The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians

Abstract

Right click to open a feedback form in a new tab to let us know how this document benefits you.This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ 1 The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians. AbstractThe literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part I of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i) be inducers only in high doses; (ii) frequently combine with inhibitory properties; and (iii) take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i) sexual hormones, (ii) vitamin D, (iii) thyroid hormones, (iv) lipid metabolism and (v) folic acid.Footnote: Table 1 and 3 were included in second part of this article but they are included here to facilitate reading.

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

“…Both the median plasma concentration and the dose-adjusted plasma concentration of 9-OH-RIS and AM were about 2-fold lower than in the control group, revealing results that are in line with correction factors for potent inducers, such as CBZ, as suggested by de Leon et al 4,31 The comparison of the plasma and the dose-adjusted plasma concentrations of RIS between the CBZ and the control group did not yield statistically significant differences. However, the numeric difference has to be taken into account, that is, in case of RIS C/D ratio, the median value for CBZ patients was 0.66 (ng/mL)/mg, whereas it was 1.16 (ng/ mL)/mg in the control group.…”

“…There has been considerable evidence regarding the pharmacokinetic profile of CBZ and especially its DDI with other antiepileptic drugs, illustrating a major inducing effect of CBZ on CYP3A4 as well as similar effects on activities of other CYP isoenzymes, including CYP2A6, CYP2C9, CYP2C19, CYP2B6, CYP1A2, UGTs, and P-glycoprotein. 31,36,37 Moreover, Yatham and colleagues 38 detected 40% lower plasma concentrations of RIS AM values in CBZ-treated patients compared with patients receiving RIS and VPA or lithium. These findings are in agreement with data from a small clinical sample reporting a CYP3A4-mediated interaction between CBZ and RIS, leading to decreased plasma levels of the parent compound RIS.…”

“…However, the mechanism and the clinical significance of possible interactions have not been fully elucidated and different pharmacokinetic effects on concomitantly applied have been shown, for example, acting simultaneously as an inhibitor but also as an inducer of clozapine and olanzapine metabolism. 31 A recent study indicates that VPA might inhibit 9-OH-RIS (paliperidone) metabolism increasing its oral bioavailability. 32 Carbamazepine is frequently prescribed as a mood stabilizer or for mood and aggression control in patients with bipolar disorders and schizophrenia spectrum disorders.…”

A Method for Deciding About the Possible Safety of Modafinil and Armodafinil in Patients With Seizure Disorder

“…Antiepileptic drugs susceptible to this interaction include carbamazepine, clobazam, and others. 36 Modafinil and armodafinil also inhibit CYP2C9/19 37,38 ; this can increase the levels and hence the efficacy (and adverse effects) of antiepileptic drugs metabolized by these enzymes. Susceptible drugs include phenobarbitone, primidone, phenytoin, and others.…”

“…Susceptible drugs include phenobarbitone, primidone, phenytoin, and others. 36 Other common antiepileptic drugs such as valproate, lamotrigine, topiramate, gabapentin, and levetiracetam are probably little affected by ar/mod pharmacokinetic interactions.…”