The Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) is a well-established instrument, designed to assess potentially remediable behavioral symptoms in Alzheimer’s disease (AD) patients as well as to evaluate treatment outcome. It consists of 25 symptoms grouped into seven categories. Each symptom is scored on the basis of severity on a four-point scale. A knowledgeable caregiver is queried and items are scored on the basis of symptoms noted in the preceding two weeks. Reliability, construct validity and criterion validity data for the BEHAVE-AD have previously been published. Because of the significance of psychopathology in dementia, it is necessary to optimally describe and define the nature, magnitude and prevalence of behavioral symptomalogy. Accordingly, a frequency component was added to each of the 25 items of the BEHAVE-AD scale. The objective of the present report is to describe this new Behavioral Pathology in Alzheimer’s Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) and to establish its inter-rater reliability. In this investigation the BEHAVE-AD-FW scale was administered to caregivers of 28 patients with either mildly impaired cognitive function or a dementia diagnosis. Two clinicians separately and independently rated the responses. Analyses determined that the intraclass correlation coefficients (ICCs) for the frequency component varied between 0.86 and 0.97 for each of the seven BEHAVE-AD categories (ps < 0.001). ICCs for the frequency-weighted scores (item severity score x item frequency score) ranged from 0.69 to 0.98 for the seven symptom categories (ps < 0.001). For the BEHAVE-AD-FW total scores, the ICC was 0.91 (P < 0.001). These results indicate that the frequency-weighted component is a reliable addition to the BEHAVE-AD scale.

In older as well as younger people, antipsychotic medication is commonly used to treat psychoses. In clinical practice, antipsychotic medication is also used to control severe behavioral disturbances such as agitation, wandering, self-mutilation, as well as assaultiveness. Neuroleptic and non-neuroleptic drug treatments are used to control severe agitation and disruptive behavior.

Among typical neuroleptics, very low doses (e.g., 0.25 mg of haloperidol 1–4 times per day) may be effective and limit the development of severe extrapyramidal reactions.

Recent experience suggests that the atypical neuroleptics, olanzaine, risperidone, and quetiapine, are also useful for controlling severe agitation in elderly demented nursing home residents.

The benzamides are also known for the treatment of behavioral disturbances in Europe, but there is little experience in the U.S.A.

Although research studies in this area are virtually nonexistent, growing clinical experience sugests that the following may be quite useful: 1) trazodone; 2) buspirone (Buspar®); 3) anticonvulsants (e.g., valproate); and 4) β-blockers.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D2 (IC50 = 110–320 nM) and D3 (IC50 = 180 nM) receptors in vitro but lacks affinity for dopamine D1 and D4 receptors and for non-dopaminergic receptors including H1, α1, α2-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED50 ∼ 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10–30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas.

In behavioral experiments in rats, lower doses of tiapride (ED50 = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED50 = 60 mg/kg, ip) were required to block stereotyped movements.

In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED50 = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED50 = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3–30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance.

The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D2 and D3 receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

The quality of human cognitive performance appears today as one of the main components of quality of life, whatever the age. Ageing by itself and most of the diseases affecting the central nervous system alter higher brain functions such as memory, vigilance and attention. Dementia is the most acute example, with a cascade of behavioral and psychological consequences (BPSD), which are the main cause of the caregiver’s burden and need specific pharmacotherapy. In this respect, the problem will be the choice of the best drug in situations such as wandering, agitation, violence, and screaming. The psychotropics, however, should not deteriorate the already disturbed cognition of the patients. This is the reason why we propose to establish for each drug, and notably for the antipsychotics, a precise and exact ‘cognitive mapping’; in other words, to measure the effects of drugs on the different components of cognition. The results of such studies will be predictive of the future phase III clinical trials and therapeutic responses. As an illustration of this approach we shall relate two studies, TIATEM (phase I) and TIAGE (phase III/IV), leading to the determination of a good cognitive safety profile of an atypical neuroleptic drug, tiapride.

Agitated behaviors such as uncooperativeness with necessary care, motor hyperactivity, and verbal or physical aggression are some of the most commonly reported complications in dementia and organic disorders in elderly subjects. These symptoms present greater clinical challenges and management issues than the cognitive deficits. Antipsychotics are the most commonly used psychotropic agents for treating these types of symptoms.

The aims of this article are to review clinical studies with tiapride, a substituted benzamide, and more specifically to present recent data coming from two double-blind, randomized studies in elderly subjects.

The first study versus melperone was conducted in Germany, with over 176 hospitalized demented patients, and indicated that tiapride was as effective and safe as melperone.

More recently, a multicentre, international, double-blind, three-parallel group study compared a 21-day treatment of tiapride to haloperidol and placebo and included 306 demented elderly patients with agitation and aggressiveness. The results showed that tiapride and haloperidol were significantly effective in the treatment of agitation and aggressiveness compared to placebo. The tiapride safety profile was found to be better than haloperidol for clinical acceptability, particularly for significantly fewer extrapyramidal symptoms in the tiapride group.