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Keppra rage

• Mechanism unknown
• The other SV2A modulator (brivaracetam) does not cause prominent irritability
• Pyridoxine hypothesis: levetiracetam may interfere with vitamin B6 metabolism → ↓ GABA synthesis → ↓ inhibitory tone

What Keppra rage is

Irritability, anger, aggression and mood change on levetiracetam

• Irritability, hostility, aggression, anxiety and depression — the most common reason levetiracetam is stopped [3]
• About one patient in seven; largely independent of dose [2][3]
• More likely with a prior psychiatric history, intellectual disability or fast titration [3][4]
• Usually appears in the first weeks and reverses on withdrawal [3]

How common — the numbers

Levetiracetam vs brivaracetam, the same target

• Pooled data: aggression 4.2% vs 1.2%, irritability 6.2% vs 2.5%, nervousness 3.2% vs 0.7% (levetiracetam vs brivaracetam) [2]
• Epi2020 (486 adults): levetiracetam correlated with aggression, nervousness, restlessness and depression on the Liverpool Adverse Events Profile; brivaracetam correlated negatively with all of them [1]
• Mean adverse-event score 41.9 on levetiracetam vs 35.9 on brivaracetam [1]
• Switching to brivaracetam resolves the behavioral effects in roughly two thirds [4]

Mechanism unknown

Even the antiseizure mechanism is not fully characterized [12]

• Levetiracetam’s target is SV2A, a synaptic-vesicle protein involved in calcium-dependent transmitter release; binding damps epileptiform bursting without changing normal excitability [12]
• SV2A sits on GABA and glutamate terminals alike — the same action that stops seizures can shift the excitatory–inhibitory balance in limbic and prefrontal circuits that govern mood and impulse control [3][13]
• No single validated mechanism explains the behavioral effect; three hypotheses follow

Hypothesis 1 — SV2A engagement in normal brain

Where the drug binds may matter as much as what it binds

• SV2A is expressed throughout the brain, not only at the seizure focus [13]
• In glioma patients, tumors with LOW SV2A expression left more drug to bind normal peritumoral brain — and neuropsychiatric adverse events were far more frequent; high tumoral SV2A appeared protective [6]
• Consistent with the behavioral effect arising from SV2A engagement in healthy limbic and cortical circuitry [6]

Hypothesis 2 — off-target AMPA modulation

Levetiracetam does more than bind SV2A

• Levetiracetam also negatively modulates postsynaptic AMPA glutamate receptors, opposes negative modulators of GABA and glycine currents, and partially inhibits N-type calcium channels [3][12]
• The leading synthesis: SV2A binding plus this GABA/glutamate modulation is what raises aggression above other antiseizure drugs [3]
• Perampanel, a selective AMPA antagonist, also causes aggression — support for glutamate modulation as the culprit, though the region- and dose-dependence is complex [1][3]

The brivaracetam contrast

The most informative single piece of evidence

• Brivaracetam binds SV2A 15–30× more tightly than levetiracetam and lacks the AMPA action [3][13]
• If SV2A occupancy alone drove aggression, the higher-affinity drug should be worse; it is gentler — pointing at the non-SV2A actions [3]
• Rat model: levetiracetam-treated animals attacked twice as fast and showed five times more aggressive behaviors than controls; brivaracetam-treated animals behaved like saline [5]
• Indirect meta-analytic comparisons have not reached significance, so the difference is consistent rather than proven [2]

Hypothesis 3 — pyridoxine (vitamin B6)

Less cofactor, less GABA?

• Pyridoxal-5-phosphate is the cofactor of glutamic acid decarboxylase, the enzyme that makes GABA [7][8]
• Proposed: levetiracetam interferes with pyridoxine metabolism → ↓ GABA synthesis → ↓ inhibitory tone → irritability [7][8]
• Retrospective series: about 72% improved on adjunctive pyridoxine [7]
• The randomized trials missed their primary between-group endpoints, with secondary analyses favoring pyridoxine [9][10][11]
• Biologically plausible; unproven

What to do about it

Practical handling

• Screen for psychiatric history before starting; warn the patient and family what to watch for [3]
• Titrate slowly; behavioral effects are largely dose-independent, so dose reduction helps less than expected [2][3]
• Adjunctive pyridoxine is low-risk with mixed evidence [8]
• Switching to brivaracetam is the intervention with the best evidence and can be done overnight [1][4]

Behavioral side effects across antiseizure drugs

Epi2020 adverse-event profiles [1] and the class review [3]

• Perampanel (AMPA antagonist): the least tolerated — aggression, nervousness and the highest overall adverse-event burden; the only independent drug predictor of a poor profile [1][3]
• Levetiracetam: aggression, nervousness, restlessness, depression [1]
• Topiramate and zonisamide: concentration and memory problems, word-finding difficulty, depression; psychosis rarely [1][3]
• Phenobarbital and primidone: depression; hyperactivity in children [3]
• Benzodiazepines: disinhibition and paradoxical agitation, mostly in children and the elderly [3]
• Valproate: tremor, hair loss, weight gain — but mood-stabilizing, not behaviorally toxic [1]
• Lamotrigine, lacosamide, carbamazepine, oxcarbazepine and brivaracetam: favorable behavioral profiles (lamotrigine: concentration and skin; carbamazepine family: memory) [1]

References

Numbered as cited on the slides

• [1] Willems LM, et al. Adverse event profiles of antiseizure medications and the impact of coadministration on drug tolerability in adults with epilepsy (Epi2020). CNS Drugs 2023;37:531–544
• [2] Fröling E, et al. Reassessing the adverse event profiles of levetiracetam and brivaracetam: a systematic review and meta-analysis. J Neurol 2026
• [3] Lyndon S, Dworetzky BA, Baslet G. Psychiatric and behavioural side effects of antiseizure medications in epilepsy. J Neurol 2025
• [4] Watkins LV, et al. Rapid switching from levetiracetam to brivaracetam in pharmaco-resistant epilepsy: a naturalistic case control study. J Neurol 2023
• [5] Sanon NT, et al. Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model. Epilepsy Behav 2018
• [6] Romoli M, et al. Synaptic vesicle protein 2A tumoral expression predicts levetiracetam adverse events. J Neurol 2019
• [7] Romoli M, Perucca E, Sen A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: a systematic review. Epilepsy Behav 2020
• [8] Besag FMC, Vasey MJ, Sen A. Current evidence for adjunct pyridoxine (vitamin B6) for the treatment of behavioral adverse effects associated with levetiracetam: a systematic review. Epilepsy Behav 2023
• [9] Mahmoud A, et al. Amelioration of levetiracetam-induced behavioral side effects by pyridoxine: a randomized double-blind controlled study. Pediatr Neurol 2021
• [10] Cheraghmakani H, et al. Pyridoxine for treatment of levetiracetam-induced behavioral adverse events: a randomized double-blind placebo-controlled trial. Epilepsy Behav 2022
• [11] Thananowan P, et al. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events in pediatric and adolescent epilepsy: a prospective, double-blind, randomized, placebo-controlled trial. Epilepsy Behav 2025
• [12] Levetiracetam prescribing information (DailyMed): the mechanism of the antiepileptic effect is unknown
• [13] Strzelczyk A, Schubert-Bast S. Psychobehavioural and cognitive adverse events of anti-seizure medications for the treatment of developmental and epileptic encephalopathies. CNS Drugs 2022

Drugs with this mechanism (1)

• Levetiracetam — Widely used, kinetically clean anticonvulsant; irritability and mood effects common.

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