G. Oteri

Effects of Psychotropic Drugs on Seizure Threshold

Psychotropic drugs, especially antidepressants and antipsychotics, may give rise to some concern in clinical practice because of their known ability to reduce seizure threshold and to provoke epileptic seizures. Although the phenomenon has been described with almost all the available compounds, neither its real magnitude nor the seizurogenic potential of individual drugs have been clearly established so far. In large investigations, seizure incidence rates have been reported to range from ∼0.1 to ∼1.5% in patients treated with therapeutic doses of most commonly used antidepressants and antipsychotics (incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%). In patients who have taken an overdose, the seizure risk rises markedly, achieving values of ∼4 to ∼30%. This large variability, probably due to methodological differences among studies, makes data confusing and difficult to interpret. Agreement, however, converges on the following: seizures triggered by psychotropic drugs are a dose-dependent adverse effect; maprotiline and clomipramine among antidepressants and chlorpromazine and clozapine among antipsychotics that have a relatively high seizurogenic potential; phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine and trazodone among antidepressants and fluphenazine, haloperidol, pimozide and risperidone among antipsychotics that exhibit a relatively low risk. Apart from drug-related factors, seizure precipitation during psychotropic drug medication is greatly influenced by the individual’s inherited seizure threshold and, particularly, by the presence of seizurogenic conditions (such as history of epilepsy, brain damage, etc.). Pending identification of compounds with less or no effect on seizure threshold and formulation of definite therapeutic guidelines especially for patients at risk for seizures, the problem may be minimised through careful evaluation of the possible presence of seizurogenic conditions and simplification of the therapeutic scheme (low starting doses/slow dose escalation, maintenance of the minimal effective dose, avoidance of complex drug combinations, etc.). Although there is sufficient evidence that psychotropic drugs may lower seizure threshold, published literature data have also suggested that an appropriate psychotropic therapy may not only improve the mental state in patients with epilepsy, but also exert antiepileptic effects through a specific action. Further scientific research is warranted to clarify all aspects characterising the complex link between seizure threshold and psychotropic drugs.

The Efficacy of Valproate‐Lamotrigine Comedication in Refractory Complex Partial Seizures: Evidence for a Pharmacodynamic Interaction

Summary: Purpose: To assess the comparative therapeutic value of valproate (VPA), lamotrigine (LTG), and their combination in patients with complex partial seizures resistant to other established antiepileptic drugs (AEDs).

Antidepressant Drugs and Seizure Susceptibility: From In Vitro Data to Clinical Practice

The use of antidepressant drugs (ADs) in patients with epilepsy still raises uncertainties because of the widespread conviction that this class of drugs facilitates seizures. A detailed knowledge of this issue in its various aspects may help in optimal management of patients suffering concurrently from epilepsy and depression. This article reviews the available data in vitro in animals and humans concerning the known potential of various ADs to induce epileptic seizures. Emphasis has been placed on those variables that may generate confusion in interpreting the results of the various studies. Most ADs at therapeutic dosages exhibit in nonepileptic patients a seizure risk close to that reported for the first spontaneous seizure in the general population (i.e., <0.1%). In patients taking high AD doses, seizure incidence rises markedly and may reach values up to 40%. With a patient history of epilepsy and/or concomitant drugs that act on neuronal excitability, low or therapeutic AD doses may be sufficient to trigger seizures. Experimental data are in partial conflict with human data on the relative potential seizure risk of the various ADs. Therefore, a reliable scale for assigning a relative value to an individual AD or to single AD classes cannot be made. It appears fair to say that maprotiline and amoxapine exhibit the greatest seizure risk, whereas trazodone, fluoxetine, and fluvoxamine exhibit the least. Some ADs may also display antiepileptic effects, especially in low doses, in experimental models of epilepsy and in humans, but the mechanism of this action is largely unknown. The available data suggest that ADs may display both convulsant and anticonvulsant effects and that the most important factor in determining the direction of a given compound in terms of excitation/inhibition is drug dosage. It is probable that drugs that increase serotonergic transmission are less convulsant or, even, more anticonvulsant than others. Because of mutual pharmacokinetic interactions between antiepileptic drugs and ADs, with consequent marked changes in plasma concentrations, it remains to be established whether or not plasma AD levels that are effective against depression also facilitate seizures. Finally, exploring the mechanisms through which ADs modulate neuronal excitability might open new possibilities in antiepileptic drug development.

Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs.

Purpose:  Older enzyme‐inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels.

Sodium Valproate and Valpromide: Differential Interactions with Carbamazepine in Epileptic Patients

Summary: To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ‐10,11‐epoxide (CBZ‐E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate‐treated group, plasma CBZ‐E levels increased by 101% (range, 29–238%) within 1 week of combined therapy (p < 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM‐treated patients, the elevation of plasma CBZ‐E levels was much greater. In this group, plasma CBZ‐E increased by 330% (range, 110–864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ‐E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a pro‐drug of VPA. Although both VPA and VPM increase CBZ‐E levels—probably by inhibiting the enzyme epoxide hydrolase—the interaction caused by VPM is of much greater magnitude and potential clinical significance.

Effects of steroid hormones on muscle reinnervation after nerve crush in rabbit

The ability of an association of three steroid hormones to influence the reinnervation process and the trophism of rabbit muscles denervated by crush of the sciatic nerve was investigated. The beginning of reinnervation was established with electromyographic recordings from the tibialis anterior muscle. The distance from the site of crushing to the point where the motor nerve enters the tibialis anterior muscle was then measured in each animal, and the nerve regeneration velocity (mm/day) was calculated: a slightly but significantly higher (P less than 0.001) mean value was found in treated animals compared with untreated ones. When soleus and extensor digitorum longus (EDL) muscles were histochemically examined 50 days after lesion, a larger mean diameter of type 2c fibers was found in treated than in untreated animals, pointing out a possible useful effect of the treatment. On the contrary, the size reduction of EDL type 2b fibers was more pronounced in treated rabbits, indicating a catabolic influence of the drugs on this fiber type.

Antiepileptic drugs and MTHFR polymorphisms influence hyper-homocysteinemia recurrence in epileptic patients

Summary:  The influence of antiepileptic drugs (AEDs) and/or common polymorphisms (677C → T, 1298A → C) of the methylene‐tetrahydrofolate‐reductase (MTHFR) gene on the recurrence time of hyper‐total‐homocysteinemia (tHcy > 13 μmol/L) was investigated in 59 hyper‐homocysteinemic patients (34M/25F, 20–49 years). Plasma tHcy and folate were assayed before and after 1‐month folate supplementation (5mg/day), and after 2, 4, and 6 months. Four MTHFR polymorphism groups were identified with the following tHcy (μmol/L) and folate (nmol/L) levels (mean ± SD): (a) MTHFR677TT/1298AA, 24 patients, 36.0 ± 4.8, 4.1 ± 0.7; (b) MTHFR677CT/1298AC 27.1 ± 2.7, 5.3 ± 1.0 (n = 15); (c) MTHFR677CT/1298AA 16.6 ± 3.6, 6.8 ± 1.0 (n = 11), all taking enzyme‐inducing AEDs; and (d) MTHFR677TT/1298AA 24.5 ± 3.2, 5.6 ± 1.1 (n = 9), treated with new AEDs. After folate therapy, plasma t‐Hcy and folate were normal in all patients. At 6 months, 43 patients (72.9%) exhibited hyper‐tHcy, the greater proportion belonging to the EI‐AED‐MTHFR677TT/1298AA (39%). Knowledge of the hyper‐tHcy recurrence time after folate therapy discontinuation may help in optimizing folate supplementation pulses.

Hyperhomocysteinemia in patients with epilepsy: Does it play a role in the pathogenesis of brain atrophy? A preliminary report

Purpose:  Brain atrophy (BA) is observed in 20–50% of patients with epilepsy. Hyper‐total‐homocysteinemia (hyper‐tHcy), which occurs in 10–40% of patients, is considered to be a risk factor for cardiovascular diseases and BA. The present study was aimed at investigating the possible association of hyper‐tHcy with BA in a population of patients with epilepsy.

Valproic acid-ethosuximide interaction: a pharmacokinetic study.

Summary: The present pharmacokinetic study was designed to investigate the possible interaction between valproic acid (VPA) and ethosuximide (ESM) in humans. Six drug‐free healthy volunteers, four men and two women, 18–42 years of age, received a single oral dose of 500 mg ESM before and during a treatment with VPA at 800‐ to 1,600‐mg daily doses. The second ESM dose was given 9 days after VPA administration was started. In this latter condition, a significant (p < 0.05) increase in ESM serum half‐life, from 44 to 54 h on average, and a significant (p < 0.05) decrease in total body clearance, from 11.2 to 9.5 ml/min on average, were observed. Other pharmacokinetic parameters were unchanged and showed values similar to those reported in the literature. Serum VPA levels ranged between 66.8 and 95 μg/ml. Two subjects showed no evidence of interaction. Although a great interindividual variability in the occurrence of VPA‐ESM interaction can be observed, the present study indicates that VPA is able to inhibit the metabolism of ESM. Possible factors affecting this interaction are hypothesized and discussed.

Interaction of carbamazepine-10.11-epoxide, an active metabolite of carbamazepine, with valproate : a pharmacokinetic study

Summary: The mechanism responsible for the valproate (VPA)‐induced elevation of serum carbamazepine‐10,11‐epoxide (CBZ‐E) levels was investigated in 6 normal subjects who received single oral doses of CBZ‐E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d.)]. VPA caused a significant prolongation of CBZ‐E terminal half‐life (t± from 6.3 ± 1.2 to 9.0 ± 2.0 h, mean values ± SD) and decreased CBZ‐E clearance (from 90.6 ± 18.8 to 63.2 ± 16.1 ml h ‐1 kg‐1, mean values ± SD) without affecting CBZ‐E apparent volume of distribution (from 0.82 ± 0.19 to 0.81 ± 0.241 kg‐1, mean values ± SD). These findings indicate that VPA impairs the elimination of CBZ‐E, presumably by inhibiting its metabolism.