Newly Discovered Tricks of an Old Dog: Why Carbamazepine Exacerbates Absence Seizures

Abstract

Actions of the Antiseizure Drug Carbamazepine in the Thalamic Reticular Nucleus: Potential Mechanism of Aggravating Absence Seizures

Jang SS, Agranonik N, Huguenard JR. Proc Natl Acad Sci USA. 2025;122(31):e2500644122.

Carbamazepine (CBZ) is a widely used antiepileptic drug effective in managing partial and generalized tonic-clonic seizures. Despite its established therapeutic efficacy, CBZ has been reported to worsen seizures in another form of epilepsy, generalized absence seizures, in both clinical and experimental settings. In this study, we focused on thalamic reticular (RT) neurons, which regulate thalamocortical network activity in absence seizures, to investigate whether CBZ alters their excitability, thereby contributing to the exacerbation of seizures. Using ex vivo whole-cell patch-clamp electrophysiology, we found that CBZ selectively inhibits the tonic firing of RT neurons in a dose-dependent manner without affecting burst firing. At the RT-thalamocortical synapse, CBZ significantly increases the failure rate of GABAergic synaptic transmission, with greater effects on somatostatin—than parvalbumin-expressing RT neurons. In vivo EEG recordings and open-field behavior in Scn8a^med± mouse model confirmed that CBZ treatment exacerbates absence seizures, increasing both seizure frequency and duration while reducing locomotor activity. In addition, CBZ further amplifies the preexisting reduction in tonic firing of RT neurons in Scn8a^med± mice. These findings uncover a mechanism by which CBZ exacerbates absence seizures through selective inhibition of RT neuron excitability and disruption of GABAergic synaptic transmission. This work provides mechanistic insights into the paradoxical effects of CBZ and suggests potential avenues for optimizing epilepsy treatment strategies.

Commentary

Epilepsy is a problem of excitation–inhibition imbalance. This can occur in isolated locales, leading to focal seizures, or in key nodes, such as the thalamus, with global impact on epileptic networks leading to generalized seizures. Basic research has helped to narrow mechanisms governing excitation and inhibition in these circuits. This research has been leveraged to develop the dozens of pharmacological therapies available to combat epilepsy. A common approach to reducing excitation is through sodium channel blockade, which impedes neuronal depolarization. This is generally effective in both focal and generalized seizures. However, it was recognized early on that one of the first used sodium channel blockers, carbamazepine, exacerbated absence seizures, a form of generalized seizure. ¹ There are newer generations of carbamazepines, oxcarbazepine, and eslicarbazepine, which are readily prescribed for epilepsy, but these too exacerbate some generalized, including absence, seizures. Why carbamazepines should exacerbate absence seizures is not understood. Absence seizures in particular are thought to be mediated by a calcium channel-mediated loss of inhibition in inhibitory networks in the thalamus, specifically in inhibitory gamma-aminobutyric acid (GABA)-ergic reticular thalamic neurons. Here the authors hypothesized that carbamazepine might exert action on these inhibitory networks to worsen absence seizures. ²

First, using whole-cell patch-clamp electrophysiology from thalamic reticular neurons in mouse horizontal brain slices with an intact thalamocortical circuit, they determined that carbamazepine selectively and dose-dependently inhibited firing of thalamic reticular neurons. Further analyses in three temporal windows revealed that there was no effect on early, phasic/burst activity of these neurons. Rather, carbamazepine reduced firing in the middle and late temporal windows that are consistent with an effect on tonic activity.

To further evaluate whether the effect of carbamazepine was specific to tonic activity, studies were performed with measures to reduce burst activity. The effect of carbamazepine was not affected by these measures, namely electrical inactivation of T-type calcium channels or by pharmacological blockade of T-type or L-type calcium channels, confirming a selective effect on tonic activity.

Second, they expressed the excitatory opsin, channelrhodopsin-2 (ChR2), in inhibitory neurons under the control of the vesicular gamma-aminobutyric acid (GABA) transporter and then optogenetically stimulated the neurons with different frequencies of blue laser light with or without carbamazepine present. Stimulation of the thalamic reticular neurons in the presence of a glutamate receptor (ie, excitatory) blocker reliably led to postsynaptic currents in thalamocortical neurons, suggesting that these were inhibitory postsynaptic currents. This was verified electrically by holding membrane potential at different voltages and through pharmacological blockade of GABA_A receptors. Thus, carbamazepine reduced GABAergic transmission at thalamic reticular synapses onto thalamocortical neurons.

Third, to evaluate subsets of inhibitory neurons, they selectively expressed ChR2 in parvalbumin or somatostatin expressing neurons and again stimulated neurons with laser light in the presence or absence of carbamazepine. They found a greater effect when stimulating somatostatin-expressing GABAergic neurons than when the parvalbumin-expressing GABAergic neurons were stimulated, which was a bit surprising as parvalbumin-expressing inhibitory neurons are thought to play a greater role in absence seizures. Nevertheless, this highlights the differential regulation of this process by inhibitory neuron subtypes.

Finally, they moved to an in vivo model to evaluate the impact of carbamazepine on seizures in a mouse model of epilepsy associated with a sodium channel mutation, namely the Scn8a haploinsufficient mutant mouse (Scn8a^med/+). Scn8a encodes the voltage gated sodium channel Na_V1.6. Scn8a^med/+ mice display spontaneous absence seizures characterized by spike-and-wave discharges (SWDs). These SWDs are abolished by treatment with ethosuximide, ³ an absence seizure-specific antiseizure medicine. Carbamazepine increased the frequency and duration of SWDs in Scn8a^med/+ mice, consistent with absence seizures, with no effect in wild-type mice. SWDs were associated with a reduction in locomotor activity, as assessed by open-field monitoring, which suggests increased periods of behavioral arrest due to an increased number of absence seizures. In Scn8a^med/+ mice, there is a known reduction in action potential firing in thalamic reticular neurons. ³ The authors confirmed this observation in their study. Carbamazepine further reduced action potential firing from thalamic reticular neurons in Scn8a^med/+ mice, especially in the later time window, suggesting a preferential reduction in tonic activity.

This well-designed and well-executed study provides some explanation for the long-appreciated paradoxical effect of carbamazepine on some generalized seizure types. More needs to be done to understand how carbamazepine affects other cell types and whether these effects could also contribute to the exacerbation of absence seizures. More would also need to be done to understand why other antiseizure drugs that also generally reduce neuronal excitability, and presumably would reduce excitability of thalamic reticular neurons, do not also exacerbate absence seizures. This will likely be explained by nuances in the mechanism of action of different drugs. However, as speculated by the authors, in many cases the inactivation is activity- or use-dependent, and thalamic reticular neurons may be particularly susceptible to this due to their extremely high basal firing rate. Ideally, small variations in mechanism contributing to side effects could be leveraged into pharmacological dissection of the specific biochemistry of the molecule to engineer a designer drug to eliminate this side effect associated with carbamazepine.

Carbamazepine and other antiseizure medicines can have profound effects on sleep and wakefulness, ⁴ leading to sleep–wake disturbances that contribute significantly to morbidity in patients with epilepsy. ⁵ Excessive somnolence, in particular, is a common complaint among patients with epilepsy treated with antiseizure medicines. Transitions between sleep and wakefulness are regulated in part by the phasic versus tonic firing patterns of the thalamus. ⁶ Perhaps mechanisms uncovered in the current study could help to explain the effect of carbamazepine on increased somnolence and other sleep–wake disruptions as well.

Though there are many other antiseizure medicines besides carbamazepine that can be deployed to reduce generalized seizures such as absence seizures, the fact remains that about a third of epilepsy patients cannot achieve seizure control with currently available therapies. ⁷ This severely impacts quality of life, amplifies morbidity, and places them at high risk for mortality from sudden unexpected death in epilepsy, or SUDEP. ⁸ Epileptic syndromes that feature multiple generalized seizure types, such as Lennox–Gastaut syndrome (LGS), can be particularly challenging to treat. ⁹ Of course, there is risk for SUDEP among patients with LGS. Many seizure types in LGS are exacerbated by carbamazepine. Novel and improved therapies are desperately needed to combat morbidity and mortality associated with medically refractory epilepsies. Continuing to make strides with basic research at uncovering seemingly small nuances in mechanisms that could improve seizure control with a favorable side-effect profile will continue to be critical in the campaign for no seizures and no side effects.