Psychopharmacology in Autism

LUKE Y. TSAI, MD
Autism is a neurobiological disorder. The core clinical features of autism include impairment in social interaction, impairments in verbal and nonverbal communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Autism often has coexisting neuropsychiatric disorders, including seizure disorders, attention deficit hyperactivity disorder, affective disorders, anxiety disorder, obsessive-compulsive disorder, and Tourette disorder. No etiology-based treatment modality has been developed to cure individuals with autism. However, comprehensive intervention, including parental counseling, behavior modification, special education in a highly structured environment, sensory integration training, speech therapy, social skill training, and medication, has demonstrated significant treatment effects in many individuals with autism. Findings from preliminary studies of major neurotransmitters and other neurochemical agents strongly suggest that neurochemical factors play a major role in autism. The findings also provide the rationale for psychopharmacotherapy in individuals with autism. This article reviews studies of neurochemical systems and related psychopharmacological research in autism and related neuropsychiatric disorders. Clinical indications for pharmacotherapy are described, and uses of various medications are suggested. This article also discusses new avenues of investigation that may lead to the development of more effective medication treatments in persons with autism. Key words: autism, neuropsychiatric disorders, neurotransmitters, psychopharmacotherapy.

BE -endorphin; CMI clomipramine; CSF cerebrospinal fluid; HVA homovanillic acid; OCD obsessive-compulsive disorder; R-BH4 6R-L-erythro5,6,7,8-tetrahydrobiopterin; 5-HT 5-hydroxytryptamine (serotonin).

INTRODUCTION In 1943, Kanner (1) described a group of 11 children with characteristic features of inability to develop relationships with people, extreme aloofness, delay in speech development, noncommunicative use of speech, repeated simple patterns of play activities, and islets of unusual ability. However, Kanner believed that only two features were of diagnostic significance: autistic aloneness and obsessive insistence on sameness. He used the term infantile autism to describe this previously unrecognized disorder. Research in the past five decades has changed the original concept of unitary disorder (ie, infantile autism) to the current concept of a spectrum disorder (ie, pervasive developmental disorder) that has several subtypes, including autistic disorder, Rett disorder, childhood disintegrative disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified, including atypical autism) (2). This review, however, focuses on

From the University of Michigan Medical School; and Developmental Disorders Clinic, Child and Adolescent Psychiatric Hospital, University of Michigan Medical Center (L.Y.T.), Ann Arbor, MI. Address reprint requests to: Luke Y. Tsai, MD, Child and Adolescent Psychiatric Hospital, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0390. Received for publication June 4, 1998; revision received March 5, 1999.

autistic disorder because reports on psychopharmacotherapy have involved mainly subjects with autistic disorder. The review includes mainly studies performed during the last 15 years because the definition and diagnostic criteria of autistic disorder have been more consistent since 1980, when the third edition of the Diagnostic and Statistical Manual of Mental Disorders was published (3). For convenience, the term autism is used for autistic disorder in the remainder of this article. The core clinical features of autism include impairment in social interaction, impairments in verbal and nonverbal communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. However, in addition to the core autistic symptoms, many investigators have reported other behavioral and/or psychiatric symptoms in persons with autism: about 60% have poor attention and concentration; 40% are hyperactive; 43% to 88% exhibit morbid or unusual preoccupation; 37% have obsessive phenomena; 16% to 86% show compulsions or rituals; 50% to 89% demonstrate stereotyped utterance; 70% exhibit stereotyped mannerism; 17% to 74% have anxiety or fears; 9% to 44% show depressive mood, irritability, agitation, and inappropriate affect; 11% have sleep problems; 24% to 43% have a history of selfinjury; and 8% have tics (4). In the past, these additional symptoms were considered associated features of autism (2, 3). Now, more investigators argue for considering these behaviors and symptoms as features of coexisting neuropsychiatric disorders, such as attention deficit hyperactivity disorder, affective disorders, obsessive-compulsive disorder, and Tourette disorder (5). The clinical symptoms in persons with autism may differ at different chronological ages. In early childhood, hyperactivity, stereotyped behaviors, irritability,

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and temper tantrums may be prominent, whereas ticlike behaviors, aggressiveness, and self-injurious behavior may characterize the child later. In adolescence and adulthood, particularly in higher-functioning individuals, depression or obsessive-compulsive phenomena may develop and interfere with functioning (6). Today, there is a consensus that autism is a neurobiological disorder. However, no specific biological marker has been identified as the cause of autism. Hence, no treatment modality specifically based on cause has been developed to cure individuals with autism. Nevertheless, comprehensive intervention, including parental counseling, behavior modification, special education in a highly structured environment, sensory integration training, speech therapy, social skill training, and medication, has demonstrated significant treatment effects in many individuals with autism. The specific purpose of using psychotherapeutic medications in autism is to ameliorate the psychiatric or behavioral symptoms that are interfering with the individuals ability to participate in educational, social, work, and family systems as well as to enhance the positive response to other forms of intervention in persons with autism. Intriguing research findings in the relationship between neurotransmitters and clinical features of other neuropsychiatric disorders have led researchers to studies of major neurotransmitters and other neurochemical factors in autism. Although the studies are usually preliminary and often compounded by problems inherent in neurochemical research (eg, assay methods, measurements of body fluids, and confounding variables of age, sex, etc.), the findings from the preliminary studies strongly suggest that neurochemical factors play a major role in autism (7). The findings also provide the rationale for psychopharmacotherapy in individuals with autism. A recent survey study found that about one-third of persons with autism were taking some psychotropic drug or vitamin for autism or associated behavior or psychiatric problems (8). This article reviews studies of neurochemical systems and related psychopharmacological research in autism and related neuropsychiatric disorders. This article also discusses new avenues of investigation that may lead to the development of more effective medication treatments in persons with autism. hyperserotonemia: 1) increased platelet volume, 2) enhanced platelet uptake and storage of 5-HT, 3) increased synthesis of 5-HT, and 4) decreased catabolism of 5-HT. Geller et al. (10) reported no significant differences in platelet volume between autistic patients and control subjects. Platelet volumes and blood serotonin concentrations also did not correlate. Although some studies have found that the platelets handling of 5-HT seemed to be normal in autism (11, 12), Cook et al. (13) found that a subgroup of relatives of hyperserotonemic autistic children had an increased rate of platelet 5-HT uptake. However, they also found that another subgroup of relatives of hyperserotonemic autistic probands had decreased platelet 5-HT2 receptor binding. The results suggest heterogeneity within hyperserotonemia of autism. Several studies have not found any difference between autistic and normal subjects in 5-HT synthesis (14). However, DEufemia et al. (15) found that the serum tryptophan to large neutral amino acids ratio, a reliable marker of tryptophan availability for brain serotonin synthesis, was significantly lower in 40 children with autism than in 46 control children. Although this finding does not explain the hyperserotonemia, it does suggest that low brain tryptophan availability could be one possible mechanism involved in the alteration of serotonergic function in autism. The occurrence of hyperserotonemia in autistic persons does not seem to be the result of decreased catabolism of serotonin (14). Although there was a preliminary finding of a negative correlation between whole-blood 5-HT level and verbal-expressive/symbolic abilities in 18 autistic patients and their first-degree relatives (16), no consistent correlation has yet been found between blood serotonin level and any autistic behaviors or symptoms. Moreover, hyperserotonemia has also been found in some children who are severely retarded. Clearly, the mechanism and importance of hyperserotonemia in autism remain unresolved.

Serotonin Binding Todd and Ciaranello (17) reported that about onethird of the autistic children in their study had an unusual antibody circulating in their blood and spinal fluid. This antibody seemed to attack the receptor for serotonin. Cook et al. (13) found a subgroup of hyperserotonemic autistic children with decreased 5-HT2 binding.

SEROTONIN FUNCTION STUDIES Hyperserotonemia Many studies have consistently reported that about one-third of autistic individuals have hyperserotonemia (9). There are several possible explanations for the

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Serotonin Responsivity Numerous studies in animals and humans have shown that plasma prolactin levels are increased after the administration of agents that augment central serotonergic transmission. Hoshino et al. (18) reported blunted prolactin release after administration of the 5-HT precursor L-5-hydroxytryptophan (3 mg/kg) to six autistic children. McBride et al. (19) reported that seven male autistic adults had substantially blunted prolactin release in response to a 60-mg oral dose of fenfluramine (an indirect 5-HT antagonist) compared with age- and gender-matched healthy control subjects. These results suggest that central serotonergic responsivity is decreased in some individuals with autism. Serotonin and Genetic Liability Several studies have found a positive correlation of both platelet-rich plasma 5-HT and platelet-poor (free) plasma 5-HT between the autistic probands and their first-degree relatives (20, 21). High levels of platelet serotonin have also been reported in autistic probands of multiple-incidence families (ie, at least two autistic children) compared with autistic probands of singleincidence families, as well as higher levels of platelet serotonin in single-incidence families as compared with normal control subjects. These findings suggest that the 5-HT level in autistic subjects may be associated with heterogeneic genetic liability to autism (22).
TABLE 1. Age Range of Subjects (y) 35 318 324 618 612 3.58.7 Adults Adults 18 26 1321 Adults 819 728 30 20 Adults 612 Adults Adults 910

SEROTONIN-RELATED PHARMACOLOGICAL STUDIES Fenfluramine Fenfluramine is an indirect 5-HT agonist that releases 5-HT presynaptically and blocks its reuptake from 5-HT neurons. Earlier studies reported behavioral improvement associated with improvement in IQs (23, 24). However, subsequent multicenter study data showed less positive effects (25) (see Table 1). Several independent research groups reported no significant improvements with fenfluramine as compared with placebo (26). There is considerable doubt of the efficacy of fenfluramine in persons with autism. Furthermore, there are some recent reports of association of serious regurgitant cardiac valvular disease in patients taking fenfluramine. Hence, fenfluramine should not be considered as a therapeutic agent for autism.

Clomipramine CMI is an antiobsessional drug that belongs to the class of tricyclic antidepressants. Although CMI affects norepinephrine and dopamine neuronal uptake, its most potent action is to inhibit 5-HT reuptake. CMI has been shown to be effective in the treatment of OCD (27). In a study that compared CMI, desipramine, and placebo, CMI was superior to placebo in reducing hyperactivity, stereotypies, compulsive and ritualized

Serotonin-Related Pharmacological Studies Sample Size 3 14 81 24 5 7 5 18 1 1 4 2 4 23 1 1 30 9 42 5 4 Dose Design mg/d Double-blind, Double-blind, Double-blind, Double-blind, Open Open Open Open Open Open Open Open Open Open Open Open Double-blind, Open Open Open Open placebo-controlled placebo-controlled placebo-controlled placebo-controlled 40 1.5 (mean) 1.5 (mean) 4.3 (mean) 3.14 (mean) 185 (mean) 75200 No data 10 (mean) 2040 20 2030 1080 150 100 150300 2550 122 (mean) 25150 15 mg/kg per day

Drug

Reference

Fenfluramine

Clomipramine

Fluoxetine

Fluvoxamine

Sertraline

Buspirone

23 24 25 28 29 30 31 32 33 34 35 36 37 38 40 41 42 43 44 45 46

152 (mean) 200

placebo-controlled

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behaviors, and anger. Adverse effects associated with CMI were grand mal seizure, prolongation of the QT interval, and tachycardia (28). Although in one study CMI seemed to reduce adventitious movements and compulsions in some young autistic children (29), another study reported that 6 of 7 children became worse on CMI; behavioral toxicity was severe, and constipation was common (30) (Table 1). In adults with autism, CMI (31, 32) showed a significant improvement in social interaction , a significant reduction in repetitive behavior, and a decrease in aggression. Patients tolerated the drug well and had no severe adverse effects other than dry mouth (31, 32) (Table 1). Fluoxetine Fluoxetine is a potent and selective 5-HT uptake inhibitor that has been shown to be effective in the treatment of depression and OCD (27). In the autistic population, fluoxetine has been reported to improve trichotillomania (33), mood and ritualistic behavior (34), depressive symptoms (35), and obsessive-compulsive and social behaviors (36 38) (Table 1). The side effects of fluoxetine are restlessness, hyperactivity, agitation, decreased appetite, and insomnia (38). Fluvoxamine Fluvoxamine is a potent 5-HT uptake inhibitor that has been shown to be effective in the treatment of depression and OCD (27). Controlled studies of fluvoxamine in children with autism have not been reported, although there was a significant increase in agitation, aggression, insomnia, and other forms of behavioral activation and limited efficacy in one pediatric sample (39). In adults with autism, fluvoxamine has been shown to have therapeutic effects in the reduction of obsessive-compulsive symptoms and aggression, an increased desire to pursue social relationships, improved interpersonal interaction, and less withdrawal from human contact (40 42) (Table 1). Except for mild sedation and nausea in a few patients, fluvoxamine was well tolerated with no significant adverse effects (42). Sertraline Sertraline is a potent, selective 5-HT uptake inhibitor that has been shown to be effective in the treatment of depression and OCD (27). Controlled studies of use of sertraline in children with autism have not been reported. In open trial studies, sertraline improved transition-induced anxiety and agitation in autistic children (43) and symptoms of impaired reciprocal social interaction, aggression, and repetitive behavior in some adults. Adverse side effects included headache, agitation, weight gain, and reduced appetite (44, 45) (Table 1). Buspirone Buspirone is a 5-HT1A partial agonist that is used for the treatment of generalized anxiety disorder (27). One study reported a reduction in hyperactivity and stereotypic behavior in some children with autism. No adverse effects were observed (46) (Table 1). DOPAMINE FUNCTION STUDIES Studies of dopamine in autism have focused on the measurement of HVA, the main metabolite of dopamine. Some investigators have found that autistic children do not differ from other diagnostic groups in the level of HVA in CSF (47, 48). However, the CSF level of HVA was found to be higher in the more severely impaired children, especially those with greater locomotor activity and more severe stereotypies (47). Gillberg and Svennerholm (49) found elevated CSF HVA levels in 13 medication-free autistic children compared with matched control subjects. Two studies found no difference in plasma HVA level between autistic children and control subjects (50, 51). Furthermore, HVA concentrations have not been shown to correlate with any autistic behaviors or symptoms. Nevertheless, dopamine agonists, such as stimulants, have been noted to cause worsening of preexisting stereotypies, aggression, and hyperactivity in autistic children (52). Such an observation suggests a role of the dopamine system in autistic symptomatology. DOPAMINE-RELATED PHARMACOLOGICAL STUDIES Haloperidol Haloperidol is a dopaminergic blocking agent that has been systematically studied in large samples of hospitalized autistic children, under careful monitoring and under double-blind and placebo-controlled conditions (53, 54). Although haloperidol did not alter the core symptoms of autism, it was reported that haloperidol, at doses ranging from 0.25 to 4.0 mg/d, improved coordination, self-care, affect, and exploratory behavior; reduced stereotypies, withdrawal, hyperactivity, fidgeting, and temper tantrums; increased social relatedness; and facilitated learning in the laboratory (53). Within an age range of 2.3 to 8.2 years,

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haloperidol was more effective in older than younger children, and children with disruptive symptoms seemed to be the best responders (55). At optimal doses, no severe side effects of haloperidol have been noted. Excessive sedation is most common above optimal doses or during dose regulation, followed by acute dystonic reactions, a Parkinson-like syndrome, and akathisia. Long-term side effects of haloperidol include weight gain, withdrawal dyskinesia, and tardive dyskinesia. Campbell et al. (56) conducted a prospective study of 82 autistic children, ages ranging from 2.3 to 8.2 years, to define the occurrence of drug-related dyskinesias. Patients received haloperidol 0.25 to 10.5 mg/d for 0.8 to 78.5 months (mean, 18.1 months). Twentyfour of the 82 children developed dyskinesias, 21% during haloperidol administration and 79% during drug withdrawal. The dyskinesias tended to involve the orofacial muscles, tongue, and arms, and girls seemed to be at greater risk. Although all of the dyskinesias were reversible, the time course for them varied from 7 days to 7.5 months. Withdrawal dyskinesia usually occurs within 2 weeks of haloperidol withdrawal. Hence, it is recommended that dosage increments be gradual and made on a regular basis. When a child is stabilized, the medication should be discontinued about every 4 to 6 months to determine whether further medication treatment is needed and to evaluate the development of withdrawal dyskinesia (57). Because moderately to severely affected autistic children tend to need longer-term administration of medication, Perry et al. (58) studied the effects of haloperidol given for 6 months in 60 autistic outpatients (age, 2.37.9 years) who had previously shown clinically significant improvement on haloperidol. Haloperidol doses ranged from 0.5 to 4.0 mg/d. Long-term haloperidol administration was found to be effective in reducing maladaptive symptoms in these children. However, 59% of these children had a significant return of symptoms during the 4-week placebo period. Children who had an angry or labile affect, loud voice, and negative and uncooperative behaviors had more marked behavioral deterioration during haloperidol withdrawal. Pimozide Pimozide is a potent dopamine antagonist. It is effective in reducing motor and vocal tics in Tourette disorder (59). In a multicenter study that compared pimozide to haloperidol in 87 autistic children and adolescents, the two drugs were equally effective compared with placebo, based on global ratings. A significant reduction occurred in some types of aggression, including injury and violence to others and breaking furniture (54). Pimozide in doses of 3 to 6 mg/d improved hypoactivity and global measures of behavioral change in eight autistic children aged 4.2 to 8.3 years (60). Side effects of pimozide include sedation, parkinsonian symptoms, and T-wave change on the electrocardiogram (59). It is recommended that pretreatment laboratory studies include an electrocardiogram, vital signs, blood count, and liver function profile. These measures should be monitored periodically.

L-Dopa L-Dopa is a precursor to dopamine (an agonist). There has been no clinical trial of L-dopa in autistic subjects since the studies of Ritvo et a1. (61) and by Campbell et al. (62), both of which had negative findings.

Amisulpride and Bromocriptine Bromocriptine is a dopamine agonist. Simon-Soret and Borenstein (63) reported significant improvements in ratings of withdrawal, disturbances of communication, bizarre responses to the environment, and stereotypies after autistic subjects received 7.5 mg/d of bromocriptine. Dollfus and Petit (64) reported the effects of amisulpride (a dopamine antagonist) and bromocriptine in nine children with autism (age, 4 13 years). Amisulpride (1.5 mg/kg per day) was associated with an improvement on the autistic scale of the Behavioral Summarized Evaluation (behavioral inhibition and withdrawal symptoms), and bromocriptine (0.15 to 0.20 mg/kg per day) treatment was associated with improvement in symptoms of hyperactivity and inattention on the Conners Parent Teacher Questionnaire.

EPINEPHRINE AND NOREPINEPHRINE FUNCTION STUDIES Epinephrine and norepinephrine are often discussed concurrently because of their similar effects on behavior. There were no differences between autistic persons and control subjects in CSF, plasma, and urinary excretion of 3-methoxy-4-hydroxyphenyleneglycol, the principal metabolite of brain norepinephrine, or in urinary excretion rates of epinephrine, norepinephrine, and vanillylmandelic acid (52, 65). In platelets, both epinephrine and norepinephrine were significantly lower in the autistic group than in the control group (50).

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EPINEPHRINE- AND NOREPINEPHRINERELATED PHARMACOLOGICAL STUDIES Desipramine Desipramine is a relatively selective norepinephrine uptake inhibitor. Gordon et a1. (66) found that in a 5-week study of desipramine (40 mg/d) in seven children with autism (mean age, 9.6 years), desipramine was rated as better than placebo and was helpful in reducing hyperactivity. Side effects included mild disturbances in sleep, dry mouth, and constipation. There was no serious cardiac or central nervous system side effect. Blockers blockers are medications that block -adrenergic receptors and reduce overall norepinephrine neurotransmission. It has been reported that propranolol (a blocker) was effective in reducing severe and treatment-resistant aggressiveness directed against others or oneself. These reports, however, are based on uncontrolled trials or case reports involving diagnostically heterogeneous nonautistic subjects (26). In an open trial of propranolol in eight hospitalized adults with autism, Ratey et al. (67, 68) reported a reduction in aggressive, impulsive, and self-injurious behaviors and improvement in speech and socialization. However, seven of the eight patients were receiving concomitant neuroleptic or mood-stabilizing drugs during the trial. Clonidine Clonidine is an 2-adrenergic receptor agonist that decreases norepinephrine neurotransmission. It has been reported that clonidine has therapeutic value in Tourette disorder (69). It is less effective in reducing tics than haloperidol and pimozide but has fewer side effects than haloperidol. It was tried in autism because of its behavioral effects. In a double-blind, placebocontrolled crossover study, clonidine (0.150.20 mg/d) was given to eight autistic boys, aged 5 to 13 years, who had been previously treated with methylphenidate, neuroleptics, or desipramine without effect (70). Teacher and parent ratings indicated modest improvement in hyperactivity and irritability. Sedation and decreased blood pressure were the most frequent side effects, and many of the children eventually developed tolerance to the therapeutic effects of clonidine. NEUROPEPTIDE STUDIES Certain peptides have been shown to act as neurotransmitters and affect pain perception, emotion, appetite, and sexual behavior. Some studies have reported abnormal urinary peptide patterns in autistic subjects (71, 72), but the meaning of these findings is unclear. Lower serum H-endorphin level was noted in a group of autistic children compared with schizophrenic children and normal control subjects (73). The mean CSF endorphin fraction II levels were found to be higher in autistic children than in normal children. Children with autism whose CSF endorphin levels were above the highest control value had decreased pain sensitivity (74). Ross et al. (75) reported higher baseline levels of CSF BE in autistic children than in control subjects; whereas Gillberg et al. (76) found low CSF BE in autistic subjects. Sandman et al. (77) reported low plasma BE in autistic individuals. Willemsen-Swinkels et al. (78) suggested that the reduced plasma BE concentrations in autistic individuals might be related to self-injurious behavior because the BE level of the autistic subjects with severe self-injurious behavior was significantly lower than that of autistic subjects without such behavior. A potential role of opiate in autism was suggested by opiate-induced behaviors in animals that resemble autistic behaviors (79). Also, certain maladaptive behaviors in autistic persons are reminiscent of the symptoms seen in adult opiate addicts as well as babies exposed to opiates in utero (80).

NEUROPEPTIDE-RELATED PHARMACOLOGICAL STUDIES Opiate Antagonists Naltrexone, an opiate antagonist, has been reported in small-sample studies as having positive effects on hyperactivity, attentiveness, verbalization, social relatedness, self-injury, and scores on the Childhood Autism Rating Scale (81 85). The therapeutic changes occurred at doses of 0.5 to 2.0 mg/kg per day. The effect of naltrexone on self-injurious behavior was tested in a larger sample (41 autistic children; age, 2.9 7.8 years) using a double-blind, placebo-controlled design with daily administration of naltrexone at a dose of 1 mg/kg per day (86). Administration of naltrexone was associated with a significant reduction of hyperactivity. However, in a subsample of children with mild to moderate self-injurious behavior, only a few children showed improvement in such behavior. Naltrexone had no effect on self-injurious behavior in 33 mentally retarded adults with autism and/or selfinjurious behavior (87). Untoward effects associated with naltrexone were few and mild. There were no

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adverse effects on liver function or electrocardiographic changes. Effects on weight were minimal. A double-blind, placebo-controlled crossover study in 23 autistic children (age, 37 years) showed that naltrexone decreased hyperactivity and irritability and had no effect on social and stereotypic behavior (88). In a randomized, double-blind, crossover study of 24 autistic children, aged 3.0 to 8.3 years,1 mg/kg day of naltrexone was given to each subject. Eleven of the 24 children showed modest improvement of behavior based on parent and teacher Clinical Global Impression Scale ratings (89). Gonzalez et al. (90) studied the relationship between plasma naltrexone levels and clinical response in 17 hospitalized autistic children using a doubleblind, placebo-controlled, parallel-groups design with a fixed dose. No relationship was found between plasma level of naltrexone and scores on the 14 selected Childrens Psychiatric Rating Scale items, Clinical Global Impression Scale, Global Clinical Consensus, and the Childrens Psychiatric Rating Scale hyperactivity factor. Ernst et al. (91) measured plasma BE level in 13 autistic children, aged 3.7 to 11.7 years, at the end of naltrexone treatment. Although naltrexone did not seem to have a specific effect on plasma BE levels, there was a strong correlation between plasma BE levels and severity of stereotypies in all children. Other investigators, however, have not found any positive effects of naltrexone in persons with autism (92, 93). It seems that the efficacy of naltrexone in reducing self-injurious and hyperactivity in individuals with autism still awaits critical assessment. Nevertheless, naltrexone merits further study in persons with autism and moderate to severe self-injury and in those with severe hyperactivity who do not respond to other medications commonly used for managing self-injurious behavior or hyperactivity. PSYCHOPHARMACOLOGICAL STUDIES OF DRUGS WITH MULTIPLE NEUROTRANSMITTER FUNCTIONS Stimulants The amphetamines and methylphenidates may enhance central nervous system catecholamine (norepinephrine and dopamine) release from sympathetic nerve terminals and inhibit reuptake in the caudate nucleus. It is now generally accepted that stimulants are efficacious in decreasing restless, impulsive behaviors and in improving attention span in children and adolescents with attention deficit hyperactivity disorder. The effects of stimulants have not been extensively studied in individuals with autism. Aman (95) reviewed the effect of stimulants in developmental disorders and concluded that there is no role for the use of stimulants in the autistic population. However, the studies included in the reviews involved mostly lower-functioning autistic children. There are now reports of positive effects (eg, decreased hyperactivity and impulsiveness, and improved attention and concentration) of stimulants in certain autistic children, particularly those with higher-functioning autism (26, 96).

Risperidone Risperidone is a new antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives. It is a potent dopamine Type 2 (D2) and serotonin Type 2 (5-HT2) receptor antagonist. It has efficacy against both the positive and negative symptoms of schizophrenia and has significant advantages over both the conventional dopamine-blocking neuroleptics and the atypical antipsychotic clozapine (97). Risperidone has also been reported to be effective in treating tic disorders, including Tourette disorder (98), and OCD (99). There are reports of positive effects of risperidone in small samples of children and adolescents with autism (26, 100 103). Risperidone seems to be effective in improving hyperactivity and in reducing the frequency and intensity of temper outbursts and aggression. However, it tends to cause significant weight gain in children and adolescents in a relatively short period of time, an effect that seems to occur to the same degree in adult patients (39). Data on the long-term side effects of risperidone, particularly tardive dyskinesia, in the autistic population are not available because of the relatively short period of use of the medication. However, there have been reports of possible tardive dyskinesia in children treated with risperidone. This medication should be closely moni-

Adrenocorticotropic Hormone Analog (Org 2766) Buitelaar et al. (94) studied Org 2766, a synthetic analog of ACTH 4 9, in 14 children with autism using a double-blind, placebo-controlled crossover study design. At a dose of 20 mg/d, Org 2766 seemed to have an activating and stimulating effect on behavior, as evidenced by increases in locomotion, changing toys, and talkativeness. A decrease in stereotypic behavior was also observed. Parents rated 11 of the 14 children and investigators rated 8 of the 14 as showing improvement. No adverse events or side effects were observed.

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tored for any side effects whenever it is used in autistic patients. STUDIES OF VITAMINS AND OTHER AGENTS Vitamin B6 and Magnesium The proponents of orthomolecular psychiatry claim that mega doses of certain vitamins will ameliorate or prevent such mental disorders as schizophrenia, mental retardation, and autism. Several investigators have reported that autistic individuals showed significant improvement during vitamin B6 (pyridoxine) and magnesium treatment. The dose of pyridoxine ranged from 15 to 30 mg/kg per day or 700 to 1000 mg/d; and the dose of magnesium ranged from 10 to 15 mg/kg per day or 380 to 500 mg/d. However, the treatment periods were rather short (2 weeks to 30 days), and the behavior scales used to evaluate the outcomes were not specific to autism. Other investigators have failed to confirm the positive findings. A review of this issue by Pfeiffer et al. (107) concluded that even though the majority of studies report a favorable response, the interpretation of these findings needs to be tempered because of methodological shortcomings inherent in many of the studies. Vitamin B12 and Folic Acid Lowe et al. (108) gave folic acid and vitamin B12 to an unselected group of children with autism. No significant change of behavior was noted in these children. Nonetheless, Hagerman et al. (109) reported behavioral improvement in prepubertal boys with fragile X syndrome treated with folate 10 mg/d. This finding calls for a trial of folate in autistic children because about 8% of autistic people also have fragile X syndrome (110). Gillberg et al. (111) gave folate to four autistic boy with the fragile X syndrome but found no significant behavioral change. Melatonin Tetrahydrobiopterin R-BH4 is a cofactor for tyrosine hydroxylases in the biosynthetic pathway of catecholamines and serotonin. Fernell et al. (106) reported a study in which R-BH4 was given to six children with autism (age, 35 years). After 3 months of treatment, all parents reported improvement in social functioning and in the numbers of words or sounds that the children used. The posttreatment positron emission tomography study showed that the dopamine D2 receptor binding in the caudate and putamen decreased by about 10% toward the normal level. However, the clinical significance is unclear because of the small sample size and minuscule change in receptor binding. An abnormal circadian pattern of melatonin was found in a group of young adults with autism (112). Melatonin, at a dose ranging from 1 to 10 mg, had been effective in some autistic children with sleep problems. Serious side effects have not been observed (26, 113), although melatonin-induced seizures in children with disabling neurological conditions and chronic severe sleep disorders were recently reported (114). PROBLEMS WITH PREVIOUS CLINICAL STUDIES Although it is unclear what causes autism, a variety of neurochemical abnormalities have been reported.

Clozapine Clozapine is an atypical antipsychotic medication that blocks receptors of dopamine and serotonin. Zuddas et al. (104) reported results of an open-label trial on clozapine in two 8-year-old boys and a 12-year-old girl with autism and hyperactivity, fidgeting or aggressiveness, and minimal clinical response to classic neuroleptics. After 3 months, clozapine treatment markedly improved the target behaviors. All three children reported transient sedation and enuresis. There was no other adverse side effect. However, because of the significant risk of agranulocytosis reported in schizophrenia literature, clozapine should be reserved for the most severe cases and the complete blood count should be monitored closely.

Imipramine Imipramine blocks presynaptic neuronal uptake of both norepinephrine and serotonin. Ten preschool autistic and schizophrenic children, aged 2 to 6 years, were administered imipramine (mean maximum tolerated dose, 34.5 mg/d). Two of the 10 children were rated as markedly improved, and the others were rated as unchanged or worse (105). Although imipramine decreased affective blunting, anger, and withdrawal and stimulated speech production in some of the children, it also increased psychotic speech, behavioral disorganization, and excitation in others who had psychotic features.

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Hence, it is reasonable to speculate that dysregulated neurochemical systems exist in some individuals with autism. However, the neurochemical metabolites are usually measured in blood or urine. These data may not reflect brain levels and their significance is not clear. Nevertheless, this is an important topic for further research to improve our understanding of the pathogenic role of neurochemical factors as well as to enhance the development of effective medical treatment in autism. Significant progress has been made in the past few years regarding the efficacy and safety of pharmacotherapeutic agents in the treatment of persons with autism. However, clear conclusions concerning the efficacy and safety of these agents cannot be made because the findings are based mostly on small sample sizes, imprecisely defined subjects, open studies without placebo control, invalidated outcome measures, and short-term effects. FUTURE PHARMACOLOGICAL RESEARCH DIRECTION Future research should emphasize multicenter collaborative investigation. Such an approach will enlarge sample sizes, enhance interrater reliability in diagnosis of disorders (to obtain more homogeneous groups of patients for study), and ensure the consistency of assessment of treatment results. Future psychopharmacological studies in autism should use a standardized, controlled study design, which would allow comparison of efficacy between medication treatment, nonmedication intervention (such as behavioral treatment), and the combination of both. The measure of treatment effects should emphasize both behavior-cognition and blood level estimations of drugs. Organ imaging techniques, such as positron emission tomography and magnetic resonance imaging, should also be emphasized in future psychopharmacological studies in autism to enhance the knowledge of drug and neurotransmission receptors relationship in autism. Such an emphasis would enable the development of new strategies for specific pharmacological interventions that are based on underlying neurochemical abnormalities. Preliminary clinical data seem to show that drugs associated with serotonin functions may be useful in reducing repetitive and compulsive behaviors and aggression and in improving social relatedness in some individuals with autism. Although dopamine functionrelated drugs are very effective in the treatment of tics, stereotypies, and psychotic symptoms, they tend to cause drug-induced and withdrawal-related dyskinesias. Future studies should explore the efficacy and safety of the recently developed atypical neuroleptics, such as olanzapine and clozapine, which tend to have lower risks of extrapyramidal side effects. Drugs that influence epinephrine or norepinephrine do not seem to be useful in treating the core symptoms of autism. They may, however, be useful for reducing explosive tantrums with self-injurious behavior and/or aggression. The role of neuropeptides (eg, naltrexone) in the treatment of autism is not clear. They seem to have some therapeutic effect in reducing aggression, selfinjury, and hyperactivity and in increasing social behaviors. Both short-term and long-term controlled studies of the above classes of drugs in larger samples of children and adults with autism are warranted to determine their efficacy and safety in the treatment of autism. Future investigations should also explore efficacy and safety of the following drugs in the autistic population. Guanfacine Guanfacine is another -adrenoceptor agonist with a longer excretion half-life, decreased sedative side effects, and more selective binding profile than those of clonidine. It has been reported to show effectiveness in treating children with attention deficit hyperactivity disorder (115) and in children with both attention deficit hyperactivity disorder and Tourette disorder (116). Lithium Lithium has been reported to have a mood-reducing effect on manic disorder in adults with autism. It may also reduce aggressiveness and hyperactivity in some individuals. The role of lithium in children is unclear; results from only a few controlled studies are available. It seems that lithium is effective in reducing aggressive behavior in children of normal intelligence diagnosed as having conduct disorder. There are uncontrolled studies that suggest lithium may have an antiaggressive effect in children with mental retardation (26). Oxytocin Function and Related Pharmacological Studies Oxytocin is a nineamino acid peptide. It has been shown that intracerebroventricular administration of oxytocin can induce maternal behavior and other prosocial activities in a variety of animals (117). The delivery of oxytocin antagonists to the brain has been

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shown to result in avoidance of social interaction in certain animals. Recently, Modahl et al. (118) investigated the midday plasma oxytocin levels in 29 autistic and 30 age-matched normal children. It was found that the autistic group had significantly lower plasma oxytocin levels than the normal group and that the oxytocin level increased with age in the normal group but not in the autistic group. An elevated oxytocin level was found to correlate with higher scores on social and developmental measures for the normal children but was associated with lower scores for the autistic children, particularly those identified as aloof. It is difficult to infer central oxytocin function from a peripheral measurement. Nonetheless, the data reported by Modahl et al. (118) seem to suggest that central oxytocin function plays a role in autism. Additional studies of brain oxytocin function may lead to effective drug treatment in social behaviors in autism. Immune Function and Related Pharmacological Studies Warren et al. (119 121) reported several immune system abnormalities in autistic patients. Lymphocyte abnormalities included reduced responses to T-cell mitogen concanavalin A, a reduced response to B-cell mitogen pokeweed, a decreased number of T lymphocytes and altered helper/T-suppressor cell ratio, significantly reduced natural killer cell activity, and significantly reduced plasma concentration of C4b protein. These findings seem to suggest that depressed immune function, autoimmune mechanism, or faulty immune regulation may be associated with the pathogenesis of autism. Additional study may lead to the development of effective immune function based drug treatment in autism. For example, Scifo et al. (122) reported a double-blind crossover study of naltrexone at doses of 0.5, 1.0, and 1.5 mg/kg every 48 hours in 12 autistic patients ranging in age from 7 to 15 years. Naltrexone significantly reduced autistic symptoms in 7 of the 12 subjects. A significant increase of T-helper inducers (CD4 CD8 ) and a significant reduction of T-cytotoxic suppressor cells (CD4 CD8 ), resulting in normalization of the CD4/CD8 ratio, accompanied the behavioral improvement. This finding may lead to the development of an immunological screening for psychopharmacological therapy with opiate antagonists. Anticonvulsants Epilepsy occurs in one-fourth to one-third of persons with autism. Although the most common type of seizure is the generalized tonic-clonic seizure, various types have been observed (4). There has been no systematic study of anticonvulsants in persons with autism. It is unclear whether anticonvulsants may be helpful in improving other clinical symptoms of autism in addition to their effects in controlling seizure disorders. For example, divalproex sodium (Depakote) has been used as a mood stabilizer. It may be an effective drug for autistic individuals with irritability and aggressive behaviors. Additional studies may help answer this question. CLINICAL INDICATIONS FOR PHARMACOTHERAPY AND SUGGESTIONS FOR DRUG OF CHOICE This section identifies comorbid neuropsychiatric disorders or behavioral problems that are potentially responsive to medication. Suggestions for drug of choice are based on the previously described studies and the authors more than 15 years of clinical experience. Disturbance of Motility, Short Attention, Impulsive Behaviors, or Attention Deficit Hyperactivity Disorder Clonidine, guanfacine, or imipramine may be considered in low- or middle-functioning autistic individuals with or without other neurological disorders, such as seizure disorders or Tourette disorder. Naltrexone may be considered for patients who do not respond to clonidine, guanfacine, or imipramine. In highly functioning individuals without other neurological disorders, stimulants, such as methylphenidate or dextroamphetamine, may be tried first. Guanfacine, clonidine, or naltrexone may be considered in patients who do not respond to stimulants or in those who have other neurological disorders. Resistance to Change, Repetitive Thoughts, Perseverative Talking, Repetitive, Ritualistic or Compulsive Behaviors, Abnormal Attachments, and Obsessive-Compulsive Disorder Clomipramine, fluoxetine, sertraline, or paroxetine should be considered first in individuals who do not have seizure disorders. In individuals with seizure disorders, clomipramine should be avoided. Fluvoxamine should be considered in adults only. Stereotyped Movements or Behaviors, Motor and/ or Vocal Tics, or Tourette Disorder Haloperidol or pimozide should be considered first. Risperidone, clonidine, or fluoxetine may be tried in

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individuals who do not respond to haloperidol or pimozide. Excessive Fear, Worry, Anxiety, or Generalized Anxiety Buspirone should be tried first. Fluoxetine, sertraline, fluvoxamine, or paroxetine may be tried in individuals who do not respond to buspirone. Irritability, Labile Mood, Frequent Crying or Laughing Spells, Sleep Disturbances, or Major Depressive Disorder Tricyclic antidepressants, such as desipramine, or other serotonin reuptake blocker antidepressants should be considered in depressed autistic individuals with a strong family history of unipolar affective illness. Close monitoring of the drug response is critical in these patients because the author and others have observed depressive episodes switching to hypomanic episodes in some cases (26). Lithium or divalproex may be the drug of choice in manic-like patients with a family history of bipolar affective illness. Delusions, Hallucinations, Bizarre Behaviors, or Schizophrenia Haloperidol, thiothixene, risperidone, or olanzapine should be considered first. Clozapine may be considered for those who do not respond to these drugs. Self-Injury Effective pharmacotherapy for self-injurious behavior has not been achieved. At present, if self-injurious behaviors develop as a part of Tourette disorder, the above medications for Tourette disorder should be considered first. Naltrexone, trazodone, or fluoxetine may be considered in individuals who do not respond to these medications and if effective intensive behavioral treatment is not available to these individuals. Aggressive Behaviors In individuals who frequently exhibit aggressive behaviors and who do not respond to behavioral interventions, risperidone or haloperidol may be the drug of choice. Trazodone, carbamazepine, valproate, lithium, or propranolol may be considered in patients who fail to respond to risperidone or haloperidol treatment. Unusual Sleeping Patterns Unusual sleeping patterns are common. Tsai (26) found that about 30% of the parents of children with autism in a special clinic reported moderate to severe sleep problems. Some autistic children seem to need much more time to settle down for sleep (ie, have initial insomnia) and/or need less sleep than most normal children. Melatonin may be considered as the first choice. Some autistic children may respond to antihistamines, such as diphenhydramine and hydroxyzine, or to clonidine. However, in daily practice, some parents of autistic children report paradoxical excitatory responses with antihistamines. In more severe cases, imipramine, trazodone, or zolpidem may be considered. Enuresis Some children with autism tend not to respond to toilet training before age 7. In the treatment of enuresis in children more than 7 years old who fail to respond to nonmedical means, imipramine and desmopressin (DDAVP) may be considered. Social Withdrawal In individuals who are not interested in social activities, naltrexone and fluoxetine may be considered. In individuals whose social withdrawal is related to depressive disorder, serotonin reuptake inhibitors may be considered. Because many individuals with autism may also have several comorbid neuropsychiatric disorders, it is possible that multiple drugs would be prescribed for the same individual by one or more physicians. It is crucial that each prescribing physician have full knowledge of what medications have been or are being prescribed and their potential interactions are. Patients should be informed about the potential side effects of each prescribed medication and the potential interactions of these medications. REFERENCES
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