Risperidone in AutismPaper by Dr Kalpana Shekhawat 10/5/2011

Ruptech Educational India

To determine the efficacy and safety of risperidone for people with autism spectrum disorder& to study benefits of low dosage Risperidone in Autism.

Objectives

To determine the efficacy and safety and tolerability of risperidone for people with autism spectrum disorder& to study benefits of low dosage Risperidone in Autism.

Risperidone is a drug used in Psychiatric Medicine to treat cases of Schizophrenia, a form of insanity. It acts on certain specific receptors on the brain that help to modify the behavior of persons so afflicted.

Exact cause of Autism is not known but is believed to be multi factorial, with a strong genetic influence.

There is a 60-90% concordance rate for monozygotic twins and a 0% concordance rate for di zygotic twins. The genetic component of Autism is heterogeneous attributed to as many as 100 genes and genetic abnormalities in Autism have been identified in mitochondrial genes and in all chromosomes except 14 and 20. It is believed that multiple genes interact with varied environmental causes to produce the disorders, and that the causative genes may vary from one population to another. Because of the complex heterogeneity and the variable behavioral phenotype of Autism, linkage studies have not identified specific chromosomal regions that are universally believed to harbor the genes causing it is initiated by at least 6 to 7 major genes and about 3 to 4 times that number of minor genes, causing a wide variety of medical pathologies. One of those genes that may have something to do with the presence of the HOXA1 gene coupled with the presence of mercury in the body. The metal gets incorporated into the neural proteins to cause their dysfunction. This causes the characteristic abnormal dissociated behavior patterns seen in children with Autism Spectrum disorder.

Limitations:

Limited resources were available therefore a very small control group.

Exclusion criteria:

Children with known allergy to Risperidone

Liver & Kidney disorder Juvenile diabetes

Inclusion Criteria:

Age 5-16 years Only diagnosed autistics by a Pediatric Neurologist.

Material Required: Syp Risinia (prescribed by their pediatrician)

Sample Size: Planned 60 children, reduced to 4 children (2girls and 2boys) due to limited resources available.

ABSTRACT Background:

Autistic children presents with psychiatric symptoms, pharmacotherapy is sometimes used to ameliorate target behaviors. The behaviors include hyper activity, tantrums, and physical aggression, self-injurious behavior, stereotypies, and anxiety symptoms, especially obsessive-compulsive behaviors. The older neuroleptics were limited in their usefulness because of their tendency to produce extrapyramidal symptoms and tardive dyskinesia. Open-label trials of atypical neuroleptics (risperidone, olanzapine) have shown effectiveness in treating these behaviors, and in some instances, have also improved social relatedness.

Naltrexone, an opiate antagonist was also originally touted as useful, especially for self-injurious behavior, but its utility has not yet been proven. Clomipramine, a tricyclic antidepressant that inhibits serotonin reuptake, has demonstrated usefulness in reducing compulsions and stereotypies in autistic children. However, it does lower the seizure threshold, can cause agranulocytosis, and has cardio toxic and behavior toxicity effects. Other medications used to treat psychiatric symptoms in autistic children include stimulants, selective serotonin reuptake inhibitors (SSRIs), and clonidine. The SSRIs, in particular, appear to be somewhat effective in diminishing hyperactive, agitated, and obsessive-compulsive behaviors although there have not yet been sufficient, controlled studies regarding their utility.

Autistic spectrum disorder encompasses a wide variety of behavioral and communicative problems. Both the core features and non-core features of autism have been targeted in a variety of therapies. Atypical antipsychotic medications, including risperidone, have been used for symptom and behavior improvement and have shown beneficial outcomes, particularly in certain aspects of the disorder. However, given the nature of the condition presenting in young patients, the risks of these potentially long term therapies must be weighed against the benefits.

Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited.

Risperidone:

DRUG CLASS AND MECHANISM:

Risperidone is an atypical antipsychotic drug that is used for treating schizophrenia, bipolar mania and autism. Other atypical antipsychotic drugs include Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon), Aripiprazole (Abilify) and paliperidone (Invega). Atypical antipsychotics differ from typical antipsychotics due to the lesser degree of extrapyramidal (movement) side effects and constipation.

The mechanism of action of risperidone is like other anti-psychotics, risperidone affects the way the brain works by interfering with communication among the brain's nerves. Nerves communicate with each other by making and releasing chemicals called neurotransmitters. The neurotransmitters travel to other nearby nerves where they attach to receptors on the nerves. The attachment of the neurotransmitters either stimulates or inhibits the function of the nearby nerves. Risperidone blocks several of the receptors on nerves including dopamine type 2, serotonin type 2, and alpha 2 adrenergic receptors. It is believed that many psychotic illnesses are caused by abnormal communication among nerves in the brain and that by altering communication through neurotransmitters, risperidone can alter the psychotic state. Risperidone was approved by the FDA in December, 1993.

PRESCRIPTION: Yes

PREPARATIONS: Tablets: 1, 2, 3, and 4 mg. Suspension: 1 mg/ml. Orally disintegrating tablets: 1, 2, 3, and 4 mg.

STORAGE: Tablets should be kept at room temperature, 15-25 C (59-77 F).

PRESCRIBED FOR:

Risperidone is used to treat schizophrenia, bipolar mania [as a sole therapy or combination therapy with lithium (Eskalith, Lithobid) or valproate (Depakene, Depacon) Clinical studies involving small numbers of patients have shown some benefit in using risperidone for stuttering and Tourette syndrome (non FDA-approved uses). Another non-FDA approved use of risperidone is for obsessive-compulsive disorders.

DOSING:

Risperidone can be prescribed once or twice daily. Initial dosing is generally 2 mg/day. Dose increases can occur in increments of 1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In children, risperidone should be initiated at 0.5 mg once daily, and can be increased in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Risperidone can be given with or without meals. The recommended dose of Risperdal Consta is 25 mg injected into the deltoid or gluteal muscle every two weeks. Patients who have never received risperidone are started on oral risperidone in order to evaluate tolerability. Patients then may be transitioned to Risperdal Consta if oral risperidone is tolerated

DRUG INTERACTIONS: Risperidone may interfere with elimination by the kidneys of clozapine (Clozaril), a different type of antipsychotic medication, causing increased levels of clozapine in the blood. This could increase the risk of side effects with clozapine.

Serotonin reuptake inhibitors such as paroxetine(Paxil), Sertraline (Zoloft), and fluoxetine (Prozac) when taken with risperidone causes the metabolism (breakdown) of risperidone by the liver to be inhibited, which in turn causes elevated blood levels of risperidone, and may increase the risk of adverse reactions.

Antifungal drugs such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral) when taken with risperidone cause the metabolism (breakdown) of risperidone by the liver to be inhibited, which in turn causes elevated blood levels and may increase the risk of adverse reactions.

PREGNANCY: There are no adequate studies of risperidone in pregnant women. Some unwanted effects have been reported in animal studies. Risperidone can be used in pregnancy if the physician feels that the benefits outweigh the potential but unknown risks.

NURSING MOTHERS: Risperidone is excreted in human breast milk. Women receiving risperidone should not breastfeed.

ADVERSE EFFECTS: The most commonly adverse effects associated with risperidone are extra pyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes), dizziness, hyperactivity, tiredness, abdominal pain, fatigue, fever and nausea. Risperidone may cause a condition called orthostatic hypotension during the early phase of treatment (the first week or two). Patients who develop orthostatic hypotension have a drop in their blood pressure when they rise from a lying position and may become dizzy or even lose consciousness.

Studies involving risperidone suggest an increased risk of hyperglycemia-related adverse reactions as seen in diabetes. Although there is no clear link between risperidone and diabetes, patients should be tested during treatment for elevated blood sugars. Additionally, persons with risk factors for diabetes, including obesity or a family history of diabetes, should have their

fasting levels of blood sugar tested before starting treatment and periodically throughout treatment to detect the onset of diabetes. Any patient developing symptoms that suggest diabetes during treatment should be tested for diabetes.

USES: Risperidone is used to treat certain mental/mood disorders (such as schizophrenia, manic phase of bipolar disorder, occasionally irritability associated with autistic disorder). This medication can help us to think clearly and function in daily life. This is a psychiatric medication (antipsychotic-type) that works by helping to restore the balance of certain natural substances in the brain (neurotransmitters).This medication may also be used in combination with other medication to treat depression.

Autism the problem and Epidemiology

The autism spectrum, also called autism spectrum disorders (ASD) or autism spectrum conditions (ASC), with the adjective autistic sometimes replacing the noun autism, is a spectrum of psychological conditions characterized by widespread abnormalities of social interactions and communication, as well as restricted interests and repetitive behavior.

Autism forms the core of the autism spectrum disorders. Asperger syndrome is closest to autism. People with Asperger syndrome have no significant delay in language development PDD-NOS is diagnosed when the criteria are not met for a more specific disorder. Some sources also include Rett syndrome and childhood disintegrative disorder which share several signs with autism but may have unrelated causes; other sources combine ASD with these two conditions into the pervasive developmental disorders.

Autism characteristics

The defining characteristics of autism spectrum disorders are qualitative impairments of social communication and interaction, along with restricted and repetitive activities and interests. Individual symptoms occur in the general population and appear not to associate highly, without a sharp line separating pathological severity from common traits other aspects of ASD, such as atypical eating, are also common but are not essential for diagnosis; they can affect the individual or the family.

An estimated 0.5% to 10% of individuals with ASD show unusual abilities, ranging from splinter skills such as the memorization of trivia to the extraordinarily rare talents of prodigious autistic savants

Making and maintaining friendships often proves to be difficult for children with autism. For them, the quality of friendships, not the number of friends, predicts how lonely they are, despite the common belief that they prefer to be alone. Being on the autism spectrum does not keep children from understanding race and gender stereotypes in a society; like normal children they can learn aspects of stereotypical behavior by observing their parents' actions.

Autism therapies

The main goals of treatment are to lessen associated deficits and family distress, and to increase quality of life and functional independence. No single treatment is best and treatment is typically modified to the child's needs. rigorous, sustained special education programs and behavior therapy early in life can help children acquire self-care, social, and job skills. Available approaches include applied behavior analysis (ABA), developmental models, structured teaching, speech and language therapy, social skills therapy, and occupational therapy ABA therapy has a strong research base but it maybe limited by diagnostic severity and IQ.

In a recent study by Russo et al., researchers at Albert Einstein College of Medicine of Yeshiva University have provided new evidence that, children with autism spectrum disorders (ASD) process sensory information including sound, touch and vision differently to typically developing children. This research provides support for decades of clinical and anecdotal observations by occupational therapists practicing sensory integration therapy that individuals with ASD have difficulty coping with multiple sources of sensory information. These findings offer an opportunity for occupational therapists to develop objective measures to facilitate more empirical evaluation and understanding of sensory processing disorders and sensory integration therapy

Epidemiology of autism

The prevalence rate of all pervasive developmental disorders appears to be 58.7 per 10000 children. This prevalence rate includes Autism (22/10000), Asperger syndrome (11/10000), Pervasive developmental disorder not otherwise specified (24.8/10000) and child disintegrative disorder (0.9/10000).this is consistent with previous research that identified all pervasive development disorders as (60/10000).this incidence of diagnosis of autism may have increased. there is evidence that increased in the number of children identified with autism is likely related to changes in the definition of and diagnostic criteria for autism, as well as improvements in the recognition of autism at younger ages. An increase in the availability of diagnostic services, treatment facilities, professionals trained in childhood developmental disorders has greatly increased the capacity of the healthcare system to identify and treat children with autistic spectrum disorder at younger age.

Methods:

Random trail of risperidone in 4 children diagnosed with ASD as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 16 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks, data were recorded.

Dosage: Risinia syrup 1mg bi daily

Procedure: In this study 4 children were identified, who were already on risperidone in dosage (1mg bidaily) prescribed by their pediatricians. Each child was assessed for severe tantrum, aggression, self injurious behavior etc, primary outcome measures were the scores on the irritability subscale of the Aberrant behavior checklist and the rating on the Clinical Global Impression-Improvement(CGI-I) scale at 8 weeks.

Report

Study result of effect of Risperidone in children with Autism

Time period – 8 weeks, 10th Dec 10 to 4th Feb 11 Dose of medicine-1mg/BID as prescribed by their pediatricians. Age groups-5-8yrs

Total no. of children

Age group Boys Girls Risperidone given

Placebo given

4 5-8yrs 2 2 2 2

Outcome of Therapy

Out come measures

Scale earlier Scale with Risperidone

Scale with Placebo

Irritability score 4 2 4

Clinical Global Impression

Improvement scale

4 3 4

Weight gain 0 4 1Increased Appetite 0 3 0

Fatigue 1 4 1.5-2Drowsiness 0 3 1

Dizziness 0 2 0Drooling 0 0 0

*Criteria’s measured at a scale of 1-5

Adverse events in 2 children with Autism who responded to Risperidone in an 8 weeks trial.

Adverse EventNumber of children moderate

or severe event Moderate Severe

Nasal congestion 2 0Appetite increase 2 0

Coughing 0 0Anxiety 0 0

Difficulty falling asleep 0 0Fever 0 0

Skin irritation 0 0Vomiting 0 0

Accidental injury 0 0Constipation 0 0

Drowsiness/sedation 2 0Enuresis 0 0

Headache 0 0Hyper salivation 0 0

Sore throat 0 0Depression 0 0

Diarrhea 0 0

Difficulty urinating 0 0Dyskinesia 0 0

Earache 0 0Restlessness/agitation 0 0

Sinus condition 0 0Stomach /abdominal discomfort 0 0

Tiredness/fatigue 2 0Tremor 0 0

Weight gain 2 0Muscle rigidity 0 0

Other 0 0

Clinical Global Impression (CGI) Improvement Ratings for 2 children with Autism, who responded to Risperidone in 8 weeks trial:

Rating Week 0 Week 4 Week 8

Very much improved 0 0 1

Much improved 0 0 1

Minimally improved 0 2 0

No change 2 0 0

Worse 0 0 0

(much worse) 0 0 0

Total 2 2 2

Discussion

Risperidone may be well-tolerated and effective treatment for up to 6 months for children with autism complicated by tantrums, aggression, and self-injury. As measured by the primary indices of response, the CGI improvement scale and the Aberrant Behavior Checklist irritability subscale, improvements associated with risperidone administration were maintained with very good tolerability. Furthermore, gradual substitution of placebo for risperidone was associated with a greater return of aggression, temper outbursts, and self-injurious behavior than in the subjects who continued to receive risperidone in the discontinuation phase. Risperidone may be an efficacious treatment for short- and intermediate-term management of serious behavioral problems in children with autism.

As in our study of short-term risperidone efficacy risperidone was also associated with continued maintenance of improvements on the Aberrant Behavior Checklist subscales for hyperactivity, stereotypic behavior, and lethargy/social withdrawal.

The largest extended study of neuroleptic treatment for autistic disorder was the examination of the effects of haloperidol over a 6-month period. In that study 60 children treated with a mean dose of 1.23 mg/day of haloperidol were classified as "good responders." After 6 months of treatment, 33 (63%) of 52 subjects were rated as "much improved." Autism factor ratings derived from the Children’s Psychiatric Rating Scale obtained on entry and at 6 months showed an average decline of 23% from baseline. Upon abrupt withdrawal of haloperidol, only 14% of the children were rated as much worse and 50% showed at least mild deterioration.

In an open-label prospective study of risperidone for 11 children with autistic disorder, Zuddas et al. noted that 10 of the 11 showed enduring improvement over the 12-month observation period. Another open trial of risperidone enrolled 22 subjects with autistic disorder. Of these, 15 subjects showed significant improvement at a mean dose of 1.2 mg/day for up to 7 months of treatment. Additional published observations include positive responses maintained over a 4-month period in responders and improvement maintained during a 2-year treatment history in two adults with autistic disorder It should be noted that few earlier studies defined specific entry criteria for aggression or disruptive behavior, but, taken together, the available accounts suggest that risperidone’s benefit for aggression, severe tantrums, and self-injury accompanying autistic disorder persisted over these intermediate treatment periods (6–12 months), although additional long-term treatment data focusing on managing severe and challenging behaviors are clearly needed.

A key clinical question concerns the length of continued treatment with risperidone for this clinical indication. The return of aggression, tantrums, and agitation was there in the placebo group as in the subjects who continued to take risperidone. 1 of 2 children in the placebo group did not relapse during the 2-month discontinuation period, demonstrating some degree of variability in outcome. It is conceivable that more gradual drug tapering may have moderated the observed relapse in the risperidone group or that dose reduction, rather than complete medication discontinuation, may have been sufficient to maintain treatment gains. It is also

conceivable that concomitant behavioral treatment reinforcing replacement behaviors could protect against relapse following risperidone withdrawal. Nevertheless, the high rate of relapse observed in our study suggests caution when withdrawal of effective treatment for these target symptoms is considered. At a minimum, clinicians should document a clear period of stable functioning before initiating medication taper and ensure that appropriate psychosocial supports are in place to minimize relapse risk. No factors predicting relapse were identifiable given the modest number of subjects in the discontinuation phase of this study, but they certainly form an important future research question. Longer-term follow-up information on outcome may help make decisions about maintenance treatment.

Although adverse events associated with risperidone exposure were observed to be common in this study, most were not deemed clinically significant, and many were not attributed to risperidone. No cases of dyskinesia were observed during treatment or upon withdrawal. The absence of dyskinesia in this study may be noteworthy given the report by Campbell and colleagues that 30% of 118 subjects showed dyskinesia following withdrawal of haloperidol after a similar duration of treatment, although the more gradual taper used in this study may be responsible for the finding. Weight gain associated with treatment was significant and some, especially since antipsychotic-related weight gain has been associated with diabetes and other adverse outcomes. Longer-term observations to determine the clinical significance of weight gain as well as other adverse events are needed to evaluate the risk-benefit ratio for risperidone treatment in children with autistic disorder.

There were several limitations in this investigation. First, although the data collection period in this phase of the study spanned up to a maximum total of 8 weeks of risperidone exposure, this does not completely mimic clinical practice, as many patients receive treatments like risperidone for longer time periods. Also, there was no systematic effort to reduce or constrain individual daily doses over time, leaving some uncertainty about the lowest possible long-term dose. This limitation notwithstanding, the relatively low mean dose (approximately 2.0 mg/day) of risperidone used in this study was effective in managing the specific target symptoms of aggression, agitation, and self-injury. This mean dose was remarkably similar to the doses in several other studies .The possibility of solidifying these gains or even extending the benefit of risperidone treatment by combining it with behavior therapy was not explored in this investigation but is an important research question for future studies. Finally, the safety observations of the study were limited to a maximum of 8 weeks of risperidone exposure in a relatively very small study group. Thus, our data may be insufficient to estimate precisely the long-term risks of risperidone in children.

In summary, intermediate-length treatment with risperidone appeared to be associated with the maintenance of reductions in aggression, agitation, self-injury, and irritability from short-term treatment. There was little evidence of accommodation to the effects of risperidone, and the medication appeared to be well tolerated in a group of children and adolescents with autistic disorder. Additional studies on predictors of stable improvement, longer-term safety, and approaches combining other interventions are of interest.

Conclusion:

Risperidone may be well-tolerated and may be effective at treating behavioral symptoms associated with pervasive developmental disorders (PDD) and autism, according to the results of a trial conducted on 4 children with confirmed diagnosis of PDD.

Risperidone can be beneficial in some features of autism. However there are limited data available from our study with small sample size, limited inferences. In addition, long-term follow-up is also lacking. Further research is necessary to determine the efficacy of risperidone in clinical practice.

The main limitation of this study is the less number of children in control group and short duration of follow up.

However it is concluded that the drug Risperidone is a beneficial drug for children in the Autism spectrum disorder and more research on a large span of patients will produce more concrete results towards reaching more effective handling of ASD.

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