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11th International Conference on Alzheimer’s Disease (ICAD)

Chicago, Illinois / July 26-31, 2008

Behavioural symptoms or psychiatric disturbances affect 50% to 80% of patients with Alzheimer’s disease (AD) and are important determinants of patient distress, caregiver burden and outcome. They also lead to a requirement for increased healthcare resources and care costs at any stage of AD. In a number of retrospective and observational studies, the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist memantine has been shown to have beneficial effects on several functional and behavioural symptoms.

AD Behavioural Symptoms Increase Resource Utilization

At the clinic visit (baseline), patients and caregivers answered clinical, demographic and resource utilization (RU) questionnaires. The clinical questionnaire included an assessment of behavioural symptoms by Neuropsychiatric Inventory (NPI) and the RU inventory assessed antidementia and antipsychotic treatment, informal caregiver time spent, use of social services, ambulatory care and hospitalization over the previous three months. At six and 12 months, RU was assessed for a three-month recall period by telephone interview.

The patients were elderly (mean age 78.0 ± 7.9 years), with a mean Mini-Mental State Examination (MMSE) score at baseline of 16.1 ± 7.5 and a mean Global Deterioration Scale score of 4.5. Most patients had mild or moderate dementia and all were taking a cholinesterase inhibitor.

Their most prevalent behavioural symptoms were apathy/indifference (62.2%), depression/dysphoria (47%), anxiety (45.9%), irritability/lability (41%) and agitation/aggression (27.2%). RU was significantly increased in the presence of any type of behavioural symptom except apathy. The highest increases in resource use were observed in patients symptomatic at baseline for agitation/aggression, anxiety, delusions, hallucinations, irritability/lability and aberrant motor behaviour symptoms.

At baseline, 14% of the patients were receiving antipsychotic treatment, which increased to 19% and 22% at six and 12 months, respectively. A significantly higher proportion of patients who were symptomatic for agitation/aggression, delusions, hallucinations, irritability/lability or aberrant motor behaviour received antipsychotic therapy. At baseline, patients with anxiety were significantly more likely to have been admitted to hospital on at least one occasion than patients without anxiety (20% vs. 10%, respectively; P=0.010).

At the six- and 12-month follow-ups, patients symptomatic for delusions, hallucinations, agitation/aggression, or aberrant motor behaviour and patients with anxiety only were significantly more likely to have spent time in a home care facility than patients without these symptoms. Dr. Orgogozo suggested that the beneficial effects of memantine on behavioural symptoms such as agitation/aggression, delusions, hallucinations, and irritability/lability could translate into a reduction of increased health care resources associated with these symptoms. Decrease in Key Behavioural Symptoms

A new meta-analysis of data from six US and European phase III, randomized, placebo-controlled, six-month clinical trials of memantine has shown that treatment reduced four key behavioural symptoms, as measured by NPI, in patients with moderate to severe AD. Dr. Gauthier explained the analysis focused on a cluster of symptoms from the NPI, because the total NPI score, which comprises 12 items, can be difficult to interpret due to the heterogeneity of the symptoms. The study concentrated on the most burdensome symptoms known to have a major impact in terms of resource use, e.g. agitation/aggression and irritability, as well as psychotic symptoms such as hallucinations and delusions that often require the use of atypical neuroleptics.

Four of the six trials included in the meta-analysis administered memantine as monotherapy (20 mg/day) and two as combination therapy alongside stable cholinesterase inhibitor therapy. The population analyzed was the subgroup of 1717 patients with moderate to severe AD (MMSE score <20). From baseline to week 24/28, NPI symptom cluster score was significantly decreased in the patients given memantine compared with those given placebo (P=0.006), with a weighted mean difference of -0.78 (95% CI, -1.33 to -0.23; observed cases [OC] analysis). This outcome was supported by the corresponding last observation carried forward (LOCF) analysis (P=0.002). Patients on memantine were also 60% less likely to have emergence of this symptom cluster on OC analysis (odds ratio [OR] 1.60; 95% CI, 1.13 to 2.28; P=0.009). The corresponding LOCF analysis also supported this result (P=0.03).

Dr. Gauthier stated that the analysis suggests that treatment with memantine in these patients could reduce caregiver distress and delay patient institutionalization. It could reduce the use of atypical neuroleptics such as risperidone and other psychotropic drugs. The effect of memantine on behaviour is being investigated prospectively in an ongoing Canadian randomized clinical trial. It will determine whether addition of the drug prevents the need for psychotropics while at the same time improving cognition, Dr. Gauthier explained. He added that the mechanism of action underlying the effect on symptoms such as agitation/aggressivity remains unknown.

Discontinuation Associated with Worsening Symptoms

Anecdotal reports from nursing home healthcare providers suggest that the discontinuation of memantine treatment in patients with AD often leads to deterioration of the patients’ general health. An analysis of medical records from nursing home residents with AD in the US showed that memantine discontinuation was associated with an increase in AD symptoms. Investigators led by Dr. Constantine Lyketsos, Chair, Department of Psychiatry, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, used data obtained from medical charts of 521 men and women, mean age 83 years, who were diagnosed with AD and had been resident in one of 113 nursing homes for <u>></u>90 days. Their mean Cognitive Performance Scale (CPS) score was 3.5 and imputed MMSE score was 11.2. Most patients were taking memantine in combination with a cholinesterase inhibitor and over 50% were also on a psychotropic drug. In addition, 273 received memantine continuously for <u>></u>90 days and 248 took memantine continuously for <u>></u>30 days followed by discontinuation for <u>></u>60 days.

Changes in AD symptoms over the 60 days’ post-baseline were scored based on a scale from the emergence or resolution of a particular symptom (+1 or -1 point, respectively) or the worsening or improvement of an existing symptom (+0.5 or -0.5 points). Compared with patients who continued on memantine, a significantly higher percentage of residents who discontinued had a total AD symptom change score of <u>></u>2 (43.6% vs. 19.8%) or <u>></u>3 (29.0% vs. 12.5%) (both P<0.001). After adjustment for baseline age, weight, gender, race, CPS score, number of comorbid conditions and number of concomitant psychotropic medications at baseline, memantine discontinuation was associated with significantly higher adjusted odds of experiencing worsening/emergence of AD symptoms, defined as a total AD symptom change score of <u>></u>2 (OR 3.26) or <u>></u>3 (OR 2.86), respectively (both P<0.001).

Analysis of individual symptoms showed that patients who discontinued memantine had a significantly greater AD symptom score for 13 out of 31 items. After correction for multiple comparisons, mean score for seven items remained statistically significant: resistance to care and agitation/aggression (behavioural); inability to eat or drink or move in the room (functional); failure to display cognitive skills; and display of disorganized speech and confusion (cognition). Resistance to care, agitation/aggression and the inability to eat/drink are particularly difficult symptoms to manage in a nursing home setting, the investigators noted.

Residents who discontinued memantine had a significantly higher mean total AD symptom change score compared with those who continued on treatment (2.02 vs. 0.68, P<0.001). On average, discontinuation was associated with a score increase of 2.02, which is equivalent to approximately two newly emerged symptoms or worsening of four existing symptoms, the investigators explained. Continuing memantine was associated with a symptom increase of only 0.68 points.

Dr. Lyketsos and his colleagues have chart data for a further 30 days in these patients and expect to present the additional analyses in the near future.