Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

Abstract

Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs

“…The seizures in GEPRs are induced by aminophylline and other xanthines alone or in coadministration with quinolones [96,144,145], electroshock [146], flurothyl [112], hyperbaric conditions [147], pentylenetetrazol [146], and barbiturate withdrawal [148] and some typical/atypical antipsychotics [149].…”

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…WAG/Rij rat progenitors, weighing about 60 g (4 weeks old), were originally purchased from Charles River Laboratories s.r.l. (Calco, Lecco, Italy) and the rats used in these protocols were all obtained from our breeding colony at the University of Catanzaro animal facility, as previously described [11,36]. WAG/Rij rats were housed three/four per cage and kept under stable environmental conditions, humidity (60 ± 5%) and temperature (21 ± 2 °C), in a room with 12/12 h reversed light/dark cycle (lights on at 20.00).…”

Drugs that lower the seizure threshold

“…30,31 First-generation antipsychotics have only a modest effect. Clozapine is associated with concentration-dependent electroencephalographic abnormalities and, in practice, seizures affect 3-6% of clozapine-treated patients.…”

“…35 In contrast to most other antipsychotics, aripiprazole does not lower the seizure threshold during use, and may indeed have anticonvulsant properties. 30,36 However, a rebound pro-convulsant effect may occur on withdrawal. 30 …”