Adverse effects of antiseizure drugs little changed over 30 years

Dr Zhibin (Ben) Chen

by Anne Crawford

An international study led by Monash University scientists has shown that tolerability to antiseizure medication (ASM) has not improved over 30 years. This was despite the advent of nearly 20 ‘second-generation’ drugs – those developed after 1980 – designed to better the earlier treatments.

Tolerability is a key determinant of the effectiveness of epilepsy treatment; greater effort to improve it was needed in ASM development, the paper urges.

The study, published recently in JAMA Neurology, tracked nearly 1800 newly diagnosed epilepsy patients prescribed their first ASMs at a specialist epilepsy clinic in Glasgow between July 1982 and October 2012. They were followed up until April 2016 or death.

Dr Zhibin (Ben) Chen from the Central Clinical School’s Department of Neuroscience said no systematic review of the overall effects of the newer drugs in a real-world clinical setting had previously been conducted.

The researchers recorded the adverse effects associated with various antiseizure medications including depression, other psychiatric symptoms, neurocognitive changes, nausea and other gastrointestinal tract problems, and idiosyncratic reactions such as skin rashes.

These were compared between three epochs (July 1982-June 1992, July 1992-June 2002, and July 2002-April 2016). The study found that despite differences in intolerable adverse effect rates and in the types of adverse effects between the medications, that there was no difference in the overall adverse effects rates to the initial treatment across the three epochs.

Nearly one in six ASMs prescribed was discontinued because of intolerable AEs, often at low doses. The AE rates for the first- and second-generation ASMs were not significantly different, Dr Chen said.

“Despite the increased use of many second-generation drugs, the overall tolerability of drug treatment has not improved in the past 30 years, though some individual second-generation drugs may have better tolerability,” he said.

The second-generation ASMs did, however, have some important advantages over their older counterparts and in general provided more options for treating people with epilepsy.

“They expand our arsenal against the disease,” Dr Chen said.

The second-generation ASMs were less likely to cause interactions with other drugs; had lower risk for long-term complications (including osteoporosis, sexual dysfunction, and vascular disease); were generally safer; and some of the newer ASMs were safer for women of childbearing potential.

The paper complemented an earlier study this year by Monash University researchers that found that despite the increased use of anti-epileptic medications long-term seizure control – the main measure of efficacy – had not fundamentally improved over 30 years either.

“We believed it was important to look at whether the efficacy of these drugs had improved over 30 years,” Dr Chen said. “It was quite surprising and disappointing – we found there was no overall improvement in the treatment of epilepsy,” he said.

“Effectiveness is determined not only by efficacy, but also safety and tolerability, which have rarely been specifically studied. So this study assessed overall tolerability of antiseizure medications with the aim of completing the story of overall effectiveness of antiseizure medication over the past 30 years.”

First author on the tolerability study was Dr Alsfouk from the University of Glasgow, Glasgow, Scotland.

Alsfouk BAA, Brodie MJ, Walters M, Kwan P, Chen Z. Tolerability of Antiseizure Medications in Individuals With Newly Diagnosed Epilepsy. JAMA Neurol. 2020 Feb 24. doi: 10.1001/jamaneurol.2020.0032.