Original Authors: Paul Perry, Ph.D, BCPP, Sam Kuperman,
M.D.
Latest Revisers: Paul Perry, Ph.D. and Samuel Kuperman,
M.D.
Creation Date: 1996
Last Revised: January 2003
Peer Review Status: Internally Peer Reviewed
AUTISM
Autism is a clinical syndrome characterized by qualitative impairment of social interaction, verbal and nonverbal communication, imaginative activity, and a markedly restricted repertoire of activities and interests. Within the first 3-6 months of their lives, parents may note the child does not develop a normal pattern of smiling or cuddling response. As they grow older, they do not progress through developmental milestones such as learning to say words or speak sentences. Instead, they seem aloof, detached, and withdrawn. Instead of developing a pattern of relating warmly to their parents, they may instead engage in self-stimulating behavior such as rocking or head banging. By age 2 or 3 years, it is usually clear that there is something wrong, and the features of the disorder continue to become more obvious over time as the child fails to develop normal verbal or interpersonal communication skills.
Although the etiology of the disorder is unknown, it is associated with a number of neuropathological conditions which include perinatal insults, congenital rubella, and phenylketonuria. No specific treatment is available that alters the course of the illness. There are a number of neurochemical dysfunctional findings in autism. These include an increase in platelet serotonin concentrations especially in mental retarded autistics. Additional biochemical aberrations include an increase in norepinephrine plasma concentrations and up-regulation of dopamine receptors are noted (Gilman et al 1995). There are a number of controlled drug trials that have demonstrated an improvement in the mental status abnormalities such as decreasing aggressiveness, obsessive-compulsive behaviors and self-stimulating behaviors. Therapeutic agents that included in this review are fenfluramine, haloperidol pimozide, risperidone, clonidine, and naltrexone. Stimulants such as amphetamines usually result in increases in activity, irritability, explosiveness and stereotypic behavior when administered to autistic patients. An exception to this lack of effectiveness of stimulants are the moderate to high functioning autistics who have ADHD-like symptoms. This type of patient does benefit from stimulant medication.
Haloperidol
One therapeutic approach in the treatment of patients with infantile autism involves the use of dopamine antagonists. The dopaminergic system of the brain affects motor behaviors. Its abnormalities involve excess motor activity and stereotypes similar to those observed in autistic patients. Intellectually subnormal autistic children, particularly those with severe hyperactivity and stereotypes, were found to have excess dopaminergic activity as measured by high levels of homovanillic acid in the CSF (Cohen et al 1977). Thus it seems sensible that the administration of a dopamine antagonists such as haloperidol to autistic patients should result in a decrease motor symptoms such as hyperactivity, fidgetiness, and stereotypes thereby facilitating behavior and learning. Ernst et al (1993) have noted that the severity of the stereotypes correlates with the increase in the plasma beta-endorphin (bE) levels. Chronic haloperidol treatment was able to reduce both the stereotypes and the bE concentrations whereas chronic naltrexone treatment was not.
The effects of haloperidol on learning and behavioral symptoms in infantile autism were tested by Anderson et al (1984) in 40 autistic (DSM-III) (29 boys, 11 girls) ranging in age from 2.3 to 6.9 years. Using a double-blind study design, patients were randomized to two treatment sequences, i.e., haloperidol-placebo-haloperidol or placebo-haloperidol-placebo. Each treatment period lasted 4 weeks. Haloperidol doses ranged from 0.5 to 3.0 mg/d. Three rating scales were utilized, i.e., Children's Rating Scale, CGI, and Conners Parent-Teacher Questionnaire. All three scales showed significant improvement while the children were receiving haloperidol. There was no clinically significant effect seen in discriminant learning when the drug was given although there was a weak trend that the group who received haloperidol twice did better. Haloperidol significantly decreased maladaptive behaviors in these children. They found that while on the drug the children performed at a level equal to that of children taking placebo who had a developmental quotient of 20 points higher. Parents of 36 patients asked that their children remain on the haloperidol after the completion of the study. No adverse effects were observed.
Anderson et al. (1989) conducted a second double-blind placebo controlled crossover study to replicate his earlier findings regarding the effect of haloperidol on the learning and behavioral symptoms. A total of 45 autistic (DSM-III) children, 35 boys and 10 girls with an age range of 2.0 to 7.6 years were recruited. There were three treatment groups to which the children were randomly assigned following a 2 week placebo lead-in period. The three groups were: haloperidol-placebo-placebo, placebo-haloperidol-placebo, and placebo-placebo-haloperidol. This study was conducted over 14 weeks. Doses ranged from 0.25 to 4.0 mg/d (0.16-0.18 mg/kg/d). The Children's Psychiatric Rating Scale showed a trend toward improvement while on haloperidol. The CGI scale suggested a significant benefit of haloperidol therapy on the global improvement and efficacy indices. Only one item on the Conners Parent Teacher Rating Scale, temper outburst, showed significant improvement. The treated children were characterized as being calmer without being sedated, showed decreases in hyperactivity, temper tantrums, withdrawal and stereotypes, and showed increase in relatedness. The tests of discriminant learning concluded that haloperidol was unable to facilitate learning. However, the drug did not have an aversive effect on learning and this is an important practical finding regarding a patient population where the majority of individuals are mentally handicapped with severe learning difficulties.
The one significant drawback regarding the use of neuroleptics in the symptomatic treatment of autism involves their potential for inducing tardive dyskinesia. Campbell et al (1983) conducted a prospective tardive and withdrawal dyskinesia surveillance in 82 autistic children treated with haloperidol over 2-60 months. The study was designed to facilitate a high expression of withdrawal dyskinesia by repetitive drug withdrawal every 6 months. By 11 months, 25% of the children exhibited dyskinesia, 40% by 2.5 years, and 75% by 3 years and 5 months. Importantly, it is difficult to distinguish between the emergence of dyskinesias and a breakthrough of autistic symptomatology.
Conclusion. The administration of conservative doses of haloperidol to autistic children results in significant decreases in hyperactivity, negativism, and stereotypes and in some cases has been shown to facilitate learning. On follow-up, haloperidol is therapeutically effective for up to 4-1/2 years and helped many autistic children remain with their families as well as remain in educational programs without producing any adverse effects on IQ. Although haloperidol appears to be useful in the treatment of infantile autism, the utility of the drug is limited by the risk of tardive dyskinesia. It would seem appropriate that future research with neuroleptics in the treatment of autism be targeted at drugs that do not cause tardive dyskinesia such as clozapine or more practically one of its congeners that does not cause bone marrow suppression or sedation. An outline of the two haloperidol trials is presented in Table 1.
Risperidone
McDougle et al (1998) conducted a 12-week double-blind placebo-controlled parallel design trial contrasting the therapeutic efficacy of risperidone to placebo in the treatment of adults with autism (n=17) or pervasive developmental disorder NOS (n=14). For patients completing the study, 8 (57%) if 14 patients treated with risperidone were categorized as responders (2,9 ± 1.4 mg/d) compared with none (0/16) in the placebo group (p < 0.002). Individual symptoms that responded to risperidone included repetitive behavior, aggression, anxiety, depression, irritability, and overall behavioral symptoms of autism. Measurable changes in social behavior and language did not occur. The only notable adverse effect was mild sedation. Extrapyramidal side effects, EKG changes and seizures did not occur.
A multisite study conducted by the Research Units on Pediatric Psychopharmacology Autism Network (McCracken et al 2002) conducted a 8-week double-blind placebo-controlled parallel design trial contrasting the therapeutic efficacy of risperidone to placebo in the treatment of pre-pubescent autistic children (2-8 yo). Response was defined as a 25% decrease in irritability and CGI improvement change being rated as much improved or very much improved. A greater number of patients responded to risperidone (34/49) than placebo (6/52). In two-thirds (23) of the children who responded the response was sustained for 6 months. Risperidone adverse effects were prominent. Mean weight gain from risperidone was 2.7 kg within 8 weeks. Other adverse effects that occurred more often than in the placebo group included increased appetite, fatigue, drowsiness, dizziness, and drooling. Malone et al (2002) has suggested the late occurring extrapyramidal side effect of tardive dyskinesia may be a potential problem with risperidone. Two (15%) of 13 children treated for 7 months with risperidone experience withdrawal dyskinesias when risperidone was discontinued.
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Table 1. Controlled studies of DA antagonists in autistics. |
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|
Study |
Dose (mg/d) |
Population |
Results |
|
Anderson et al 1984 |
HLP 0.5-3.0 mg/d Placebo |
Autism |
Improvement: |
|
Anderson et al 1989 |
HLP |
Autism |
Improvement: |
Antidepressants
Gordon et al (1993) attempted to determine whether clomipramine, a potent serotonin reuptake inhibitor tricyclic antidepressant with unique anti-obsessional properties, is differentially effective for obsessive-compulsive and stereotyped motor behaviors in autistic disorder in contrast to placebo and the noradrenergic agonist predominant tricyclic, desipramine. Following a 2-week, single-blind placebo washout phase, 12 autistic subjects completed a 10-week, double-blind, crossover comparison of clomipramine and placebo. Twelve different subjects completed a similar comparison of clomipramine versus desipramine. Thirty male and female autistic patients were enrolled, and 24 completed the study. Following dose titration over a three week period, the mean clomipramine dose was 4.3 ± 0.8 mg/hg/d while the mean desipramine dose was 4.0 ± 1.2 mg/kg/d. For both drugs the dose could not exceed 5.0 mg/kg/d. Clomipramine was superior to both placebo and desipramine on ratings of autistic symptoms (including stereotypes), anger, and compulsive, ritualized behaviors (P < 0.05), with no differences between desipramine and placebo. Clomipramine was equal to desipramine and both tricyclic agents were superior to placebo for amelioration of hyperactivity. Biological links between compulsions and stereotyped, repetitive behaviors in autistic disorder should be explored.
McDougle et al (1996) conducted a 12-week double-blind placebo-controlled parallel design trial contrasting the therapeutic efficacy of the SSRI, fluvoxamine 200-300 mg/d (mean = 277 mg/d) to placebo in the treatment of adults (18-53 yo) with autism (n=30). A positive response was defined as a CGI improvement scale rating as much improved or very much improved. Eight (53%) of 14 patients treated with fluvoxamine were categorized as responders compared with none (0/15) in the placebo group (p < 0.001). The individual autistic symptoms that responded to fluvoxamine were repetitive behaviors, maladaptive behaviors, aggression, and in improving some aspects of social relatedness especially language usage. The only notable adverse effect was mild sedation and nausea in a few patients.
Fenfluramine
Fenfluramine is an atypical phenylethylamine anorexigenic medication with CNS activity that includes reduction of brain serotonin (5-HT) and serotonin's major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). It also increases dopamine turnover as evidenced by an increasing the excretion of its principle metabolite, homovanillic acid (HVA). It is hypothesized that autism is somehow related to a dysfunctional serotonergic system that results in the sensory and perceptual abnormalities observed in these patients. The hypothesis is supported by the observation that 1/3 of autistic children are hyperserotonemic, which is thought to be associated with severe behavioral abnormalities and severe intellectual subnormality.
The first double-blind controlled trial that evaluated the efficacy of fenfluramine in the treatment of autism was conducted by a August et al (1984). They studied 10 autistic (DSM-III) outpatients ranging in age from 5 to 13 years old. Eight normal children served as a control group. A two week placebo lead-in period was done first which was then followed in all of the children with 4 weeks of placebo, 16 weeks of fenfluramine and then 8 weeks of placebo. Patients received 1.5 mg/kg/day in two daily doses. Whole blood 5-HT levels were measured in all subjects. Signal averaged EEGs were performed twice during the initial base-line period, after 8 weeks of fenfluramine treatment and after 4 weeks of placebo following fenfluramine treatment. Parents also rated their children once a week. Intelligence testing was conducted seven times during the study. Nine patients completed the study. Serotonin levels were reduced in all nine patients after fenfluramine treatment by a mean of 62%. They returned to baseline levels after 2 months of placebo treatment. According to the Conners' Abbreviated Parent-Teacher Questionnaire there was a significant reduction in the disruptive behavioral symptoms (motor hyperactivity, distractibility, and affect) were observed after fenfluramine therapy but the symptoms returned to baseline following the treatment change back to placebo. There was no effect on intellectual functioning as measured by the WISC-R. Seven of the nine completers were mildly to severely mentally retarded. The authors concluded that the effect of fenfluramine may be especially useful in those children who are excessively overactive and distractible or have severe affective disturbances.
Yarbrough et al (1987) conducted a double-blinded cross-over study of fenfluramine in the treatment of maladaptive behaviors in autism. Twenty patients were studied, 17 male and 3 female with an age range of 9 to 28 years old. Patients functioning level ranged from either 10 to 67 months or an IQ ranging from 12 to 51. Each subject served as his own control. Patients received 2 mg/kg/d (maximum = 120 mg/d) and placebo for 15 weeks. In this study the patients were observed in the classroom and their own living area. Each morning and afternoon they were observed in both of these sites by trained raters. The observation intervals were 15 seconds long and the observation period was 10 minutes long. There were 20 observation intervals in each observation period. Videotape sessions were also used to rate the patients. During these sessions the patient was given four tasks to perform. Two of the tasks the patient had already mastered and the other two were not mastered when the study began. The tasks remained the same throughout the study. Each patient participated in two sessions during four observation periods during each phase of the study. Twenty-one behavioral variables were selected from the Modified Ritvo-Freeman Real Life Rating Scale. The general areas of behavior evaluated included sensory-motor behavior, effectual reactions, sensory responses, relationship to people, and language. No significant clinical differences in the 21 variables studied were obvious after fenfluramine administration. They could not conclude that the use of fenfluramine in autistic patients reduced maladaptive behaviors. Adverse drug reactions that included primarily insomnia and increases in tension, and agitation were noted in 65% of patients. Additionally, 45% demonstrated possible withdrawal effects from fenfluramine administration such as agitation, hyperirritability, insomnia and aggression.
Ross et al ( 1987) utilized a double-blind crossover design to study the efficacy of fenfluramine in autism. Unlike the previous studies, they hypothesized that the mechanism of autism is related to endorphins. Thus they attempted to correlated fenfluramine response to CSF beta-endorphin (BE) activity. They proposed that for fenfluramine to be effective it should reduce elevated CSF BE concentrations in the patients. Nine autistic children (DSM-III) between the ages of 3 to 12 years, eight of whom were males were studied. Patients were randomized to either placebo or fenfluramine for 16 weeks and then crossed-over for additional 16 weeks. Patients received 1.5 mg/kg/day (maximum = 60 mg/d). A one month baseline placebo lead-in period was conducted to establish the baseline evaluation parameters. Three patients were found to respond to the fenfluramine therapy with reduction in echolalia, perseveration and motor disturbances and an increase in attention and social awareness. Upon withdrawal these symptoms returned to baseline within one month. BE content in the CSF was significantly higher in the autistic group than in the controls. The results suggest that possibly too small a dose may have been utilized in the patients. After fenfluramine therapy the BE levels demonstrated a nonsignificant decrease toward baseline. The only adverse effects observed were a 3-4 day period of lethargy or grogginess and 2.5% loss in weight that returned to baseline within two months of discontinuing the drug.
Beeghly et al (1987) carried out a double-blind placebo-controlled crossover study comparing fenfluramine to placebo. There were nine autistic (DSM-III) children (7 boys and two girls) enrolled in this study whose ages ranged from 7 to 14 years old and their IQs from 36 to 112. Patients received 1.5 mg/kg/day for 4 months and placebo for 4 months in a randomized design. Behavior ratings forms (Conners) were filled out by parents weekly and the patients were rated (Real Life Rating Scale) by observers during two 15-minute observation periods each month. Blood samples wee collected to determine serotonin levels as well as fenfluramine and norfenfluramine plasma concentrations. Two patients failed to complete the study. Of these 7 who completed the study two improved enough that their parents asked for them to continue on the drug. There was no significant improvement in either of the behavior ratings while on the drug. Serotonin levels were decreased on a average of 58% while on fenfluramine. The two children who requested to continue on the drug because of perceived benefit from the drug had the total fenfluramine (fenfluramine + norfenfluramine) levels that were more than twice as high as the mean total concentration of the other patients. This observations suggests that there may be a minimum effective fenfluramine blood level necessary to achieve a therapeutic response. Thus the dose of the drug ought to be titrated upward in patients to a point of either response or unacceptable adverse effects as the dosing endpoint. The data in this study were too few to discern if fenfluramine's treatment effect was due to non-specific sedation or a direct result of the decrease in the serotonin levels in the patient.
Levinthal et al (1993) treated 15 autistic children with 60 mg fenfluramine or placebo in a double-blind A-B-A protocol followed immediately by double-blind placebo-controlled crossover administration of fenfluramine (total duration 62 weeks). Both biochemical and clinical outcomes were examined. Biochemically, fenfluramine led to an increase in dihydroxyphenylacetic acid (DOPAC), a dopamine metabolite and decreases in whole-blood serotonin (5-HT), plasma norepinephrine, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), norepinephrine's metabolite. The decrease in whole-blood 5-HT was seen only during treatment with fenfluramine. However, NE levels did not return to baseline as long as 8 weeks after the first fenfluramine treatment period. Increases in DOPAC were greater during the second fenfluramine treatment period than the first. Persistent changes in catecholamine regulation may be related to previously reported long-term effects on CNS 5-HT after fenfluramine. Clinically, fenfluramine led to a modest decrease in parent, but not teacher, ratings of hyperactivity and to a small reduction in sensorimotor abnormalities. Abnormal social and effectual responses also decreased, but this was not directly related to fenfluramine treatment. Effects on cognition were equivocal. Hyperserotonemic subjects did not differ from normoserotonemic subjects in clinical response. Overall, no significant advantage for the use of fenfluramine could be established.
Conclusion. Fenfluramine may beneficially affect autistic patients by its ability to decrease CNS serotonin or beta-endorphin levels. However, the studies suggest that only a minority of patients were benefited by the therapy. It seems that the too small a dose of the drug is being utilized. Thus future studies and treatments should be aimed a using doses greater than 1.5-2.0 mg/kg/d. The five fenfluramine efficacy studies are presented in Table 2.
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Table 2. Controlled studies of 5-HT agonist, fenfluramine, in autistics. |
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|
Study |
Dose (mg/d) |
Population |
Results |
|
August et al 1984 |
placebo x 2 weeks |
10 autistics |
decreased 5-HT by 62% Conners - improvement in
hyperactivity, affect, & distractibility |
|
Yarbrough et al 1987 |
FFA 2 mg/kg/d (max=120 mg/d) placebo |
Autism |
Real Life Rating Scale: |
|
Ross et al 1987 |
FFA 1.5 mg/kg/d (max=60 mg/d) |
Autism |
decreased bE not significant (low dose=?) |
|
Beeghly et al 1987 |
FFA 1.5 mg/kg/d placebo |
Autism |
7 completers |
|
Levinthal et al 1993 |
FFA (max=60 mg/d) vs PLB over 62 weeks |
n=15 |
hyperactivity decreased according to parents but
not teachers |
Naltrexone
In the late 1970s, it was noted that neonatal rats and chicks exposed to high levels of opiates showed autistic-like withdrawal after they were born. Opiate treated animals exhibit unusual motor flurries much like autistic children's hyperactivity. Additionally, they exhibited other unusual postures and perseverative behaviors and fail to evince normal separation anxiety when removed from their mothers. Likewise as previously noted by Ross et al (1987) there is an increase in CSF beta-endorphin (bE) activity in autistic patients. Researchers have noted similar behavior pattern between autistics and opiate addicts such as social withdrawal, self-stimulation, and high levels of pain tolerance.. It is speculated that disturbances in brain opioid levels may block psychosocial development at its earliest stages leading to failures in language acquisition and other idiosyncrasies in learning. The theory as to why abnormal opiod levels cause self-injury, and why opiate antagonist drugs may decrease SIB is explained by the hypothetical "addiction theory." The theory proposes that purpose of self-injurious behavior (SIB) is to promote pain-induced release of endogenous opiates. The use of the opiate antagonist, naltrexone in the treatment of autism is reasonable since it antagonizes endogenous opiate receptor activity. There are a large number of uncontrolled reports supporting the effectiveness of naltrexone in the treatment of autism. However, the five controlled trials that are available far less encouraging.
The first controlled study of naltrexone in the symptomatic treatment of autism was reported by Sandman et al (1988). The patients were four severe to profoundly mentally retarded adult (23-26 yo) male autistics. The patients had long history of SIB that was treatment refractory. They used a double-blind, latin square design comparing naltrexone 25, 50 and 100 mg to placebo. Each dose was evaluated for a week with the medication being administered for only 2 days of the week. Patients were evaluated for SIB twice daily with the aid of a video tape camera. The authors found a dose-dependent decrease in SIB with no effect on patient activity and stereotypes. The authors reported that they measured beta-endorphin levels in 40 individuals showing SIB. Significantly elevated beta-endorphin levels were observed in the SIB group over controls. Thus the investigators concluded that beta-endorphin levels may be involved in the mechanism of SIB and naltrexone may reduce SIB by blocking beta endorphins.
Campbell et al (1990) conducted a double-blind, placebo-controlled study designed to assess critically the effects of naltrexone on behavioral symptoms and learning in autistic children, and its safety in 18 children (14 males, 4 females), ages 3-8 years. Subjects were randomly assigned to naltrexone (0.5-1.0 mg/kg/d) or placebo and received daily doses over a period of 21 days. Naltrexone was superior to placebo according to blind Clinical Global Consensus Ratings (unpublished scale). However, other behavioral rating measures did not confirm this result. There was only a suggestion that naltrexone reduced fidgety and hyperactive behavior and tended to alleviate overall symptomatology in older children. The explanation between the discrepancy between the CPRS/CGI measures and the Clinical Global Consensus Ratings was that the most dramatic and consistent changes during naltrexone administration in each child were decreases of withdrawal and increases of verbal production and communicative speech. It was felt that the Consensus rating took these symptoms into account whereas the CPRS and CGI did not. Naltrexone did not appear to affect discriminant learning. Results were preliminary and, owing to the small sample size, were regarded as only suggestive.
Scifo et al (1991) studied the effects of naltrexone in treatment of 12 autistic (DSM-III-R) children (7-16 years, 10 males). Doses of 0.5, 1.0, 1.5 mg/kg, and placebo were administered once every 48 hours in a single evening dose for 5 weeks each according to a randomized double-blind cross-over design. The behavioral evaluation was conducted using the specific Behavioral Summarized Evaluation and Childhood Autism Rating scales,. Significant reductions of autistic symptomatology were observed in seven (58%) of the children. There was no correlation between the plasma b-endorphin levels and the clinical condition.
Zingarelli et al. (1992) examined the clinical effects of naltrexone on autistic behavior in a group of eight patients, 5 males and 3 females with an age range of 19 to 39 years old and an IQ ranging from 9 to 30. Using a double-blind crossover placebo controlled randomized assignment design, one group received naltrexone during the first and third treatment periods while the second group naltrexone during the second and fourth treatment periods. Each treatment period was 3 weeks long and after each period there was a one week washout placebo period. Naltrexone and its major metabolite 6-b-naltrexol have short half-lives of approximately 10 and 14 hours respectively. Naltrexone 50 mg/d po (0.6-1.1 mg/kg/d) was administered. The number of episodes of target symptoms were recorded at the end of each 8 hour A.M. and P.M. work shift and an observer time-sampled each patient for 10 minutes twice a week. No consistent patterns due to drug treatment were seen. One patient showed a decrease in all four of his time-sampled behaviors during active treatment. It was concluded that the drug has no clinical effect on the self-injurious behaviors and maladaptive idiosyncratic mannerisms which were monitored. However, if the results of the plasma bE concentrations are considered these findings are not surprising. bE concentrations actually increased significantly with naltrexone treatment. Ross et al (1987) noted in their fenfluramine study that morphine pretreatment potentiates and naloxone antagonizes fenfluramine-induce depletion of striatal and hypothalamic serotonin stores. Thus it would seem that instead of an opiate antagonist, an opiate agonist ought to be administered to these patient to obtain a therapeutic effect.
Campbell et al compared naltexone 0.5 mg/kg/d for 1 week and 1.0 mg/kg/d for 2 weeks to placebo in a five week parallel design trial in 41 autistic children (2.9-7.8 years). Naltrexone reduced hyperactivity and had no effect on discriminant learning. There was a trend that suggested a reduction in SIB. The authors recommended that naltrexone may only benefit SIB in autistics with moderate to severe SIB. Even more discouraging was a crossover design study by Willemsen-Swinkels et al (1995) in 32 mentally retarded adults (7 autistics, 16 autistic + SIB, 9 SIB). Naltrexone 50 or 100 mg/d for 4 weeks was not more effective than placebo in reducing SIB and the 50 mg/d actually exacerbated stereotypic behavior.
It is hypothesized that there may be a subgroup of autistic patients who can respond to naltrexone. Bouvard et al (1995) treated 10 autistic children (5-14 yo) with naltrexone 0.5 mg/kg/d vs placebo for 28 days each. Only 4/10 of the subjects exhibited a "strong response." These subjects were chemically characterized by the fact that they had elevated vasopressin and serotonin levels at baseline and secondly that they had the most robust decrease in their elevated beta-endorphin concentrations. The authors also noted an ordering effect in that it may take upwards of a month to see the effects of naltrexone disappear.
Conclusion. Despite encouraging anecdotal reports, there are now 8 double-blind placebo controlled trials that conclude that naltrexone is at best minimally effective in the treatment of autism. Naltrexone should not be utilized as a first line drug in the treatment of autism. Table 3 summarizes the eight studies.
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Table 3. Controlled studies of naltrexone in autistics. |
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Study |
Dose (mg/d) |
Population |
Results |
|
Sandman 1988 |
NTX 25, 50, and 100 mg po vs placebo |
4 autistics with severe to profound MR |
SIB decreased |
|
Campbell et al 1990 |
NTX 0.5-1.0 mg/kg/d or placebo |
18 autistics |
Improvement on global rating but only slight improvement
in hyperactivity & fidgeting |
|
Scifo et al 1991 |
NTX 0.5, 1.0, 1.5 mg/kg/d, and placebo |
12 autistics |
decreased autistic symptoms 7/12 (58%) |
|
Zingarelli et al 1992 |
NTX 0.6-1.1 mg/kg/d or placebo |
8 Autism |
No effect on SIB or mannerisms bE levels went up |
|
Campbell et al 1993 |
NTX 0.5-1.0 mg/kg/d vs placebo |
41 autistics |
NTX = placebo |
|
Kolmen et al 1995 |
NTX 1.0 mg/kg/d vs placebo |
13 autistics |
parent global,impulsivity/ hyperactivity, and restlessness improved only teacher global rating improved 8/13 improved in home, school, and clinic setting, i.e., 2/3 settings |
|
Bouvard et al 1995 |
NTX 0.5 mg/kg/d vs placebo |
10 autistics |
only 4/10 had a "strong response" responders at baseline
had elevated vasopression and serotonin levels |
|
Willemsen-Swinkels et al 1995 |
NTX 50 or 100 mg/d vs placebo crossover x 28 days
each |
32 mental retardates |
a heterogeneous population that was unable to exhibit any beneficial effect of NTX on SIB and autistic behavior. |
Clonidine
Since the administration of norepinephrine agonists such as amphetamines or methylphenidate worsen the behavior of autistic patients, it seems logical that the administration of a norepinephrine antagonist such as clonidine would be benefit these patients. Fankhauser et al (1992) studied the effectiveness of transdermal clonidine in nine male autistic patients aged between 5-33 years old. Using a double-blinded placebo-controlled crossover design, patients were randomly assigned to receive either 4 weeks of transdermal clonidine 5 mcg/kg/d or transdermal placebo. The crossover occurred following a 2 week wash-out period. Clinician ratings were done seven times over the course of the study in 20-30 minute observations. Parents also rated the children on a weekly basis. According to the results of the Real Life Rating Scale, the patients demonstrated improvement in 3 of 5 categories, social relationships, sensory responses and effectual reactions. There was no significant improvement in language and specific sensory motor behavior. The CGI indicated that the drug produced significant improvement on the severity of illness, global improvement, and therapeutic efficacy indices. The clonidine was shown to produce a calming effect in many of the patients which improved their ability to carry out social interactions and also reduced inattention and repetitive behaviors. Predictably the clonidine caused a substantial amount of fatigue and sedation during the first two weeks of treatment.
Secretin
Secretin is a neuropeptide hormone secreted by cell in the upper GI tract in response to food entering the stomach, thereby causing the secretion of water, bicarbonate, and the pancreatic enzyme pepsin. The only current medical indication for secretin is as a single IV injection during upper GI endoscopy to stimulate and assess pancreatic function. Horvath et al (1998) noted dramatic improvement in the behavior of three autistic children following upper GI endoscopy in which secretin was administered. The children were reported to have improved in terms of both socialization and communication abilities within several weeks of the injections. To date 5 double-blind, placebo-controlled trials using either one or two IV doses of secretin over observational periods ranging from 3 to 16 weeks have found secretin to be an ineffective treatment for autism in the 287 study participants. At this point in time, no scientific evidence exists to support the use of secretin as a treatment for autism.
Summary
From the review of these studies it seems that the most effective drug therapy would be haloperidol at a dose of approximately 0.05 mg/kg/d based on controlled trials involving 90 autistic patients. The most interesting study to date is the Gordon (1993) study that concluded that the SSRI-TCA, clomipramine had the most dramatic effect on the symptoms of autism. Haloperidol and clomipramine pharmacotherapy is followed by three second-line treatments that include fenfluramine (> or = 1.5 mg/kg/d, n=63), naltrexone (0.5-1.1 mg/kg/d, n=138), and clonidine (0.005 mg/kg/d, n=9). The fenfluramine and naltrexone have at best what appears to be an underwhelming effect on autistic behaviors for either to be used regularly as sole therapy. The fenfluramine studies suffer from a lack of sufficient doses (>1.5 mg/g/d). The naltrexone studies conclude that the only autistic target symptom affected by the drug is SIB. Clonidine has only been studied in 9 patients. Thus it is a third line drug because of a paucity of data.
REFERENCES
Anderson LT, Campbell M, Adams P, et al (1989). The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 19:227-39.
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