Antiepileptic drugs: affective use in autism spectrum disorders

Antiepileptic Drugs: Affective Use in Autism Spectrum Disorders Adriana Di Martino, MD* and Roberto F. Tuchman, MD† Antiepileptic drugs are widely administered to individuals with autistic spectrum disorders. There are several reasons for the use of antiepileptic drugs in autistic spectrum disorders, including the high incidence of epilepsy in these individuals, the anecdotal reports suggesting an improvement of communication and behavior in autistic subjects with epileptic discharges, and the increased awareness that some disruptive behaviors may be manifestations of an associated affective disorder. In this study, data on the current use of antiepileptic drugs in the treatment of autism, and on the association of affective disorders with epilepsy and autism, are reviewed. The evidence supporting the hypothesis that there may be a subgroup of autistic children with epilepsy and affective disorders that preferentially respond to antiepileptic drugs is still very preliminary, and further investigations with double-blind controlled studies are needed. Although the role of antiepileptic drugs at the present time is not established, there is evidence that autism, epilepsy, and affective disorders commonly co-occur, and that they may share a common neurochemical substrate, which is the common target of the psychotropic mechanism of action of different antiepileptic drugs. © 2001 by Elsevier Science Inc. All rights reserved. Di Martino A, Tuchman RF. Antiepileptic drugs: Affective use in autism spectrum disorders. Pediatr Neurol 2001;25:199-207.

Introduction Autistic spectrum disorders (ASD) or pervasive developmental disorders (PDD) (ASD and PDD are used interchangeably in this review) encompass a heterogeneous group of children with deficits at the level of language, social communication, and a restricted reper-

From the *Department of Neuroscience; Child Neurology and Psychiatry; University of Cagliari; Cagliari, Italy; and the †Department of Neurology; Dan Marino Center; Miami Children’s Hospital; Weston, Florida.

© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00276-4 ● 0887-8994/01/$—see front matter

toire of activities or repetitive behaviors. This behaviorally defined disorder may occur from a variety of insults to the developing brain. Approximately 30% of children with autism have regression in communication [1]. Approximately one third of children on the autistic spectrum develop epilepsy [2-5]. In addition, a significant minority of autistic children without epilepsy present epileptiform discharges, especially during sleep, and these discharges are predominantly over the perisylvian head regions [6]. The relationship of language and epilepsy to the behaviors that define ASD raises broad and important issues. To understand the relationship between abnormal electrical activity in the brain and autism, a broader understanding of the role of epilepsy and, more specifically, of epileptiform activity on cognitive, language, behavioral, and mood disorders is needed. The term transient cognitive impairment is used to describe individuals with epileptiform electroencephalogram (EEG) discharges in association with a momentary disruption of adaptive cerebral function [7]. It has also been demonstrated that focal interictal spikes may transiently disrupt aspects of cortical functioning corresponding to the neuroanatomic location in which they occur [8,9]. Despite continued interest in this subject the actual role of clinical or subclinical epilepsy in children with language and behavioral deficits remains unknown. One of the current controversies among clinicians is whether there is a subgroup of individuals in whom epileptiform discharges, in the absence of seizures, may be responsible for all or part of the cognitive, language, and behavioral dysfunction present in that individual. There is insufficient research that supports or refutes this hypothesis and only anecdotal evidence exists, suggesting that treatment of epileptiform discharges thought to be producing specific dysfunction in selected aspects of cognition, language, or behavior may make a positive difference. Despite the lack of knowledge in this area, antiepileptic

Communications should be addressed to: Dr. Tuchman; Director; Dan Marino Center; Department of Neurology; Miami Children’s Hospital; 2900 South Commerce Parkway; Weston, FL 33331. Received November 10, 2000; accepted March 5, 2001.

Di Martino and Tuchman: Affective use of Antiepileptic Drugs 199

Table 1.

Antiepileptics in patients with autism and related conditions

Patient

Age

3

Child

2 3 1 2 2

Child Child Child Child Adult

1 2

Child Child

2

Adolescent

13

Child/adolescent

Diagnosis

Seizure

Abnormal EEG

AED

Epilepsy Control

Behavior Improvement

Reference Citation

Asperger ADHD (2) BPD (1) AUT AUT PDD AUT AUT BPD (1) RCD (1) Asperger AUT TS AUT BPD AUT (12) Rett (1)

⫺

⫺

VPA

/

⫹

[21]

⫺ ⫺ ⫺ ⫺ ⫺

⫹ ⫹ ⫹ ⫹ ⫺

VPA VPA VPA VPA VPA

⫹ ? ⫹ ⫹ ⫾

⫹ ⫹ ⫹ ⫹ ⫹

[20] [18] [15] [12] [14]

⫹ ⫹ (1)

⫹ ⫹

CBZ CBZ

⫾ ⫹

⫺ ⫹

[19] [16]

1⫹

1⫹

CBZ

⫹ (1)

⫹

[13]

⫹

⫹

LMG

*

⫹ (8)

[17]

* After 4-month treatment (including the 13 autistic patients): 5 of 50 (11%) were seizure free; 16 of 50 (36%) had more than 30% reduction of seizures; 24 of 50 (53%) had no improvement. Abbreviations: Abnormal EEG ADHD AED AUT BPD CBZ LMG

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

Presence of focal spikes or sharp waves Attention–deficit-hyperactivity disorder Antiepileptic drugs Infantile autism Bipolar disorder Carbamazepine Lamotrigine

PDD RCD TS VPA ⫹ ⫺ ⫾

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

Pervasive developmental disorder Rapid cycling disorder Tuberous sclerosis Valproic acid Present Not present Temporal seizure control

drugs are administered widely to children with ASD. One common reason for this is that children with ASD have a high rate of seizure disorders. More recently antiepileptic drugs in children with ASD are being used because children with ASD often have, or later develop, symptoms and behaviors that are consistent with the diagnosis of affective disorders in addition to those that qualify them for their primary diagnosis [10]. In a recent study, it was revealed that in a sample of 838 children with ASD, 15.2% were taking antiepileptic drugs either as an antiepileptic (valproate, carbamazepine, and phenytoin) or for behavior dysfunction (carbamazepine and clonazepam) [11]. We have a limited understanding of how antiepileptic drug therapy could ameliorate language and behavioral disorders or their effects on affective disorders. The purpose of this study is to review the clinical and basic science evidence that supports the hypothesis that antiepileptic drugs in ASD target neuronal systems common to epilepsy and affective disorders.

A review of the literature on affective disorders in children and adolescents with epilepsy and in children and adolescents with autism using the words affective disorders, children, and adolescents were matched with epilepsy, behavioral disorders, and pervasive developmental disorders (PDD), respectively, was performed. The name of each drug was associated to the term mechanism of action. From approximately 1000 articles, 95 English language articles were selected and reviewed. These articles were on the behavioral effects of antiepileptic drugs on ASD/PDD with or without epilepsy, and the association between affective disorders and epilepsy in children and adolescents plus affective disorders and autism. Articles on antiepileptic drugs’ neurochemical effects, particularly on serotonin, GABA, dopamine, epinephrine, and intracellular systems and reviews on the hypothesized psychotropic mechanisms of action of antiepileptic drugs published between 1994 and 2000 were reviewed. The studies that specifically dealt with developmental issues were selected, although adult studies were cited for the continuity of and the relevance to the topic of discussion. The results of this review are divided into the following three sections: (1) use of antiepileptic drugs in individuals with ASD; (2) literature on affective disorders in epileptic and in autistic children and adolescents; and (3) hypothesized psychotropic mechanisms of action of affective antiepileptic drugs.

Materials and Methods

Results

A Medline search using the words autism, anticonvulsant, valproic acid, carbamazepine, lamotrigine, gabapentine, topiramate, and vigabatrine was conducted. We use the term affective antiepileptic drugs to indicate that the antiepileptic drugs reviewed in this study not only have beneficial effects on seizures but may also have an effect on behavior and mood.

A total of 10 case reports or open-label studies on antiepileptic drugs in individuals with ASD were reviewed (Table 1) [12-21]. These studies included the following: two adults and 29 children and adolescents between the ages of 22 months and 14 years of age. The diagnosis of

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ASD was in accordance with DSM III-R or DSM-IV criteria. Two of the studies [16,20] used standardized scales for the diagnosis and measurement of symptom severity during treatment. Mental retardation was present in 21 of 31 individuals described in the above studies, and varied from mild to severe [13,14,16,17,20]. Epilepsy was present in 18 of 31 individuals and, when specified, the type of seizures included generalized and complex partial seizures. EEG abnormalities in the absence of clinical seizures were present in six of 31 individuals described in the studies reviewed. Five individuals had focal epileptic discharges in the frontal, central, and parietal regions or generalized spikes. One individual exhibited slowing of the background without epileptiform discharges. Affective symptoms (manic, hypomanic, or depressive episodes) were recognized in seven of 31 individuals, and a specific diagnosis was present in five: bipolar disorder (n ⫽ 4) and rapid cycling affective disorder (n ⫽ 1) [13,14,21]. Only two studies used specific diagnostic criteria for mood disorders [14,21]. Neuroimaging studies were performed in 17 of 31 individuals studied. Structural imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) was abnormal in limbic regions in two patients [16] and normal in two [13,15]. The other 13 individuals were from the study of Uvenbrant et al. [17] and no specific information is available, although the investigators state that MRI and single-photon emission computed tomography (SPECT) results were abnormal in 50% and 100% of the total sample, respectively. In all patients, blood chemistry studies, chromosome analysis (including cultures for fragile X), amino acids level, and lactate concentration were normal. Antiepileptic drugs were used to control epilepsy in all 18 patients with epilepsy (four valproic acid; 13 lamotrigine; and one carbamazepine) and in five of six individuals with abnormal EEGs but no seizures (four valproic acid; one carbamazepine). In the seven children with affective symptoms and no clinical or subclinical seizures, antiepileptic drugs were used as mood stabilizers. Valproic acid was effective both in controlling seizure and epileptiform abnormalities in all eight children. Carbamazepine was efficacious in three children and was not tolerated in one child. In the Uvenbrant et al. study [17], lamotrigine was administered to a population of 50 epileptic individuals, 13 of them with diagnosis of ASD. Lamotrigine was reported to be totally or at least partially efficacious in controlling seizures in 46% of the total sample, but it was not specified how many of the 13 subjects with ASD responded. An improvement in communication skills, both for expressive and comprehensive language, was reported for all eight patients treated with valproic acid, in eight of 13 treated with lamotrigine, and in two of three treated with carbamazepine. None of the studies used specific language assessment tests. In six of eight patients treated with valproic acid an improvement in socialization skills was

also reported. Improvements in communication and socialization skills were correlated with improvements in either abnormal EEG or seizure control. Affective symptoms improved in all seven patients with mood disorders, and none of these individuals had seizures or epileptiform EEGs after treatment with valproic acid and carbamazepine (see Table 1). Epilepsy and Affective Disorders In children and adolescents with epilepsy there is a high frequency (30-60%) of neurobehavioral problems [22-28]. Mood disorders in adults with epilepsy are frequent [29-32], but there are no available data about the prevalence of mood disorders in children and adolescents with epilepsy. The emerging literature on mood and epilepsy in childhood consists of case reports relying on a broad diagnostic classification system, suggesting that there is a high incidence of neurotic or emotional disorders, including anxiety and depression, and an increased risk for suicide in young individuals with epilepsy [33]. The absence of data on affective morbidity in young individuals with epilepsy may have to do with the difficulty in diagnosing childhood affective disorders. In fact, the presentation of mood disturbances in children and adolescents differs from the episodic course classically ascribed to the illness. Bipolar disorder in children presents with rapid cycling and mixed episodes [34]. Labile and erratic mental excitement, irritability, and belligerence frequently characterize manic episode in the younger individual, and mixed manic-depressive features are more frequent than euphoria in this population. These symptoms may represent the child’s baseline state, often have a chronic and, at times, rapidly fluctuation course rather than a marked change in functioning [35]. Children with depression can present with irritability, temper tantrums, somatic complaints, and auditory hallucinations whereas adolescents with depression tend to display sleep and appetite disturbances, delusions, and suicidal ideation and attempts more frequently than younger children [36]. In epileptic adults, affective morbidity is more selectively associated with the partial epilepsy of mesial temporal lobe (limbic) origin [31,32,37]. In children and adolescents, temporal lobe epilepsy has been associated with attention and impulsivity, hyperactivity, aggressive behavior, and psychosis [27,28]. There is a lack of data on affective illness in children and adolescents, and a possible association with epilepsy remains to be clarified. Affective Disorders and Autism Many early studies have described several psychiatric symptoms associated with the core autistic symptoms [38,39]. A series of more recent case reports has suggested an association between autism and affective disorders [10,13,40-43]. In addition, obsessive-compulsive disorder,

Di Martino and Tuchman: Affective use of Antiepileptic Drugs 201

Table 2.

Effect of AED on neurotransmitters function GABA

CBZ 1GABAA activity [80, 81] VPA 1GABA [82-84]; 2GABA-T, 1GAD [85] LMG 1GABA [86] GBP 1GABA, GAD [88] TPM 1GABAA activity [87] VGB 1GABA [80]

Glut

5-HT

NMDA block [89] 1 5-HT [63, 94] [61]; 1 TRP [95] 2NA [99] 2Glut [90]

1TRP, 5-HT, 5HIAA [65, 96] [67, 68] 7 [97] 2Glut [91, 92] 15-HT [69, 70]; 1 5-HT3 [98] 2BCAA-T [93] 15-HT [71]; 1 5HIAA [72] AMPA block [87] / 2Glut [80]

Abbreviations: BCAA-T ⫽ Branched chain aminoacid aminotrnsferase DA ⫽ Dopamine 5-HIAA ⫽ 5-Hydroxyindole acetic acid 5-HT ⫽ Serotonin GABA ⫽ ␥-Aminobutyric acid GABA-T ⫽ GABA transaminase

GAD Glut HVA TRP / 7

⫽ ⫽ ⫽ ⫽ ⫽ ⫽

Possible Mechanisms of Action of Affective Antiepileptic Drugs and Other Antiepileptic Drugs An improvement in a variety of behavioral manifestations when epilepsy is pharmacologically or surgically controlled has been reported. An interesting question that at present cannot be answered is if the antiepileptic drug effects and psychotropic effects of antiepileptic drugs are mediated by the same mechanisms. Valproic acid and carbamazepine are potent inhibitors of amygdala-kindled seizures [48]. There is recent evidence that new affective antiepileptic drugs, such as topiramate [49], lamotrigine [50], and vigabatrine [51], are inhibitors of amygdala-

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Dopamine Activity 1DA [102]

1NA (Hipc./BS), 2(HPT) [68]; 1DA, HVA [68, 96] 7 [100] [66, 100, 103] 1NA [69] 2NA [101]

/

schizophrenia, and Tourette’s syndrome have also been significantly associated with autism [43-47]. Recognizing affective disorders in subjects with ASD is more complicated than in the general population, especially in lower functioning patients. Our present understanding is that children and adolescents with ASD are more likely to develop chronic and recurrent mood disturbance than single episodes of mood disturbances [10]. In both the manic and depressive state, children and adolescents are likely to present agitation and irritability rather then grandiosity or sadness, respectively. Other symptoms of an affective disorder in this population include changes in their attitude toward other persons or themselves (noncompliance, uncooperativeness, aggressiveness, and selfinjurious) and modification of vegetative signs (reduced or increased appetite and alterations of sleep pattern). Depressed individuals with ASD can be or manic and in some individuals an exacerbation of the symptoms of autism is what suggests an affective disorder [13]. At the present time the prevalence of affective disorders in people with ASD is unknown. There have been no studies addressing the relationship between affective disorders, epilepsy or epileptiform discharges, and ASD.

202

Norepinephrine Activity

/

1DA [104] 2DA [105]; 1HVA [72] /

/

/

Glutaminic acid decarboxylase Glutamate Homovanillic acid Triptophane No studies available No effect

kindled seizures. Kindling is a model of epileptogenesis, in which repeated intermittent administration of a subconvulsant stimulus results in the development of generalized motor seizures and ultimately, spontaneous seizures [52]. It is most readily achieved in the limbic system structures [53]. Although affective disorders and epilepsy both have a common response to electroconvulsive seizures [54] and to some antiepileptic drugs, they differ in the behavioral and physiologic manifestations, in etiologic precipitants, and by pharmocotherapeutic profiles [55]. Furthermore, an affective or behavioral disorder patient’s response to affective antiepileptic drugs is not necessarily linked to having seizures or epileptiform discharges. The efficacy of affective antiepileptic drugs may be independent of their effect on epilepsy, and affective disorders may reflect a more complex dysfunction of system limbic circuits in some way modulated by the activity of affective antiepileptic drugs. Kindling has been considered a nonhomologous model of psychiatric illness that clearly does not involve a convulsive endpoint but illustrates increasing physiologic responsive to the same stimulus over time. In this regard, kindling provides a preclinical model of the progressive increase in illness severity and shifting from precipitated to spontaneous episodes of affective disorders [56]. A possible hypothesis might be that affective antiepileptic drugs could modulate common pathophysiologic mechanisms between affective disease and epilepsy. For this reason a better comprehension of the neurobiologic process involved in the kindling model is relevant to our understanding of affective disorders and their treatment. In a variety of animal models, serotonergic mechanisms have been implicated in the rate of development of amygdala kindling: 5-HT1A agonists slow kindling development and duration, whereas the opposite occurs with 5-HT2A agonists [57,58]. Serotonin can modulate kindling progression through modulation of primary neural

mechanisms mediating the discharge of amygdala kindling, such as glutamate NMDA receptors [59,60]. A variety of antiepileptic drugs have potent effects on serotonergic tone at several molecular target points (Table 2). Carbamazepine has a bimodal effect on serotonin hippocampal levels. For example, at therapeutic concentrations, it increases 5-HT turnover and transmission without affecting 5-HT reuptake activity, whereas at high dosages, carbamazepine inhibits reuptake and turnover [61]. The serotonergic effect of carbamazepine has been directly linked to its antiepileptic drug effect in epilepsyprone gene rat strains [62,63]. The use of valproic acid has been associated with unaltered brain levels of serotonin, as well as its precursor (tryptophan) and metabolite (5HIAA) in some studies [64,65]. In other studies serotin levels have been found to increase [66-68]. Lamotrigine has recently been reported to block serotonin reuptake [69,70]. This action may only occur at doses higher than normally used. In contrast to paroxetine, lamotrigine at maximal antiepileptic-drug dose (20 mg/kg) did not increase hippocampal 5HT levels measured by in vivo microdialysis in rats, suggesting that this mechanism of action is not pertinent to its antidepressant activity [69]. Gabapentin in healthy adult volunteers increases whole blood of serotonin [71] and 5-HIAA (principle serotonin metabolite) in the cerebrospinal fluid (CSF) [72]. Conventionally, GABA is considered an inhibitory neurotransmitter, but in the limbic system, GABA appears to have a stimulatory effect on norepinephrine transmission postsynaptically and presynaptically [73] and increases serotonin levels [74,75]. Petty et al. [75-79] studied a possible role of GABA and the drugs acting on GABA transmission in affective disorders. They hypothesized that low GABA may be directly related to affective illness in adults, whereas in children and adolescents, it might be a marker for a genetic vulnerability to a mood disorders trait. It has been observed that carbamazepine and valproic acid increase GABA receptors in the hippocampus and cortex [80,81]. The effect of carbamazepine on GABA was observed to be more substantial after chronic administration, raising the possibility that the time course of carbamazepine effect on GABA turnover is parallel to the time course observed for positive psychotropic effects. After treatment with valproic acid, GABA concentrations in CSF, blood, synaptosomes, and nerve terminal are significantly increased [82,83]. Valproic acid decreases the GABA-metabolizing enzyme GABA-transaminase (GABA-T) and enhances the synthesis of glutaminic acid decarboxylase [84,85]. Lamotrigine increases GABA concentrations [86]. Gabapentine promotes the release of GABA from neurons and glia. Vigabatrin enhances the GABA levels in the central nervous system by inhibition of the enzyme GABA transaminase. Topiramate increases the activity of GABA by acting on a different site of BDZ of the GABAA receptor [87]. The other effects on GABA,

glutamate, 5-HT, NA, and dopamine activity are summarized on Table 2 [88-105]. A direct action on intracellular signaling has not been extensively studied to date, but the potent activity-dependent effects on ion channels of lamotrigine, carbamazepine, valproic acid, gabapentine, and topiramate may have an indirect action on signal transduction. The fact that different molecules have a common effect in the generation of the second messenger transduction cascade suggests that alteration of the intracellular signaling may be relevant in the pathophysiology of affective disorder. It is clear that the transduction cascades terminate in the nucleus where they are capable of modifying the expression of genes that code for neurotransmitters enzyme and receptors and neural growth factors. The efficacy of some affective antiepileptic drugs in autism could shift some research initiatives toward the role of the intracellular cascade in the pathophysiology of ASD. Discussion Our present understanding of the pathophysiology of autism and related disorders is limited, and the relationship between autism, affect, and epilepsy, although intriguing, is still not understood. At a clinical level there is a high frequency of affective psychopathology in individuals with ASD or their first-degree relatives [106-108]. There is also a high risk of developing complex partial seizures (limbic origin) in children with ASD [109,110]; temporal epileptiform discharges are more frequent in children with ASD [6]. Present evidence suggests that the dysfunction accounting for the signs and symptoms of autism involves widespread neuronal networks. Neocortical dysfunction abnormalities [111] in ascending projections from the cerebellum, brainstem [112,113], and mesial temporal involvement [114] have all been reported in individuals with ASD. Abnormalities in function of the mesial temporal structures in autism may provide a common link to the higher prevalence of seizures and mood disorders because limbic and diencephalic circuits are known to control drive and affect and are highly epileptogenic. The neurotransmitter systems effected by affective antiepileptic drugs are common to affective disorders, epilepsy, and autism. Hyperserotonemia is the most common neurochemical abnormality in children and adults with autism [115]. Positron-emission tomography studies have demonstrated that the normal high serotonin brain synthesis that occurs in childhood is disrupted in autistic children [116]. Medications that interact on serotonin transmission have been efficacious in the treatment of both affective and autistic disorders. It is interesting that in PDD children the efficacy of SSRI in ameliorate communication and behavioral symptoms is correlated to a positive familial history of affective disorder [106]. Evidence from animal models of epilepsy has suggested that serotonergic activity is deficient in widespread areas of the brain [117]. There is also some clinical evidence

Di Martino and Tuchman: Affective use of Antiepileptic Drugs 203

suggesting that SSRIs, such as fluoxetine, can have antiepileptic drug properties [118]. The affective antiepileptic drugs reviewed in this study all have a common effect on GABA, and this could be related not only to their antiepileptic drug properties but also to a psychotropic effect through GABA’s modulation of serotonin activity. Of the studies reviewed, only seven of 31 ASD/PDD patients had a specifically diagnosed mood disorder. The recognition of an affective disorder in children and adolescents with ASD is extremely difficult, secondary to the lack of communication skills and to the chronic nature of affective disorders in this population. It is possible that in some individuals behavioral problems, such as aggression, could be the clinical manifestations of an affective disorder. In the course of an affective episode, children with ASD could also present changes in their communication skills. A positive response to affective antiepileptic drugs (in terms of communication skills) may be secondary to an improvement of affective symptoms and not to a direct effect on the primary core symptom of autism. It is of interest that improvement in behavioral and communication skills correlated to control of epilepsy or epileptic discharges when present. In the studies reviewed, 85% of the literature reported that a trial with affective antiepileptic drugs (valproic acid, carbamazepine, and lamotrigine) ameliorated behavioral disturbances (irritability and aggressiveness) and improved the core autistic symptoms of socialization and communication regardless of whether seizures were controlled or not. However, we emphasize that the evidence to date on the effectiveness of affective antiepileptic drugs on autism with epilepsy is based on case reports and not on controlled clinical trials. Placebo-controlled, double-blind studies are clearly needed. There is still a great need for research in the area of the effects of antiepileptic drugs on mood and behavior in children with autism regardless of whether they have seizures or not. For example, in spite of the fact that eight of 13 epileptic autistic patients reported improvements in their behavior after a trial with lamotrigine [17], a recent double-blind, placebo-controlled trial reported a lack of significant effectiveness of lamotrigine in ASD [119]. Other antiepileptic drugs, such as carbamazepine, have a long history of anecdotal effectiveness as a mood stabilizer and, of the studies reviewed, three of four patients reported a positive response. In addition, valproic acid was reported to have a positive effect on all the individuals who received it in the studies reviewed, and a recent randomized placebo-controlled study has revealed that valproic acid is more efficacious than lithium in the long-term outcome of bipolar I disorder [120]. The limitation of all the studies reviewed is that the absence of a placebo-controlled study cannot exclude a bias in measuring improvement. Furthermore, only three of the studies reviewed used a specific standardized assessment scale for measuring changes in core autistic and associated behavioral symptoms.

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The evidence reviewed suggests that epilepsy, language, and behavior share common neuroanatomic and neurochemical neural circuits. The clinical use of antiepileptic drugs in children with ASD is secondary to anecdotal reports suggesting a role for antiepileptic drugs in children with autism and epileptiform EEGs and the increased awareness that behavioral problems in this population of children may also be a manifestation of an affective disorder. There is only anecdotal evidence to suggest that there is a beneficial role for antiepileptic drugs in children with ASD. The evidence to support the hypothesis that there may be a subgroup of ASD children with epilepsy and affective disorders that may preferentially respond to antiepileptic drugs is presently not available. The role of affective antiepileptic drugs in children with autism with or without seizures is not established. There is evidence that autism, epilepsy, and affective disorders commonly co-occur and that they may share a common neurochemical substrate. There are an increasing number of novel antiepileptic drug compounds that are becoming available for clinical use. This requires clinicians to be cognizant of the clinical relationships that exist between autism, epilepsy, and affective disorders and to be aware of emerging concepts in regards to the role of antiepileptic drug medications for the treatment of epilepsy and affective disorders. As our knowledge increases in this area, more specific recommendations will become apparent regarding the use of these medications in children with autism and related disorders.

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