) were lost to follow-up or were relocated. Nineteen patients (25.3%) had received previous neuroleptic treatment, 55 (73.3%) had not received such treatment, and information on this treatment was unavailable for one patient (Table I). Five patients (6.7%) had received previous antidepressant treatment. Almost all patients in this study (n /71) had at least one concomitant disease or medical condition (Table I). Most patients (n /49) were receiving concomitant treatment for one or more conditions, with a total of 60 concomitant treatments, including non-psychopharmacological treatments (n /52) and benzodiazepines (n /4). Dose The mean dose of risperidone at baseline was 1.19/ 0.6 mg/day (range: 0.5 /2.0 mg/day) and 1.69/ 0.7 mg/day at end-point (range: 0.5 /4.0 mg/day). The mean and median doses were similar, with a median dose of 1.0 mg/day at baseline and 1.5 mg/ day at end-point. Table I. Demographics and baseline characteristics.
Patients
Gender *, n (%) Female Male Age (years)$ Mean9/SD Diagnosis of dementia , % Vascular Mixed-type Concomitant disease , n (%) Hypertension Cardiovascular Diabetes Previous neuroleptic treatment , n (%) Haloperidol Thioridazine Levomepromazine Reasons for switching, n (%) Lack of efficacy Poor tolerance Both Other reasons Baseline NPI , Mean9/SEM
Of the 86 patients screened, 75 met the study criteria and were included, with 61 completing the trial
*Gender was not specified in four patients. $ Age was not specified in three patients.
Data analyses Analyses were based on the intent-to-treat principle and included all patients who received at least one dose of risperidone. For efficacy analyses, the last available value was used for patients who discontinued the study prematurely. Demographic, efficacy and tolerability data were summarized with descriptive statistics. Efficacy and tolerability data were analysed using non-parametric tests (Friedman’s test for overall significance followed by Wilcoxon analyses for change from baseline). Statistical significance was assumed at P B/0.05.
Results
47
37 (52.1) 34 (47.9) 76.59/7.9 86.5 13.5 47 (62.7) 18 (24.0) 17 (22.7) 10 (52.6) 6 (31.6) 3 (15.8) 12 (63.2) 2 (10.5) 3 (15.8) 2 (10.5) 21.09/1.52
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Risperidone significantly decreased the frequency and severity of overall assessed behavioural and psychological symptoms as determined by the total NPI score. This score improved over the course of the study from 21.09/1.52 at baseline to 7.29/0.70 at end-point (P B/0.001) (Figure 1). Significant improvements were also seen on subscales of behavioural symptoms (agitation, apathy/indifference, disinhibition, irritability/lability and aberrant motor behaviour) and psychotic/affective symptoms (delusions, hallucination, depression/dysphoria, anxiety, euphoria) at all time points (P B/0.001) (Table II). The largest improvements were seen in the hallucination and agitation items, where scores decreased by 73 and 76%, respectively, over the course of the study (Table II). Risperidone also improved mean scores on the CGI-S scale between baseline and all time points (P B/0.005), and the number of patients whose symptoms were rated as marked, severe, or extremely severe decreased from 25 (33%) to 13 (17%) over the course of the study. The number of patients who were rated as not ill or having only very mild symptoms increased more than two-fold from 4 (5%) at baseline to 10 (13%) at end-point. Risperidone also decreased scores on the Blessed Dementia Functional Rating Scale from a mean of 14.69/0.65 at baseline to 12.79/0.65 at month 6 (P B/ 0.001 for all time points compared with baseline). This indicated improved functional capacity over the course of treatment. Furthermore, risperidone did not worsen progressive staging, as assessed on the GDS (no significant difference in scores between baseline and month 6). Patients also showed less depression after treatment with risperidone, as shown by reductions in scores on the Cornell Scale for Depression in Dementia (Figure 2). This included significant reductions on the subscales of mood-related signs, behavioural disturbances, physical signs, cyclic functions and ideational disturbances (PB/ 0.05 for month 3 and 6 compared with baseline) (Figure 2). 25 20 Mean score
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Efficacy
15
* *
10
* *
5
* *
*
*
*
Month 1
Month 3
Month 6
0 Baseline Total
Behavioural symptoms
Psychotic/affective symptoms
Figure 1. Scores on the total NPI and subscales of behavioural symptoms and psychotic/affective symptoms (mean9/SEM) over the course of the study (n/65 /74). Statistically significant reductions from baseline were observed at all visits (*PB/ 0.001, Wilcoxon tests) following an overall significant change across the course of the study (PB/ 0.001, Friedman’s tests).
The ratings of the global opinion of the investigators supported the quantitative data, with 94% rating the efficacy of treatment with risperidone as being good or excellent. Tolerability Extrapyramidal symptoms decreased transiently over the course of the study as rated on the UKU extrapyramidal subscale, with a significantly lower score at month 3 (P B/ 0.05, compared with baseline). Analyses of the individual extrapyramidal symptoms on the UKU subscale indicated that dystonia and tremor showed overall decreases over the course of the study (P 5/0.012). A total of four adverse events (5.3%) were spontaneously reported during the study: two cases of hypotension, one case of somnolence and one of paresthesia. The two patients with hypotension discontinued the study after 1 and 3 months of treatment. The hypotension was rated by the investigator as severe in one patient and moderate in the other. Both cases were judged as being related to the treatment, necessitating discontinuation. The intensity and relationship to treatment was not specified for the other two adverse events. Except for the two cases of hypotension, no other vascular complications were reported in this study. No acute cerebrovascular adverse events were reported. Tolerability of risperidone was confirmed by the global opinion of investigators, 97% of whom rated tolerance as being good or excellent. Discussion In this study, risperidone at a mean dose of 1.6 mg/ day, was found to be an effective treatment for behavioural symptoms, such as aggression and agitation, and psychosis in patients diagnosed with vascular or mixed-type dementia. This observed dose is slightly higher than the mean effective dose of 1.0 mg/day risperidone, as observed in three large controlled trials [8/10]. Risperidone was shown to be well tolerated, particularly with respect to extrapyramidal symptoms, which did not differ significantly from baseline during the course of the study, except at month 3 when these symptoms significantly decreased. These results support those obtained with risperidone in controlled trials that included primarily patients with Alzheimer’s disease, and a smaller proportion diagnosed with vascular or mixed-type dementia (27/42%) [8 /10]. Based on recent findings in double-blind, placebocontrolled clinical trials in the treatment of behavioural disturbances and psychosis of dementia with atypical antipsychotic drugs, an increased risk of cerebrovascular adverse events (CAEs) has been observed in this elderly population [22,23]. Combined results from six double-blind placebo-con-
Risperidone in vascular or mixed-type dementia
49
Table II. Total and subscale scores on the NPI scales. Baseline
Month 6*
Month 3*
Total
21.09/1.52
12.59/1.16
8.59/0.76
7.29/0.70
Behavioural symptoms Agitation Apathy/indifference Disinhibition Irritability/lability Aberrant motor behaviour
11.49/1.05 4.49/0.40 1.59/0.22 1.79/0.31 3.79/0.34 1.59/0.34
7.19/0.72 2.29/0.25 1.19/0.17 1.09/0.20 2.29/0.22 0.99/0.20
5.09/0.53 1.59/0.15 1.09/0.16 0.79/0.13 1.69/0.18 0.59/0.11
4.79/0.50 1.29/0.12 1.09/0.14 0.79/0.12 1.59/0.18 0.59/0.11
8.99/1.05 1.89/0.33 2.19/0.33 2.39/0.30 3.29/0.35 0.79/0.17
5.99/0.80 1.19/0.28 1.19/0.20 1.69/0.25 1.99/0.25 0.59/0.11
4.19/0.45 0.79/0.15 0.79/0.14 1.39/0.18 1.49/0.16 0.49/0.09
3.69/0.40 0.69/0.14 0.59/0.09 1.19/0.15 1.29/0.13 0.49/0.08
Psychotic/affective symptoms Delusions Hallucination Depression/dysphoria Anxiety Euphoria
Data are expressed as mean9/SEM (n /56 /73). *Statistically significant decreases over the course of the study were observed for scores on the total NPI, and subscales of behavioural symptoms and psychotic/affective symptoms and all individual items (except euphoria) (PB/ 0.001, Friedman’s tests), as well as between baseline and all time points (PB/ 0.05, Wilcoxon tests).
trolled studies showed a three-fold increased risk of CAEs, including stroke as well as transient ischemic attacks, with risperidone (3.3%) compared to placebo (1.2%) [24]. Since the diagnosis of vascular dementia includes a cerebrovascular component, it is noticeable that in this study no CAEs were reported. The reason why no CAEs were observed in this study could lay in the limitations of the naturalistic setting of the study or way of reporting adverse events. Furthermore, this study population (75 patients) may not have been large enough to observe CAEs. In any case, in dementia patients where pharmacological intervention is warranted, the potential benefit should be weighted against the potential risk and the need for continuing treatment should be reassessed by their treating physician at regular intervals. Although the results obtained in this study are in line with those from the controlled clinical trials, the interpretation of the data on efficacy may be limited because of the naturalistic open-label setting and
small number of patients in this study. This is reflected in the magnitude of the effects obtained, which, with the lack of a control group, have not been corrected for placebo effects. However, the efficacy assessments that were used have been well documented and validated in elderly patients [17,19,25 /27]. Risperidone decreased the frequency and severity of various behavioural disturbances and psychological symptoms, as indicated by significant improvements in all items of the NPI, except euphoria. The largest effects of risperidone were observed on the hallucination and agitation items, which correspond with the well-documented effects of risperidone on these symptoms [8/10]. The diagnosis of dementia is usually clinical [6] and, consequently, global clinical judgements are recognized as important measures of outcome in the treatment of dementia [17]. In the present study, risperidone significantly improved scores on the CGI-S scale. This suggests that risperidone does not compromise cognitive
5 Baseline
Mean (SEM) scores
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Month 1*
4.5
Month 3
4
Month 6
3.5 3
* *
* *
*
2.5
*
2 1.5
*
*
*
*
1 0.5 0 Mood-related signs
Behavioural disturbances
Physical signs
Cyclic functions
Ideational disturbances
Figure 2. Mean (9/SEM) scores on the subscales of the Cornell Scale for Depression in Dementia over the course of the study (n /62 /74). Statistically significant reductions of all subscales from baseline were observed at month 3 and month 6 (*P B/ 0.05, Wilcoxon tests).
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A. J. Cruz-Jentoft et al.
aspects and does improve behavioural impairments in patients with vascular or mixed-type dementia. The positive effects of risperidone on the scores of the Blessed Dementia Functional Rating Scale and the GDS also support improved functional capacity over the course of treatment without affecting the activities of daily living. Significant improvements were also observed on the apathy/indifference and depression/dysphoria NPI subscale items. Furthermore, patients in the current study indicated less depression after treatment with risperidone, as determined by significant reductions in scores on the Cornell Scale for Depression in Dementia. Depression affects at least 20% of patients with dementia [28,29] and may be more prevalent in patients with vascular dementia than in those with Alzheimer’s disease [12,30]. Future research is necessary to determine whether this finding can be reproduced in and generalized to other populations with dementia, and to assess whether this effect is secondary to the reduction in other non-cognitive symptoms or due to some other mechanism. Overall, the results of this open-label naturalistic study indicate that risperidone effectively reduced the severity and frequency of behavioural disturbances and psychosis in elderly patients diagnosed with vascular or mixed-type dementia. Furthermore, risperidone was well tolerated in this elderly population, particularly with respect to extrapyramidal symptoms. Nevertheless, in view of the risk for CAEs the use of antipsychotics, including risperidone, should be targeted towards the treatment of those patients in whom psychological and behavioural symptoms of dementia such as psychosis, agitation and aggression are prominent and associated with significant distress, functional impairment or danger to the patient. Moreover, the need for continuing pharmacological treatment should be reassessed on a regular basis. Key points . Risperidone significantly decreased the frequency and severity of overall assessed behavioural and psychological symptoms in patients with vascular or mixed-type dementia . The largest improvements were seen in the hallucination and agitation items, where scores decreased by 73 and 76%, respectively, over the 6-month period . Risperidone treatment improved functional capacity and did not worsen progressive staging over the course of treatment . Patients in the current study indicated less depression after treatment with risperidone. . Risperidone was well tolerated in this elderly population, particularly with respect to extrapyramidal symptoms
Acknowledgements The authors would like to thank the following members of the Spanish Group for the Study of Risperidone in Vascular Dementia: Agu¨era Ortiz L, Arcenilla Rodrı´guez B, Cervera Dı´az C, Delgado Sa´nchez G, Dura´n Alonso JC, Entrala Bueno A, Espejo Sua´rez J, Frades Payo B, Garcı´a Ribas G, ´ beda JM, Girona Ga´lvez JC, Gonza´lez Klett Giro´n U M, Guerrero Sa´nchez G, Herna´ndez Ramos FJ, Higues Pascual F, Jime´nez Torres EF, Lara Lara M, Luja´n Ortega JM, Martı´nez Aguayo FJ, Martı´nez Martı´nez P, Mendoza Rodrı´guez A, Mereder Hengstl S, Morin˜igo Domı´nguez A, Olazaran Rodrı´guez FJ, Pastor Rull M, Prat Rojo J, Rexach Cano L, Rey Costas C, Sa´nchez Herna´ndez F, Serra Rexach JA, Sumalla Sun˜er J, Tejeiro Mertinez J, Valls Cardu´s J, Va´zquez Va´zquez MA, Viguera Romero J, Vin˜uela Ferna´ndez F, Vivancos Matellano F, Yusta Izquierdo A. Statement of interest Supported by a grant from Janssen-Cilag Spain. Dr Cruz-Jentoft has served as a consultant to JanssenCilag, S.A., Spain. Drs Buro´n, Diago and Gallego are full employees of Janssen-Cilag S.A., Spain.
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ORIGINAL ARTICLE
Risperidone in the treatment of behavioural and psychological symptoms of dementia in patients diagnosed with vascular or mixed-type dementia
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´ N2, JESU ´ -ANTONIO BURO ´ S I. DIAGO2 & ALFONSO J. CRUZ-JENTOFT1, JOSE RICARDO GALLEGO2 1
Hospital Ramo´n y Cajal, Servicio de Geriatria, Madrid, Spain and 2Medical Department, Janssen-Cilag, Madrid, Spain
Abstract Objective . Studies have found that the atypical antipsychotic drug, risperidone, reduces non-cognitive symptoms, such as aggression, agitation, and psychosis, in patients with Alzheimer’s disease. This study assessed whether these effects extend to patients with vascular or mixed-type dementia. Methods . In this multicentre, open-label, prospective study, 75 elderly patients with vascular or mixed-type dementia and concomitant behavioural and psychological symptoms were treated with risperidone for up to 6 months. Results . Risperidone decreased the frequency and severity of overall behavioural and psychological symptoms, as determined by the Neuropsychiatric Inventory, to a mean total score of 7.29/0.7 at end-point compared with 21.09/1.5 at baseline (PB/0.001). Risperidone improved functional capacity (Blessed Dementia Rating Scale, Reisberg’s Global Deterioration Scale) and depression (Cornell Scale for Depression in Dementia). A total of four adverse events (5.3%) were spontaneously reported: two cases of hypotension, one of somnolence, and one of paresthesia. Scores on the Udvalg for Kliniske Undersogeler extrapyramidal symptom subscale remained stable from baseline to endpoint. Conclusion . Overall, these findings indicate that risperidone was effective in reducing behavioural and psychological symptoms and was well tolerated, particularly with respect to extrapyramidal symptoms, in this elderly population diagnosed with vascular or mixed-type dementia.
Key Words: BPSD, mixed-type dementia, open-label, risperidone, vascular dementia
Introduction Dementia is a disabling condition of global cognitive decline, often accompanied by non-cognitive behavioural symptoms, such as aggression and agitation, and psychosis. Dementia has many causes, but most cases are due to Alzheimer’s disease or brain damage resulting from lack of vascular perfusion (vascular dementia) [1]. Mixed-type dementia incorporates elements of both these aetiologies. Although deficits in memory, language, visuospatial skills, complex cognition, emotion and personality are the core criteria for dementia, accompanying behavioural symptoms and psychosis of dementia are frequently more problematic. These symptoms include verbal and physical aggression, agitation, delusion, hallucination, anxiety, wandering, apathy and depression [2]. These symptoms have been linked to patient distress, decreased quality of life, caregiver burden and institutionalization [3 /5].
The primary goals for the treatment of patients with dementia are to improve quality of life and maximize functional performance by enhancing cognition, mood and behaviour [6]. Due to the significant effects of non-cognitive symptoms on quality of life, the treatment of these symptoms has become an important component of dementia therapy. Treatments include non-pharmacological strategies (such as emotion- and stimulation-oriented therapies), as well as pharmacological interventions (primarily with antipsychotic medication) [6]. Pharmacotherapy with conventional neuroleptic drugs, such as haloperidol, provides a small benefit in the treatment of dementia patients with behavioural symptoms, with only 18% more patients showing an improvement compared with those who received placebo [7]. Furthermore, the use of these drugs is limited because they are associated with extrapyramidal motor symptoms, especially in the elderly patient. Risperidone was the first
Correspondence: A. J. Cruz-Jentoft, Unidad de Geriatrı´a, Hospital Ramo´n y Cajal, Ctra. Colmenar km 9,100, Madrid, Spain. Tel: 34-913-368172. Fax: 34913-368431. E-mail: [email protected]
(Received 21 June 2004; accepted 5 October 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014729
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atypical antipsychotic shown to be effective at low doses in treating behavioural and psychotic symptoms of dementia, such as aggression, agitation and psychosis, in nursing-home residents, as reported by three large placebo-controlled clinical trials [8/10]. These trials also demonstrated that there were no differences between the severity of extrapyramidal symptoms in patients who received low-dose risperidone (i.e. lower than 1.5 mg) or placebo. In contrast, these symptoms were significantly more severe in patients who received haloperidol [9]. The controlled trials of risperidone have primarily included patients with Alzheimer’s disease [8/10], with a proportion of patients diagnosed with vascular or mixed-type dementia. Although there are several differences between the symptoms of dementia of the Alzheimer type and vascular or mixed dementias, differential diagnosis between these subtypes of dementia is often challenging for the clinician. In a recent post mortem study, a 56.5% incidence of vascular pathology in 173 autopsy-confirmed AD patients was observed, compared to 42.4% control patients [11], revealing that proper accurate diagnosis of these patients can be difficult. They further concluded that brain weight and severity of cognitive decline did not correspond to the degree of vascular pathology. Sultzer et al. observed that patients with vascular dementia had more severe behavioural retardation, depression and anxiety than those with Alzheimer’s disease who were at a similar level of cognitive impairment [12]. Groves et al. found that patients with vascular dementia were more depressed, more functionally impaired and less cognitively impaired than those with Alzheimer’s disease [1]. The diagnostic criteria for vascular dementia are different from those of the Alzheimer type: the former include the presence of cerebrovascular disease, a temporal correlation of dementia with cerebrovascular disease and often a sudden or step-wise deterioration [1,13]. Patients with vascular dementia may show more motor symptoms than those with Alzheimer’s disease [1]. In fact, an expert panel has concluded that focal motor or sensory signs (except fluent aphasia and apraxia) suggest a diagnosis of vascular dementia or mixed-type dementia and Alzheimer’s disease [6]. Given these symptomatological and pathophysiological dissimilarities, it may be that patients with vascular or mixed-type dementia respond differently to pharmacotherapy than those with dementia of the Alzheimer type. Therefore, the present study was undertaken to assess the efficacy and safety of treatment with risperidone in elderly nursing-home residents with behavioural and/or psychological symptoms diagnosed with vascular or mixed-type dementia.
Methods Patients This study included both Spanish institutionalized and community-dwelling patients who were eligible for study participation if they were diagnosed with dementia with a vascular component according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders / 4th edition (DSM-IV) [14] and were deemed to be in treatment with an antipsychotic due to concomitant behavioural and psychological symptoms. Dementia must have been of the vascular or mixed-type according to the Hachinski scale of dementia, with scores ]/4 [15]. No radiological investigations were performed. Patients who were being treated with other antipsychotic drugs were eligible if they were experiencing problems with tolerability, or if efficacy of their current medication was inadequate. Based on the physician’s examination and the patient’s medical history, those with pure Alzheimer’s or Lewy body diseases were excluded, as were those with disorders of consciousness (e.g. delirium) and those whose dementia was attributable to an identifiable organic aetiology (e.g. hypothyroidism, normotensive hydrocephalus). In addition, patients were excluded if they had a history of severe mental illness other than dementia or any other severe concomitant disease that would contraindicate inclusion in the study or had the potential to interfere with the study parameters. Patients who had received risperidone within the last 3 months were not eligible. Patients could be discontinued from the study for lack of efficacy, intolerance of the study medication, the need to maintain concomitant treatment with other antipsychotic or antidepressant drugs for more than 2 weeks, or any other reason that necessitated withdrawal from risperidone. The study was designed according to Spanish regulations applicable over the study period. The local Spanish Health Authority was informed and agreed with the design and characteristics before the start of the study. Patients were treated with risperidone according to doses and regimens determined by their physician. Design and procedures This was a multicentre, open-label, 6-month, prospective study of risperidone for the treatment of behavioural and psychotic symptoms in patients with vascular or mixed-type dementia. Treatment with risperidone was initiated at doses of 0.5 or 1.0 mg/ day, depending on the severity of symptoms, and increased by 0.5 mg/day until optimal doses within the recommended range were reached (0.5 /1 mg twice daily). For patients who were being treated with conventional neuroleptic drugs at entry to the study, these drugs were gradually withdrawn over
Risperidone in vascular or mixed-type dementia 1 week (haloperidol, pimozide) or 1 /2 weeks (thioridazine, levomepromazine) once maintenance doses of risperidone were reached. Data were collected at baseline and at months 1, 3 and 6.
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Outcome measures Efficacy measures included the Neuropsychiatric Inventory (NPI) [16], Clinical Global Impression of Severity (CGI-S) [17], progressive staging using the Global Deterioration Functional Scale (GDS) [18], and the global opinion of the investigator (deficient, normal, good or excellent). Depression was assessed using the Cornell Scale for Depression in Dementia [19], which rates symptoms (grouped into clusters of mood related signs, behavioural disturbances, physical signs, cyclic functions and ideational disturbances) on a scale of 0 /absent to 2/severe. Functional skills were assessed using the Blessed Dementia Functional Rating Scale [20], which consists of 22 items grouped into the subsets of everyday activities, changes in self-care habits and changes in personality, interests and drives. These subsets were assessed individually and then the total score calculated. Tolerability was assessed on the Udvalg for Kliniske Undersogeler (UKU) extrapyramidal symptom subscale [21], the global impression of the investigator (deficient, normal, good or excellent), and by recording adverse reactions that were reported during guided history assessment (extrapyramidal reactions) or spontaneously by patients/ caregivers (other reactions). Only extrapyramidal symptoms were assessed at every visit in a structured way. Adverse reactions were judged for their intensity (mild, moderate, severe) and relationship to treatment (remote, possible, probable, very probable). Use of antiparkinsonian and other medications was also monitored.
(81.3%, Table I). Patients had a mean age of 76.5 years and the genders were equally represented (52.1% female) in the study population. Over the entire study period, a total of 14 patients (18.7%) discontinued treatment prematurely. Two of these patients died (2.7%) during the course of the study: one patient died of bronchoaspiration and one of acute pulmonary oedema, and these deaths were rated by the investigator as not being related to the drug treatment., Two patients (2.7%) were withdrawn because of intolerance of the study medication and another patient (1.3%) stopped treatment due to clinical improvement. Four patients (5.3%) discontinued for other reasons. In addition, five patients (6.7%) were lost to follow-up or were relocated. Nineteen patients (25.3%) had received previous neuroleptic treatment, 55 (73.3%) had not received such treatment, and information on this treatment was unavailable for one patient (Table I). Five patients (6.7%) had received previous antidepressant treatment. Almost all patients in this study (n /71) had at least one concomitant disease or medical condition (Table I). Most patients (n /49) were receiving concomitant treatment for one or more conditions, with a total of 60 concomitant treatments, including non-psychopharmacological treatments (n /52) and benzodiazepines (n /4). Dose The mean dose of risperidone at baseline was 1.19/ 0.6 mg/day (range: 0.5 /2.0 mg/day) and 1.69/ 0.7 mg/day at end-point (range: 0.5 /4.0 mg/day). The mean and median doses were similar, with a median dose of 1.0 mg/day at baseline and 1.5 mg/ day at end-point. Table I. Demographics and baseline characteristics.
Patients
Gender *, n (%) Female Male Age (years)$ Mean9/SD Diagnosis of dementia , % Vascular Mixed-type Concomitant disease , n (%) Hypertension Cardiovascular Diabetes Previous neuroleptic treatment , n (%) Haloperidol Thioridazine Levomepromazine Reasons for switching, n (%) Lack of efficacy Poor tolerance Both Other reasons Baseline NPI , Mean9/SEM
Of the 86 patients screened, 75 met the study criteria and were included, with 61 completing the trial
*Gender was not specified in four patients. $ Age was not specified in three patients.
Data analyses Analyses were based on the intent-to-treat principle and included all patients who received at least one dose of risperidone. For efficacy analyses, the last available value was used for patients who discontinued the study prematurely. Demographic, efficacy and tolerability data were summarized with descriptive statistics. Efficacy and tolerability data were analysed using non-parametric tests (Friedman’s test for overall significance followed by Wilcoxon analyses for change from baseline). Statistical significance was assumed at P B/0.05.
Results
47
37 (52.1) 34 (47.9) 76.59/7.9 86.5 13.5 47 (62.7) 18 (24.0) 17 (22.7) 10 (52.6) 6 (31.6) 3 (15.8) 12 (63.2) 2 (10.5) 3 (15.8) 2 (10.5) 21.09/1.52
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A. J. Cruz-Jentoft et al.
Risperidone significantly decreased the frequency and severity of overall assessed behavioural and psychological symptoms as determined by the total NPI score. This score improved over the course of the study from 21.09/1.52 at baseline to 7.29/0.70 at end-point (P B/0.001) (Figure 1). Significant improvements were also seen on subscales of behavioural symptoms (agitation, apathy/indifference, disinhibition, irritability/lability and aberrant motor behaviour) and psychotic/affective symptoms (delusions, hallucination, depression/dysphoria, anxiety, euphoria) at all time points (P B/0.001) (Table II). The largest improvements were seen in the hallucination and agitation items, where scores decreased by 73 and 76%, respectively, over the course of the study (Table II). Risperidone also improved mean scores on the CGI-S scale between baseline and all time points (P B/0.005), and the number of patients whose symptoms were rated as marked, severe, or extremely severe decreased from 25 (33%) to 13 (17%) over the course of the study. The number of patients who were rated as not ill or having only very mild symptoms increased more than two-fold from 4 (5%) at baseline to 10 (13%) at end-point. Risperidone also decreased scores on the Blessed Dementia Functional Rating Scale from a mean of 14.69/0.65 at baseline to 12.79/0.65 at month 6 (P B/ 0.001 for all time points compared with baseline). This indicated improved functional capacity over the course of treatment. Furthermore, risperidone did not worsen progressive staging, as assessed on the GDS (no significant difference in scores between baseline and month 6). Patients also showed less depression after treatment with risperidone, as shown by reductions in scores on the Cornell Scale for Depression in Dementia (Figure 2). This included significant reductions on the subscales of mood-related signs, behavioural disturbances, physical signs, cyclic functions and ideational disturbances (PB/ 0.05 for month 3 and 6 compared with baseline) (Figure 2). 25 20 Mean score
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Efficacy
15
* *
10
* *
5
* *
*
*
*
Month 1
Month 3
Month 6
0 Baseline Total
Behavioural symptoms
Psychotic/affective symptoms
Figure 1. Scores on the total NPI and subscales of behavioural symptoms and psychotic/affective symptoms (mean9/SEM) over the course of the study (n/65 /74). Statistically significant reductions from baseline were observed at all visits (*PB/ 0.001, Wilcoxon tests) following an overall significant change across the course of the study (PB/ 0.001, Friedman’s tests).
The ratings of the global opinion of the investigators supported the quantitative data, with 94% rating the efficacy of treatment with risperidone as being good or excellent. Tolerability Extrapyramidal symptoms decreased transiently over the course of the study as rated on the UKU extrapyramidal subscale, with a significantly lower score at month 3 (P B/ 0.05, compared with baseline). Analyses of the individual extrapyramidal symptoms on the UKU subscale indicated that dystonia and tremor showed overall decreases over the course of the study (P 5/0.012). A total of four adverse events (5.3%) were spontaneously reported during the study: two cases of hypotension, one case of somnolence and one of paresthesia. The two patients with hypotension discontinued the study after 1 and 3 months of treatment. The hypotension was rated by the investigator as severe in one patient and moderate in the other. Both cases were judged as being related to the treatment, necessitating discontinuation. The intensity and relationship to treatment was not specified for the other two adverse events. Except for the two cases of hypotension, no other vascular complications were reported in this study. No acute cerebrovascular adverse events were reported. Tolerability of risperidone was confirmed by the global opinion of investigators, 97% of whom rated tolerance as being good or excellent. Discussion In this study, risperidone at a mean dose of 1.6 mg/ day, was found to be an effective treatment for behavioural symptoms, such as aggression and agitation, and psychosis in patients diagnosed with vascular or mixed-type dementia. This observed dose is slightly higher than the mean effective dose of 1.0 mg/day risperidone, as observed in three large controlled trials [8/10]. Risperidone was shown to be well tolerated, particularly with respect to extrapyramidal symptoms, which did not differ significantly from baseline during the course of the study, except at month 3 when these symptoms significantly decreased. These results support those obtained with risperidone in controlled trials that included primarily patients with Alzheimer’s disease, and a smaller proportion diagnosed with vascular or mixed-type dementia (27/42%) [8 /10]. Based on recent findings in double-blind, placebocontrolled clinical trials in the treatment of behavioural disturbances and psychosis of dementia with atypical antipsychotic drugs, an increased risk of cerebrovascular adverse events (CAEs) has been observed in this elderly population [22,23]. Combined results from six double-blind placebo-con-
Risperidone in vascular or mixed-type dementia
49
Table II. Total and subscale scores on the NPI scales. Baseline
Month 6*
Month 3*
Total
21.09/1.52
12.59/1.16
8.59/0.76
7.29/0.70
Behavioural symptoms Agitation Apathy/indifference Disinhibition Irritability/lability Aberrant motor behaviour
11.49/1.05 4.49/0.40 1.59/0.22 1.79/0.31 3.79/0.34 1.59/0.34
7.19/0.72 2.29/0.25 1.19/0.17 1.09/0.20 2.29/0.22 0.99/0.20
5.09/0.53 1.59/0.15 1.09/0.16 0.79/0.13 1.69/0.18 0.59/0.11
4.79/0.50 1.29/0.12 1.09/0.14 0.79/0.12 1.59/0.18 0.59/0.11
8.99/1.05 1.89/0.33 2.19/0.33 2.39/0.30 3.29/0.35 0.79/0.17
5.99/0.80 1.19/0.28 1.19/0.20 1.69/0.25 1.99/0.25 0.59/0.11
4.19/0.45 0.79/0.15 0.79/0.14 1.39/0.18 1.49/0.16 0.49/0.09
3.69/0.40 0.69/0.14 0.59/0.09 1.19/0.15 1.29/0.13 0.49/0.08
Psychotic/affective symptoms Delusions Hallucination Depression/dysphoria Anxiety Euphoria
Data are expressed as mean9/SEM (n /56 /73). *Statistically significant decreases over the course of the study were observed for scores on the total NPI, and subscales of behavioural symptoms and psychotic/affective symptoms and all individual items (except euphoria) (PB/ 0.001, Friedman’s tests), as well as between baseline and all time points (PB/ 0.05, Wilcoxon tests).
trolled studies showed a three-fold increased risk of CAEs, including stroke as well as transient ischemic attacks, with risperidone (3.3%) compared to placebo (1.2%) [24]. Since the diagnosis of vascular dementia includes a cerebrovascular component, it is noticeable that in this study no CAEs were reported. The reason why no CAEs were observed in this study could lay in the limitations of the naturalistic setting of the study or way of reporting adverse events. Furthermore, this study population (75 patients) may not have been large enough to observe CAEs. In any case, in dementia patients where pharmacological intervention is warranted, the potential benefit should be weighted against the potential risk and the need for continuing treatment should be reassessed by their treating physician at regular intervals. Although the results obtained in this study are in line with those from the controlled clinical trials, the interpretation of the data on efficacy may be limited because of the naturalistic open-label setting and
small number of patients in this study. This is reflected in the magnitude of the effects obtained, which, with the lack of a control group, have not been corrected for placebo effects. However, the efficacy assessments that were used have been well documented and validated in elderly patients [17,19,25 /27]. Risperidone decreased the frequency and severity of various behavioural disturbances and psychological symptoms, as indicated by significant improvements in all items of the NPI, except euphoria. The largest effects of risperidone were observed on the hallucination and agitation items, which correspond with the well-documented effects of risperidone on these symptoms [8/10]. The diagnosis of dementia is usually clinical [6] and, consequently, global clinical judgements are recognized as important measures of outcome in the treatment of dementia [17]. In the present study, risperidone significantly improved scores on the CGI-S scale. This suggests that risperidone does not compromise cognitive
5 Baseline
Mean (SEM) scores
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Month 1*
4.5
Month 3
4
Month 6
3.5 3
* *
* *
*
2.5
*
2 1.5
*
*
*
*
1 0.5 0 Mood-related signs
Behavioural disturbances
Physical signs
Cyclic functions
Ideational disturbances
Figure 2. Mean (9/SEM) scores on the subscales of the Cornell Scale for Depression in Dementia over the course of the study (n /62 /74). Statistically significant reductions of all subscales from baseline were observed at month 3 and month 6 (*P B/ 0.05, Wilcoxon tests).
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A. J. Cruz-Jentoft et al.
aspects and does improve behavioural impairments in patients with vascular or mixed-type dementia. The positive effects of risperidone on the scores of the Blessed Dementia Functional Rating Scale and the GDS also support improved functional capacity over the course of treatment without affecting the activities of daily living. Significant improvements were also observed on the apathy/indifference and depression/dysphoria NPI subscale items. Furthermore, patients in the current study indicated less depression after treatment with risperidone, as determined by significant reductions in scores on the Cornell Scale for Depression in Dementia. Depression affects at least 20% of patients with dementia [28,29] and may be more prevalent in patients with vascular dementia than in those with Alzheimer’s disease [12,30]. Future research is necessary to determine whether this finding can be reproduced in and generalized to other populations with dementia, and to assess whether this effect is secondary to the reduction in other non-cognitive symptoms or due to some other mechanism. Overall, the results of this open-label naturalistic study indicate that risperidone effectively reduced the severity and frequency of behavioural disturbances and psychosis in elderly patients diagnosed with vascular or mixed-type dementia. Furthermore, risperidone was well tolerated in this elderly population, particularly with respect to extrapyramidal symptoms. Nevertheless, in view of the risk for CAEs the use of antipsychotics, including risperidone, should be targeted towards the treatment of those patients in whom psychological and behavioural symptoms of dementia such as psychosis, agitation and aggression are prominent and associated with significant distress, functional impairment or danger to the patient. Moreover, the need for continuing pharmacological treatment should be reassessed on a regular basis. Key points . Risperidone significantly decreased the frequency and severity of overall assessed behavioural and psychological symptoms in patients with vascular or mixed-type dementia . The largest improvements were seen in the hallucination and agitation items, where scores decreased by 73 and 76%, respectively, over the 6-month period . Risperidone treatment improved functional capacity and did not worsen progressive staging over the course of treatment . Patients in the current study indicated less depression after treatment with risperidone. . Risperidone was well tolerated in this elderly population, particularly with respect to extrapyramidal symptoms
Acknowledgements The authors would like to thank the following members of the Spanish Group for the Study of Risperidone in Vascular Dementia: Agu¨era Ortiz L, Arcenilla Rodrı´guez B, Cervera Dı´az C, Delgado Sa´nchez G, Dura´n Alonso JC, Entrala Bueno A, Espejo Sua´rez J, Frades Payo B, Garcı´a Ribas G, ´ beda JM, Girona Ga´lvez JC, Gonza´lez Klett Giro´n U M, Guerrero Sa´nchez G, Herna´ndez Ramos FJ, Higues Pascual F, Jime´nez Torres EF, Lara Lara M, Luja´n Ortega JM, Martı´nez Aguayo FJ, Martı´nez Martı´nez P, Mendoza Rodrı´guez A, Mereder Hengstl S, Morin˜igo Domı´nguez A, Olazaran Rodrı´guez FJ, Pastor Rull M, Prat Rojo J, Rexach Cano L, Rey Costas C, Sa´nchez Herna´ndez F, Serra Rexach JA, Sumalla Sun˜er J, Tejeiro Mertinez J, Valls Cardu´s J, Va´zquez Va´zquez MA, Viguera Romero J, Vin˜uela Ferna´ndez F, Vivancos Matellano F, Yusta Izquierdo A. Statement of interest Supported by a grant from Janssen-Cilag Spain. Dr Cruz-Jentoft has served as a consultant to JanssenCilag, S.A., Spain. Drs Buro´n, Diago and Gallego are full employees of Janssen-Cilag S.A., Spain.
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