Ketamine and Seizures: Vital Neurophysiology and Treatment

Ketamine, a dissociative anesthetic with medical and psychiatric applications, has complex effects on the nervous system. While widely used for anesthesia and depression treatment, its role in seizure activity remains under investigation. Some studies suggest anticonvulsant properties, while others indicate proconvulsant potential under certain conditions.

Understanding how ketamine interacts with neural circuits provides insight into its potential benefits and risks concerning seizures.

Key Properties in Neurological Context

Ketamine affects the nervous system through receptor interactions, neurotransmitter modulation, and network-level changes in brain activity. Unlike traditional anesthetics that primarily enhance inhibitory signaling, ketamine disrupts excitatory transmission, altering consciousness, perception, and neuronal excitability. This mechanism has led to its use in anesthesia, pain management, and psychiatric treatment, but also raises questions about its influence on seizure susceptibility.

A defining characteristic of ketamine is its ability to induce a dissociative state by selectively inhibiting excitatory pathways while preserving aspects of cortical and subcortical function. This occurs through its antagonism of N-methyl-D-aspartate (NMDA) receptors, which are central to synaptic plasticity and excitatory neurotransmission. By blocking these receptors, ketamine reduces sustained depolarization required for prolonged neuronal firing, potentially suppressing excessive excitatory activity linked to seizure propagation. However, this same mechanism may also lead to paradoxical effects by transiently disinhibiting cortical circuits, facilitating abnormal synchronization in some cases.

Beyond NMDA receptor antagonism, ketamine influences other neurochemical systems that contribute to its complex neurological profile. It enhances glutamate release in certain brain regions, particularly the prefrontal cortex, by increasing presynaptic activity at non-NMDA glutamatergic synapses. This surge in glutamate can activate downstream pathways, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, which may either stabilize or destabilize neural networks depending on the existing state of excitability. Additionally, ketamine interacts with gamma-aminobutyric acid (GABA)ergic interneurons, opioid receptors, and monoaminergic systems, all of which shape its effects on brain function.

NMDA Receptor Dynamics

The NMDA receptor is a ligand-gated ion channel critical for excitatory neurotransmission, synaptic plasticity, and neuronal network stability. It is characterized by a voltage-dependent magnesium block, allowing calcium and sodium influx only under sufficient depolarization. Its function is regulated by subunit composition, phosphorylation states, and interactions with co-agonists like glycine and D-serine, which influence gating properties and downstream signaling. Ketamine primarily acts as a noncompetitive NMDA receptor antagonist, altering excitatory synaptic transmission and cortical dynamics.

By binding to the receptor’s PCP site within the ion channel pore, ketamine prevents calcium influx, disrupting long-term potentiation (LTP), a process critical for synaptic strengthening and memory formation. This blockade dampens sustained neuronal firing that contributes to hyperexcitability. However, ketamine’s effects on NMDA receptors vary across brain regions. In the prefrontal cortex, ketamine-induced NMDA receptor inhibition paradoxically enhances glutamate release through a disinhibitory mechanism involving GABAergic interneurons. This regional variability underlies ketamine’s complex psychotropic and neurophysiological effects, including its rapid antidepressant action and potential influence on seizure susceptibility.

Ketamine’s pharmacokinetics, including its metabolism into active metabolites like hydroxynorketamine (HNK), influence the duration and extent of NMDA receptor blockade. Some metabolites exhibit reduced antagonistic activity while still modulating downstream pathways such as brain-derived neurotrophic factor (BDNF) upregulation. Subunit-specific differences in NMDA receptor composition, such as the presence of GluN2A versus GluN2B subunits, further shape ketamine’s effects by regulating calcium permeability and excitatory-inhibitory balance.

Modulation of Excitatory and Inhibitory Synapses

Ketamine’s effects on excitatory and inhibitory synapses result from its interactions with multiple neurotransmitter systems, leading to shifts in synaptic balance. While NMDA receptor antagonism reduces excitatory glutamatergic transmission, ketamine also alters synaptic plasticity by modulating presynaptic neurotransmitter release and postsynaptic receptor sensitivity. These effects vary by brain region, neuronal subtype, and dosage.

A key consequence of ketamine exposure is increased glutamate release in the prefrontal cortex through disinhibition. By targeting NMDA receptors on fast-spiking GABAergic interneurons, ketamine suppresses inhibitory control over excitatory pyramidal neurons. This reduction in GABAergic activity leads to a surge in extracellular glutamate, activating non-NMDA glutamate receptors such as AMPA and kainate receptors. While this excitatory burst promotes neuroplasticity, as seen in ketamine’s antidepressant effects, it may also contribute to abnormal synchronization in certain neural networks.

Ketamine’s influence on inhibitory circuits extends beyond NMDA receptor blockade. It modulates GABA-A receptor function in a dose-dependent manner. At anesthetic concentrations, ketamine enhances inhibitory tone by potentiating GABAergic signaling, contributing to its sedative effects. Conversely, at subanesthetic doses, it may reduce inhibitory control, increasing excitability in some regions while dampening it in others. This bidirectional modulation contributes to ketamine’s unpredictable effects on neuronal excitability.

Relevance to Seizure Generation

Ketamine’s relationship with seizure activity is complex, shaped by its dose-dependent effects on neural excitability and network synchronization. At lower, subanesthetic doses, ketamine has been observed to transiently increase cortical excitability, potentially facilitating seizure-like discharges in individuals with predisposing neurological conditions. Case reports and electroencephalographic (EEG) studies have documented increased gamma oscillations and hypersynchronous cortical activity following low-dose administration, suggesting a potential proconvulsant effect. Animal models have similarly shown increased susceptibility to epileptiform activity, particularly in neocortical circuits.

Conversely, at anesthetic doses, ketamine exhibits anticonvulsant properties. Clinical studies have demonstrated its efficacy in terminating refractory status epilepticus, particularly in patients unresponsive to conventional GABAergic treatments like benzodiazepines and barbiturates. This effect is thought to stem from ketamine’s ability to suppress excessive excitatory transmission while preserving cerebral perfusion, a critical factor in prolonged seizure management. Additionally, its role in modulating neuroinflammatory pathways and reducing excitotoxic damage has been explored as a contributing mechanism to its anticonvulsant effects.