Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability

We compared the long-term retention rates of several newly licensed antiepileptic drugs (AEDs) in a residential community of adults with chronic epilepsy and learning disability. Data relating to duration of therapy, maximum dose, and tolerability of six new AEDs-gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TIA), and topiramate (TPM)-were collected. Drug retention at 2 years was 85% (OXC), 57% (LTG), 56% (LEV), 45% (TPM), 24% (TIA) and 15% (GBP). OXC was used mainly as a substitute for carbamazepine. LTG, LEV, and TPM were all associated with retention rates higher than those of GBP or TIA. TPM had the highest rate of adverse event development at the maximum tried dose (60%), whereas LEV had the lowest (16%). Experience from this single epilepsy community study indicated limited impact for GBP or TIA but higher retention of OXC, LEV, LTG, and TPM in patients with chronic epilepsy and learning disability.     

Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long‐term studies?

OBJECTIVE: A review of long-term open-label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs). METHODS: From more than 500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year. RESULTS: No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty-two studies reported the number of patients withdrawing due to adverse effects. LEV was the best-tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40-60% and LEV had a retention rate of 60-75%. CONCLUSION: One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.     

Comparative retention rates and long-term tolerability of new antiepileptic drugs.

OBJECTIVE: Retention rates of five new anti-epileptic medications (AEDs) were compared in order to evaluate their long-term tolerability and efficacy. METHOD: We acquired the retention data on levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM), and zonisamide (ZNS) from the electronic database. The data included patient's age, gender, seizure type, current and previous medications, dosage, main reasons for discontinuation, and duration of therapy. The retention rates of these AEDs were evaluated at 4, 12, 24, 52, and 104 weeks. RESULTS: A total of 828 new AED exposures were obtained (LEV=196, LTG=251, OXC=97, TPM=156, ZNS=128) from patients with partial or generalized epilepsy. At 2 years, retention rate was highest with LTG (74.1%), followed by ZNS (60.2%), OXC (58.8%), LEV (53.6%), and TPM (44.2%). When these AEDs were discontinued, it was mainly due to inefficacy (29.5%) and sedating side-effects (20.5%), and commonly within 6 months into therapy. Several important AED specific side-effects leading to discontinuation were identified, including behavioral or irritability from LEV, rash from LTG and OXC, nausea from OXC and ZNS, hyponatremia from OXC, and kidney stones from TPM and ZNS. CONCLUSION: Comparing retention rates of new AEDs can provide useful insight into their tolerability and efficacy. This study showed highest retention rate with LTG, which was significantly different from ZNS (p=0.0025), LEV (p<0.0001), OXC (p=0.0024), and TPM (p<0.0001). Beside ineffectiveness, other leading causes of discontinuation were adverse behavioral effects with LEV, rash with LTG and OXC, and sedation for TPM and ZNS.     

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Purpose:   Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)–induced seizures in mice.
Methods:   Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone–AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.
Results:   Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.
Conclusions:   Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.     

Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro

Changes within the immune system have been reported to contribute to the pathophysiology of bipolar disorder and epilepsy. Interestingly, overlapping results regarding the cytokine system have been found for both diseases, namely alterations of interleukins IL-1β, IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α). However, the effect of mood stabilizers and antiepileptic drugs (AEDs) on these cytokines has not been systematically evaluated, and their effect on IL-17 and IL-22, other immunologically important cytokines, has not been reported. Therefore, we systematically measured levels of IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in stimulated blood of 14 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was supplemented with the mood stabilizers or antiepileptic drugs primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), valproic acid (VPA), oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), lithium, or no drug. IL-1β production was significantly decreased by PRM, CBZ, LEV, LTG, OXC, PB and lithium. IL-2 significantly decreased by PRM, CBZ, LEV, LTG, VPA, OXC, TPM and PB. IL-22 significantly increased by PRM, CBZ, LEV, OXC, TPM and lithium and decreased by VPA. TNF-α production significantly decreased under all applied drugs. The mechanism of action and side effects of mood stabilizers and AEDs may involve modulation of IL-1β, IL-2, IL-22 and TNF-α signaling pathways. IL-22 may be a research target for specific therapeutic effects of mood stabilizers and AEDs. These drugs might influence cytokine production by modulating ion channels and γ-aminobutyric acid (GABA) receptors of immune cells.     

Pharmacodynamic and pharmacokinetic characterization of interactions between levetiracetam and numerous antiepileptic drugs in the mouse maximal electroshock seizure model: an isobolographic analysis

PURPOSE: Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV) METHODS: With isobolographic analysis, the mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test evaluating motor performance and the step-through passive-avoidance task assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. RESULTS: LEV in combination with TPM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, was supraadditive (synergistic) in the MES test. Likewise, the combination of LEV with CBZ (at the fixed ratio of 16:1) and LEV with OXC (8:1 and 16:1) were supraadditive. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated LEV/AED combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. CONCLUSIONS: These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.     

The New Antiepileptic Drugs and Women: Efficacy, Reproductive Health, Pregnancy, and Fetal Outcome

Summary: As new antiepileptic drugs (AEDs) become available, physicians will define their appropriate use in particular patient populations. For women, the issues in clude gender-specific efficacy and tolerability, including the impact of the AED on reproductive health. Women with epilepsy who are treated with established AEDs ap pear to be at risk for compromised bone health, for dis turbances in fertility, menstrual cyclicity, ovulatory func tion, and sexuality and, with some AEDs, for failure of hormonal contraception. Finally, pregnancy outcome may be adversely affected by the established AEDs, all of which are human teratogens. Felbamate (FBM), gabap-entin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were reviewed. The preclinical development pro cess had not addressed all the issues of concern to women. Although gender-specific efficacy is routinely evaluated, impact on reproductive health is not. FBM, GBP, LTG, TGB, TPM, and VGB have similar efficacy in women and men. It is not known whether the new AEDs will affect bone health, fertility, the menstrual cycle, and sexuality. FBM, GBP, LTG, TGB, and probably VGB do not interfere with hormonal contraception. Whether these new AEDs are good choices for the pregnant woman with epilepsy awaits further experience in human pregnancy. However, animal reproductive toxicology studies appear promising. The limited number of human pregnancy ex posures do not, thus far, signal a significant number or particular type of adverse outcomes. However, only with improved postmarketing surveillance can essential infor mation about teratogenic effects be acquired in an accept ably short time.     

Basic Science

Jarogniew J. Luszczki , Marta M. Andres , Piotr Czuczwar , Anna Cioczek-Czuczwar , Neville Ratnaraj , Philip N. Patsalos , and Stanislaw J. Czuczwar
Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with current front-line antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV), recently introduced as an effective AED for refractory partial seizures. The mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test, evaluating motor performance, and the passive avoidance task, assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. LEV in combination with TPM exerted supraadditive (synergistic) interactions in the MES test. Likewise, the combinations of LEV with CBZ and OXC were supraadditive in this test. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.     

Interaction between anticonvulsants and human placental carnitine transporter

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.     

Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.     

Bone mineral density in adult patients treated with various antiepileptic drugs

There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 168 adult consecutive outpatients treated with AEDs for more than 2 years, and who underwent measurement of the BMD. We compared the incidence of decreased BMD among the patients treated with 6 different AEDs: carbamazepine (CBZ), oxcarbazepine (OXC), valproic acid (VPA), lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV). Among the patients on monotherapy, reduced BMD was present significantly most often in patients treated with LEV and those treated with OXC. In the group of patients on polytherapy there was no significant difference in the incidence of low BMD among patients treated with various AEDs. Our data suggest that patients on long-term treatment with LEV have a higher risk for affection of bone density.     

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Gewichtsveränderungen unter Antiepileptikagabe

Antiepileptic drugs (AED) are usually taken for a number of years. Therefore, long-term tolerability is of great importance for the choice of an AED. Weight change is a highly relevant side effect and can be associated with increased morbidity and mortality. Unfortunately, several AEDs and especially some of the newer AEDs induce weight changes. Weight gain has been observed with valproate (VPA) and pregabalin (PGB) but also with gabapentin (GBP) and questionably with carbamazepine (CBZ). Weight loss, on the other hand, has been associated with long-term treatment with topiramate (TPM), zonisamide (ZNS), felbamate (FBM) and was also reported for rufinamide (RFM) and stiripentole (STP). Lamotrigine (LTG), phenytoine (PHT), the barbiturates, levetiracetam (LEV), lacosamide (LCM), and oxcarbazepine (OXC) are considered to have no systematic effect on body weight. The weight change observed was frequently associated with a change in appetite and food consumption in the same direction. Genetic factors are likely relevant for the AED-related weight change.     

Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED₅₀ values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.     

Preclinical profile of combinations of some second-generation antiepileptic drugs: an isobolographic analysis

PURPOSE: The need for an efficacious treatment of patients with intractable seizures is urgent and pressing, because approximately 30% of epilepsy patients worldwide are still inadequately medicated with current frontline antiepileptic drugs (AEDs). This study sought to determine the interactions among some newer AEDs [topiramate (TPM), felbamate (FBM), oxcarbazepine (OXC), and lamotrigine (LTG)] in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in mice, by using the isobolographic analysis. METHODS: Evaluation of the anticonvulsant and acute adverse (neurotoxic) effects in mice produced by the AEDs in combinations at the fixed ratios of 1:3, 1:1, and 3:1 allowed the assessment of their preclinical profile and the determination of benefit indices (BIs) for all individual combinations. RESULTS: Combinations of TPM+FBM at the fixed ratios of 1:3, 1:1, and 3:1 offered supraadditive (synergistic) interactions against electroconvulsions and subadditivity (antagonism) in terms of acute neurotoxic effects in the chimney test (BIs ranged between 1.90 and 2.59, the best combinations from a preclinical point of view). The examined combinations of TPM+OXC also were advantageous due to synergistic interactions in the MES, and additivity in terms of acute neurotoxic effects produced by the AEDs (BIs ranged between 1.35 and 1.71). In contrast, OXC+FBM exerted subadditive (antagonistic) interactions in the MES test and additive interactions in terms of acute motor impairment of animals (BIs ranged between 0.53 and 0.71). The worst combination was observed for OXC+LTG, at the fixed ratio of 1:1, displaying subadditivity (antagonism) against electroconvulsions and supraadditivity (synergy) with respect to neurotoxicity (BIs, 0.43). The remaining combinations of OXC+LTG tested (i.e., 1:3 and 3:1) exerted additivity in the MES test and supraadditivity in the chimney test (BIs 0.54 and 0.49, respectively). None of the studied AEDs affected the brain concentrations of other AEDs, so the existence of any pharmacokinetic interactions to be responsible for the observed effects is improbable. CONCLUSIONS: Based on the current preclinical data, the pharmacological profile of combinations of TPM+FBM and TPM+OXC evaluated with isobolography was beneficial and might be worth recommendation to further clinical practice. In contrast, utmost caution is required during the use of OXC+FBM or OXC+LTG in clinical practice, because of the high risk of neurotoxic adverse effect appearance.     

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.