Adverse psychiatric and behavioral effects of

antiepilepticsSun Ah Park

Neurology

SoonchunhyangUniversity

Bucheon Hospital

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

010203040506070

Memory problem

Decreased concentration

Fatigue

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

TPM ZNS LEV PHT

LTG

Psychosis

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

BZO

OXC GBP GVG

ZNS CBZ PHT VPA PGB

Cognition

LTG LEV

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

CBZ LMT VPA

FBMLEVTPMZNS

Depresssion

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

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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)

Depression

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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