Treating Agitation in Alzheimer's Disease: Efficacy of Memantine

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Donald S. Robinson, MD. Treating Agitation in Alzheimer's Disease: Efficacy of Memantine. Primary Psychiatry. 2008;15(6):28-30

Alzheimer's disease is a progressive neurodegenerative disorder of increasing prevalence, clinically manifested by memory impairment and declining cognition. Approximately 25 million people worldwide suffer from dementia as a result of Alzheimer’s disease.1 Greater than 50% of individuals with Alzheimer’s disease experience agitation, aggression, delusions, or hallucinations during the course of their illness.2 These behavioral disturbances of Alzheimer’s disease pose difficult management problems because existing agents are not fully effective and safe; better pharmacotherapy is needed. Antipsychotics are widely prescribed to treat behavioral disturbances in Alzheimer’s disease patients, although recent safety concerns with the atypical antipsychotics have led to more restrictive labeling imposed by the Food and Drug Administration.


Prevalence of Agitation in Alzheimer’s Disease Patients

Long-term observation of patients with mild-to-moderate Alzheimer’s disease randomized to placebo treatment as part of a 1-year double-blind, controlled trial found agitation to be the most common symptom.3 Agitation/aggression occurred in 54% of patients over 1 year of observation, followed next in incidence by depression (50%) and psychosis (36%). Agitation was associated with greater cognitive impairment. Presence of psychotic symptoms correlated both with more rapid cognitive decline and with age. In a 2-year observational study tracking behavioral and psychological symptoms in Alzheimer’s disease patients, agitation and aggression were the most frequent as well as persistent symptoms and, in addition to psychotic symptoms, were harbingers of more rapid progression of the disorder.4

Numerous health economic surveys5 implicate behavioral symptoms in Alzheimer’s disease as significant independent predictors of need for institutionalization and higher patient care costs. The magnitude of the cost differential associated with behavioral problems in Alzheimer’s disease patients averaged an additional $10,000 to $15,000 per year compared with those without these clinical manifestations of Alzheimer’s disease.


Antipsychotic Therapy in Alzheimer’s Disease

Antipsychotics are widely used to treat dementia in elderly patients. According to a statewide survey of Medicare beneficiaries in nursing homes, >25% of patients received treatment with an antipsychotic.6 Antipsychotics have been a mainstay of pharmacologic therapy for agitation and aggressive behavior despite limited effectiveness and recent safety concerns.7,8

Over the last decade, atypical antipsychotics largely replaced first-generation antipsychotics as the preferred treatment for behavioral disturbances in elderly patients with dementia because of perceived safety advantages over traditional antipsychotics and other psychotropic drugs, including the benzodiazepines and anticonvulsants. Safety advantages include less orthostatic hypotension or adverse effects on cardiac repolarization (prolonged QT), less sedation, and decreased liability for movement disorders.

The unexpected findings of higher mortality and incidence of stroke during atypical antipsychotic treatment of Alzheimer’s disease patients in placebo-controlled trials led to warnings and restrictions in product labeling of antipsychotics imposed by the FDA.6,8 There was a consistent pattern of small but significant increases in mortality and strokes in trials of each of the atypical antipsychotics compared with placebo treatment.8,9 The Committee for the Safety of Medicines in the United Kingdom has imposed similar constraints on the use of atypical antipsychotics in dementia patients.

Trials have shown that atypical antipsychotics provide only modest benefits for the behavioral symptoms of Alzheimer’s disease. In the absence of aggressive behavior, there were no differences in improvement of agitation between antipsychotic and placebo treatment.8 Both risperidone and quetiapine lacked efficacy compared with placebo treatment for treating agitation in patients receiving institutional care.8,9 Quetiapine treatment was associated with greater cognitive decline than with placebo treatment, and its anticholinergic properties may contribute to poorer therapeutic response.

In addition, there is evidence in one clinical trial that neuroleptic drug treatment may actually accelerate cognitive decline and induce pathologic changes characteristic of Alzheimer’s disease.10 It is also postulated that suppression of neurotropic factor by antipsychotics may accelerate accumulation of pathologic substrates in brains of Alzheimer’s disease patients.8


Memantine for Agitation and Aggression in Advanced Alzheimer’s Disease

Memantine is the first of a new class of agents for the treatment of Alzheimer’s disease acting on the glutamatergic system. Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for treatment of patients with moderately severe and severe Alzheimer’s disease. Dysfunction of glutamatergic neurotransmission, manifested by neuronal excitotoxicity, is implicated in the etiology of Alzheimer’s disease. Memantine acts as a non-competitive, low potency antagonist at NMDA receptors and inhibits prolonged influx of calcium ions, causing neuronal excitotoxicity.11,12 In general, memantine therapy is well tolerated clinically because it has low potency as an NMDA receptor antagonist and differs from treatment with the more potent NMDA antagonists, which offer neuroprotective effects but often have unacceptable side effects.

The efficacy and tolerability of memantine was established in a series of placebo-controlled trials that show significant, albeit modest, therapeutic benefits in Alzheimer’s disease.13-15 Memantine treatment produces improvement in multiple domains, including global, cognitive, functional, and behavioral. A recent retrospective meta-analysis of pooled data from the efficacy trials examines outcomes in patients with agitation, aggression, or psychosis before trial entry.16 Patients who scored ≥1 on any of three Neuropsychiatric Inventory (NPI) items assessing agitation/aggression, delusions, or hallucinations within 4 weeks of entry into the trial were analyzed separately. Of the 983 patients in the total study population, 593 (60%) manifested agitation, aggressive behavior, or psychosis prior to treatment (placebo=287, memantine=306). This subgroup with pre-existing behavioral symptoms resembled the overall patient sample in demographics, Mini-Mental Status Exam scores, and symptom severity (except for NPI score).

Across the trials, 454 patients had pre-existing agitation/aggression, 336 delusions, and 172 hallucinations.13-15 Improvement on the NPI behavioral symptom cluster was significantly better with memantine than with placebo treatment at both 3 months (P=.0014) and 6 months (P=.0004). At 6 months, memantine treatment showed significant benefit compared with placebo on measures of cognition (P<.001), activities of daily living (P<.001), and clinician/caregiver impression of change in clinical status (P<.001). In addition, memantine treatment was tolerated better than placebo treatment, with fewer discontinuations from the study treatment over the 6 months. The incidence of withdrawals due to agitation and psychosis among placebo-treated patients was 3-fold higher than with memantine treatment (7.5% versus 2.6%, respectively, P<.01).

For patients randomized to placebo treatment in the trials, behaviorally disturbed patients at trial entry experienced significantly greater decline in clinical status and activities of daily living than placebo-treated patients without pre-existing symptoms. For those patients with neither prior agitation/aggressive behavior or psychosis, significantly fewer memantine-treated patients (P<.01) went on to develop behavioral symptoms during the 6 months of treatment compared with placebo, indicating preventive benefit with memantine therapy.


Conclusion

Behavioral disturbances and psychotic symptoms in Alzheimer’s disease are associated with rapid disease progression and increased costs of care. Although safety concerns about increased mortality and stroke and changes in product labeling have tempered their use, antipsychotics remain the mainstays of drug therapy for these symptoms of dementia in the elderly. A pooled analysis of efficacy trials of the NMDA antagonist memantine indicates that it is superior to placebo for treating and preventing behavioral symptoms in Alzheimer’s disease patients; however, the therapeutic benefit appears to be modest. PP


References

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Footnotes:

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.
Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, PGxHealth, Pfizer, Schering Plough, Somerset, and Takeda.

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