NEWS FROM THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE: Old Drug, New Treatment for Apathy in Alzheimer's Disease

Neurology Today
4 October 2012; Volume 12(19); p 28–29

Bain, Lisa J.

In a small trial, investigators reported that patients with mild to moderate Alzheimer's disease seemed to improve on some measures of apathy, but the findings did not reach statistical significance.

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VANCOUVER, BC—Apathy is one of the most common neuropsychiatric symptoms associated with Alzheimer's disease, complicating management, adversely affecting patients' quality of life, and increasing caregiver burden.

“There is no question in my mind that this kind of apathetic behavior is associated with worse outcome because they don't get social or cognitive stimulation, and they don't get physical activity,” said geriatric psychiatrist Anton Porsteinsson, MD, in an interview with Neurology Today.

Dr. Porsteinsson, director of the AD-CARE program at the University of Rochester Medical Center, commented on new data presented here at the Alzheimer's Association International Conference (AAIC) reporting success in treating apathy with methylphenidate (Ritalin), a drug commonly used to treat attention deficit hyperactivity disorder (ADHD).

“What excites me about this study is that apathy is an overlooked behavior,” said Dr. Porsteinsson. “This is one of the most common behavioral disruptions in dementia but has received limited attention.”

DR. ANTON PORSTEINSSON: “There is no question in my mind that this kind of apathetic behavior is associated with worse outcome because they don't get social or cognitive stimulation, and they don't get physical activity.”

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Jacobo Mintzer, MD, professor in the neurosciences department of the Medical University of South Carolina and the Ralph H. Johnson Veteran's Administration Medical Center, who led the study and presented the data at AAIC, echoed Dr. Porsteinsson's concern. “Alzheimer's disease robs patients of their ability to communicate with their loved ones and apathy makes that problem substantially worse,” said Dr. Mintzer.

Based on evidence suggesting that dopaminergic neuronal loss associated with neurodegeneration may underlie AD-associated apathy, the Apathy in Dementia Methylphenidate Trial (ADMET) was designed to test the efficacy and safety of methylphenidate for the treatment of apathy in AD. Methylphenidate blocks both the dopamine and norepinephrine transporters (DAT and NET), resulting in an increase in post-synaptic dopamine and norepinephrine levels. Lower striatal DAT has been shown to correlate with apathy but not other neuropsychiatric symptoms in patients with AD.

The investigators focused on patients with mild to moderate AD. To be included in the international, multicenter, randomized, double-blind study — which was funded by the National Institute on Aging, patients had to have shown clinically significant apathy severe enough to warrant consideration of pharmacological intervention. Patients with agitation or psychosis were excluded.

Sixty patients were randomized to receive drug or placebo. Subjects started out with a dose of 5 mg. twice per day; after three days if no adverse effects were seen, the dose was increased to 10 mg. twice per day. Adherence was excellent, with 88 percent of pills taken according to pill counts. Subjects were evaluated at baseline and after six weeks of treatment with the Apathy Evaluation Scale (AES), the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (CGIC) scale, which had been modified to reflect apathy outcomes, the Neuropsychiatric Index (NPI) Apathy score, and the Mini Mental State Exam (MMSE) to assess cognition and detect possible cognitive toxicity. Six-week data were available for 57 of the 60 subjects.

The AES assesses 18 behaviors on a 1–4 scale, resulting in scores that range from 18 to 72, with higher scores indicating more severe apathy. The mean baseline score of subjects in ADMET was 51, which reflects severe apathy. “This means that they showed clear and observable decrements in goal directed behavior,” said Dr. Mintzer.

After six weeks of treatment, patients receiving methylphenidate showed a significant improvement in apathy and clinical global impression of change. AES scores improved by an average of 1.9 points for the treatment arm compared to a worsening by 0.6 points for the placebo group, for an estimated treatment effect of 2.5 points (p=0.23).

While this was not sufficient to reach statistical significance, Dr. Mintzer said he thinks that the sample size was simply too small. He noted, for example, that the estimated treatment effect based on NPI-Apathy scores was 1.8 points out of a possible total of 12, which did reach statistical significance (p=0.02). In addition, on the CGI-C, 21 percent of treated patients were rated by clinicians as being either moderately or markedly improved, compared to only 3 percent of placebo patients, for an odds ratio of 3.7 (p=0.02). The incidence of adverse effects was low although there was a trend towards greater anxiety and weight loss in the methylphenidate-treated group.

Dr. Porsteinsson said that while the improvement in the NPI-apathy score did not suggest a tremendous change, it would be a clinically observable change. Moreover, the fact that the CGI-C showed an improvement as well shows that the improvement was apparent to clinicians. “If I were to speculate what that would translate into, it would basically be more alertness, being more awake, maybe napping less, not being quite as resistive to going out and doing things, attending to their personal care, and showing a little more initiative.”

He said he was surprised at how low the placebo response was. “I think this shows that apathy is not necessarily a type of behavior that responds well to increased activity or encouragement, that it is more of a hard biological symptom.”

Dr. Mintzer noted that while the treatment is not thought to be disease modifying, “We believe methylphenidate could improve the level of interaction between the patient, family, and environment and that would increase substantially the quality of life for patients and their families.”

A confirmatory trial with a larger pool of patients and a longer treatment period is needed to validate these results, Dr. Porsteinsson said.

“I think it is quite likely that we're going to see increased use of methylphenidate, but I think it will be somewhat measured because of multiple concerns about psychotropics in elderly, and the fact that this is only a 60-subject, six-week study.”

DR. JACOBO MINTZER: “We believe methylphenidate could improve the level of interaction between the patient, family, and environment and that would increase substantially the quality of life for patients and their families.”

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