Management of agitation, aggression, and psychosis associated with dementia: A pooled analysis including three randomized, placebo-controlled double-blind trials in nursing home residents treated with risperidone

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Abstract

This analysis used pooled data from three randomized, placebo-controlled trials that examined the efficacy and safety of risperidone for the treatment of agitation, aggression, and psychosis associated with dementia in elderly nursing home residents to assess the risk-benefit of the use of risperidone in this population.

The efficacy data (risperidone n = 722, placebo n = 428) were obtained from the Cohen-Mansfield agitation inventory (CMAI) and behavioral pathology in Alzheimer's disease (BEHAVE-AD) total and subscales. Additionally, clinical global impression (CGI) assessments were performed. Subgroup analyses were performed by type of dementia, severity of dementia, presence or absence of somnolence as an adverse event, and presence or absence of psychosis at baseline. Safety assessments included evaluation of treatment emergent adverse events, Extrapyramidal Symptom Rating Scale, ECG and vital signs, and Mini-Mental State Examination (MMSE). The mean dose of risperidone at end point was 1.0 mg/day (0.02 S.E.).

The observed mean change at end point was significantly higher for risperidone than for placebo on CMAI total score (−11.8 versus −6.4, respectively; p < 0.001), total aggression score (−5.0 versus −1.8, respectively; p < 0.001), BEHAVE-AD total score (−6.1 and −3.6, respectively; p < 0.001), and psychotic symptoms score (−2.1 and −1.3, respectively; p = 0.003). The main treatment effects of risperidone were similar in all subgroup analyses. Additionally, risperidone-treated patients scored significantly better than placebo-treated patients on the CGI scales at end point.

The incidence of treatment-emergent adverse events was comparable between risperidone (84.3%) and placebo (83.9%). More patients discontinued due to adverse events in the risperidone-treated group (17.2%) than in the placebo group (11.2%). Differences in adverse event incidences between placebo and risperidone were observed for extrapyramidal symptoms (EPS), mild somnolence and the less common cerebrovascular adverse events (CAE). Risperidone induced neither orthostatic, nor anticholinergic side effects nor falls nor cognitive decline.

Of all atypical antipsychotics, risperidone has the largest database of double-blind controlled trials to support its efficacy and safety in the treatment of agitation, aggression, and psychosis associated with dementia. At the recommended doses, risperidone displayed a favorable risk-benefit profile. Risperidone was well tolerated with respect to EPS, somnolence, and anticholinergic side effects in this elderly population. In view of the risk for CAEs, risperidone, should be targeted towards the treatment of those patients in whom psychotic and behavioral symptoms of dementia are prominent and associated with significant distress, functional impairment or danger to the patient.

Introduction

Dementia, regardless of its cause, is a clinical syndrome that expresses itself in three domains: (1) neuropsychological, or cognitive deficits such as memory loss, aphasia, apraxia, and agnosia; (2) psychiatric and behavioral disturbances, also known as behavioral and psychological symptoms of dementia (BPSD); and (3) difficulties in carrying out activities of daily living. The incidence of dementia generally increases with age [1], [2], [3], leading to growing humanitarian and economic concerns for countries with aging populations.

Over the past decade, research into BPSD has intensified, as it has become clear that these symptoms cause tremendous distress for both patient and caregiver. One of the main causes of institutionalization [4], [5], BPSD include verbal and physical aggression, psychotic symptoms, agitation, anxiety, and depression; they affect up to 90% of people with dementia at some point during their illness [6], [7], [8], [9], [10].

Until the mid 1990s, conventional neuroleptic drugs such as haloperidol were the primary pharmacological treatment for BPSD. Although conventional neuroleptics are significantly more effective than placebo in the treatment of dementia, their effect size is modest [11]. Additionally, conventional neuroleptics are frequently associated with extrapyramidal and anticholinergic side effects, which are particularly troublesome in the elderly [12].

Recent research has assessed the effects of the newer generation of atypical antipsychotic drugs on BPSD. When compared with conventional neuroleptics, these drugs are associated with significantly fewer extrapyramidal side effects [13] and a lower incidence of tardive dyskinesia in elderly patients [14]. Three randomized, controlled trials have found that risperidone is effective and well tolerated in treating BPSD [15], [16], [17].

The present study is an analysis of pooled data from these three randomized, placebo-controlled trials. A fourth large placebo-controlled clinical trial in patients with psychosis of Alzheimer's disease is currently being evaluated and is, therefore, not included in the current pooled database. The three trials had similar designs and used the same well-validated and accepted scales, i.e. the behavioral pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield agitation inventory (CMAI) and clinical global impression scales, to evaluate neuropharmacological interventions in patients with BPSD [18]. Patients in the three trials had comparable demographic characteristics and all received risperidone for 12 weeks in similar dose ranges (0.25–1.0 mg b.i.d.). In addition to efficacy, a pooled safety analysis was performed to assess the risk-benefit of risperidone in treating BPSD in these elderly patients.

Section snippets

Patient selection

Eligible patients were at least 55 years old, lived in an institution, and had scores of ≥4 on the Functional Assessment Staging scale and ≤24 on the Mini-Mental State Examination (MMSE) [19], [20]. Patients had to have been diagnosed according to DSM-IV criteria with dementia of the Alzheimer's type, vascular dementia, or a combination of the two (i.e. mixed dementia), together with BPSD that were at least mildly troubling to their caregivers or dangerous to themselves (see Table 1 for details

Patient disposition and characteristics

The total number of patients in the three trials included in this pooled analysis was 1191 of whom 744 received risperidone and 447 placebo (115 patients treated with haloperidol in the De Deyn et al. trial [16] were not considered in this analysis). The efficacy analyses included 1150 patients: 722 who were randomized to risperidone and 428 to placebo. In total, 36 patients originally included were excluded due to protocol violations; five more were excluded for lack of post-baseline efficacy

Discussion

For this first analysis of an atypical antipsychotic agent in the treatment of BPSD based on pooled efficacy and safety data, observations from three randomized, placebo-controlled trials that examined risperidone in elderly nursing home residents, were combined [15], [16], [17]. The trials’ similarities: in design; patient characteristics; efficacy and safety scales; dosages of risperidone; and treatment duration, justified pooling the data. Analyzing pooled data is useful because larger

Acknowledgement

This study received financial and material support from Johnson & Johnson Pharmaceutical Research & Development.

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