Antipsychotic, antidepressant, and cognitive-impairment properties of antipsychotics: rat profile and implications for behavioral and psychological symptoms of dementia

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.