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Adverse psychiatric and behavioral effects of antiepileptics Sun Ah Park Neurology Soonchunhyang University Bucheon Hospital

Adverse Psychiatric and Behavioral Effects of Antiepileptics - Excelente Presentacion

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  • Adverse psychiatric and behavioral effects of

    antiepilepticsSun Ah Park



    Bucheon Hospital

  • 2012 AAN survey 1914 pts, 37 yr-old, 17yrs of epilepsy


    Memory problem

    Decreased concentration


  • Quality of life (measured on a quality-of-life scale) significantly decreased if there was 1 or more seizures in the last 4 weeks.

    Depression and anxiety were increased if there was a recent seizure.

  • 81 DRE vs. 168 WCE

    Park et al., 2010

  • CASE 17 year-old girl Symptomatic focal epilepsy, daily

    seizures, for 15 years After 8 weeks, starting co-medication

    with XXX, the patient had confusion, anxiety, keep repeating same sentences, visual hallucinations, and refuse to eat or drink.

    But she had no more seizures.

  • She was treated with Levetiracetam, 3g/day Valproate 1.25 g/day Pregabalin 0.3 g/day Vigabatrin 2g/day

  • AEDs induced psychosis Psychosis in epileptic patient, not

    related to AEDs Acute confusion due to other causes

  • GVG-induced psychosis, 2.5%

    Risk factor for GVG-induced psychosis,History of psychotic episodesForced normalization of a symptomatic Rt-

    hemispheric epilepsy

  • Psychiatric Psychosis Depression Aggressive behavior Irritability

    Cognitive- Language impairment- Cognitive slowing

    Psychiatric / Cognitive Effect of AEDs

  • AEDs PAE or CAE Psychiatric useBarbiturates Depression, Hyperactivity,

    Decreased cognitionSedative-hypnotic withdrawal

    Benzodiazepine Decreased cognition, anterogradeAmnesia, paradoxical aggression/disinhibition,dependence and withdrawal

    Anxiety disorders, Alcohol withdrawal

    Carbamazepine Cognitive adverse effects Bipolar disorderEslicarbazepine Somnolence, fatigue; minimal

    cognitive effectsEthosuximide Anxiety, depression, confusion,

    psychosisBipolar disorder

    Felbamate Depression, anxiety, irritabilityGabapentin aggressive behaviors in children,

    dependence and withdrawal, delusions

    Lacosamide Cognitive effects (dose dependent); Psychosis

  • AEDs PAE or CAE Psychiatric useLamotrigine Aggression (intellectually impaired

    PWE), psychosis, delirium, decreasedcognition, agitation, hyperactivity

    Bipolar disorder

    Levetiracetam Irritability, emotional lability,decreased cognition

    Oxcarbazepine Decreased cognitionPhenytoin Decreased cognition; encephalopathy

    ; psychosis, adverse behavioral effectsBipolar disorder

    Pregabalin Limited negative cognitive effects:sedation, decreased arousal, and decreased attention

    Generalized anxiety disorder

    Retigabine Confusion, amnesia, abnormalthinking; somnolence, fatigue

  • AEDs PAE or CAE Psychiatric useRufinamide Somnolence, fatigue, agression

    ; behavioral disturbances, depressionTiagabine New-onset seizures in patients

    without epilepsy, depression Topiramate Depression, psychosis, decreased

    cognition, confusion, suicidality, psychomotor slowing

    Valproate Decreased cognition,Encephalopathy, decreased IQ secondary to fetal exposure

    Bipolar disorder

    Vigabatrin Depression, psychosis, aggressionZonisamide Cognitive deficits; behavioral

    disturbances, psychosis, depression, agitation

  • Psychosis 2~3 times higher in epilepsy anger/hostility behavior, aggressive or

    agitated behavior, irritability, and emotion liability.

    OthersAggressive behavior

    PsychosisAffective behavior




    PGB Others

  • 5/12: psychiatric symptom

  • Rate Psychosis mechanismZNS VDSC, TCC EC dopamine level in

    striatum and hippoTPM VDSC, AMPK/KA, GABA, CA,

    LCC~23.9% (Mula, 2003)

    LEV Modulation of SV2A, -inhibition of GABA and glycine-gated currents by zinc, partial inhibition of VGCC

    5/58 (discontinuation), decrease with time (20/56, 36% 1M 8/56, 14% 6M)

    CA: Carbonic anhydraseLCC: L-type calcium channelTCC: T-type calcium channelVDSC: voltage-dependent sodium channelVGCC: voltage-gated calcium channel

  • Intelligence, Previous and family psychiatric history

    Previous febrile convulsion Underlying lesion AEDs Induced (days ~ years) But, persisted or recurred despite of

    discontinuation, 20~40%

  • Forced normalization ~ Alternative psychosis Association of psychotic state with rapid

    normalization of the EEG Antagonism between epilepsy and psychosis Neurochemical changes induced by AEDs,

    GABA, Dopamine, Glutamate

  • Cognitive dysfunction Hard to compare Different seizure types Poor and variable definition of cognitive

    functions Measure cognitive scale Not including executive functions

  • TPM Barbiturates






  • Rate CAETPM 44%, 13% (elderly)

    Dose/titration speed-related

    Memory loss, language problems, psychomotor slowing

    PB Frequent Lower IQ, memory, attention, many domains

    ZNS 4~12%, 27~35%, Dose-related

    Memory loss, attention problems, verbal fluency

    PHT Dose-related Not that much; [Memory, attention, motorperformance, concentration]

    CBZ Dose-related Poorer verbal fluency, memory, complex cognitive processing under the stress

    VPA Little effect, less than PHT, CBZ; rarely, parkinsonism with memory loss and psychomotor slowing (5/364); Cognitive decline in case of intrauterine exposure

    PGB Dose-related Memory

  • Drugs lowering folic acid levels mental disturbances and mood change Role of folic acid in several important CNS

    transmethylation reactions linked to monoamine metabolism

    no evidence for the therapeutic use of folatesupplementation

    FA FA Barbiturates Carbamazepine or Lamotrigine

  • PolytherapyWith VPA, TPM, CBZ Not with LEV

    Dose-related PHT, CBZ, TPM, VPA

  • Depression Measuring depression scale Suicidal rate Mechanism Drug-induced folate deficiency Enhanced GABA transmission (?) GABA

    enhancer can be effective in depressionMore in patients with HS

  • Barbiturates BZOTGB GVG




  • Suicide ~200 placebo controlled trials of 11

    AEDs involving 44,000 patients 0.43% risk with AED vs. 0.22% risk in

    placebo, 3~5 high High, PWE with a psychiatric diagnosis, 13, anxiety and bipolar illness

    Recommended warning for all patients prescribed AEDs

  • Arana et al., NEJM, 2010

  • Arana et al., NEJM, 2010



  • **

  • Biological vulnerability History of febrile convulsion Limbic abnormality, functional

    abnormality > structural abnormality Hippocampal sclerosis TLE with HS: vulnerable to TPX related

    deression Forced normalization, Alternative

    psychosis, unknown mechanism

  • Variables related to person Type of epilepsy Temporal lobe epilepsy

    More prevalent in females Younger or older patients Longer history of epilepsy History of febrile convulsion Personal psychiatric history, underlying

    cognitive dysfunction

  • Variables related to the drug Interaction between the drug and the

    underlying brain disorderSedating Activating

    fatigue,cognitive slowing,

    weight gain

    potentiation of the GABA inhibitory neurotransmission

    anxiogenic,antidepressant properties

    mediate the attenuation of glutamate excitatoryneurotransmission

  • CASE 33-yr old man with TLE Monthly seizure TPM, LEV, PHT, PB Difficulty concentrating, failing ability to

    remember lists, wt fluctuation, poor sleep quality, easily frustrated, irritable, and took little pleasure, depressed mood on most days (but wore after a cluster of seizures)

  • Whats the psychiatric/cognitive problems?

    Depression, anxiety, cognitive dysfunction

  • What to do for him? 1. AEDs change2. Seizure control

  • Managements Co-morbid condition should be considered Should be alert!At start

    Exclude the iatrogenic causes: dosage and kinds of AEDs Consider mood stabilizing agents

    When PSE developed

    Psychotherapy, Cognitive behavioral therapy Start medication Consultation to psychiatrists

    If persists

  • Psychosis Atypical antipsychotics are preferred Relatively low rate of inducible seizure by

    antipsychotics, 0.5~1.2% Avoid rapid titration, high doses,

    clozapine, chlorpromazine, loxapine

  • Cognitive function LEV, LMT is beneficial?

  • Depression rating scale Symptom checklist-90-revised (SCL-90-R) Scale for suicide ideation-Beck (SSI-Beck)


  • Anxiety Approaches are similar to those for

    depression, SSRIs and SNRIs, paroxetine, escitalopram, venlafaxine

    Avoid long-term use of BZO

  • References Andersohn F, et al., Neurology 2010 Arana A et al., NEJM 2010 Barry JJ et al., Epilepsy Behav 2008 Continuum lifelong learning Neurol 2010;16(3) Eddy CM, et al., The Adv Neurol Dis, 2011 Kaufman KR, Epilepsy Behav 2011 Mula M, et al. Epilepsia 2007 Mula M, et al., Epilepsia 2003 Mula M, Neuropsychiatry, 2011 Noguchi, et al., Epilepsy Behav 2012

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