Abstract
Many dementia patients exhibit behavioral and psychological symptoms (BPSD), including psychosis and depression. Although antipsychotics are frequently prescribed off-label, they can have marked side effects. In addition, comparative preclinical studies of their effects are surprisingly scarce, and strategies for discovery of novel pharmacotherapeutics are lacking. We therefore compared eight antipsychotics in rat behavioral tests of psychosis, antidepressant-like activity, and cognitive impairment as a basis for preclinical evaluation of new drug candidates. The methods used in this study include inhibition of MK-801-induced hyperactivity, forced swim test (FST), passive avoidance (PA), spontaneous locomotor activity, and catalepsy. The drugs exhibited antipsychotic-like activity in the MK-801 test but with diverse profiles in the other models. Risperidone impaired PA performance, but with some dose separation versus its actions in the MK-801 test. In contrast, clozapine, olanzapine, lurasidone, and asenapine showed little or no dose separation in these tests. Aripiprazole did not impair PA performance but was poorly active in the MK-801 test. Diverse effects were also observed in the FST: chlorpromazine was inactive and most other drugs reduced immobility over narrow dose ranges, whereas clozapine reduced immobility over a wider dose range, overlapping with antipsychotic activity. Although the propensity of second-generation antipsychotics to produce catalepsy was lower, they all elicited pronounced sedation. Consistent with clinical data, most currently available second-generation antipsychotics induced cognitive and motor side effects with little separation from therapeutic-like doses. This study provides a uniform in vivo comparative basis on which to evaluate future early-stage drug candidates intended for potential pharmacotherapy of BPSD.
Highlights
Dementia is a syndrome of progressive deterioration of cognitive abilities associated with psychiatric and behavioral disturbances and difficulties in carrying out daily functions (Hersch and Falzgraf 2007)
Mood deficits and depressive symptoms are very common in patients suffering from dementia (Hersch and Falzgraf 2007), and the present study shows that antipsychotics used in the treatment of behavioral and psychological symptoms of dementia (BPSD) have distinct effects in the forced swim test (FST), a classic model of antidepressant-like activity (Fig. 2)
All the antipsychotics possess sub-optimal profiles, mostly by eliciting memory-impairment or sedation at antipsychotic-like range of doses—side effects that may be of particular concern for elderly dementia patients with preexisting cognitive deficits and motor difficulties
Summary
Dementia is a syndrome of progressive deterioration of cognitive abilities associated with psychiatric and behavioral disturbances and difficulties in carrying out daily functions (Hersch and Falzgraf 2007). The global prevalence of dementia is estimated to be 3.9 % in individuals over the age of 60 years (Ferri et al 2005), and a large majority of these (as many as 60 % of communitydwelling dementia patients) experience behavioral and psychological symptoms of dementia (BPSD) at some time. The most troublesome symptoms include psychosis (delusions and hallucinations), depression, dis-inhibition, irritability, verbal and physical aggression, agitation, and anxiety (Jeste et al 2008). Between 40 and 60 % of patients suffering from dementia experience depressive symptoms at some stage of the disease (Hersch and Falzgraf 2007), and the prevalence of psychotic symptoms can reach 63 % for delusions and up to 41 % for hallucinations in certain patient populations (Jeste et al 2008).
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