Method for treating expressive language disorder in humans with autism

Abstract

Provided is a pharmacological method for treating expressive language disorder in autistic human children or adults. A therapeutically effective dose of a succinimide anticonvulsant, such as ethosuximide, methsuximide, phensuximide, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from expressive language disorder, preferably for an extended period, such as six months or more. Language acquisition is retained even after treatment is discontinued.

Description

Technical Field

[0001] Background of the Invention The present invention relates to pharmacological methods for treating the expressive language disorders exhibited by children and adults suffering from autism.

Background Art

[0002] The term "Autism Spectrum Disorder" (ASD) is used by neurologists to describe a range of conditions whose main feature is low / limited social interaction. The conditions typically appear by the age of two and are reported to affect 1 in 44 children in the United States and over 75 million children worldwide. Patients with ASD may exhibit social maladjustment or, on the contrary, ignore others and reject attempts to communicate with them. Autism lies at one end of the spectrum and is characterized by patients who are uninterested in communicating with others. They ignore their parents and peers. Also clear in this group is an expressive language / communication disorder. Most autistic patients have little to no developed expressive language, remain silent, are not talkative, and are isolated throughout their lives. Spontaneous language is rare. There is a lack of impulse to communicate through meaning. They may utter two- or three-word phrases, but these phrases are uttered simply in response to questions, not from desire or the urge to speak.

[0003] For example, a person with autism may be able to answer the question "What did you do this weekend?", but lacks the ability to add to or continue the conversation. They may answer "Watched a movie", but do not continue the conversation with "So what did you do?" or "Saw a good movie. Have you seen this movie?" Thus, the central language / communication disorder in autism is characterized not only by a lack of expressive language, but also by the inability to engage in conversation in order to perform mutual and reciprocal exchanges of words. The term "autism" was coined in 1945 by Dr. Kanner to describe this unique set of language and behavioral problems encountered in young patients. These children did not want to communicate through meaning. They preferred to be alone, away from others, and not rely on others, and thus were said to be autistic.

[0004] This language disorder in autism is in contrast to the communication problems in other ASD patients, especially those with Asperger's syndrome and pervasive developmental disorder (PDD). Patients with Asperger's syndrome do not have a language / communication disorder. They speak in complete sentences that are easily understood. They can continue a conversation. Their disorder is social. They prefer limited social interactions, are clumsy, and are unaccustomed to simple social conversations. They tend to be intelligent and often have better skills and more interest in hard sciences, such as engineering or computer science. On the other hand, patients with PDD tend to have problems with attention and learning and are often several levels below their peers. Thus, although they want to and can speak in complete sentences, they do not know how to engage in conversation. They are socially maladjusted. In conversation, they mainly talk in great detail about their own interests without showing interest in or showing interest in the feelings or actions of others. For example, they talk about their interests in dinosaurs or computer games rather than what others want to talk about.

[0005] Patients with mental retardation are not considered to be part of the ASD group. They may have simple or limited expressive language, but are interactive and interested in being with other people. Unlike autistic patients who often ignore others and even reject acknowledging their presence, they are interested, gesture, hug, and attempt to communicate with others.

[0006] There are currently no treatments approved by the FDA for childhood autism. If there are any, only very few pharmacological interventions specifically target expressive language.

[0007] Individuals with ASD generally have a higher risk of developing epilepsy, but the relationship between ASD and epilepsy is complex. In both neurology and psychiatry, antiepileptic drugs (AEDs), such as valproate, lamotrigine, levetiracetam, etc., have been widely used to treat other disorders, but the medical community has not recognized that AEDs may have a role in treating expressive language disorders in autistic patients. For example, the 2008 review paper (Landmark, C. J., Antiepileptic Drugs in Non-Epilepsy Disorders, CNS Drug Review, 2008: 22(l):27-47) lists some first- and second-generation AEDs and their use in treating many disorders, but does not describe autism, ASD, or expressive language disorders. The antiepileptic drug ethosuximide is not listed or discussed in this paper.

[0008] Kaufman, K.R., Antiepileptic Drugs in the treatment of psychiatric disorders, Epilepsy & Behavior 21 (2011), 1-11 provides an overview of 21 AEDs, stating that "here, the negative psychotropics, approved indications in psychiatry, off-label studies used in psychiatry, and the main uses in psychiatry are presented with a literature review." Ethosuximide is discussed on page 2, where the author mentions that there was off-label use for the treatment of bipolar disorder in psychiatry, but there were no approved indications or main uses for ethosuximide. In Table 2, Kaufman shows that ethosuximide has been studied as a possible treatment for mood disorders.

[0009] A 2011 BioMed Central research article, Frye, R E, et al., Traditional and non-traditional treatments for autism spectrum disorder with seizures: an on-line survey, BMC Pediatrics (2011), 11 :37 (http: / / www.biomedcentral.com / 1471-2431 / l l / 37) describes the results of an online survey completed by parents of children with ASD and epilepsy. This study evaluated the effects of several AEDs (valproic acid, lamotrigine, levetiracetam, ethosuximide, etc.) and non-AED treatments on seizure control and other aspects of the patients' lives. Compared to non-AED treatments, AEDs were thought to improve seizures but worsen other clinical factors, namely, sleep, communication, behavior, attention, and mood.

[0010] Korean Patent Application Publication No. 20140135676 (Soo et al.) (English abstract) discloses a composition for preventing and treating "concentration disorders" diseases - attention deficit hyperactivity disorder, schizophrenia, frontal lobe epilepsy, and autism. Several non-specific T-type calcium channel inhibitors are listed, including mibefradil, tetramethrin, ethosuximide, SUN-N8075, etc.

[0011] US Patent Application Publication No. 2004 / 0058997 (Daniel et al.) discloses a method for treating "personal attachment disorder and lack of social interaction" in patients to whom antispasmodic drugs (e.g., valproic acid, valproate, or its enteric-coated derivatives, carbamazepine, oxcarbazepine, zonisamide, lamotrigine, ethosuximide, felbamate, levetiracetam, methsuximide, phenytoin, primidone, tiagabine, topiramate) are administered. Autism is not described, and no efficacy data are provided. Disorders that can benefit from the treatment process are listed, including "schizotypal personality disorder, schizoid personality disorder, avoidant personality disorder, paranoid personality disorder, Asperger's syndrome, pervasive developmental disorder, and clinically problematic social introversion that does not meet the thresholds for official mental disorders according to current diagnostic criteria, e.g., DSM-IV".

[0012] International Publication No. 2020 / 208564 (Roman et al.) discloses carbamoyl cyclohexane derivatives for treating ASD, attention deficit hyperactivity disorder (ADHD), and other conditions. The derivatives are used alone or in combination with one or more adjunctive therapeutic agents selected from a broad set of pharmaceuticals: stimulants / nootropics, antipsychotics, antidepressants, anxiolytics, antihypertensives, antiepileptics, anesthetics, and antispasmodics. Efficacy data were obtained using a rodent model of ASD based on prenatal exposure to valproate (valproic acid, VPA), and the effect of the derivatives on the social communication function in offspring of ASD-phenotype rats was evaluated by monitoring ultrasonic vocalizations induced by maternal deprivation. No efficacy data from humans are disclosed.

[0013] U.S. Patent Application Publication No. 2019 / 0194287 (Bowrey et al.) discloses treatments for various neuropsychiatric disorders, neurodegenerative diseases, and cerebrovascular accidents, where a viral vector containing a designer receptor exclusively activated by designer drugs (DREADD) was administered to a patient's eye. After DREADD was expressed, an agonist was administered to the DREADD that expressed the agonist. In one embodiment, one or more additional therapeutic agents (selected from a group of over 200 listed compounds) are also administered to the patient. Autism is identified as one of 13 neuropsychiatric disorders, but no data specific to autism for expressive language disorder is disclosed. Summary of the Invention Means for Solving the Problems

[0014] Summary of the Invention The present invention provides a pharmacological method. A therapeutically effective amount of a succinimide antispasmodic agent (e.g., ethosuximide, methsuximide, phensuximide, or a pharmaceutically acceptable salt thereof) is preferably administered to a human with autism for a long period of time. In one embodiment, the drug is administered daily or twice a day for at least 1 month, more preferably at least 3 months, more preferably at least 6 months, thereby improving a person's expressive ability and the ability to converse with others.

[0015] Brief Description of the Drawings The present invention is better understood when considered in conjunction with the accompanying drawings, which is a graph illustrating the effect of administering ethosuximide ("ETS") over time to patients with autism according to one aspect of the present invention. Brief Description of the Drawings

[0016]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0017] Detailed Description In a first aspect of the present invention, a pharmacological method for treating expressive language disorder in autistic human children or adults is provided. A therapeutically effective dose of a succinimide anticonvulsant is preferably administered to a patient suffering from expressive language disorder over a long period, for example, one month, two months, three months, six months, or more. Non-limiting examples of succinimide anticonvulsants include ethosuximide, methsuximide (also known as mesuximide), and phensuximide, and their structural formulas (I - III) are shown below. Ethosuximide (2 - ethyl - 2 - methylsuccinimide):

Chemical formula

Chemical formula

Chemical formula

[0018] The use of ethosuximide, methsuximide, and phensuximide as antiepileptic drugs is well established. Ethosuximide is a drug of choice for treating absence seizures in childhood. It is known to block T-type calcium channels and is not known to affect mood or behavior. Ethosuximide is sold by Pfizer Inc. (NY, NY) under the brand name Zarontin®. It is available in capsule and syrup forms. Methsuximide is also sold by Pfizer under the brand name Celontin®. Phensuximide is sold under the trademark Milontin®.

[0019] As an alternative to using any of the antispasmodic compounds of Formulas I - III, a pharmaceutically acceptable salt thereof is administered to an autistic patient, preferably for an extended period, such as 1 - 6 months or more. A non-limiting example is ethosuximide hydrochloride, which is prepared by treating ethosuximide with hydrochloric acid. More generally, any pharmaceutically acceptable salt of ethosuximide, methsuximide, or phensuximide can be utilized. Synthetic methods for preparing pharmaceutical salts are found in standard texts such as Handbook of Pharmaceutical Salts (P. Heinrich Stahl and Camille G. Wermuth, eds.), published jointly by Verlag Helvetica Chimica Acta (Zurich, Switzerland) and Wiley-VCH (Weinheim, Germany), 2008, chapter 11, pp. 249 (hereinafter referred to), which is incorporated herein by reference.

[0020] Autistic patients presenting with expressive language disorder symptoms should be evaluated by a pediatric neurologist before treatment is initiated, with special attention paid to the patient's language abilities and limitations. In one embodiment of the invention, ethosuximide, methsuximide, or phensuximide, or a pharmaceutically acceptable salt of ethosuximide, methsuximide, or phensuximide is administered to the patient. The patient's language skills should be evaluated regularly before treatment is initiated and during a series of treatments. It is preferable to administer the drug at least daily for at least 1 month, more preferably for at least 2 months, more preferably for at least 3 months, and even more preferably for 6 months or more. The drug can be administered once a day, but good results are seen with twice-daily (b.i.d.) administration.

[0021] The drug dosage is determined by the patient's age and weight, and younger, lighter patients typically receive lower dosages than older children, teenagers, and adults. Dosages can be expressed as milligrams of drug per kilogram of body weight per day (mg / kg / day), or on an absolute basis (e.g., 1000 mg / day), a twice-daily (b.i.d.) basis (e.g., 500 mg b.i.d.), etc. In one embodiment, the drug is administered at a dosage of 10 - 60 mg / kg / day. For younger, smaller children, appropriate dosage ranges are 20 - 40 mg / kg / day, 20 - 30 mg / kg / day, or 20 - 22 mg / kg / day. Positive effects are seen even at low dosages as low as 10 or 11 mg / kg / day. For teenagers and adults, appropriate dosages are 150 - 1000 mg b.i.d., more preferably 500 - 1000 mg b.i.d.

[0022] Two non-limiting examples may be helpful: (1) A 5-year-old patient weighing 44 lb (20 kg); dosage: (22 mg / kg / day) × 20 kg = 440 mg / day or 220 mg b.i.d., (2) A 15-year-old patient weighing 110 lb (50 kg); dosage: (40 mg / kg / day) × 50 kg = 2000 mg / day, or 1000 mg b.i.d.

Example

[0023] Experimental methods, examples, and results To assess the effectiveness of ethosuximide as a pharmacological treatment for expressive language disorder, 24 human patients were treated with ethosuximide (ETS) for at least 1 month, more preferably 6 months or more. Throughout the series of treatments, typically every 1 - 3 months, their language, social, and behavioral skills were monitored. The study participants (subjects) were divided into four treatment groups based on their neurodevelopmental level (mental state): normal IQ (NIQ), borderline IQ (BIQ), mild mental retardation (mMR), and moderate mental retardation (moMR). Language skills (expressive, receptive), social behavior (social interaction, eye contact, participation), and mood (emotion, irritability, lability) were evaluated at various time points. Verbal output was categorized using a 7 - point scale (0 - 6), where 0 = non - verbal, 1 = echolalia (the patient can respond by repeating the speaker's words as they are), 2 = single word (the patient can respond with a single word), 3 = phrase (the patient can respond with a simple phrase), 4 = sentence (the patient can respond with a complete sentence), 5 = spontaneous speech (the patient can speak spontaneously), and 6 = reciprocal conversation (the patient can have a real conversation with another person). The 7 - point scale for evaluating expressive language is summarized in Table 1.

[0024]

Table 1

[0025] The social behavior and mood symptoms, based on those described in the Aberrant Behavior Checklist, an established behavioral assessment system used in the evaluation of patients with intellectual disabilities (see Aman, M G., et al., “The Aberrant Behavior Checklist: A behavior rating scale for the assessment of treatment effects,” American Journal of Mental Deficiency, 89(5):485-491 (1985), which is incorporated herein by reference), were also categorized on a 7-point scale (0±3). Patients had zero values at baseline (pre-treatment scores), and plus scores (+1 to +3) or minus scores (-1 to -3) were given if their symptoms improved or deteriorated, respectively, mildly, moderately, or severely. Social behavior and mood data are presented below in Table 8.

[0026] The demographic characteristics of the patients (number, gender, age, mental status, prescription drug dosage, and length of treatment (Rx)) are summarized in Table 2.

[0027]

Table 2

[0028] Tables 3 and 4 provide further details of the patients' demographic characteristics based on mental status and duration of treatment.

[0029]

Table 3

[0030]

Table 4

[0031] It is common for individuals with autism to receive one or more pharmaceuticals as a treatment for various conditions and symptoms including attention deficit / hyperactivity disorder, irritability, mood swings, anxiety, seizures, and the like. Many of the subjects undergoing ETS treatment as described herein took other pharmaceuticals intermittently or throughout the entire duration of the ETS trial. These are summarized in Table 5.

[0032]

Table 5

[0033] As can be seen from Table 5, subjects in the NIQ and BIQ groups typically took fewer concomitant pharmaceuticals than subjects in the mMRI and moMRI groups.

[0034] To evaluate the onset of drug efficacy and action, each patient was monitored for changes in language, social behavior, and mood at various times after the start of ETS treatment. Table 6 summarizes the behavioral characteristics observed for each function (expressive language, mood, behavior) at t = 1 month after the start of treatment and at t = 3 months after the start of treatment.

[0035]

Table 6

[0036] The overall effectiveness of ethosuximide as a treatment for expressive language disorder is illustrated in Figure 1, which presents expressive language scores as a series of histograms for four mental state groups (NIQ, BIQ, mMR, and moMR). Subjects were scored before treatment (baseline, BL) and 6 months later (Rx). Figure 1 presents data for patients who received ETS treatment for more than 1 month. The number of subjects (N) in each group, as well as the mean expressive language scores at baseline (BL) and 6 months later (Rx), can be summarized as follows: For subjects in the NIQ group (N = 8), expressive language increased from 2.5 to 4.4. For the BIQ group (N = 4), the mean score increased from 1.7 to 2.75. For the mMR group (N = 6), the mean score increased from 1.3 to 2.5. For the moMR group (N = 2), the mean score increased from 0.5 to 1.0. For each group, N reflects the number of patients who received ETS treatment for more than 1 month.

[0037] All four groups of patients improved after ETS treatment. The improvement in expressive language scores seen in the normal IQ group (N = 8) is particularly impressive. The mean (average) score for these 8 patients increased to 4.4 by the end of the trial, an improvement of approximately 2 points (1.9). Notably, their language skills improved on average from the ability to use a few words or speak in phrases to the ability to respond in complete sentences or, indeed, to speak spontaneously.

[0038] Figure 2 presents expressive language data for two autistic subjects treated with ETS according to the present invention: Patient A, a 3.5-year-old boy with absence epilepsy and a normal IQ, and Patient B, also a 12-year-old boy with a normal IQ. Both patients showed some spontaneous speech by 9 months from the start of treatment with ETS.

[0039] Patient A's expressive language improved slowly during the first three months of ETS treatment. When first evaluated (baseline, BL), he could only speak single words (score of 2). One month after the start of ETS treatment, he spoke more words. Three months later, he progressed from using single words to using phrases (score of 3). By 6 - 9 months, he was responding with complete sentences, and by 9 - 12 months, he could speak spontaneously and even ask questions.

[0040] Regarding Patient B, similar improvements in speech were noted over a period of 6 - 9 months. Before treatment, Patient B would repeat the words of others and speak a few two - word phrases. Three months after the start of treatment with ETS, he seemed more focused and calm. He spoke three - and four - word phrases. By the 6th month, Patient B could speak in sentences, and by the 9th month, he could sometimes engage in spontaneous conversation.

[0041] Table 7 provides specific examples of the improvement in expressive language shown by Patients A and B at various points during ETS treatment.

[0042]

Table 7

[0043] The effect of ethosuximide on long - term language acquisition was comparable to the time course of language development in normal (non - autistic) children. Non - autistic children at 12 - 15 months of age typically have a vocabulary of 4 - 6 words and can respond to simple questions without using words. Their spoken language is not always clear. By 18 - 23 months of age, the vocabulary can increase to 50 words, and the children can use two - word phrases and even combine words such as "more milk". From 2 - 3 years old, children can use three - word sentences. The data in Figures 2 and 3 reveal a similar trend in the development of autistic children treated with ethosuximide for 6 months or more.

[0044] Patients younger than 12 years old who were taking ETS also received speech and ABA (applied behavior analysis) therapy. Speech therapy was often given in 30-minute sessions twice a week, while ABA therapy was given 5 days a week for 2 - 3 hours a day. ABA therapy aims to train autistic patients to be more interested in social environments and has little to do with spoken language. These two therapies were beneficial because they gave patients opportunities to practice language skills in a supportive environment to improve language and social skills. These roles cannot be underestimated, but they are not easily measurable.

[0045] Ethosuximide was well tolerated at all ages evaluated. Common side effects reported in the literature for patients receiving ethosuximide treatment for childhood absence epilepsy include abdominal distress, diarrhea, weight loss, hyperactivity, drowsiness, leukopenia, and depression. These symptoms were rarely reported or observed in the patients participating in the study described in this specification. After 6 months or less, 11 patients stopped taking ETS. Five of these patients dropped out for non-medical reasons.

[0046] Patients who received ETS treatment for 6 months or more showed the greatest improvement in expressive language skills. In particular, when the treatment was stopped after 6 months, the patients did not lose their language acquisition. Figure 3 graphs the progress of expressive language for two patients who stopped ETS treatment after 6 months. Patient C was a 3-year-old autistic girl, and Patient D was a 12-year-old autistic boy. The times when the two patients interrupted ETS treatment are indicated by * and # respectively. Patient C received ETS treatment for 6 months, and her expressive language skills improved steadily. Then she interrupted the treatment. Patient D interrupted the treatment after 9 months. In particular, even after the ETS treatment was stopped, the patients' language skills did not decline or stagnate. In fact, when evaluated several months later, this continued to improve for both patients. This suggests that ethosuximide can activate the resting language network in the brain.

[0047] Advantageously, treatment with ethosuximide also results in improvements in other symptom domains, such as social behavior and mood, with the greatest gains seen in patients showing the greatest improvement in expressive language skills. Table 8 shows improvements above baseline in expressive language, social behavior, and mood after 6 months of ETS treatment. Patients with normal IQ who were treated with ethosuximide for more than 1 month had an average improvement in expressive language skills of approximately 2 points on the point scale of Table 1. Similarly impressive were the gains seen in social behavior and mood using the abnormal behavior checklist method described above (+2 points and +1.2 points, respectively). All groups, particularly the NIQ group, improved in social behavior after 6 months of ETS treatment. Most groups improved in mood, except for the moMR group, which showed no change.

[0048]

Table 8

[0049] Ethosuximide is typically prescribed to treat absence seizures, but the beneficial effects of ETS treatment on expressive language realized by the present invention are not due to the anti-seizure effects of ethosuximide. Of the 24 autistic patients considered here, only 7 had seizures. Three had childhood absence seizures and 4 had focal seizures. ETS treatment improved expressive language skills in both seizure and non-seizure patients.

[0050] Ethosuximide is known to block T-type calcium channels, but its mechanism of action in reducing expressive language impairment in autistic patients remains undetermined. Without being bound by theory, it is possible to speculate that ethosuximide acts on the brain's endogenous cannabinoid system or in a novel network that affects neurogenesis.

[0051] Regardless of its mechanism of action, several points can be noted. Improvements in expressive language and social skills were evident in autistic patients even one month after starting daily treatment with ethosuximide. These improvements progressed during treatment. The greatest gains occurred in patients treated for six months or more. In particular, the best results were seen in younger patients and those with normal IQ when ethosuximide treatment was combined with speech therapy and / or applied behavior analysis (ABA) therapy. (Older children in the study tended to have more behavioral problems and often did not receive social therapy.) Ethosuximide also works in adults, especially when combined with daily ABA therapy or similar treatments. Most notably, patients who discontinued treatment did not lose their language gains.

[0052] Ethosuximide drug therapy can be used to treat expressive language disorders in autistic patients, including those who are non-epileptic (have not experienced clinical seizures), epileptic (have experienced seizures), and those who manifest epileptiform abnormalities on electroencephalogram (EEG) but have not experienced clinical seizures.

[0053] Upon reading this disclosure, it will be apparent to those skilled in the art that the invention can be characterized in another way, namely, the invention comprises ethosuximide, fenethylline, methsuximide, or a pharmaceutically acceptable salt thereof for use in the therapeutic treatment of expressive language disorders in human autistics. In one embodiment, the active pharmaceutical ingredient (ethosuximide, fenethylline, methsuximide, or a pharmaceutically acceptable salt thereof) is administered to human autistics once or twice a day, for at least one month, preferably for at least three months, more preferably for at least six months or more, thereby reducing the expressive language disorder in human autistics.

[0054] In another aspect, the present invention can be characterized as a medicament for use in the therapeutic treatment of expressive language disorder in autistic humans, having as its active pharmaceutical ingredient ethosuximide, fenisuximide, methsuximide, or one or more of its pharmaceutically acceptable salts. Such a medicament can be prepared by formulating the active pharmaceutical ingredient with one or more additives, non-limiting examples of which include fillers, carriers, excipients, processing aids, preservatives, colorants, and the like.

[0055] Other embodiments and modifications within the scope of the present invention may be apparent to those skilled in the art upon reading the present disclosure. The present invention is limited only by the claims and their equivalents.

Claims

1. A pharmaceutical composition comprising ethosuximide for use in a method for treating an expression language disorder in a human child with autism who is not epileptic, comprising administering the ethosuximide to a human with autism who is not epileptic in a dose and for a period of time sufficient to alleviate the child's expression language disorder, wherein the dose is at least 300 mg / day.

2. The pharmaceutical composition according to claim 1, wherein the dose is 10 to 60 mg / kg / day (number of milligrams of ethosuximide per day of body weight), and the child is administered at least 300 mg of ethosuximide per day.

3. The pharmaceutical composition according to claim 1, wherein the aforementioned period is at least six months.

4. The pharmaceutical composition according to claim 2, wherein the dose is 20 to 40 mg / kg / day.

5. The pharmaceutical composition according to claim 1, wherein the dose is 150 to 1000 mg b. i. d.

6. The pharmaceutical composition according to claim 1, wherein the dose is 150 to 500 mg b. i. d.

7. The pharmaceutical composition according to claim 1, wherein the dose is 500 to 1000 mg b. i. d.

8. The pharmaceutical composition according to claim 1, wherein the ethosuximide is administered twice a day.

9. The pharmaceutical composition according to claim 1, wherein the ethosuximide is administered orally.

10. The pharmaceutical composition according to claim 1, wherein the dose and duration are sufficient to raise the child's expressive language skills by at least 1 point on a 7-point scale (where 0 = non-verbal, 1 = repeating what others say, 2 = single words, 3 = phrases, 4 = sentences, 5 = spontaneous speech, and 6 = reciprocal speech (real conversation with another person)).

11. The pharmaceutical composition according to claim 10, wherein the ethosuximide is administered for a period of time sufficient to raise the child's expressive language skills by at least 1.5 points.

12. The pharmaceutical composition according to claim 10, wherein the ethosuximide is administered for a period of time sufficient to raise the child's expressive language skills by at least two points.

13. The pharmaceutical composition according to claim 10, wherein the child has at least a normal IQ.

14. A pharmaceutical composition comprising ethosuximide for use in a method for treating an expression language disorder in an adult with autism who is not epileptic, comprising administering the ethosuximide to an adult with autism who is not epileptic in a dose and for a period of time sufficient to alleviate the expression language disorder of the adult, wherein the dose is at least 500 mg / day and the period is at least 3 months.

15. The pharmaceutical composition according to claim 14, wherein the period is at least six months.

16. The pharmaceutical composition according to claim 14, wherein the dose is at least 250 mg b. i. d.

17. The pharmaceutical composition according to claim 14, wherein the dose is at least 500 mg b. i. d.

18. The pharmaceutical composition according to claim 14, wherein the dose is at least 375 mg b. i. d.

19. The pharmaceutical composition according to claim 14, wherein the ethosuximide is administered twice a day.

20. The pharmaceutical composition according to claim 14, wherein the ethosuximide is administered orally.

21. The pharmaceutical composition according to claim 14, wherein the dose and duration are sufficient to raise the adult's expressive language skills by at least 1 point on a 7-point scale (where 0 = non-verbal, 1 = repeating what others say, 2 = words, 3 = phrases, 4 = sentences, 5 = spontaneous speech, and 6 = reciprocal speech (real conversation with another person)).

22. The pharmaceutical composition according to claim 21, wherein the ethosuximide is administered for a period of time sufficient to raise the expressive language skills of the adult by at least 1.5 points.

23. The pharmaceutical composition according to claim 21, wherein the ethosuximide is administered for a period of time sufficient to raise the expressive language skills of the adult by at least two points.

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