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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.

SUBMITTER: Citraro R

PROVIDER: S-EPMC4322085 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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Comparative analysis of the treatment of chronic antipsychotic drugs on epileptic susceptibility in genetically epilepsy-prone rats.

Citraro Rita R Leo Antonio A Aiello Rossana R Pugliese Michela M Russo Emilio E De Sarro Giovambattista G

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20150101 1

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 treatm ...[more]

PMID: 25404052

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Project description:Epilepsy is a major neurological disorder that affects approximately 1% of the population. The processes that lead to the development of epilepsy (epileptogenesis) are largely unknown. Levetiracetam is a novel antiepileptic drug (AED) that in the kindling model inhibits epileptogenesis in addition to being effective in controlling established epilepsy. The mechanisms of action of levetiracetam as an AED and an antiepileptogenic drug are unknown. By identifying the effect of chronic levetiracetam therapy on gene expression in the brain we hope to be able to identify genes that are involved in epileptogenesis. By comparing the gene expression profiles of levetiracetam and phenytoin treatments, we hope to be able to distinguish between genes that are important for the antiepileptic (anti-seizure) effect and genes that are important for the antiepileptogenic effect of levetiracetam. Phenytoin is a well-established AED; its mechanism of action involves inhibition of sodium channels. In contrast to levetiracetam, available data suggest that phenytoin in certain situations may enhance rather than inhibit the development of epilepsy. ,We will identify changes in gene expression in the hippocampus, frontal cortex, and brain stem caused by chronic treatment (3 months) with levetiracetam or phenytoin. We will search for differences in the gene expression profiles after chronic treatment with the two drugs, to explain the different clinical effects of the two drugs.,We hypothesize that chronic treatment with levetiracetam leads to changes in the expression of genes that are involved in both the antiepileptogenetic and antiepileptic effect of the drug, whereas chronic treatment with phenytoin affects genes that may be related to pro-epileptogenetic as well as antiepileptic effects of that drug. We further hypothesize that i) regional differences in the effects of levetiracetam and phenytoin may reflect important functional differences in the actions of these two drugs, and ii) there may be different mechanisms involved in their anti-seizure effect. Male Wistar rats receive levetiracetam (150 mg/kg x 2), phenytoin (75 mg/kg x 2) or control solution (N=7 in each group) through a gastric tube twice daily for 90 days. Experimental animals and controls are housed together in the same cages in groups of three, facilitating paired comparisons among the three groups in animals that have experienced the same environment throughout the 3 month experimental period. Four hrs after the last dose animals are anesthetized, decapitated, and total RNA is extracted from brain stem, frontal cortex, and hippocampus. RNA will be sent to the TGEN facility for hybridization to the rat U230A chips. The number of chips needed is (2 drugs + 1 control) * (3 brain regions) * (7 animals per group) = 63 chips. We will initially select those genes for analysis that are called present by the Affymetrix software in 4 or more animals for at least one of the 6 experimental groups. Then t-tests with Benjamini & Hochberg correction for protection against multiple comparisons will be used to identify genes that are differentially expressed at a false discovery rate of .05 among any of the six groups. We will be primarily interested in the following expression profiles, analyzed as paired comparisons by the Affymetrix software: 1. phenytoin vs control in hippocampus, 2. phenytoin vs control in brain stem, 3. levetiracetam vs control in hippocampus, 4. levetiracetam vs control in brain stem. We will then compare the profiles of both drugs in each brain region (e.g. phenytoin vs levetiracetam in hippocampus) to select genes that are drug-specific. We will also take a Venn diagram approach to identify genes that are drug-specific across both brain regions tested.

Project description:ObjectiveTo study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME).MethodsPeople with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females.ResultsWe included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001).SignificanceIn people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.

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Comparative analysis of the treatment of chronic antipsychotic drugs on epileptic susceptibility in genetically epilepsy-prone rats.

Publications

Comparative analysis of the treatment of chronic antipsychotic drugs on epileptic susceptibility in genetically epilepsy-prone rats.

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