RESEARCH ARTICLE
Memantine improves goal attainment and reduces caregiver burden in Parkinson’s disease with dementia Iracema Leroi1,2, Richard Atkinson3 and Ross Overshott4 1
Institute of Brain Behaviour and Mental Health, Manchester Academic Health Sciences Centre, UK Manchester Mental Health and Social Care Trust, UK 3 Lancashire Care NHS Foundation Trust, UK 4 Greater Manchester West NHS Foundation Trust, UK Correspondence to: I. Leroi, E-mail: [email protected] 2
Objective: Memantine,
an uncompetitive antagonist of N-methyl-D-aspartate receptors, may have a role in managing symptoms associated with dementia in Parkinson’s disease (PDD), although its role in improving patient-reported outcomes (PROs) has not been extensively investigated. PROs may be more sensitive than standard psychometric measures for detecting change in complex conditions such as PDD. The aim of this study was to examine the effect of memantine on PROs: individually determined goals and health-related quality of life. We also examined memantine’s effect on caregiver burden. Methods: This 22-week double-blind randomised controlled trial evaluated participants with PDD on 20 mg of memantine or placebo. Outcome measures were Goal Attainment Scaling (GAS), the Parkinson’s Disease Questionnaire-8 and the Zarit Burden Inventory. Results: A significantly greater proportion of participants on memantine (64%) had better than expected GAS outcomes compared with those on placebo (7%) (p = 0.007). Furthermore, the improvement in mean GAS score, as well as mean caregiver burden score, from baseline to drug discontinuation was significantly greater in those on memantine compared with those on placebo (p = 0.03 and 0.04, respectively). Significant differences in quality of life were not seen. Conclusions: In this study, memantine improved individually set goals and caregiver burden in PDD. This suggests that clinimetric measures such as GAS may be more sensitive than conventional psychometric measures in detecting improvements in people with PDD. Copyright # 2014 John Wiley & Sons, Ltd. Key words: Parkinson’s disease dementia (PDD); memantine; goal attainment; caregiver burden; quality of life History: Received 21 August 2013; Accepted 20 December 2013; Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4077
Introduction People with Parkinson’s disease (PD) commonly develop dementia (Johansen et al., 2010), with about 80% being affected if they live with the disease for long enough (Hely et al., 2008). The physical and the cognitive limitations that accompany dementia associated with PD (PDD) can markedly reduce the opportunities of those affected for constructive socialisation and independent living. This, in turn, can lead to significantly greater disability, more impaired healthrelated quality of life (QoL) and greater caregiver burden (Leroi et al., 2012). Medication management Copyright # 2014 John Wiley & Sons, Ltd.
of PDD, in the form of the cholinesterase inhibitors, is symptomatically effective and has been shown to improve cognitive functioning, behavioural disturbances and activities of daily living (Rolinski et al., 2012). Our group has previously examined the efficacy of memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, in improving cognition and function in PDD (Leroi et al., 2009). Efficacy results from this and subsequent studies in PDD have been mixed (Aarsland et al., 2009; Emre et al., 2010; Litvinenko et al., 2010). These studies used mainly psychometric, cognitive rating scales or global rating scales as their key outcomes with little Int J Geriatr Psychiatry (2014)
I. Leroi et al.
emphasis on clinimetric, non-cognitive measures such as patient-reported outcomes (PROs). Parkinson’s disease dementia is a complex and multifaceted disease with both motor and non-motor symptoms, including cognitive impairment and neuropsychiatric symptoms. All these clinical manifestations should be considered as potential outcomes in a PDD treatment trial. In dementia studies, psychometric measures of cognition are used most often as outcome measures (Burns, 2002; Emre et al., 2010). In spite of this, the clinical relevance of cognitive measures in treatment trials in AD and PDD has been questioned, as they may not address important aspects of outcome and may not appropriately identify responders to therapy (Olin et al., 1996; Sampaio, 2007). An alternative is to use clinimetric measures, which have been recommended by the Food and Drug Administration (FDA, 2009) and the European Agency for the Evaluation of Medicinal Products (EMEA, 2005). One such clinimetric measure is the Clinician’s Interview-Based Impression of Change plus Caregiver Input (Broich, 2007), and recent randomised controlled trials of memantine in PDD have used a similar measure, the clinical global impression of change (Aarsland et al., 2009; Emre et al., 2010). These clinimetric measures may capture more clinically useful information than merely a cognitive scale; however, such global scales may still not be sensitive enough to map the effects that are clinically meaningful for clinicians, caregivers and patients (Rosen et al., 1984). Instead, PROs, which may be more pragmatic and meaningful for patients and caregivers (Rockwood et al., 2007, 2010), focus on patient–caregiver–clinician-desired outcomes and could provide more clinically relevant information to identify a meaningful response to treatment. One example of a PRO that has been shown to increase the sensitivity and relevance of outcome measures in dementia treatment studies is Goal Attainment Scaling (GAS) (Rockwood et al., 1996). GAS offers a patient-centred outcome that is similar to global assessments but more specifically measures individual problems identified by patients, their caregivers and clinicians in a collaborative manner. These problems or foci are elicited by an open-ended introductory question, which leads to a discussion of the goals of treatment (Rockwood et al., 1996). Identified problems are categorised into various domains that can then be sequentially monitored. GAS has been shown to be feasible, valid and responsive when used in studies involving older people and in non-PDD studies (Stolee et al., 1992; Rockwood et al., 1993, 1996). Unanticipated changes that conventional Copyright # 2014 John Wiley & Sons, Ltd.
psychometric measures may fail to capture can be identified by this method (Rockwood et al., 2006). Therefore, GAS may be ideally placed to assess PDD, a complex condition with multiple clinical foci that can vary significantly between people. Furthermore, by taking contextual information into account, PROs may be a more accurate way to measure improvement in PDD than traditional psychometric measures. Here, we used GAS, a PRO, to examine the response to a pharmacological intervention, memantine, in PDD. We also used the Parkinson’s Disease Questionnaire8 (PDQ-8) (Jenkinson et al., 1998), to assess healthrelated QoL as an additional PRO, and the Zarit Burden Inventory (ZBI) (Zarit et al., 1980) to assess caregiver burden. We hypothesised that there would be significant differences in goal attainment between those on memantine compared with those on placebo, despite the lack of significant differences in the previously reported primary cognitive outcomes (Leroi et al., 2009). Methods This study was approved by the regional research ethics committee, and the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 1983. Participants gave informed consent. All participants had the capacity to give consent for the study, and the caregivers were also asked to sign an assent form on behalf of the PD participant. Study design
This was a secondary analysis of our original doubleblind, placebo-controlled, parallel group, fixed-dose clinical trial of memantine 20 mg daily or placebo. The full methodology, including details of inclusion and exclusion criteria, as well as details of the recruitment process and randomisation, has been published previously (Leroi et al., 2009). Participants
Patients (n = 25) were included in the study if they fulfilled UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria for PD (Hughes et al., 1992) and subsequently developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria at least 1 year after the onset of motor symptoms (PDD) (APA, 2005). All participants retrospectively met the consensus criteria for possible Int J Geriatr Psychiatry (2014)
Memantine improves goals in Parkinson’s disease dementia
and probable PDD (Emre et al., 2007) and had a mini mental state examination (MMSE) score of
Memantine improves goal attainment and reduces caregiver burden in Parkinson’s disease with dementia Iracema Leroi1,2, Richard Atkinson3 and Ross Overshott4 1
Institute of Brain Behaviour and Mental Health, Manchester Academic Health Sciences Centre, UK Manchester Mental Health and Social Care Trust, UK 3 Lancashire Care NHS Foundation Trust, UK 4 Greater Manchester West NHS Foundation Trust, UK Correspondence to: I. Leroi, E-mail: [email protected] 2
Objective: Memantine,
an uncompetitive antagonist of N-methyl-D-aspartate receptors, may have a role in managing symptoms associated with dementia in Parkinson’s disease (PDD), although its role in improving patient-reported outcomes (PROs) has not been extensively investigated. PROs may be more sensitive than standard psychometric measures for detecting change in complex conditions such as PDD. The aim of this study was to examine the effect of memantine on PROs: individually determined goals and health-related quality of life. We also examined memantine’s effect on caregiver burden. Methods: This 22-week double-blind randomised controlled trial evaluated participants with PDD on 20 mg of memantine or placebo. Outcome measures were Goal Attainment Scaling (GAS), the Parkinson’s Disease Questionnaire-8 and the Zarit Burden Inventory. Results: A significantly greater proportion of participants on memantine (64%) had better than expected GAS outcomes compared with those on placebo (7%) (p = 0.007). Furthermore, the improvement in mean GAS score, as well as mean caregiver burden score, from baseline to drug discontinuation was significantly greater in those on memantine compared with those on placebo (p = 0.03 and 0.04, respectively). Significant differences in quality of life were not seen. Conclusions: In this study, memantine improved individually set goals and caregiver burden in PDD. This suggests that clinimetric measures such as GAS may be more sensitive than conventional psychometric measures in detecting improvements in people with PDD. Copyright # 2014 John Wiley & Sons, Ltd. Key words: Parkinson’s disease dementia (PDD); memantine; goal attainment; caregiver burden; quality of life History: Received 21 August 2013; Accepted 20 December 2013; Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4077
Introduction People with Parkinson’s disease (PD) commonly develop dementia (Johansen et al., 2010), with about 80% being affected if they live with the disease for long enough (Hely et al., 2008). The physical and the cognitive limitations that accompany dementia associated with PD (PDD) can markedly reduce the opportunities of those affected for constructive socialisation and independent living. This, in turn, can lead to significantly greater disability, more impaired healthrelated quality of life (QoL) and greater caregiver burden (Leroi et al., 2012). Medication management Copyright # 2014 John Wiley & Sons, Ltd.
of PDD, in the form of the cholinesterase inhibitors, is symptomatically effective and has been shown to improve cognitive functioning, behavioural disturbances and activities of daily living (Rolinski et al., 2012). Our group has previously examined the efficacy of memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, in improving cognition and function in PDD (Leroi et al., 2009). Efficacy results from this and subsequent studies in PDD have been mixed (Aarsland et al., 2009; Emre et al., 2010; Litvinenko et al., 2010). These studies used mainly psychometric, cognitive rating scales or global rating scales as their key outcomes with little Int J Geriatr Psychiatry (2014)
I. Leroi et al.
emphasis on clinimetric, non-cognitive measures such as patient-reported outcomes (PROs). Parkinson’s disease dementia is a complex and multifaceted disease with both motor and non-motor symptoms, including cognitive impairment and neuropsychiatric symptoms. All these clinical manifestations should be considered as potential outcomes in a PDD treatment trial. In dementia studies, psychometric measures of cognition are used most often as outcome measures (Burns, 2002; Emre et al., 2010). In spite of this, the clinical relevance of cognitive measures in treatment trials in AD and PDD has been questioned, as they may not address important aspects of outcome and may not appropriately identify responders to therapy (Olin et al., 1996; Sampaio, 2007). An alternative is to use clinimetric measures, which have been recommended by the Food and Drug Administration (FDA, 2009) and the European Agency for the Evaluation of Medicinal Products (EMEA, 2005). One such clinimetric measure is the Clinician’s Interview-Based Impression of Change plus Caregiver Input (Broich, 2007), and recent randomised controlled trials of memantine in PDD have used a similar measure, the clinical global impression of change (Aarsland et al., 2009; Emre et al., 2010). These clinimetric measures may capture more clinically useful information than merely a cognitive scale; however, such global scales may still not be sensitive enough to map the effects that are clinically meaningful for clinicians, caregivers and patients (Rosen et al., 1984). Instead, PROs, which may be more pragmatic and meaningful for patients and caregivers (Rockwood et al., 2007, 2010), focus on patient–caregiver–clinician-desired outcomes and could provide more clinically relevant information to identify a meaningful response to treatment. One example of a PRO that has been shown to increase the sensitivity and relevance of outcome measures in dementia treatment studies is Goal Attainment Scaling (GAS) (Rockwood et al., 1996). GAS offers a patient-centred outcome that is similar to global assessments but more specifically measures individual problems identified by patients, their caregivers and clinicians in a collaborative manner. These problems or foci are elicited by an open-ended introductory question, which leads to a discussion of the goals of treatment (Rockwood et al., 1996). Identified problems are categorised into various domains that can then be sequentially monitored. GAS has been shown to be feasible, valid and responsive when used in studies involving older people and in non-PDD studies (Stolee et al., 1992; Rockwood et al., 1993, 1996). Unanticipated changes that conventional Copyright # 2014 John Wiley & Sons, Ltd.
psychometric measures may fail to capture can be identified by this method (Rockwood et al., 2006). Therefore, GAS may be ideally placed to assess PDD, a complex condition with multiple clinical foci that can vary significantly between people. Furthermore, by taking contextual information into account, PROs may be a more accurate way to measure improvement in PDD than traditional psychometric measures. Here, we used GAS, a PRO, to examine the response to a pharmacological intervention, memantine, in PDD. We also used the Parkinson’s Disease Questionnaire8 (PDQ-8) (Jenkinson et al., 1998), to assess healthrelated QoL as an additional PRO, and the Zarit Burden Inventory (ZBI) (Zarit et al., 1980) to assess caregiver burden. We hypothesised that there would be significant differences in goal attainment between those on memantine compared with those on placebo, despite the lack of significant differences in the previously reported primary cognitive outcomes (Leroi et al., 2009). Methods This study was approved by the regional research ethics committee, and the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 1983. Participants gave informed consent. All participants had the capacity to give consent for the study, and the caregivers were also asked to sign an assent form on behalf of the PD participant. Study design
This was a secondary analysis of our original doubleblind, placebo-controlled, parallel group, fixed-dose clinical trial of memantine 20 mg daily or placebo. The full methodology, including details of inclusion and exclusion criteria, as well as details of the recruitment process and randomisation, has been published previously (Leroi et al., 2009). Participants
Patients (n = 25) were included in the study if they fulfilled UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria for PD (Hughes et al., 1992) and subsequently developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria at least 1 year after the onset of motor symptoms (PDD) (APA, 2005). All participants retrospectively met the consensus criteria for possible Int J Geriatr Psychiatry (2014)
Memantine improves goals in Parkinson’s disease dementia
and probable PDD (Emre et al., 2007) and had a mini mental state examination (MMSE) score of
