Critical Appraisal

Done by :Fatimah Al-Shehri.King Abdul-Aziz university.

Supervised by: Dr.Omar Jamjoom.

Introduction 1-What's autism?

2-Causes. 3-Symptoms.

4-Diagnosis.5 -Treatment.

Introduction: Definition :

Is known as a complex developmental disability. It results of a neurological disorder that has an effect on normal brain function, affecting

development of the person's communication and social interaction skills.

introductionCauses of autism:

1-Genetic predisposition.2Maternal illness during pregnancy.

3-Difficulty during pregnancy.4-Neurological &metabolic factors.

5-Impared immune system.

introduction

Pathophysiology:There is an imbalance of oxidative stress and anti-oxidative stress in children with autism.

IntroductionSymptoms:

1-Social-interaction difficulties.2-Communication challenges.

3-Repetitive behaviors.4-Speech problems.

IntroductionDiagnosis:

1-No medical test that can diagnose autism .2-Parents are the first to notice that their

child is showing unusual behaviors.

3-The Modified Checklist of Autism in Toddlers (M-CHAT) :is a list of informative questions about your child.

M-CHAT:

M-CHAT:

Introduction

Treatment:1-Behavioral treatments.

2-Medicines. 3-Treatment of the additional

medical conditions.

The Study of the critical appraisal.

Background:The aim of the study:

To examined the efficacy and safety of N-Acetylcysteine (NAC) augmentation for treating irritability in children & adolescents with (ASD).

Thesis of the study:Glutathione plays a significant role in defense against oxidative stress in autism.The level of glutathione in the cerebellum and temporal cortex of patients with autism are markedly decreased . The levels of reduced glutathione is lowered in autistic patients.

Background

Thesis of the study:N-acetylcysteine (NAC) is an antioxidant precursor to Glutathione .Considering the role of glutathione in autism and the effect of NAC on glutathione level, it is hypothesized that NAC as an augmentation agent decreases

irritability score.

Method:A- Diagnosis of autism: was made using DSM-IV-TR criteria. All interviewers were conducted by an experts child and adolescent psychiatrist.Assessments were performed by resident of

psychiatry trained to use the questionnaire an checklist.

Method:

.

B- Study design : It was a randomized double blinded study with two parallel groups .

C- Allocation: the patients were randomly allocated into one of the two groups using a random number generator.

Method:D-Intervention:

Resperidone started at 0.5mg/day and it was titrated up to 2g/day during 3 weeks for children less than 30kg.

The dose of children more than 30kg was up to 3mg/day.The dose of resperidone was not fixed and it could be changed considering clinical symptoms and adverse

effects.

E-Blinding :Double blinded ,both NAC and placebo tablets were administered in the form of effervescent. The other

group received risperidone plus placebo tablets . The shape ,size ,taste & color of NAC &placebo were

identical.

Method: Exclusion criteria

:Inclusion criteria:

1-Psychotic disorders. 1-Age between 3.5 to 26 years old from both genders.

2-Active substances abuse, unstable medical conditions.

2-Level of intelligence wasn’t excluded.

3-Evedence of active liver diseases. Seizures

disorders.

3-The participants should be able to take the medication.

4-Unstable hypertension or cardiac disease. Unstable asthma.

4-The patients were free from concomitant medications.

5-Kidney disease ,taking concomitant medications with glutamatergic effects (dextromethorphan,D.cycloserine,amantadine,memantine,lamotrigine,riluzole)

5-The dose of the medication should not be ,markedly changes during 2 weeks prior entering into the study.

6-Hypersensitivity to NAC .

Concomitant medications during the trial

Method:Statistical analysis:

Uses: Test:

Was used to perform statistical analyses . SPSS

Was used to compare the gender ratio between thetwo groups.

Chi-Square test

To compared the mean of age between the two groups .

Independent t-test

Used to examine the effect of interventions on the subscales scores of ABC.

ANOVA

Using Last Observed Carried Forward (LOCF) with at least one post-treatment evaluation was used to handle missing data.

Intent-to-Treat (ITT).

Was calculated to measure effect size. The Cohen’s.

Was set for being statistically significant. P value less than 0.05

Results

Flow chart for the clinical trial N-Acetylcysteine + risperidone versus Placebo+risperidone .

ResultsThe primary outcome was :Irritability.

The secondary outcomes : the adverse effects (Extrapyramidal symptoms).

Comparison of irritability scores between(NAC+Risperidone) group with

(Placebo +Risperidone) group .

Side effects:

Conclusion:NAC+risperidone decreased irritability in this

trial .This improvement in the NAC+risperidone group was more than that of the placebo+risperidone group.

Future trials with larger sample sizes, longer durations, and higher doses are required in order to examine the possible effects of NAC on autism

Competing interests:The authors declare that they have no competing interests.

Limitation of this study:1-The sample size was small.

2-The duration of current trial was very short .3-It is not clear whether the symptom will relapse

after the discontinuation of NAC .4-It is not examined whether this effect will be stable

in long term .

In order to have a more homogenous group, further studies should not include a wide range of children .

Finally, the concomitant use of risperidone may limit the efficacy of obtained results. Therefore, the efficacy of higher doses of NAC should be investigated in further trials .

Validity:Comment: Yes/No Validity (is the study valid?)

1-Randomization:It was randomized trial.

Yes . 1-Were patients randomized to treatment groups?

1-Ages between 3.5-16 years.

2-Some patients were taking concomitant medications during the trial.

Yes. 2-Were the treatment and the control groups similar at

the beginning of the trial ?

Comment: Yes/No: Validity (is the study valid?)

2-Allocation:The patients were randomly allocated into one of the two groups using a random number generator.

Yes. Was the randomization concealed?

Validity:Comment: Yes/No Validity (is the study valid?)

3-Blinding: Double blinded both (investigators and patients were blinded).

Yes . 1-Were measures objective or were the patients and clinicians kept blind to which treatment was being received? Who was blinded?

It wasn’t mentioned. No . 2-Compliance: was it assessed ,How

Some patients were using other medications for other concomitant illnesses.

Yes they treated equally.

3-Co-intervenstion?were groups treated equally?

1-Small sample size.2-Duration of the

trial very Short.

3 -Concomitant use of rispredone.

No. 4-Contamination: was it mentioned?

Validity:

Comment :Yes/No Validity (is the study valid?)

Intension to treat analysis or not?

It was ITT trial. Yes. 1-Were all patients who entered the trial accounted for ? And were they analyzed in the groups to which they

were randomized?

Sponsor?

This study was supported by grant from Shiraz University of Medical Sciences to prof.Ahmed Ghanizadeh.

1-How was the study funded?

Results Comment: Yes/

No:What are the study results?

Irritability. 1-What was the primary endpoint?

Lethargy,social withdrawal,sterotopic behaivor,hyperactivity ,noncomliance,noappropriate speech, adverse effects.

2-What was the secondary endpoint?

The irritability scale score decrease from 13.2to 9.7 in the NAC

+Risperdone group P-Value=<0.035(statistically significant

and clinically significant. ) The secondary endpoint :there were no difference between the two groups.

Yes. 3-Was there statistically significant difference between the treatments?

4-Was it clinically significant?

Results The mean (SD) scores of ABC subcsale in (NAC +risperdone) group and (Placebo+risperdone )group.

ResultsHow are the results expressed?

Day time drowzness:

EER=(Events in E group/total in E-group)=4/20=0.2

CER=(Events in C group/total in C group)=2/20=0.1

RR=EER/CER=0.2/0.1=2

100%((RRR=1-RR=1-2=1

ARR=CER-EER=0.1(10%)

NNT=100/ARR=100/10=10

For every 10 patients treated with NAC one patient will experince daytime drowzness.

Applicability:comment: Yes/

No:How can we apply the study

results to our patients?

Its not feasible because the sample

size was very small.

Yes. 1 -Will the intervention (NAC) be feasible in my settings?

Patients criteria matches the Criteria of our patients.

Yes. 2-Were the patients in this study

similar to my patients?

No potential harms ,it has a usual side effects which already presents in other medications the patients already use(risperdone).

Yes. 3-Will the potential benefits of treatments outweigh the potential harms of treatment for my patients?

its not coasty.

Yes ,because its well tolerated .

4-Potential costs (Cost effectiveness, direct vs. indirect costs ).

5-Will my patients prefer this intervention?