Autism Spectrum Disorder

Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurobiological disorder characterized by early onset, cognitive impairment, lack of social skills and stereotyped behaviors. The possible causes of ASD are follows: genetic and chromosomal variations, impairment in white matter connectivity and gary matter diffusivity, environmental factors, under-connectivity of functional brain regions and over-connectivity between neural assemblies. According to the Centers for Disease Control and Prevention (CDC) statistics, it is estimated that one in 68 newborns may suffer this disorder, and it affects four times number of females than males.

In current practice, there is no curative treatment for autism but the recommended treatment for autism involves educational therapy, speech therapy, sensory integration therapy and auditory therapy. Researchers have found some pharmacological agents to be effective in improving behavioral symptoms of ASD such as neurotransmitter reuptake inhibitors (fluoxetine), tricyclic antidepressants (imipramine), anticonvulsants (lamotrigine), atypical antipsychotics (clozapine), acetylcholinesterase inhibitors (rivastigmine), etc.

Case Study

In this trial, patient recruitment is a key challenge. The American psychiatric association's diagnostic and statistical manual gives a clear definition of autism, which can be used when recruiting patients. In addition, this diagnosis was corroborated by the Autism Diagnostic Interview Revised which was administered by an experienced child psychiatrist.

Another challenge is statistical analysis. Results are presented as mean±S.D. differences and were considered significant at pf0.05. A two-way repeated measures analysis of variance was used. The two groups were considered as a between subjects factor (group) and the five measurements during treatment were considered as a within-subjects factor (time) in the analyses. To compare the baseline data, differences in frequency of side-effects and frequency of extrapyramidal symptoms with the two treatments were assessed using Fisher’s exact test.

Design:

A 10 weeks, parallel group, placebo-controlled trial.

Participants:

The experiment was carried out at children's out-of-patient clinic of Roozbeh Hospital (TUMS) and recruited 40 patients (Figure 1).

The eligibility criteria to be met by all participants are as follows:

  • The children meet DSM IVTR criteria for diagnosis of autism (APA, 2000).
  • The children ages between 4 and 12 years.

The existence of any exclusion criteria will prevent participants from participating in this experiment. Exclusion criteria include the following conditions:

  • Children with schizophrenia or psychotic disorders
  • Having a history of drug or alcohol abuse or tardive dyskinesia
  • Having received any antipsychotic drug treatments 6 months prior to enrolment or having any significant active medical problem
  • Children with severe mental retardation
  • Children with active clinical seizures

A diagram shows the disposition of all subjects screened for the study.

Figure 1. A diagram shows the disposition of all subjects screened for the study.

Length of Enrollment Period:

10 weeks

Interventions:

Participants (n = 40) were randomly assigned to two groups of the same size, and received 10 weeks of treatment with memantine plus risperidone (n = 20) and placebo plus risperidone (n = 20), respectively. The dose of risperidone was titrated up to 3 mg/d and memantine was titrated to 20 mg/d. Participants were started on 5 mg/d memantine once daily. This was titrated up or down in 5-mg increments every week. These children were gradually titrated up to a maximum dose of 15 mg/d for children weighing between 10 and 40 kg and 20 mg/d for children weighing >40 kg. Children were assessed at baseline and after 2, 4, 6, 8 and 10 weeks of starting medication protocol.

Main Outcomes:

  • The irritability subscale of ABC-C (ABC-C is a 58-item tool to evaluate the existence and severity of disruptive behaviors and designated for rating the individuals with developmental disabilities)- primary outcome measure
  • Extrapyramidal symptoms rating scale - assessing extrapyramidal symptoms
  • Clinical complications and side-effects
  • Fisher’s exact test - assessing differences in frequency of side-effects and frequency of extrapyramidal symptoms with the two treatments

Results:

Compared with the placebo group, patients in the experimental group improved on multiple indicators of major outcomes. In the five types of behavioral anomalies assessed by ABC-C, the mean (S.D.) scores of the two groups of patients are shown in table 1. In irritability subscale, the difference between the two treatments was significant, as indicated by the effect of groupsrtime interaction (F=21.48, d.f.=1.78, pf0.001). In lethargy/social withdrawal subscale, the difference between the two treatments was not significant, as indicated by the effect of groupsrtime interaction (F=2.56, d.f.=1.43, p=0.10). In stereotypic behavior subscale, the difference between the two treatments was significant, as indicated by the effect of groupsrtime interaction (F=30.42, d.f.=1.53, pf0.01). In hyperactivity/non-compliance subscale, the difference between the two treatments was significant, as indicated by the effect of groupsrtime interaction (F=153.50, d.f.=1.53, pf0.01). In inappropriate speech subscale, the difference between the two protocols was not significant, as indicated by the effect of groupsrtime interaction (F=2.04, d.f.=2.20, p=0.13).

Table 1. Mean±S.D. of the two treatment arms on the five subscales of Aberrant Behavior Checklist–Community rating scale

Mean±S.D. of the two treatment arms on the five subscales of Aberrant Behavior Checklist–Community rating scale

Extrapyramidal symptoms were observed in five and six patients in the memantine and placebo groups respectively. No significant difference was observed between the two groups.

Eight side-effects were observed over the trial, out of the 25 side-effects that the checklist included. The difference between the two groups in the frequency of side effects was not significant (Table 2).

Table 2. The number of patients with side-effects

The number of patients with side-effects

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References:
1. Ghaleiha A, Asadabadi M, Mohammadi M R, et al. (2013) ‘Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial’, International Journal of Neuropsychopharmacology, 2013, 16(4):783-789.
2. Bhat S, Acharya U R, Adeli H, et al. (2014) ‘ Autism: cause factors, early diagnosis and therapies’, Rev Neurosci, 2014, 25(6):841-850.
3. Meng-Chuan L, Lombardo M V, Simon B C. (2014) ‘ Autism’,  Lancet, 2014, 383(9920):896-910.
4. Kumar B, Prakash A, Sewal R K, et al. (2012) ‘ Drug therapy in autism: a present and future perspective’, Pharmacological Reports, 2012, 64(6):1291-1304.

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