Gabapentin as a possible treatment of behavioral alterations in Alzheimer disease (AD) patients

Sir, Cognitive de®cits in multiple areas and functional impairment in everyday activities are the clinical hallmarks of Alzheimer's disease (AD). Although the primary symptoms of AD are memory impairment, AD patients also develop secondary symptoms known as behavioral disruption. Whilst psychotropic drugs are frequently used to control these symptoms, they have the potential for signi®cant side-eects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonisms and akathisias. The spectrum of behavioral symptoms in AD re ̄ects alterations in a variety of cerebral processes (Mega et al., 1996), including sensory-perceptual functions, the regulation of motor behavior, emotions and vegetative functions. Behavioral disturbances may have a contribution to the overall morbidity of the disease, and is the major cause of institutionalization (O'Donnell et al., 1992; Kaufer, 2000), causing inadequate nutritional and sleep alterations, and enhancing cognitive disruption. The major non-cognitive behavioral impairments are the following: depression, anxiety, agitation, delusions and insomnia. Agitation occurs frequently in AD and is often cited as an important factor for drug therapy introduction, in particular for neuroleptic or benzodiazepines. Precipitating factors for agitation should be sought such as physical discomfort, which is not correctly expressed, most of the time by the patient him/herself, excessive sensory stimulation or improper environment. Mild outbursts can sometimes be handled behaviorally by distracting patients or allowing them to wander in an enclosed place. But, if agitation is suciently troublesome and without obvious remedial cause it must be adequately treated. Now, the problem is what is the most adequate treatment; one non-placebocontrolled study demonstrated similar reduction in agitation with haloperidol, oxazepam and diphenhydramine (Coccaro et al., 1990). Two reviews (Schneider et al., 1992; Terry et al., 1998) and two non-placebo-controlled studies (Devanand et al., 1989; Coccaro et al., 1990) demonstrate small improvements in behavior with neuroleptics. A recently completed placebo-controlled trial of Risperidone in agitated AD demonstrated a small reduction in agitation (Terry et al., 1988). Olanzapine at doses of 5±10 mg per day may be useful in reducing agitation (Terry et al., 1988), but more studies would be necessary to understand the role of these drugs. Sometimes, however, neuroleptics, even the non-traditional, also called atypical, cannot be used; there are dierent causes, such as previously diagnosed ECG abnormalities (even Risperidone should be used with particular caution in patients with known cardiovascular disease), in patients with previously evidenced seizures, and in patients with narrow angle glaucoma, or with clinically signi®cant prostatic hypertrophy or with history of paralitic ileus (in all these cases, even Olanzapine should be used cautiously) (Physicians Desk Reference (PDR), 2000). We describe four patients (three males and one female, mean age 73.6  5.1 years old), suering from AD probable, according to NINCS-ADRDA criteria (McKahn et al., 1984), who suered from behavioral symptoms, in particular agitation, aggression and anxiety, with delusions. Their Neuropsychiatric Inventory (Cummings et al., 1994) mean average is of 46.6  7.2, which cause a very important caregiver distress, as measured by the mean Relative Stress Scale (Greene et al., 1982) score of 65.3  5.4. All the four patients underwent to cholinergic therapy, but sedative therapy has to be used. However, the major problem in all the four patients is a concomitant pathology, which is an obstacle to the introduction even of an atypical neuroleptic. Two of them suered for an important clinical prostatic hypertrophy, one of them for a narrow angle glaucoma and the last one, the woman, has suered from two episodes of paralytic ileus (and associated dolicomegacolon). We were forced to use a dierent type of drug, and our choice fell on Gabapentin, which crosses the blood±brain barrier very well and certainly seems to decrease the norepinephrine from neural tissue and increase GABA turnover in the brain. It shows clear anxiolytic-like eects in preclinical models of anxiety, increasing exploration of the lit portion of a dark box in mice. Apart from the general well tolerated administration and practically no side-eects, its role in clinical anxiety disorders has been demonstrated; whilst it is as ecacious as the benzodiazepines, it seems to lack the side-eects of the available anxiolytic drugs (Hener, 1998). Therapy was de®ned with three administrations of 300 mg per day of Gabapentin, associated with previously assumed cholinergic treatment. Gabapentin was easily tolerated, without drop out, and the results were quite surprising. Behavior meliorated, as stated by NPI (Cummings et al., 1994), with P < 0.05 and as stated by RSS (Greene et al., 1982), with P < 0.01, as evidenced after 1 month therapy, and moreover as performed by a global maintenance of the trend, after 6 months of follow-up. Again, four patients are not a sucient number to make a clear statement for the eventual therapeutical use of this anticonvulsivant as behavior treatment. However, our cases of AD were complicated by well known stated contraindication for the commonly used neuroleptics, although they responded successfully to the proposed therapy and there was no deterioration of their clinical situation.