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Gauthier S., Loft H. and Cummings J.

Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease (AD) by memantine: a pooled data analysis. Gauthier S., Loft H. and Cummings J. International Journal of Geriatric Psychiatry 2008; 23: 537-45.

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Gauthier S., Loft H. and Cummings J.

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  1. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease (AD) by memantine: a pooled data analysis Gauthier S., Loft H. and Cummings J. International Journal of Geriatric Psychiatry 2008; 23: 537-45

  2. Behavioral Symptoms – a Distressing Aspect of AD • Behavioral symptoms • are common in moderate to severe AD • represent an aspect of disease burden that is physically, emotionally, and economically challenging • correlate with accelerated disease progression • There is a need for treatment options for patients with behavioral symptoms • Behavioral symptoms are a burdening and stressful factor for the family and caregiver Gauthier et al., Int J Geriar Psychiatry 2008

  3. Included Phase III Studies Phase III, double-blind, placebo-controlled, 6-month trials Study No. MMSE Inclusion Number of treated patients Range (Meana) Placebo Memantine MEM-MD-10 10 – 22 (17.3) 202 201 Peskind et al. 2006 LU-99679 11 – 23 (18.7) 152 318 Bakchine et al. 2007 MEM-MD-12 10 – 22 (16.9) 216 217 Porsteinsson et al. 2008 MRZ-9605 3 – 14 (7.9) 126 126 Reisberg et al. 2003 MEM-MD-01 5 – 14 (10.1) 172 178 Van Dyck et al. 2007 MEM-MD-02 5 – 14 (10.0) 201 202 Tariot et al. 2004 a all patients treated set Mecocci et al. XXX 2008

  4. Symptomatic Patients with MMSE < 20 at Baseline Pooled analysis of six studies (MMSE <20) Delusions Hallucinations Agitation/Agression Depression Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change Memantine Placebo Proportion of patients (%) 40 10 20 30 50 60 0 Gauthier et al., Int J Geriar Psychiatry 2008

  5. Benefits of Memantine on Behavioral Symptoms FAS, OC analysis Mean change from baseline Pooled analysis of six studies (MMSE < 20) -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0 2.5 p = 0.001 p = 0.035 Improvement p = 0.008 NPI score difference Memantine (20 mg/day) Placebo Decline 0 12 24/28 Endpoint (LOCF) Week Gauthier et al., Int J Geriar Psychiatry 2008

  6. Benefits of Memantine on Individual NPI Domains at Week 24/28 FAS, LOCF analysis Mean change from baseline Pooled analysis of six studies (MMSE < 20) p = 0.001 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change p = 0.001 Memantine Placebo NPI domain score difference p = 0.005 0.6 0.4 0.2 0 -0.2 -0.4 Decline Improvement Gauthier et al., Int J Geriar Psychiatry 2008

  7. Improvement in Patients with Baseline Symptoms at Week 24/28 LOCF analysis Pooled analysis of six studies (MMSE <20) p = 0.045 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change p = 0.028 Memantine Placebo Proportion of patients (%) p = 0.048 60 70 45 50 55 65 75 40 Gauthier et al., Int J Geriar Psychiatry 2008

  8. Percentage of Patients Remaining Asymptomatic at Week 24/28 LOCF analysis Pooled analysis of six studies (MMSE <20) Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change p = 0.002 Memantine Placebo Proportion of patients (%) p = 0.004 p = 0.050 95 75 80 85 90 100 70 Gauthier et al., Int J Geriar Psychiatry 2008

  9. Summary • Statistically significant benefit of memantine on behavioral symptoms (NPI total score) • Consistent effect on agitation/aggression  stated as the most problematic AD symptom • less emergence in patients asymptomatic at baseline • less worsening if present at onset of treatment • Anti-psychotic drugs are widely used off-label to treat behavioral symptoms in AD BUT • recent studies have shown no drug-placebo difference as well a substantial number of side effects compared to placebo (Schneider et al. 2006) • The FDA issued a Black Box warning against their use due associations with an increased mortality risk, cognitive decline, extrapyramidal symptoms, lowered blood pressure and sedation • The data support the efficacy of memantine in treating and preventing the emergence of behavioral symptoms Gauthier et al., Int J Geriar Psychiatry 2008

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