Levetiracetam is an oral anticonvulsant agent used as an adjunct medication to manage partial onset, myoclonic, and generalized tonic-clonic seizures in patients with epilepsy. The exact mechanism through which levetiracetam exerts its anti-epileptic effects is unclear, but is thought to be unique amongst other anti-epileptic medications. Current knowledge suggests that levetiracetam’s binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action. SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS - it appears to play a role in vesicle exocytosis and in the modulation of synaptic transmission by increasing the available number of secretory vesicles available for neurotransmission. Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release, but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of SV2A only under pathophysiological conditions. Levetiracetam can also inhibit the N-type voltage gated calcium channel in the presynaptic membrane. This prevents the influx of calcium ions into the presynaptic neurons. Calcium is also responsible for triggering the release of glutamate via exocytosis. Lower levels of calcium in the presynaptic neuron, decreases neurotransmitter release. By inhibiting the release of excitatory neurotransmitters like glutamate, the activation of excitatory receptors such a AMPA and NMDA glutamate receptors are reduced. These receptors allow the influx of cations like sodium and calcium ions into the post-synaptic cell when activated. Cation influx would ultimately lead to depolarization and excitation of the post synaptic neuron. If there is less glutamate released into the synapse, less AMPA and NMDA receptors are activated and the post synaptic neurons are less likely to become depolarized. Levetiracetam has also been shown to indirectly affect GABAergic neurotransmission (despite having no direct effect on GABAergic or glutamatergic receptors). The most common side effects of levetiracetam are neurobehavioral, like somnolence, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, the decline in cognition and increased suicide risk. Most of the time, side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations, and suicidal thoughts. These side effects are more common in the first month of treatment but can develop during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems.

Levetiracetam Pathway (New) References