patients' response. Genetic factors contribute to differences inpharmacodynamic sensitivity, comorbidity and clinical response. AllAEDs decrease neuronal excitability by affecting the balance betweenglutamatergic and GABAergic neurotransmission, which may beresponsible for the efficacy of these drugs in other disorders thanepilepsy. There seems to be common pathophysiological pathways inepilepsy and other neurological and psychiatric disorders such asneuropathic pain, migraine, bipolar disorder and anxiety. AEDs areincreasingly used in these disorders, and their use in otherindications is also investigated. Relevant mechanisms of action inbipolar disorder involve alterations in intracellular pathways affectingexcitability, where lamotrigine, valproate and carbamazepine haveshown similar effects as lithium on e.g. inositol turnover. In anxiety,GABAergic mechanisms are involved including inhibition of voltage-gated calcium channels by e.g. pregabalin. In neuropathic pain,inhibition of voltage-gated calcium channels by pregabalin andgabapentin decreases glutamatergic excitability from the spinal cord,while similar effects and antagonistic effects on the AMPA receptor bytopiramate seem to be important in prophylactic treatment ofmigraine.

During the last years, the use of AEDs in other disorders hasincreased and constitutes 40–50% of the total use of AEDs, asdemonstrated by our studies based on the Norwegian PrescriptionDatabase. Future directions regarding AEDs include the developmentof broad-spectrum drugs for several indications and focus on geneticstudies to explore common pathophysiological processes. Further-more, it is of importance to monitor the increased use of AEDs inother indications as a part of pharmacovigilance, as new patientgroups are introduced to AEDs and long-term effects often arescarcely documented.

doi:10.1016/j.yebeh.2012.04.047

Pharmacokinetic and pharmacodynamic interactions betweenantiepileptic drugs and psychoactive agents

P.N. Patsalos, Pharmacology and Therapeutics Unit, Department ofClinical and Experimental Epilepsy, UCL-Institute of Neurology, London,UK, Epilepsy Society, Chalfont St Peter, UK

Concomitant administration of antiepileptic drugs (AEDs) andpsychoactive drugs is becoming increasingly common, and conse-quently the possibility of pharmacokinetic and pharmacodynamicinteractions between these compounds is important. Pharmacody-namic interactions between AEDs and psychoactive drugs are notwell documented, but neurotoxic synergism has been reportedbetween lithium and valproate and with carbamazepine, carbama-zepine with aripiprazole and with fluoxetine, and valproate withquetiapine. In contrast, many pharmacokinetic interactions have beendescribed with most occurring at the metabolic level and involvechanges in cytochrome P450 (CYP) activity. Enzyme-inducing AEDs(carbamazepine, phenytoin, phenobarbital, primidone) enhance themetabolism and decrease plasma levels of many tricyclic antidepres-sants (e.g. amitriptyline, nortriptyline, imipramine, desipramine,clomipramine and doxepin), many antipsychotics (e.g. clozapine,fluphenazine, haloperidol, quetiapine and risperidone) and somebenzodiazepine (e.g. alprozolam, clobazam and clonazepam). Con-versely, some newer antidepressants (e.g. viloxazine, fluoxetine andfluvoxamine) can inhibit the metabolism of phenytoin and carbama-zepine and increase their plasma levels. Significant pharmacokineticinteractions between AEDs and lithium do not occur. Many of thenew AEDs (e.g. levetiracetam, lacosamide, vigabatrin, gabapentin andpregabalin) have a low potential for pharmacokinetic interactionwith all psychoactive drugs. Prevention and management of AED-

psychoactive drug interactions comprise avoiding highly interactingdrugs, understanding the underlying mechanism of interactions so asto anticipate the therapeutic outcome and using dosing strategiesguided by therapeutic drug monitoring of both AEDs and psychoac-tive drugs so as to circumvent undesirable consequences.

doi:10.1016/j.yebeh.2012.04.048

Refractory epilepsy: Prequel or sequel?

M.J. Brodie, Epilepsy Unit, Western Infirmary, Glasgow, Scotland, UK

Despite the development and licensing of more than a dozenantiepileptic drugs (AEDs) over the past 20 years for the adjunctivetreatment of the common epilepsies in adults, evidence is lackingthat these have had a major impact on prognosis. In our latestanalysis of outcomes in 1098 patients with newly diagnosed epilepsyfollowed for up to 25 years, a number of patterns of drug responsehave been identified. Among these, 25% of this population has neverachieved seizure freedom for a full year despite receiving treatmentwith a range of AEDs. This population often had a high density of pre-treatment seizures, concomitant psychiatric comorbidities, such asdepression, anxiety and psychosis, and a family history of epilepsy.Other groups have also found an association of prior or currentpsychiatric disturbances with suboptimum AED responses. In addi-tion, a lifetime psychiatric history predicted worse seizure outcomefollowing temporal lobectomy. All these factors support the sugges-tion that in some patients the “refractoriness” of the epilepsy waspresent before the diagnosis was made and initial treatment begunand that the presence of other symptoms of brain dysfunctioncontributes to the severity of the epilepsy. In another 15% percent ofthis population, a relapsing/remitting course was observed with somepatients developing drug resistance after years of seizure freedom.This pattern has also been reported by a number of research groups.These observations suggest that response to AEDs used singly and incombination did not influence the ultimate poor prognosis in thesedisparate patient groups. These drugs, therefore, treat the result, i.e.the seizures, but not the causation, i.e. the pathogenesis, of theepilepsy. Some patients appear to have drug-resistant epilepsy denovo, while others develop refractory epilepsy despite apparentlysuccessful pharmacotherapy. Novel approaches to the treatment ofthe process underpinning the generation and propagation of seizuresare required if this disappointing picture is to be substantialimproved.

doi:10.1016/j.yebeh.2012.04.049

Treatment of psychiatric comorbidities in people with epilepsy

M. Mula, Department of Clinical & Experimental Medicine, AmedeoAvogadro University, Division of Neurology, University Hospital Maggioredella Carità, Novara, Italy

The management of patients with epilepsy, especially those withdrug refractory syndromes, may be complicated by psychiatriccomorbidities that significantly affect prognosis, morbidity andmortality. In general terms, a careful distinction between truepsychiatric manifestations and seizure-based phenomena (i.e. peri-ictal psychiatric symptoms) is crucial, having implications in terms ofprognosis and treatment.

Guidelines of treatment for psychiatric disorders in epilepsy arestill lacking. In general terms, internationally adopted guidelines oftreatment outside epilepsy may be considered taking into account a

Abstracts 315