Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behaviour in the WAG/Rij rat model of absence epilepsy

Abstract

Background and purpose: Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold.

Experimental approach: We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment.

Key results: ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg · kg(-1) day(-1)) and risperidone (0.5 mg · kg(-1) day(-1)) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg · kg(-1) day(-1)) and duloxetine (10-30 mg · kg(-1) day(-1)) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg · kg(-1) day(-1) reduced immobility time while at 10 mg · kg(-1) day(-1) an increase was observed.

Conclusions and implications: In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour.

Figure 1

Schematic representation of experimental protocol. P45, 45 days of age.

Figure 2

Effects of ELTT groups with antipsychotic and antidepressant drugs on immobility time in the FST in WAG/Rij rats at 6 months of age (1 month after drug suspension). Immobility time expressed in s. Values are means ± SEM; data marked with * are significantly different (P < 0.05) from control group. CTRL, control group.