ANTON et al. ORIGINAL PAPERS PHARMACOLOGICAL THERAPY OF AUTISM SPECTRUM DISORDERS IN THE CLINICAL PRACTICE Andra ISAC 2, Magdalena KWASIUK 1, Roxana ȘIPOȘ 1, Ioana MICLUȚIA 1, Viorel LUPU 1, Elena PREDESCU 1 1 Iuliu Hațieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 2 Child and Adolescent Psychiatry and Addiction Clinic Children s Emergency Hospital Cluj Napoca, Romania ABSTRACT Although there is no specific pharmacological treatment for autism spectrum disorders (ASD), psychotropic medication is used frequently in clinical practice. 34 patients were included in the study, with ages between 3 and 17 years, treated in the Child and Adolescent Psychiatry Cluj Napoca, during the 1st and 31st January 2015, with a diagnosis of ASD based on DSM IV TR and ICD-10 criteria, after structured clinical interview for infant, child and adolescent disorders (KID-SCID). Exclusion criteria: major somatic disorders, incomplete medical records. The medication taken into consideration included: antipsychotics, methylphenidate, atomoxetine, antidepressants, sleep medication and mood stabilizers. The data was analyzed using SPSS 17. The average age was of 9.26 years, with a high prevalence of male patients (4:1) and the urban area. 70.5% of patients were diagnosed with typical childhood autism, 17.6% with atypical autism and 5.8% with Asperger s syndrome. 56% of patients participate in one therapy session/ week and only 4 % to less than one session/week. 79.41% have been prescribed psychotropic medication (atypical antipsychotics 23.5%, atomoxetine 8.82%, methylphenidate 14.7% and mood stabilizers 5.8%), with 23.5% of patients having been prescribed 2 or more drugs. Distribution according to gender has been consistent with scientific works and pharmacological therapy is the one described in recent papers. The high number of patients under pharmacological treatment might be explained by the low level of specific behavioral therapy, considerably below the number of recommended hours. Further research is needed to test the appropriate use, efficacy and long-term safety of psychotropic medication in the treatment of ASD. Keywords: autism spectrum disorders, pharmacological therapy, child, adolescent INTRODUCTION Autism spectrum disorders and associated comorbid disorders significantly impact social outcomes, education and health due to their early onset, their lifelong persistence and associated pervasive impairments. Corresponding Author: Andra Isac, Resident Physician, Child and Adolescent Psychiatry and Addiction Clinic Children s Emergency Hospital Cluj Napoca, National Coordinator & IT manager for the Exchange Programme at European Federation of Psychiatric Trainees Individuals with ASD have a very high prevalence of comorbid mental health conditions including attention-deficit hyperactivity disorder (ADHD), learning disabilities, oppositional or conduct disorder, emotional disorders, anxiety and other phobic disorders and chronic tic disorder [1]. Medication may be a helpful therapeutic intervention to manage disabling behavioral and/or mental health symptoms in autistic population; however, there are currently no practice guidelines in place [2]. Volume 3, Issues 3-4, July-Decembre, 2015
ISAC et al. Despite the fact that there is no standard medication for treating ASD, patients are prescribed a variety of psychotropic medications (there is scant reliable research evidence supporting this practice for adolescents and adults) [3]. To date we have very little data about the pharmacological treatment of children with ASDs and associated comorbid disorders. Information about prescribing practices and comorbidities is necessary to further research the efficacy and longterm safety of psychotropic medications in this particular patient population. The aim of this study was to investigate the status of practice in child and adolescent mental health services regarding psychopharmacological prescriptions and related comorbidities of children and adolescents with ASD diagnosis. MATERIAL AND METHOD We conducted an analytical retrospective observational study focused on a well-defined category of patients: children with autism spectrum disorders. Data was collected from 34 children aged 3 to 17 years, with a diagnosis of ASD according to the international diagnostic criteria of DSM IV TR and ICD-10 after applying the structured clinical interview for infant, child and adolescent disorders (KID-SCID). For this clinical group (ASD) the main data source was represented by the consultation files within the Child and Adolescent Psychiatry Clinic in Cluj Napoca which also serves neighboring counties. For all children enrolled in the study, we used medical data while ensuring privacy and the subjects identity protection. Children with a known medical condition (metabolic, genetic, neurological or major somatic diseases) and children with incomplete medical records were excluded from the study. We included seven categories of drugs: antipsychotics, stimulants (methylphenidate), atomoxetine, antidepressants, benzodiazepines, sleep medication and mood stabilizers. The prescriptions of each recorded patient were identified, and the proportions of the ASD sample prescribed drug treatment were calculated by drug category and by individual drug. The clinical records of each patient were screened for comorbidities. Diagnostic codes were categorized into eight groups: ADHD, ODD, mental retardation (mild, moderate, and severe), anxiety disorders, sleep disorders and language delay. The proportions of the sample with comorbidities were calculated. The statistical software used for data analysis was the SPSS 17 program. In order to describe the studied population and questionnaire data, we used univariate statistical analysis (mean, median, frequency tables). RESULTS Demographic and clinical characteristics of the ASD The mean age of the patients in the sample was 9.26 years (SD=2.92). The group was comprised of 17.65% girls and 82.35% boys, with 67.65% of them coming from an urban area and 32.35% from a rural environment. In the study sample only 2 children are not enrolled in school. 19 children go to a normal school and 13 children are enrolled in special needs school. Children suffering from cognitive disabilities are recommended to try the inclusion in a normal school with a special curriculum and if needed, with an accompanying person. Multiple categories of autism are described in the chapter for pervasive developmental disorders in ICD 10: childhood autism, atypical autism, other childhood disintegrative disorder, overactive disorder associated with mental retardation and stereotyped movements, Asperger's syndrome, Romanian Journal of Child and Adolescent Psychiatry
Pharmacological therapy of Autism Spectrum Disorders in the clinical practice other pervasive developmental disorders, pervasive developmental disorder, unspecified (ICD). In our sample 24 children were diagnosed with typical autism (correspondent term in DSM V is autism spectrum disorders), 6 children with atypical autism and 2 children with Asperger s syndrome. All the patients included in the study had at least one record of a neuropsychiatric comorbidity on or after their first recorded diagnosis of ASD on the database. The most common neuropsychiatric comorbidities were ADHD and mental disabilities (Table I). Table I. Comorbidities Table II. Types of drugs and number of patients taking them In terms of interventions 73.53 % of the patients were included in a form of psychotherapy. The majority of the children included in the study have at least 1 psychotherapy session per week. Psychotropic drugs were prescribed to 79.41% of the ASD sample. The most frequently prescribed drugs were atypical antipsychotics, atomoxetine, metilphenidate and moodstabilizers. 8 patients have prescriptions for two or more drugs. There are no prescriptions for benzodiazepines and sleep inducing drugs among the children. The most commonly prescribed atypical antipsychotic drugs were risperidone (8 patients) and aripiprazole (7 patients). However, 19 patients out of 34 don`t have prescriptions for any atypical antipsychotic. The majority of children in the studied sample (58.82%) reported behavioral problems, represented by irritability, aggressiveness, self-harm. Individuals with ASD and their family usually demand clinical care for them. In our sample 15 children received drugs for behavioral problems like irritability and aggressiveness. Although there is limited evidence to guide psychotropic medication use in the ASD population, two drugs have shown efficacy for the alleviation of behavioral symptoms in children and adolescents with autistic disorder: risperidone [4] and aripiprazole [5]. In 2006, risperidone was approved by the Food and Drug Administration (FDA) in the USA for the treatment of irritability associated with autistic disorder in 5 to 16 year olds; including aggression and deliberate self-harm. Aripiprazole was also approved by the FDA in 2009 after demonstrating efficacy in the same indication in 6 to 17 year olds [5]. In our sample 15 children out of 18 under pharmacological treatment have prescriptions for atypical antipsychotic and only 3 children have prescriptions for mood stabilizers. In childhood, there may be overlapping diagnostic between ASD and ADHD, making the differential diagnosis difficult. The most frequent comorbidity in our sample was ADHD (73.53%). Despite this, only 47% of children Volume 3, Issues 3-4, July-December, 2015
ISAC et al. with both ASD and ADHD have specific pharmacological treatment. The most prescribed drugs for the ADHD treatment by psychiatrists are stimulants and non-stimulants. In our sample this classes of ADHD drugs are prescribed equally (7 patients received metilphenidate and 8 patients received atomoxetine). DISCUSSIONS Our data offers an image of the usual prescribing pharmacological drugs practices for children with autism. We found that in our sample all the patients had at least one comorbidity recorded in their medical file following ASD diagnosis, the most common being ADHD and mental disabilities. Simonoff et al. [1] found in their SNAP cohort that 28.2% were comorbid with ADHD, 30.0% had oppositional or conduct disorder and 41.9 % had anxiety or phobias; our sample had much higher proportions of ADHD and much lower proportions of others comorbidities. These differences may appear due to communication impairment or cognitive problems in individuals [6] and diagnose difficulties. Pharmacological interventions may increase the ability of persons with ASD to benefit from education and other interventions, and to remain in less restrictive environments through the management of severe and challenging behaviors. 79.41 % of our sample received psychotropic drug prescriptions in clinical care. In contrast, Mandell et al. [7] found that 56% of Medicaid-enrolled youths with ASDs aged 0 21 years received at least one psychotropic drug. There was no more conservative use of psychotropic drugs in our ASD sample compared with the practices described in others studies. In the past two decades, advances in the pharmacological treatment of children and adolescents in psychiatry have resulted in the use of typical and atypical antipsychotics to target specific symptoms for a variety of disorders, including bipolar disorder, schizophrenia, obsessive compulsive disorders or ASD. Poor frustration tolerance, impulsivity, aggression, mood instability are among the various symptoms treated with antipsychotics. Since the late 1990s, there has been a transition from the use of typical antipsychotics such as haloperidol, chlorpromazine, and fluphenazine to atypical antipsychotics such as risperidone, olanzapine, quetiapine, and aripiprazole in the treatment of these symptoms. Recently, in children and adolescents with autism, antipsychotic medications have been used more frequently to treat symptoms of irritability, aggression, and selfinjury. In our sample almost half of the patients received atypical antipsychotics. A recent survey looking specifically at psychotropic drug use in children with pervasive developmental disorders revealed that half of the patients were currently being prescribed a psychotropic drug, and approximately 16.5% were taking an antipsychotic drug in conjunction with behavioral interventions, such as applied behavioral analysis [8]. Others studies have shown that 24 31% of individuals with ASD have taken an atypical antipsychotic. This has led to this class of medications accounting for the majority of prescriptions in the ASD population [7]. We found in our study a large proportion of specific ADHD treatment (stimulant and nonstimulant) prescriptions. The increase in the prescription of these drugs over time may reflect the increasing recognition of comorbid ADHD (and its persistence) in young people with ASDs. Our results are similar with those found by Simonoff et al. [1] or Frazier et al. [2]. More recently, optimal dosing of methylphenidate was shown to be effective in reducing ADHD symptoms in about 40 % of children with intellectual disability. Romanian Journal of Child and Adolescent Psychiatry
Pharmacological therapy of Autism Spectrum Disorders in the clinical practice Two thirds of the autistic population is reported as having moderate sleep disturbances [9]; however, no patient in our sample received sleep medication or benzodiazepines; it is likely that physicians only consider prescribing pharmacological treatments to patients with severe sleeping disorders or they avoid prescribing these classes of drugs all together. CONCLUSIONS Treatment of core and associated symptoms of autism spectrum disorder should be multimodal. Use of medication should be directed toward specific, clearly identified target symptoms or comorbid condition. The only US FDA-approved medications in individuals with ASD are risperidone and aripiprazole. They are both approved for the treatment of irritability in youths with autism. In our sample, 79.41% of children receive at least one psychotropic drug prescription, mostly for atypical antipsychotics and specific ADHD treatment (stimulant and non-stimulant). Hence, further research into the appropriate use, efficacy and longterm safety of any drugs in autistic population is warranted to support clinical practice for optimal and safe treatment of ASDs and their comorbidities. pharmacological treatments for adolescents and adults with autism spectrum disorder. Autism 11(4):335 348 4. Shea S, Turgay A, Carroll A, Schulz M, Orlik H, Smith I, Dunbar F (2004). Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics. Nov;114(5):e634-41 5. Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH, Aman MG (2009), A placebocontrolled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry. Nov;48(11):1110-9. 6. Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, Tager-Flusberg H, Lainhart JE (2006), Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. JAutismDev Disord. 7. Mandell DS, Morales KH, Marcus SC, Stahmer AC, Doshi J, Polsky DE (2008) Psychotropic medication use among Medicaid enrolled children with autism spectrum disorders. Pediatrics 121(3):e441 e448. 8. Aman M.G., Lam K., Van Bourgondien M.E. (2005). Medication patterns in patients with autism: Temporal, regional and demographic influences. Journal of Child and Adolescent Psychopharmacology, Vol. 15, No 1 9. Souders MC, Mason TB, Valladares O, Bucan M, Levy SE, Mandell DS, Weaver TE, Pinto-Martin J. (2009), Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep.;32(12):1566-78. REFERENCES 1. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a populationderived sample. J Am Acad Child Adolesc Psychiatry 47(8):921 929 2. Frazier TW, Shattuck PT, Narendorf SC, Cooper BP, Wagner M, Spitznagel EL. Prevalence and correlates of psychotropic medication use in adolescents with an autism spectrum disorder with and without caregiverreported attention-deficit/ hyperactivity disorder. J Child AdolescPsychopharmacol. 2011 Dec;21(6):571-9 3. Broadstock M, Doughty C, Eggleston M (2007) Systematic review of the effectiveness of Volume 3, Issues 3-4, July-December, 2015
ISAC et al. Romanian Journal of Child and Adolescent Psychiatry