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.