Levetiracetam - Part 2

In the second part of this series, Dr. Neishay Ayub discusses levetiracetam and one of its most common side effects, irritability. 

Show citations: 

Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat. 2008;4(3):507-523. doi:10.2147/ndt.s2937 

Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs. 2016;30(11):1055-1077. doi:10.1007/s40263-016-0384-x

Rogawski MA. Brivaracetam: a rational drug discovery success story. Br J Pharmacol. 2008;154(8):1555-1557. doi:10.1038/bjp.2008.221

Ulloa CM, Towfigh A, Safdieh J. Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. Neuropsychiatr Dis Treat. 2009;5:467-476. doi:10.2147/ndt.s4844

Wu PP, Cao BR, Tian FY, Gao ZB. Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neurosci Bull. 2024;40(5):594-608. doi:10.1007/s12264-023-01138-2

Mahmoud A, Tabassum S, Al Enazi S, et al. Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study. Pediatr Neurol. 2021;119:15-21. doi:10.1016/j.pediatrneurol.2021.02.010

Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557-559. doi:10.1016/j.yebeh.2008.07.004

Romoli M, Perucca E, Sen A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: A systematic review. Epilepsy Behav. 2020;103(Pt A):106861. doi:10.1016/j.yebeh.2019.106861

Show transcript: 

Dr. Neishay Ayub:

Hello, my name is Neishay Ayub, and today we will be discussing levetiracetam and one of its most common side effects, irritability. While levetiracetam can be remarkably helpful for patients, behavioral adverse effects were noted in post-marketing analysis and open-label studies in adult and pediatric patients. For this, physicians started using vitamin B6 supplementation, particularly in the pediatric populations. Why would physicians use B6? Well, low vitamin B6 has been associated with neuropsychiatric disorders, which could be related to the fact that vitamin B6 is an essential co-factor for several neurotransmitters that affect mood and behavior, such as serotonin, dopamine, and GABA. There is an epilepsy syndrome associated with vitamin B6 deficiency. And vitamin B6 deficiency is seen with enzyme-inducing anti-seizure medications, although levetiracetam is not an enzyme-inducing seizure medication.

These are some of the possibilities as to why vitamin B6 supplementation was initially explored. Some initial anecdotal evidence and case reports were suggested that it was helpful in reducing behavioral side effects and the need to discontinue levetiracetam. There was a meta-analysis reviewing pyridoxine use, which included 11 case reports and retrospective studies, as well as one prospective study, case-control study, which was not placebo controlled. While evidence was suggestive of a benefit, the quality of the evidence was poor due to selection, reporting, and assessment biases. Overall, the authors recommended a larger randomized, controlled, double-blind trial with adequate statistical power, well-defined eligibility criteria and standardized assessment tools to evaluate B6 efficacy in treating levetiracetam-induced irritability.

Since then, there was one small randomized, controlled, double-blind study involving 105 children for whom neuropsychiatric adverse effects were noted after levetiracetam was introduced. Children were randomized to receive a therapeutic dose of pyridoxine, which was 10 to 15 milligrams per kilogram per day, up to 200 milligrams, or a homeopathic dose of 0.5 milligrams per kilogram per day. They were scored on a behavioral checklist and monitored for up to six months. While there was a reduction in behavioral symptoms reported in the therapeutic pyridoxine group, there was no validated assessment tools used, and there was an absence of a true placebo group.

Lastly, there are a few studies reporting on adverse effects of B6 toxicity, which is possible, but it's typically seen at higher daily doses, although something to keep in mind if considering B6 supplementation.

In summary, while there has been a clinical practice of prescribing pyridoxine at 50 to 100 milligrams as a low-cost, well-tolerated adjunctive supplement, there may be a modest benefit for some patients, but the overall efficacy for the treatment of neuropsychiatric side effects for levetiracetam remain unclear, and more evidence is needed.