A Review and Comparison of Efficacy and Side Effects of Risperidone Vs

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A Review and Comparison of Efficacy and Side Effects of

Risperidone vs. Fluoxetine in the treatment of Autism

Spectrum Disorder

By

Kimberly Bolin

May 6, 2010


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Abstract

Objective: To review the current use of risperidone and fluoxetine in children

with Autism Spectrum Disorder(ASD) and compare the efficacy of each drug on

relieving major symptoms of the disorder. Method: Three papers, for each drug,were chosen on the efficacy and side effects in the treatment of children with

ASD. Results: Fluoxetine appears to produce significant improvement in global

functioning, repetitive behaviors, and anxiety. Risperidone seems to produce

significant improvement in control of activity level, stability of affects, and lesser

withdrawl. Side effects with fluoxetine were comparable to placebo while side

effects of risperidone were common and potentially serious Conclusion: Both

risperidone and fluoxetine appear to show good efficacy in treating major

symptoms of ASD but they appear to treat different symptomology. While

fluoxetine can be used with little or no side effects, risperidones propensity for

causing weight gain makes it less desirable unless severe anger, temper tantrums,

or hyperactivity are the main concerns.

Autism Spectum Disorder (ASD) is a developmental disability characterized by

global impairments in many developing systems. ASD is on the rise and its

estimated prevalence is 1 of 99 births. The DSM-IVTR defines ASD as:

(I) A total of six (or more) items from (A), (B), and (C), with at least two from (A), and

one each from (B) and (C)

(A) qualitative impairment in social interaction, as manifested by at least two of the

following:

1. marked impairments in the use of multiple nonverbal behaviors such as eye-to-

eye gaze, facial expression, body posture, and gestures to regulate social

interaction

2. failure to develop peer relationships appropriate to developmental level

3. a lack of spontaneous seeking to share enjoyment, interests, or achievements

with other people, (e.g., by a lack of showing, bringing, or pointing out objects of

interest to other people)

4. lack of social or emotional reciprocity ( note: in the description, it gives the

following as examples: not actively participating in simple social play or games,

preferring solitary activities, or involving others in activities only as tools or

"mechanical" aids )


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(B) qualitative impairments in communication as manifested by at least one of the

following:

1. delay in, or total lack of, the development of spoken language (not

accompanied by an attempt to compensate through alternative modes of

communication such as gesture or mime)

2. in individuals with adequate speech, marked impairment in the ability to initiateor sustain a conversation with others

3. stereotyped and repetitive use of language or idiosyncratic language

4. lack of varied, spontaneous make-believe play or social imitative play

appropriate to developmental level

(C) restricted repetitive and stereotyped patterns of behavior, interests and activities, as

manifested by at least two of the following:

1. encompassing preoccupation with one or more stereotyped and restricted

patterns of interest that is abnormal either in intensity or focus

2. apparently inflexible adherence to specific, nonfunctional routines or rituals

3. stereotyped and repetitive motor mannerisms (e.g hand or finger flapping or

twisting, or complex whole-body movements)4. persistent preoccupation with parts of objects

(II) Delays or abnormal functioning in at least one of the following areas, with onset prior to age

3 years:

(A) social interaction

(B) language as used in social communication

(C) symbolic or imaginative play

(III) The disturbance is not better accounted for by Rett's Disorder or Childhood Disintegrative

Disorder

It can be seen from this diagnostic criteria that ASD is a complex and varied

disorder that can devastate families and keep these children from being

contributing members of their communities. Many therapies have been used

to treat the many different aspects of ASD including, ABA, OT, PT, language

therapy, music therapy, equine therapy, behavioral modification, auditory

integration therapy, picture exchange system, sensory integration, social skills

training, and social stories. Some nontraditional medical treatments have

also been tried including chelation and gluten - casein free diets (Goin-Kochel

et al). While it has been determined that early intervention leads to the best

possible outcomes, ASD in its milder forms can be difficult to diagnose,

making early intervention impossible. Since no cure exists for ASD, drugs

such as antidepressants, antipsychotics, and anxiolitcs are used to reduce the

major symptoms of the disorder. This will allow the child to better interact

with the world thus increasing education and training opportunities in the


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hope that they will be able to interact and contribute to the community. Some

drugs have received more study than others to determine their effects on

children with ASD. Here the focus will be fluoxetine and risperidone.

Fluoxetine is a second generation antidepressant. The PDR defines fluoxetine

as: a selective serotonin reuptake inhibitor (SSRI) used to treat depression,

obsessive-compulsive disorder, panic attacks, certain eating disorders

(bulimia), and a severe form of premenstrual syndrome (premenstrual

dysphoric disorder or PMDD). This medication works by restoring the balance

of neurotransmitters in the brain, specifically serotonin. The mechanism

believed to be responsible for this is increasing serotonin levels by blocking

reuptake which then leads to a down regulation of receptors, optimizing

serotonin levels in the brain. This drug is also used to treat certain other

eating disorders (anorexia nervosa), obesity, and depression associated with

bipolar disorder. The FDA approved Fluoxetine in December 1987. Since its

approval, it has also been used offlabel to treat ASD.

DeLong and colleagues performed an open-label study of fluoxetine in 37

children (2-7years old) using non standard measures, which included various

instruments covering a wide range of functions. Assessments by

independent evaluators were included as well. Approximately 59% were

considered to have a positive result from the medication includingimprovements with language and social interactions. Side effects were minor

and included hyperactivity and agitation. This study appears to support the

use of fluoxetine in treating ASD; however, due to the lack of double blinds,

placebo controls, and no standardized outcome measures, this study is

unreliable on its own.

In a placebo controlled study by Hollander et al, the efficacy of fluoxetine was

examined in 45 children ranging in age from 5 to 16 whom had a diagnosis of

ASD. The study was conducted during a 20wk period divided into two 8-week

sessions with a 4-week waiting period in-between. Outcomes were measured

using the Childrens Yale-Brown Obsessive Compulsive Scale (CYBOCS), the

CGI adapted for global autism (CGI_AD), and a Global Autism Composite

Improvement Measure. All study participants were kept free of concurrent

medications throughout the study. Over a two week period, fluoxetine dosage

was titrated to a maximum of .8 mg/kg per day dependent upon symptoms


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and side effects. The average daily dose was 9.90 mg daily. The CYBOCS

measure showed a significant reduction in repetitive behaviors over the

placebo control group. The global autism composite improvement measure

showed no statistically significant improvement over placebo neither did the

CGI-AD. There were no difference in side effects between the fluoxetine andthe placebo group. Side effects were minimal and included sedation or

agitation. Side effects were related to dosage of fluoxetine with 16% of

participants requiring a reduction due to agitation. Efficacy was shown at low

levels which appears to have lead to far fewer side effects.

Cook and colleagues examined the efficacy of fluoxetine using an open-label

design in 23 individuals with ASD (age 7-52) and 16 individuals who had

mental retardation without ASD. The CGI was used to assess the

improvement of overall severity of symptoms and specifically, repetitive

behaviors. The dosage of fluoxetine ranged from 20mg and 80mg daily in anopen titration. 15 of the 23 ASD patients and 10 of the 16 mentally retarded

patients showed improvement in global functioning as well as a reduction of

perseverative and compulsive behaviors. Side effects were hyperactivity,

insomnia, decrease appetite, or sedation. Side effects tended to be seen more

often in nonresponders and abated after reduction or discontinuation of

treatments.

Based on these studies, fluoxetine would appear to be an effective overall

treatment for symptoms of ASD, including an increase in global functioning, adecrease in withdrawal, anxiety, and repetitive behaviors. With few side

effects, especially at lower doses, fluoxetine shows promise for treating ASD

symptoms.

Risperidone is an atypical antipsychotic. The FDA has approved risperidone

for the treatment of schizophrenia, bipolar disorder, and autism spectrum

disorder. According to the manufacturer The mechanism of action of

RISPERDAL, as with other drugs used to treat schizophrenia, is unknown.

However, it has been proposed that the drugs therapeutic activity in

schizophrenia is mediated through a combination of dopamine Type 2 (D2)and serotonin Type 2 (5HT2) receptor antagonism. RISPERDAL is a

selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)

for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2

adrenergic, and H1 histaminergic receptors. RISPERDAL acts as an

antagonist at other receptors, but with lower potency. RISPERDAL has low


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to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and

5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1

and haloperidol-sensitive sigma site, and no affinity (when tested at

concentrations >10-5 M) for cholinergic muscarinic or 1and 2 adrenergic

receptors. The clinical effect from RISPERDAL results from the combined

concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone.Antagonism at receptors other than D2 and 5HT2may explain some of theother effects of RISPERDAL.

In 2001, Masi et al. did a 16-week open trial of risperidone monotherapy in

young children with ASD. Twenty-four children between the ages of 3.6 and

6.6 years participated. Baseline assessments were taken for all physiological

measures and repeated every 4-weeks and at the end of the trial. Symptom

assessment tools used consisted of the Childrens Psychiatric Ratings Scale

(CPRS), Childhood Autism Ratings Scale (CARS), CGI-I, Childrens GlobalAssessment Scale (C-GAS), and Assessment of Intellectual Functioning usingGriffiths Developmental Scale. All subjects were started on a dose of .25mg at

bedtime. Titration was at .25mg increments weekly as needed depending on

clinical response and occurrence of side effects. Maximum dose of .75mg was

not exceeded and the average dosage was 0.49mg. Two patients did not

complete the study due to side effects. CPRS scores at the end of the trial

showed a 21% improvement over baseline with significant improvement in

the following areas (p


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other psychoactive drug during the course of the study. Baseline assessments

were made of all relevant physiological measures, including prolactin levels in

37 of the patients. Rating scales used were CARS, CPRS, CGI-I, C-GAS, and

Griffiths Developmental Scale to assess intelligence functioning. All subjects

were started on a dose of 0.25mg at bedtime. Titration at 0.25mg weeklydepending on clinical response and side effects with a maximum dose of 1mg

daily. The average length of follow-up was 7.9+/-6.8months. 25 participants

continued on risperidone while 28 discontinued its use. Optimal dosage was

0.55+/-0.2mg/daily. As with the previous study, CPRS scores at the end of

the trial showed a 21% improvement over baseline with significant

improvement in the following areas (p


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and 4 were lost to follow-up. 38 patients were enrolled in the discontinuation

phase, which left 13 who continued risperidone treatment throughout the 16-

week period. The 13 who continued treatment had mild to moderate side

effects including increased appetite, tiredness, and abnormal movements.

Although no dyskinesias were identified by the physician. The mostsignificant side effect was weight gain. However, 80% of those who continued

to receive treatment retained the improvements obtained in all areas. A

relatively low mean does of 2.0mg per day was effective for managing

aggression, agitation, and self-injury.

Based on the results from these studies, risperidone shows efficacy in treating

aggression, agitation, and angry affect. However, the myriad of side effects,

even at low doses, means that a risk vs. benefit assessment must be made

before pursuing this form of treatment.

Overall, fluoxetine was effective for improving overall global functioning,

reducing repetitive behaviors, and relieving anxiety while producing few side

effects. When these are the main issues, fluoxetine appears to be the best

choice. However, fluoxetine does not have any effect on aggression, agitation,

or angry affect and can actually cause or increase these in some children.

Risperidone does effectively reduce aggression, agitation, and angry affect, but

they should be causing severe impairment before treatment is considered due

to the high risk of intolerable side effects.


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References

DSM-IV 2005

Goin-Kotchel Robin, P., Myers, Barbara J., Mackintosh, Virginia H. Parentalreports on the use of treatments and therapies for children with autism

spectrum disorders. Research in Autism Spectrum Disorders 2007; 1:194-

209.

PDR physicians desk reference 2007.

DeLong RG, Teague LA, Kamran MM. Effects of fluoxetine treatment in young

children with idiopathic autism. Dev Med Child Neurol 1998; 40:551-562.

Hollander E, Phillips A, Chaplin W, et al. A placebo controlled crossover trialof liquid fluoxetine on repetitive behaviors in childhood and adolescent

autism. Neuropsychopharmacology 2001; 4: 119-125.

Cook EH, Rowlett R, Jaselinkis C, et al. Fluoxetine treatment of children and

adults with autistic disorder and mental retardation. J Am Acad Child Adolesc

Psychiatry 1992; 31: 739-745.

Risperidone Manufacturer

7503241Revised April 2010

Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007

Masi G, Cosenza A, Mucci M, Brovedani P. Open trial of risperidone in 24

young children with pervasive developmental disorders. J Am Acad Child

Adolesc Psychiatry 2001; 40(10): 1206-1214.

Masi G, Cosenza A, Mucci M, Brovedani P. A 3-year Naturalistic study of 53

preschool children with pervasive developmental disorders treated withrisperidone. J Am Acad Child Adolesc Psychiatry 2003; 64(9): 1039-1047.

Research Units on Pediatric Psycopharmacology Autism Network.

Risperidone treatment of autistic disorders: Long term benefits and blinded

discontinuation after 6 months. Am J Psychiatry 2005; 162: 1361-1369.


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A Review and Comparison of Efficacy and Side Effects of Risperidone Vs

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