Walter Fröscher

The Importance of Drug Interactions in Epilepsy Therapy

Summary: Long‐term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over‐the‐counter drugs and nutritional supplements are increasingly being self‐administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme‐inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme‐inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ‐epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non‐AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

Low Risk of Development of Substance Dependence for Barbiturates and Clobazam Prescribed as Antiepileptic Drugs: Results from a Questionnaire Study

There is no systematical research about the topic of dependence on antiepileptic drugs (AED) for patients with epilepsy, despite the fact that barbiturates and benzodiazepines comprise a potential risk of dependence. We hypothesize that there is no psychological substance dependence for patients with epilepsy, possibly because of their outcome expectations. The aim of the study was to examine these patients in terms of substance dependence. One hundred inpatients at the Lake Constance Epilepsy Center were asked about their experiences with AED in terms of dependence in a structured interview. We registered general statements about dependence of AED, markers for substance dependence, and outcome expectations. About 50% of the patients reported withdrawal symptoms and the development of tolerance, but less than 10% noticed loss of control and craving. Withdrawal symptoms and development of tolerance were significantly lower in a group of patients without barbiturates or clobazam versus patients with barbiturates or/and clobazam. There was no significant difference between these two groups in psychological criteria of dependence, that is, loss of control and craving. Outcome expectations of AED were clearly related to the efficacy against seizures, and only to a small amount to psychotropic effects. The study demonstrates that physiological variables of dependence are present more in patients with epilepsy with a permanent intake of barbiturates or clobazam, but psychological variables of dependence are rarely present in epileptic patients, with or without an intake of barbiturates and clobazam. These results confirm our hypothesis that substance dependence is not a major problem in benzodiazepines and barbiturates in patients with epilepsy. Outcome expectations seem to be related mainly to the anticonvulsant and not the psychotropic effect. This might be the reason for the absence of dependence.

Biofeedback treatment in patients with refractory epilepsy: Changes in depression and control orientation

Depression is a common and serious interictal problem in patients with epilepsy. The genesis of depressive disorders is multifactorial. One aetiological aspect focuses on psychosocial factors. It was hypothesized that uncontrollable, unpredictable chronic aversive events (i.e. epileptic seizures) result in cognitive deficits of external control orientation. If this is true, biofeedback training could represent a possible treatment strategy to lower depression, because biofeedback is known to mediate success experiences and control. Measures of depression and locus of control were administered to 20 patients with refractory partial epilepsy before and after biofeedback treatment. The biofeedback consisted of slow cortical potentials or breathing parameters in 10 patients each. A clear relationship occurred between depression and locus of control in the subjects. After biofeedback training control orientation moved towards a more internal locus of control. Also, depression scores were significantly reduced six months after training. Results show that in patients with refractory epilepsy depression is highly correlated with locus of control, in a way that external control orientation relates to high depression scores. Biofeedback is able to improve internal control orientation through personal success mediation.

Memory deficits and depression in patients with chronic epilepsy

Objective: In this retrospective study, we tested the hypothesis that patients with epilepsy (PWE) with moderate to major depression have more severe memory deficits than PWE with mild depression or no depression. Methods: Hundred and thirty-nine patients with chronic epilepsy were studied with the Self-Rating Depression Scale (SDS) and a neuropsychological-screening battery the day after admission on a specialised ward for PWE. For this study the data from the Memo-test for verbal memory and from the Benton-test for non-verbal memory were taken into account. For testing of the hypothesis of independence of memory deficits and grade of depression we performed a statistical analysis. Results: Eighty-three patients (59.7%) had a pathological score in the SDS, but only 36 (25.9%) scored in the range of a moderate to major depression. When all 83 patients with a pathological score in the SDS were taken into account, these patients did not differ on any cognitive measure from those without pathological score in SDS. The only significant association in our study was found between pathological results in immediate verbal recall and a score in the SDS for moderate to major depression (p = 0.038). Conclusion: Minor depressive symptoms may be a response to chronic illness without any impact on cognitive functioning. Nevertheless, a verbal memory deficit associated with major depression was observed in our study even in the presence of many confounding factors. This may be a hint for an association of severe depressive symptoms with left temporal dysfunction in PWE.

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs

Background: Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. Objective: This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. Methods: We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. Results: There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. Conclusions: Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Chapter 9 – Seizures

Psychiatric disorders such as schizophrenia, depression, and obsessive-compulsive disorder are associated with a considerably increased incidence of seizures even in drug-naive patients. Treatment with antipsychotics is also associated with an increased risk of seizures. There is robust evidence for an elevated dose-dependent seizure incidence (up to 4.5% of treated patients) under treatment with clozapine. Treatment with chlorpromazine, olanzapine, and quetiapine is also associated with a moderately increased risk of seizures, as are intoxications, rapid changes of dosages, and polypharmacy. Seizures are typically tonic–clonic and remain single events. Status epilepticus is life-threatening, but rare in patients without a history of epilepsy. In clinical practice, taking into account the ictogenic properties of substances is required only in patients with a history of seizures. Therapy with antiepileptics is usually necessary only in cases of concomitant epilepsy and if further administration of clozapine without decrease of dosage is required after the occurrence of seizures.