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    Home > Active Ingredient News > Study of Nervous System > JAMA Neurology: Does new anti-epileptic drugs increase the risk of suicide in patients?

    JAMA Neurology: Does new anti-epileptic drugs increase the risk of suicide in patients?

    • Last Update: 2021-09-11
    • Source: Internet
    • Author: User
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    In 2008, the US Food and Drug Administration Bureau ( the FDA ) issued an alert, said the anti- epileptic drugs (ASMs) will increase the suicide rate, which is based on 199 randomized placebo-controlled clinical trial meta-analysis, including 11 kinds of ASMs: Card Mazepine, febramide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, sodium valproate, and zonisamide
    .
    Among 43,892 patients treated for epilepsy (31% of the trial), mental illness (28%), and other diseases (mainly pain, 41%), the suicide rate of ASMs increased by 1.
    80 times compared with placebo
    .
    Among patients with epilepsy, the suicide rate with ASM treatment is 3.
    3%, while the suicide rate with placebo is 1.
    2%, and the risk difference is 2.
    1%
    .
    The U.
    S.
    Food and Drug Administration Advisory Committee concluded that all ASMs “constitute an increased risk of suicide (defined as suicidal ideation and behavior), and prescriptions should be accompanied by patient medication guidelines describing this risk
    .
    " Subsequent approved ASMs were A suicide warning is required
    .

    Manage FDA epilepsy


    The US FDA’s recommendations have greatly affected the prescription and development of the new ASM, and suicide is prominently listed in the ASM-related adverse events
    .
    Mandatory suicide warnings may affect patients’ willingness to take ASM and may reduce compliance.
    This is a major driver of epilepsy recurrence and is associated with an increased risk of injury and death
    .
    This also affected the design of ASM research trials
    .


    This is a major driver of epilepsy recurrence and is associated with an increased risk of injury and death
    .
    This also affected the design of ASM research trials
    .


    These recommendations have methodological limitations, including (1) heterogeneity and retrospective collection of suicide data, no standardized suicide definition; (2) no pre-specified outcome measures for post-event analysis
    .
    (3) All ASMs are classified into one category, although their risks are different, including 7 out of 11 drugs that have statistically insignificant increases, and 2 out of 11 drugs are statistically insignificant (4) Combining trials of monotherapy and adjuvant therapy; (5) Trials of different disease indications have different suicide risks; and (6) The baseline suicide risk is not considered, which may be in different studies and diseases.
    It is different from the medicine
    .



    Compared with the general population, patients with epilepsy have an increased rate of depression and suicide, especially in patients with uncontrolled seizures
    .
    These warnings indicate additional risks that can be attributed to the treatment itself
    .
    Since 2008, the FDA has approved 10 new molecular ASMs: Lakosam (2010), Retigabine/Esgabine (2011), Clobazam (2011), Penem (2012) Years), escarbazepine (2013), brivaracetam (2016), everolimus (2016), cannabidiol/Epidiolex (Greenwich Biosciences; 2018), senobamide (2019) Year) and fenfluramine (2020)
    .
    Stiripentol's approval in 2018 was based on early European data
    .


    In addition, new formulations of midazolam and diazepam (Nayzilam [UCB] and Valtoco [Neurelis] in the nasal cavity) have also been approved
    .
    The US FDA stipulates that all new drugs except one new drug must have a suicide warning, but none of them were part of the 2008 study
    .
    Suicide warnings rank first in the warnings and precautions section of the prescription information for Lakosam, Pirapani, Eslicarbazepine, and Brivaracetam , although there is no evidence to support it
    .

    prevention

    Since 2008, the pivotal ASM epilepsy trial has prospectively assessed suicide, and since 2011, it has included a valid Columbia Suicide Severity Scale (C-SSRS)
    .

    In this way, Pavel Klein of New York University and others reviewed all randomized, placebo-controlled phase 2 and phase 3 studies of new ASMs to compare the suicide rate of patients treated with ASMs and placebo to determine whether these drugs Related to an increased risk of suicide
    .
    They limited their analysis to epilepsy studies to avoid potential confounding factors, such as possible differences in suicide risk between different diseases
    .

    They limited their analysis to epilepsy studies to avoid potential confounding factors, such as possible differences in suicide risk between different diseases
    .

    They excluded studies that did not evaluate suicide (everolimus and fenfluramine) or studies that did not evaluate it prospectively (lakosam, isogabine, and clobazam)
    .
    And analyzed 5 kinds of drugs: escarbazepine, pirapani, brivaracetam, cannabidiol and senobamut
    .

    Suicidalism was evaluated in 17 randomized clinical trials of these drugs, involving 5996 patients, of which 4000 patients were treated with ASMs and 1996 patients were treated with placebo
    .

    There is no evidence of the overall risk of suicidal ideation (total hazard ratio of drug to placebo, 0.
    75; 95% CI, 0.
    35-1.
    60) or suicide attempt (hazard ratio, 0.
    75; 95% CI, 0.
    30-1.
    87) or the overall risk of any individual drug The risk increases
    .

    Among the 4000 patients treated with ASMs, 12 had suicidal ideation (0.
    30%), and among the 1996 patients treated with placebo, 7 had suicidal ideation (0.
    35%) (P=0.
    74)
    .
    Three patients who received ASMs and those who did not receive placebo attempted suicide (P = .
    22)
    .
    Unfinished suicide
    .

    The important significance of this meta-analysis lies in the discovery: There is currently no evidence that the five ASMs evaluated in this study increase the suicidality of patients with epilepsy and are worthy of issuing a suicide grade warning
    .

    There is currently no evidence that the five ASMs evaluated in this study increase the suicidal behavior of patients with epilepsy and are worthy of issuing a suicide grade warning
    .


    Original source:
    Klein P, Devinsky O, French J, et al.
    Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis.
    JAMA Neurol.
    Published online August 2, 2021.
    doi:10.
    1001/jamaneurol.
    2021.
    2480



    JAMA

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