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3/3/2014
TheBehavioral
Effectsof
AntiepilepticDrugs
Jim Thigpen, PharmD, BCPS
Assistant Professor, Department of Pharmacy Practice
ETSU Bill Gatton College of Pharmacy
Disclosure Statement of
Financial Interest
• I, Jim Thigpen
DO NOT have a financial
interest/arrangement or affiliation with
one or more organizations that could
be perceived as a real or apparent
conflict of interest in the context of the
subject of this presentation.
Notanewissue
• In May, 1978, an article was published in Pediatrics describing a study of 109 children treated with phenobarbital as a prophylaxis against febrile seizures
• 42% of the children developed “hyperactivity”
• 54% of those had the medication stopped prematurely
• Behavior was not correlated to elevated serum levels
Wolf SW, Forsyth A. Pediatrics 1978;61:728‐731.
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Really,averyold issue
• Triple bromides, the first antiepileptic drug of the modern era (introduced in 1857), was associated with “bromism”, a dose‐dependent psychiatric side effect that included disinhibition, irritability or emotional lability, depression, psychotic behavior, hallucinations, and violence
Glauser TA. Epilepsy & Behavior 2004;5:S25‐S32.
LearningOutcomes
• Describe the reported behavioral effects caused by antiepileptic drugs (AEDs)
• Discuss the proposed causes of these behavioral effects of the AEDs
• Discuss the importance of communicating these behavioral effects to patients and caregivers
Notaneasytask
• Determining the actual incidence of AED psychiatric and behavioral side effects is complicated
• Methodological difficulties between studies make comparison complicated
• The era in which the drug was approved • Phenobarbital vs carbamazepine vs vigabatrin
• Clinical trial data for monotherapy vs adjunctive therapy
• Patient selection bias
• Data analysis is frequently qualitative • Type I and type II errors can occur
• Behavior may be related to the disease, not the meds
Glauser TA. Epilepsy & Behavior 2004;5:S25‐S32.
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VarioususesofAEDs
• Epilepsy
• Pain syndromes
• Weight loss
• Psychiatric conditions
AEDsandEpilepsy
• Older medications are cheaper and come with long‐term experience, but can exhibit greater toxicity
• Newer drugs are overall better tolerated but still have side effects, often behavioral
• Expected ADEs (somnolence, nausea and dizziness) are well communicated to patients, BSEs are often overlooked
• Effective treatment depends on medication adherence across a lifetime
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375.
“AEDsandADEs”
• All effective anticonvulsants produce unwanted effects
• Toxicity
• Nystagmus from toxic phenytoin levels
• Side effects
• Somnolence from phenobarbital
• Idiosyncratic reactions
• Rash from lamotrigine
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PharmacologyofAEDs
• Blockage of voltage‐gated Na+ and Ca2+ ion channels
• Enhancement of gamma‐aminobutyric acid (GABA)‐ergic neurotransmission
• Inhibition of glutamanergic neurotransmission
• Modulation of synaptic vesicle proteins
• Modulation of K+ ion channels
• Modulation of carbonic anhydrase
Pharmacology&Behavior
• Sodium‐channel blockers
• Delay recovery of the channels from their fast‐
inactivated state, limiting the burst firing of neurons
• Increase the number of channels in their slow‐
inactivated state, decreasing their availability for propagation
• Na+ transport and homeostasis likely influence mood and behavior
Pharmacology&Behavior
Sodium‐channel blockers
Carbamazepine
Ethotoin
Phenytoin
Primidone
Lacosamide
Lamotrigine
Oxcarbazepine
Topiramate
Rufinamide
Zonisamide
Valproic acid
Felbamate
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Pharmacology&Behavior
• Calcium‐channel blockers
• Inhibition of low voltage‐activated T‐type Ca2+
channels (implicated in absence seizures)
• Inhibition of high voltage‐activated Ca2+ channels (L‐ R‐
, P/Q‐, and N‐types), involved in neurotransmitter release
• Ca2+ homeostasis is important for mood and behavior
• Genetic variations in L‐type (bipolar, depression, schizophrenia)
• Some antidepressants inhibit Ca2+ channel activity
Pharmacology&Behavior
Calcium‐channel blockers
Ethosuximide
Valproic acid
Lamotrigine
Zonisamide
Carbamazepine
Felbamate
Phenobarbital
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Topiramate
Zonisamide
Phenytoin
Pharmacology&Behavior
• GABA‐ergic neurotransmission enhancement
• Modulating GABAA receptors
• Increasing GABA levels in synaptic cleft
• GABA‐ergic synapse dysfunction may contribute to aggressive behavior and schizophrenia
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Pharmacology&Behavior
GABA‐ergic Neurotransmission
Phenobarbital/Primidone
Clobazam
Clonazepam
Tiagabine
Vigabatrin
Valproic acid
Felbamate
Topiramate
Lamotrigine
Zonisamide
Pharmacology&Behavior
• Inhibition of inotropic glutamate receptors
• Alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid/kainate antagonism
• N‐methyl‐D‐aspartate inhibition
• Aberrant regulation of glutamanergic synapses may contribute to schizophrenia and possibly mood disorders Pharmacology&Behavior
Inhibition of glutamate receptors
Phenobarbital
Lamotrigine
Topiramate
Perampanel
Carbamazepine
Felbamate
Valproic acid
Lamotrigine
Oxcarbazepine
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Otherpotentialreasons…
• Forced normalization (a.k.a. alternative psychosis)
• First described in 1953 when it was observed that EEG paradoxically normalized and seizure activity was inhibited during psychotic episodes
• Forced normalization is most commonly associated with psychosis, but hypomania/mania, depression, and anxiety also have been described • Release phenomenon
• AEDs may cause BSEs simply by suppressing seizure activity, allowing the undesired behavior to manifest
• Drug interactions
• an increase in side effects may lead to frustration and an increase in undesirable behavior (especially in disabled patients)
Besag FMC. Expert Opin. Drug Saf. 2004;3(1):1‐8
Otherpotentialreasons…
• Individual patient characteristics and individual susceptibility
• Age
• Epilepsy type
• Learning disabilities
• Comorbid psychiatric history
• Dosage, titration rate
Besag FMC. Expert Opin. Drug Saf. 2004;3(1):1‐8
Phenobarbital & Primidone (Mysoline®)
• Discovered in 1911 and initially used as a hypnotic
• Remains the most widely prescribed AED in the world
• The last published RCT ceased patient recruitment in 1987 and was published in 1996
• An updated study would be useful
• Phenobarbital’s reputation is that of an old drug that has too many side effects
• Cognitive side effects, especially in young children
• Hyperactivity is reported as high as 42%
Kwan P, Brodie MJ. Epilepsia, 2004;45(9):1141‐1149.
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Phenytoin (Dilantin®)
• Synthesized in 1908, discovered AED properties in 1938
• Very few behavioral effects
• Can be used to treat aggressive behavior • Psychosis has been reported with toxic levels
Kwan P, Brodie MJ. Epilepsia, 2004;45(9):1141‐1149.
Ethotoin (Peganone®)
• Initially marketed in 1957, patent bought from Abbott Labs in 2003, reintroduced to U.S. market
• MOA same as phenytoin, not as effective overall
• Lacks the cosmetic adverse effects of phenytoin
• Very few behavioral effects
Minck DR, Acuff‐Smith KD, et al. Teraology 1991;43(4):279‐93.
Package Insert – Peganone, Recordati Rare Diseases, Lebanon, NJ.
Valproic Acid (Depakene®, Depakote®)
• Discovered in 1882 and until 1962, was used as a “metabolically inert” solvent for organic compounds
• Anticonvulsant activity was discovered by accident
• Hostility (12%), Personality change (11%), Hyperactivity (10%), attentional difficulties (7%)
• Minor behavioral changes that typically do not persist
• Can be used to treat aggressive behavior
Lens RA, Elterman RD, et al. Pediatric Neurology 2009;41:101‐110
Glauser TA, Cnaan A, et al. N Engl J Med 2010;362:790‐9.
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Carbamazepine (Tegretol®)
• Very well studied, yet mixed results
• BAEs are infrequent compared to some AEDs
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Aggression
Irritability
Depression
Neurosis
Psychosis
• Behavioral issues are more likely to arise in a patient with underlying mental challenges
• Carbamazepine is used to treat bipolar disorder and may improve symptoms in other psychiatric issues
Friedman DL, Kastner T, et al. Am J Ment Retard 1992;96(5):541‐546
Oxcarbazepine (Trileptal®)
• Very similar to carbamazepine in side effect profile
• Is usually seen as a “mood‐leveling” drug
Besag FMC. Expert Opin Drug Saf 2004;3(1):1‐8.
Tiagabine (Gabitril®)
• In a larger (292 patients) study, serious adverse effects were reported in 19 (8%) of patients, of which 12 (63%) were behavioral‐related. • Anxiety, labile mood, paranoia, hallucinations and “unspecified psychiatric effects” were reported
• Eight out of 12 had a pre‐existing psychiatric or developmental delay
Vossler DG, Morris GL et al. Epilepsy & Behavior 2013;28:211‐216
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Vigabatrin (Sabril®)
• Well studied since 1990 (15 studies on BSEs)
• Agitation, aggression, mood changes/depression, and irritability were most common, ranging from 7 – 23%
• Psychosis was reported in 7%, also reported after improvement in seizure control (forced normalization)
• Much higher incidence in patients with a prior history
• Psychosis more often seen with a right‐sided EEG focus
• Some patients reported an improvement in mood and adjustment
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375
Clobazam (Onfi®)
• BAEs include severe aggressive outbursts, insomnia and depression (seen in children with epilepsy and developmental delay)
• Younger children (mean age 6.4 years) report more aggressive agitation, self‐injurious behavior and hyperactivity (also seen more in children who were developmentally disabled)
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375
Levetiracetam (Keppra®)
• Of 1393 patients who took LEV in all clinical trials, including placebo‐
controlled and open‐label trials, 25.4% experienced some affective symptoms
• More often seen in patients being treated for generalized epilepsy
• BAEs have been reported in up to 34% of children/adolescents
• Irritability, aggression and hyperactivity are most common
• Aggression can be severe in up to 27% of cases
• 16% stopped taking the medication due to behavioral problems
• BAEs also can occur in up to 25% of adults
• 2/3 discontinue the drug due to BAEs
• Aggression more often seen in elderly patients
• Effects are more often seen in patients with poorer seizure control, learning disability, mental retardation, or previous behavioral problems
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375
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Topiramate (Topamax®)
• Multiple mechanisms of action (Ca2+, Na+, GABA, carbonic anhydrase inhibition)
• In one study of 431 patients, psychiatric adverse events occurred in 23.9% (affective disorder, psychosis, aggression, agitation, anxiety)
• Psychosis reported as high as 12%, where it has been 0.8% in clinical trials
• Affective disorder (10.7%), aggressive behavior (5.6%), anger/hostility and anxiety have also been reported
• Some patients were reported to be seizure free just prior to symptom appearance
• High starting dose and rapid titration schedule were more likely to lead to adverse events
• Patient or family psychiatric history increases the likelihood
• May be more likely in older adults Mula M, Trimble MR, et al. Epilepsia 2003;44(5):659‐663.
Crawford P. Seizure 1998;7(3):207‐211
Khan A, Faught E, et al. Seizure 1999;8(4):235‐237
Zonisamide (Zonegran®)
• Multiple mechanisms of action similar to topiramate
• Does not cause cognitive side effects as much as topiramate
• Agitation and irritability are more frequently reported
• 9% reported in pooled data
• 6% depression
• 2% psychosis reported
• Overall AED‐attributed BSEs nearly 10%
• Treatment of bipolar disorder?
• Mixed results
Besag FMC. Expert Opin Drug Saf 2004;3(1):1‐8.
Lamotrigine (Lamictal®)
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Hyperactivity in 7%
Hostility in 7%
Personality change in 6%
Depression in 1%
• Aggression, self‐injurious behaviors, violence, insomnia and hallucinations have been seen in case reports
• Much more often seen in patients with learning disabilities
• Behavior improvement
• Positive effects on alertness, attention, and learning
• Reduced lethargy and depression, improved social functioning
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375
Glauser TA, Cnaan A, et al. N Engl J Med 2010;362‐790‐9
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Gabapentin (Neurontin®)
• In an unblinded study of 377 patients with partial epilepsy
• Confusion/disorientation was seen in 15%
• Anxiety/agitation 11%
• History of ADHD may increase risk
• Depression 10%
• More often reported in LD patients
• Case reports of aggression
Marson AG, Al‐Kharusi et al. Lancet 2007;269:1000‐1015.
Pinninti NR, Mahajan DS. J Neuropsychiatry Clin Neurosci 2001;13(3):424.
Tallain KB, Nahata MC, et al. Epilepsia 1996;37(suppl):501‐502
Pregabalin (Lyrica®)
• Think pain, not epilepsy
• Most often associated with dizziness, vertigo, incoordination, ataxia, tremor, diplopia, and blurred vision
• Mainly dose‐related
• Low incidence of euphoria (hence the C‐V status), confusion, fatigue, and attention disturbances
Zaccara G, Gangemi P, et al. Epilepsia 2011;52(4):826‐836.
Toth C. Expert Opin Drug Saf 2012;11(3):487‐502.
Lacosamide (Vimpat®)
• Most adverse reactions with lacosamide are dose‐related CNS effects (dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision)
• Being investigated for use in diabetic neuropathy
Marson AG, Al‐Kharusi et al. Lancet 2007;269:1000‐1015.
Shaibani A, Biton V, et al. European J Pain 2009;13:458‐463.
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Felbamate (Felbatol®)
• Case reports of psychosis and anxiety
• Use is restricted due to aplastic anemia and severe hepatotoxicity
• Compassionate use only
Cavanna AE, Ali F, et al. Discov Med 2010;9(45):138‐44.
Ethosuximide (Zarontin®)
• Case reports of psychosis
• Hyperactivity (9%), somnolence (9%), attention difficulties (4%), and hostility, personality change, depression (3%)
Chien J. Epilepsy & Behavior 2011;21:483‐485.
Glauser TA, Cnaan A, et al. N Engl J Med 2010;362:790‐9.
Rufinamide (Banzel®)
• A triazole derivative that is unrelated to all other AEDs
• Indicated for refractory Lennox‐Gastaut syndrome
• Efficacy in partial seizures
• Side effects consist mainly of headache, dizziness, fatigue, somnolence and nausea
Aneja S, Sharma S. Indian Pediatrics 2013;50:1033‐1040
Stafstrom CE. Neoropsych Dis Treatm 2009;5:547‐551.
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Perampenel (Fycompa®)
• Just launched in January 2014
• Most well‐known for black box warning for severe psychiatric and behavioral reactions including
• aggression & hostility seen in 8 – 20%
• irritability & anger in 2%
• homicidal ideation and threats in 0.1%
• Adverse effects are dose‐related
Serratosa JM, Villanueva V et al. Acta Neurol Scand 2013;127:30‐35.
Fycompa® package insert. Eisai Inc. www.FYCOMPA.com
Doyouhaveahistory?
• A past psychiatric history is the most significant non‐AED predictor of BSEs, occurring in nearly 25% of patients compared to 12% of those without
www.renewaldynamics.com
Eddy CM, Rickards HE, et al. J Clin Psychopharmacol 2012;32:362‐375
Givemeashortlist
• Absolutely discuss
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Levetiracetam
Topiramate
Tiagabine
Vigabatrin
Clobazam
Ethosuximide
Perampanel
• Worth mentioning
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Phenobarbital
Valproic acid
Zonisamide
Lamotrigine
Gabapentin
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HighPoints
• BAEs are difficult to pin down in clinical trials
• Selection bias • Adjunctive drug
• More common in patient population
• Other potential causes
• Forced normalization
• Reduce the incidence by going low and slow
• Essentially all drugs in the class can cause BAEs
• Remember the short list
• Very important to expect in a patient with a history
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