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Antiepileptic DrugsLessons from Psychiatry
Dr. Ennapadam.S. KrishnamoorthyMD., DCN, PhD (Lond), FRCP (Lond, Glas, Edin), MAMS (India)
Founder Director
TRIMED I NEUROKRISH
www.trimedtherapy.com I www.neurokrish.com
In this lecture
• AED’s: Looking Beyond Epilepsy- Their Relevance & Utility in Neuropsychiatry
• Parodoxical relationships: seizures, behavior and AEDs
• What relevance do these findings hold for epilepsy
How do psychiatric uses of AED’s emerge?
• Inadequate efficacy of conventional psychotropic agents in certain psychiatric disorders
• Established clinical relationships between epilepsy and behavioural disorder- convergence of neurochemistry as underlying biological substrate
• History of thymoleptic role for AED’s from the phenytoin generation
• Alternative and viable uses for novel drug- broader scope and market profile without enhancement of cost
• Recently- many examples of greater efficacy as non-AED
Bipolar DisordersLithium is not always efficacious:- Conditions like Atypical and Mixed Affective States; Bipolar Depression; Rapid Cycling Affective Disorders; respond poorly to LithiumDrugs useful in Bipolar Disorders- agents with efficacy for bipolardepressive or mixed states or for lithiumrefractory patients are particularly welcomeAED’s used in Bipolar Disorders- Valpromide, Divalproex Sodium, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate, Gabapentin, Levetiracetam, Zonisamide, Tiagabine
AED’s in Bipolar Disorders
AED Condition Special Indications
Level of Evidence
Valpromide, Divalproex & Carbamazepine
Acute Mania Non classical manic states
+++
Valpromide, Divalproex & Carbamazepine
Prophylaxis of Bipolar Disorder
Non-classical bipolar states
++
Oxcarbazepine Acute Mania and Bipolar Disorder Prophylaxis
Similar to CBZ- better tolerated with fewer SE
++
Lamotrigine Bipolar Depression Acute & Prophylaxis
Protects against manic relapse
++
AED’s in Bipolar DisordersAED Condition Special
IndicationsLevel of Evidence
Topiramate Non-classical mania
As an adjunct in treatment resistant mania
+
Levetiracetam Bipolar Disorder Mania, depression, rapid cycling
+
Zonisamide Mania and Depression
Acute treatment but not prophylaxis
+
Tiagabine Bipolar Disorder Unclear +/-
Gabapentin Bipolar Disorder Prophylaxis but not acute Treatment
+/-
Adjunctive effects of AED’s in Bipolar Disorder
• Valproate, Topiramate, Oxcarbazepine all reported useful adjuncts in- Treatment resistant mania; agitation; irritability; acute dysphoria; impulsivity; aggression; intermittent explosive disorder.- Obesity, substance abuse, suicidal ideation, co-morbid psychotic symptoms- Topiramate reportedly has benefits- Lamotrigine in the augmentation of treatment resistant Bipolar Depression
AED’s in Psychosis
• Johnson J, Bourgeois JA, Quanbeck C.Treatment of olfactory hallucinations with topiramate.J Clin Psychopharmacol. 2006 Jun;26(3):340-1.
• Heck AH, de Groot IW, van Harten PN.Addition of lamotrigine to clozapine in inpatients with chronic psychosis. J Clin Psychiatry. 2005 Oct;66(10):1333.
• Townsend MH, Wilson MS.Comorbid anxiety disorders and divalproex sodium use among partial hospital patients with psychotic disorders.Compr Psychiatry. 2005 Sep-Oct;46(5):368-70.
• Ivkovic M, Damjanovic A, Marinkovic D, Paunovic VR.Carbamazepine for acute psychosis with EEG abnormalities.Vojnosanit Pregl. 2004 Jul-Aug;61(4):399-403.
• Dietrich DE, Godecke-Koch T, Richter-Witte C, Emrich HM.Lamotrigine in the treatment of confusion psychosis. A case report.Pharmacopsychiatry. 2004 Mar;37(2):88-90.
AED’s in Psychosis- Summary• Many reports of AED’s employed as adjunctive therapy• Appear to have utility as thymoleptic agents that help control
mood swings and behavioral symptoms especially in combination with neuroleptic agents
• Older AED’s such as Valp & CBZ have been reported as useful in schizoaffective disorders
• Some case reports of AED usage in Neuropsychiatric psychoses- Divalproex Sodium in psychoses of Dementia for example
• However, no RCT’s of AED usage in psychoses; vast majority of reports are of small series/ single cases.
Other reported uses of AED’sBorderline Personality Disorder
Carbamazepine, Oxcarbazepine, Valproate and Lamotrigine
Addiction/ Craving Topiramate, Lamotrigine, Gabapentin
Migraine Divalproex sodium, Topiramate, Gabapentin, Tiagabine
Neuropathic Pain Phenytoin, Carbamazepine, Oxcarbazepine, Topiramate, Gabapentin, Pregabalin, Lamotrigine, Levetiracetam, Tiagabine
Obesity Topiramate, Zonisamide
Anxiety, social phobia Gabapentin
No AED augmentation or usage in Unipolar Depression
The majority of reports are in Bipolar Depression
There too some reports of antidepressants with adjunctive neuroleptic therapy being
more efficacious than AED’s
In this lecture
• AED’s: Looking Beyond Epilepsy- Their Relevance & Utility in Neuropsychiatry
• Parodoxical relationships: seizures, behavior and AEDs
• What relevance do these findings hold for epilepsy
The Paradox
AED’s alleviate psychopathology
AED’s also appear to induce psychopathology
Antiepileptic Drugs: Risk of Cognitive Effects
Minimal or None
Some Potentially Significant
LamotrigineGabapentinTiagabineLevetiracetamVigabatrin FelbamatePregabalin?
CarbamazepinePhenytoinValproateZonisamideOxcarbazepine
PhenobarbitalPrimidoneBenzodiazepinesTopiramate
Antiepileptic Drugs: Risk of Behavioral Disturbance
Low Intermediate Higher
CarbamazepineOxcarbazepine LamotrigineGabapentin Valproate
Zonisamide?Tiagabine?Pregabalin?
PhenobarbitalPrimidoneLevetiracetamVigabatrin Topiramate FelbamateBenzodiazepines
Models for Clinical Study
• Few models for clinical study exist• Technological advances in imaging and
genetics allow the study of the epilepsy psychiatry interface
• A model has to be predictable & replicable in order to lend itself to study
Forced Normalization- A Putative Model
• “Forced Normalization is the phenomenon characterised by the fact that, with the occurrence of the psychotic states, the EEG becomes more normal or entirely normal as compared with previous and subsequent EEG findings”
• Put more crudely, “there would seem to be epileptics who must have a pathological EEG in order to be mentally sane”
Landolt 1952, 1958
Anticonvulsant drugs and Forced Normalization
• Bromide Parant (1895)• Succinimides Landolt (1958)• Phenacemide Gibbs (1951)• Barbiturates Gibbs (1951)• Hydantoins Gibbs (1951)• Ethosuximide Wolf (1991)• Carbamazepine Drake & Perruzi (1986) • Vigabatrin Ring (1994); Thomas
(1996)
Trimble MR. Forced Normalization and the role of anticonvulsants. . In Trimble MR, Schmitz B, eds. Forced Normalization and Alternative Psychoses of Epilepsy. Petersfield: Wrightson, 1998: 169-178
Trimble MR. Forced Normalization and the role of anticonvulsants. . In Trimble MR, Schmitz B, eds. Forced Normalization and Alternative Psychoses of Epilepsy. Petersfield: Wrightson, 1998: 169-178
Anticonvulsant drugs and Forced Normalization
• Felbamate McConnell (1996)• Lamotrigine Brown (1993); Martin (1995)• Zonisamide Matsuura and Trimble (1997)• Topiramate Trimble (1998)• Tiagabine Trimble et al (2000)• Levitiracetam Krishnamoorthy et al (2002)• VNS Gatzonis et al (2000)
Krishnamoorthy ES et al. Forced Normalization at the interface between epilepsy and psychiatry. Epilepsy & Behaviour 2002; vol. 3, no. 4, 3-8..
Krishnamoorthy ES et al. Forced Normalization at the interface between epilepsy and psychiatry. Epilepsy & Behaviour 2002; vol. 3, no. 4, 3-8..
Forced Normalization has been reported with the range of epilepsy treatments
available including VNS
A predictable and replicable model for clinical study
Exclusions in PubmedOxcarbazepine & Pregabalin
Mechanisms of Forced Normalization
• Limbic kindling and secondary epileptogenesis• Neurotransmitter (dopamine & GABA/ Glutamate)
and opioid receptor phenomena• Enhanced cortical inhibition may accompany many
post-ictal states with the epileptiform activity being restricted to the mesial temporal structures by an inhibitory surround
• Ion channel disorders* (Krishnamoorthy ES et al, 2002)
Krishnamoorthy ES, Trimble MR. Mechanisms of Forced Normalization. In Trimble MR, Schmitz B, eds. Forced Normalization and Alternative Psychoses of Epilepsy. Petersfield: Wrightson, 1998: 193-207.
Krishnamoorthy ES, Trimble MR. Mechanisms of Forced Normalization. In Trimble MR, Schmitz B, eds. Forced Normalization and Alternative Psychoses of Epilepsy. Petersfield: Wrightson, 1998: 193-207.
Models of antagonism between seizures and
psychosis Stevens and Livermore (1978)
• Electrical + Pharmacological Kindling
• CA= PSYCHOSIS SEIZURES
• CA= PSYCHOSIS SEIZURES
• ANTAGONISM
Glutamate, GABA and Forced Normalization
GABA GLUTAMATE = PSYCHOSIS
GABA GLUTAMATE = EPILEPSY
In this lecture
• AED’s: Looking Beyond Epilepsy- Their Relevance & Utility in Neuropsychiatry
• Parodoxical relationships: seizures, behavior and AEDs
• What relevance do these findings hold for epilepsy
How do AED’s help in Psychiatry?
• Emerging evidence that:
- Paroxysmal psychiatric disorders may be associated with ion channel abnormalities- Calcium, sodium and peptide channels implicated
- Genetic factors concerned with Glutamate and GABA metabolism may play a role in Schizophreniform illness
Several AED adverse effects less commonly reported in Psychiatry
• Cognitive effects of Topiramate- no significant reporting in psychiatric literature
• Reproductive hormonal effects of sodium valproate preparations - similar elevation in androgen levels in both epilepsy and bipolar groups- fewer clinically significant effects in bipolar group compared to epilepsy group
• Parkinsonism and cognitive effects with valproate preparations- largely unreported in psychiatric literature
Differential impact of AED’s in Complex Epilepsy Syndromes
The Topiramate Example
•The occurrence of the anomia appears to be related to a left temporal seizure focus (1)
•The occurrence of depression and adverse cognitive effects to the presence of hippocampal sclerosis (2)
•The occurrence of adverse behavioural effects may be critically related to abolition of seizures (3)
1. Kockelmann E, Epilepsy Res 2003;54(2–3):171–8. 2. Mula M Epilepsia 2003;44(12):1573–7.
3. Mula M. Epilepsy Behav 2003;4(4):430–4.
1. Kockelmann E, Epilepsy Res 2003;54(2–3):171–8. 2. Mula M Epilepsia 2003;44(12):1573–7.
3. Mula M. Epilepsy Behav 2003;4(4):430–4.
The Mesial Temporal Epilepsy Syndrome
Affective Somatoform Features
Structural changes inAmygdala & Hippocampus
Personality FeaturesPsychotic features
AEDsSeizures
NeuropsychologicalSymptoms
AED’s in Epilepsy & PsychiatryA Model for Consideration
Generic Effects Specific Effects
Provoke Psychopathology Alleviate Psychopathology
AEDs
Epilepsy ControlBiological Factors
-Hippocampal Sclerosis-Ion Channel Disorder- Glutamate/ GABA
