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Adverse psychiatric and

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

2012 AAN survey


1914 pts, 37 yr-old, 17yrs of epilepsy
70
60
50
40
30
20
10
0

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 episodes
Forced normalization of a symptomatic Rthemispheric epilepsy

Psychiatric / Cognitive Effect of AEDs


Psychiatric
Psychosis
Depression
Aggressive behavior
Irritability

Cognitive
- Language impairment
- Cognitive slowing

AEDs

PAE or CAE

Psychiatric use

Barbiturates

Depression, Hyperactivity,
Decreased cognition

Sedativehypnotic
withdrawal

Benzodiazepine

Decreased cognition, anterograde


Amnesia, paradoxical
aggression/disinhibition,
dependence and withdrawal

Anxiety
disorders,
Alcohol
withdrawal

Carbamazepine

Cognitive adverse effects

Bipolar disorder

Eslicarbazepine

Somnolence, fatigue; minimal


cognitive effects

Ethosuximide

Anxiety, depression, confusion,


psychosis

Felbamate

Depression, anxiety, irritability

Gabapentin

aggressive behaviors in children,


dependence and withdrawal
, delusions

Lacosamide

Cognitive effects (dose dependent);


Psychosis

Bipolar disorder

AEDs

PAE or CAE

Lamotrigine

Aggression (intellectually impaired


PWE), psychosis, delirium, decreased
cognition, agitation, hyperactivity

Levetiracetam

Irritability, emotional lability,


decreased cognition

Psychiatric use
Bipolar disorder

Oxcarbazepine Decreased cognition


Phenytoin

Decreased cognition; encephalopathy


; psychosis, adverse behavioral effects

Bipolar disorder

Pregabalin

Limited negative cognitive effects:


sedation, decreased arousal, and
decreased attention

Generalized
anxiety disorder

Retigabine

Confusion, amnesia, abnormal


thinking; somnolence, fatigue

AEDs

PAE or CAE

Rufinamide

Somnolence, fatigue, agression


; behavioral disturbances, depression

Tiagabine

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

Vigabatrin

Depression, psychosis, aggression

Zonisamide

Cognitive deficits; behavioral


disturbances, psychosis, depression,
agitation

Psychiatric use

Bipolar
disorder

Psychosis
2~3 times higher in epilepsy
anger/hostility behavior, aggressive or
agitated behavior, irritability, and
emotion liability.
Others
Aggressive behavior
Psychosis
Affective behavior

Psychosis
TPM
ZNS
LEV
PHT

PGB
Others

LTG

5/12: psychiatric symptom

Rate
ZNS

Psychosis mechanism
VDSC, TCC

EC dopamine level in
striatum and hippo

TPM

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 anhydrase


LCC: L-type calcium channel
TCC: T-type calcium channel
VDSC: voltage-dependent sodium channel
VGCC: 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

Cognition
TPM
Barbiturates
BZO
ZNS
CBZ
PHT
VPA
PGB
OXC
GBP
GVG
LTG
LEV

Rate

CAE

TPM

44%, 13% (elderly) Memory loss, language problems,


Dose/titration
psychomotor slowing
speed-related

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, motor


performance, concentration]

CBZ

Dose-related

Poorer verbal fluency, memory, complex


cognitive processing under the stress

VPA

PGB

Little effect, less than PHT, CBZ; rarely,


parkinsonism with memory loss and
psychomotor slowing (5/364); Cognitive
decline in case of intrauterine exposure
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
FA

FA

Barbiturates

Carbamazepine or Lamotrigine

no evidence for the therapeutic use of folate


supplementation

Polytherapy
With 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 depression
More in patients with HS

Depresssion
Barbiturates
BZO
TGB
GVG
FBM
LEV
TPM
ZNS
CBZ
LMT
VPA

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 disorder
Sedating

Activating

fatigue,
cognitive slowing,
weight gain

anxiogenic,
antidepressant properties

potentiation of the GABA


inhibitory neurotransmission

mediate the attenuation of


glutamate excitatory
neurotransmission

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 change
2. Seizure control

Managements
At start
When PSE
developed

Co-morbid condition should be considered


Should be alert!

Exclude the iatrogenic causes: dosage and kinds of AEDs


Consider mood stabilizing agents

Psychotherapy, Cognitive behavioral therapy

If persists

Start medication
Consultation to psychiatrists

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
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