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Cognitive and fatigue side effects of anti-epileptic drugs: an analysis of phase III add-on trials

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Abstract

We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti-epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of develo** the side effects was calculated for each drug load, and the presence of a dose–response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Kee** in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability.

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Acknowledgements

This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

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Authors and Affiliations

  1. Division of Epilepsy and EEG, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road - 4036, Boston, MA, 02115, USA

    Rani A. Sarkis, Yazel Goksen & Jong Woo Lee

  2. Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Yi Mu & Bernard Rosner

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  1. Rani A. Sarkis
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  2. Yazel Goksen
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  3. Yi Mu
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  4. Bernard Rosner
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  5. Jong Woo Lee
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Correspondence to Rani A. Sarkis.

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Conflicts of interest

This study was investigator initiated and no sponsors were involved. Dr. Sarkis reports the following disclosures: has received research support from Biogen, Empatica SRL, UCB Pharma and he has received compensation for activities with DigiTrace/SleepMed. Dr. Lee reports the following disclosures: he reads EEGs in his clinical practice (25% effort) and bills for this, performs contract work with SleepMed/DigiTrace and Advance Medical, and has received funding from the NIH (NINDS R03NS091864 02, PI, 2015–2018).

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This article does not contain any studies with human participants performed by any of the authors.

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Sarkis, R.A., Goksen, Y., Mu, Y. et al. Cognitive and fatigue side effects of anti-epileptic drugs: an analysis of phase III add-on trials. J Neurol 265, 2137–2142 (2018). https://doi.org/10.1007/s00415-018-8971-z

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  • DOI: https://doi.org/10.1007/s00415-018-8971-z

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