Psychopharmacology of Autism Spectrum Disorders


Autism is a highly prevalent, highly heterogeneous disorder of unknown etiology. Studies to clearly establish the efficacy of various classes of psychoactive drugs are scarce. Nonetheless, available findings do support the efficacy of atypical antipsychotics and antidepressants in treating the core symptoms of repetitive behavior.

Psychiatric Times

May 2005


Issue 6

Autism is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction and language and communication, as well as the expression of restricted, repetitive behavior. Prevalence rates of autism have increased significantly, with some estimates in the range of one in 500 individuals affected. Although autism is highly heritable (as high as 90% concordance rate for monozygotic twins), the phenotype is quite variable. Moreover, a large number of potential genetic (e.g., chromosome 7) and environmental (e.g., toxins, viruses, food constituents) factors may be involved suggesting multiple, varying etiologies.

Thus, autism is an enormously heterogeneous disorder with a wide range of symptom expression across individuals as well as across disorders on the autism spectrum (high-functioning autism, Asperger's syndrome, pervasive developmental disorder not otherwise specified). In addition, up to 75% of individuals with autism function within the mental retardation range of intellectual development, whereas individuals with high-functioning autism or Asperger's syndrome can be highly intelligent. There is also significant comorbidity in this population, with affective and attention disorders commonly observed. All of these factors make effective pharmacological treatment a challenging proposition.

To add to the challenge, no medication is available that effectively treats the core social and communication deficits that define autism. As we shall illustrate in the following sections, that is not the case for restricted, repetitive behaviors. Nonetheless, current drug therapies have been termed palliative treatments (Gerlai and Gerlai, 2004), and behavioral interventions remain the mainstay of treatment. Thus, it is critical to focus on target symptoms or behaviors commonly associated with autism (e.g., aggression, anxiety) when discussing use of psychotropic agents.

As neither genetic nor environmental causes of autism have been identified, it has been difficult to firmly establish molecular mechanisms that would serve as potential targets for pharmacological intervention. Thus, medications that have been tested for efficacy in individuals with autism have been selected on the basis of their effectiveness in relevant disorders (e.g., obsessive-compulsive disorder, anxiety) or target symptoms (aggression, hyperactivity). These efficacy tests can be characterized by the paucity of well-controlled studies of pharmacological agents for specific symptoms or target behaviors. We will highlight some of these findings by drug class, with emphasis on the few available double-blind, placebo-controlled trials.


Historically, dopamine antagonists, particularly haloperidol (Haldol), were the mainstay of pharmacological treatment for individuals with autism (Campbell et al., 1978). Although haloperidol was reported to improve some symptoms of autism, including motor stereotypies, withdrawal and hyperactivity, its adverse effects limited its usefulness.

More recently, the atypical antipsychotics, particularly risperidone (Risperdal), have been widely used. The best evidence for the efficacy of risperidone in autism was the Research Units in Pediatric Psychopharmacology network study that involved a multisite trial of over 100 patients (McCracken et al., 2002). In this eight-week, double-blind, placebo-controlled study, 69% of patients were rated as much or very much improved versus 11% for placebo on the Clinical Global Impression-Improvement (CGI-I) scale at week 8. For the children with autism, there was a 57% decrease in Irritability subscale scores of the Aberrant Behavior Checklist (Aman et al., 1995) versus 14% for placebo. There was also improvement on the Stereotypy and Hyperactivity subscales but not on the Social Withdrawal or Inappropriate Speech subscales. Not surprisingly, weight gain was the most frequent side effect.

These results are consistent with an earlier report by McDougle et al. (1998) who demonstrated decreased aggression, repetitive behavior, irritability, anxiety and depression with risperidone under double-blind, placebo conditions.

Open-label studies and case reports of risperidone have also suggested improvements in aggression, self-injury, irritability and anxiety, as well as repetitive behaviors. Little, if any, evidence exists for improved social interaction or language and communication following treatment with risperidone or with any atypical antipsychotic. There are no double-blind, placebo-controlled trials of other atypical antipsychotics in autism, although open-label studies suggest the efficacy of olanzapine (Zyprexa) (Malone et al., 2001; Potenza et al., 1999).


It is not surprising that serotonin reuptake inhibitors (SRIs) have been tested for their efficacy in autism, given the purported role of serotonin in this disorder. Indeed, antidepressants have been the most widely prescribed psychotropic for individuals with autism (Langworthy-Lam et al., 2002). In a double-blind, placebo-controlled trial of clomipramine (Anafranil), Gordon et al. (1993) found that this medication not only reduced compulsive behavior, but also reduced stereotypies, aggression and self-injury. In a test of the selective serotonin reuptake inhibitor fluvoxamine (Luvox), McDougle et al. (1996) reported that eight of 15 adults with autism were responders, showing decreased repetitive behavior, aggression and inappropriate repetitive language. Zero of 15 in the placebo group were responders. Similar results were not found, however, when studying children with autism (McDougle et al., 2000). Only one of 18 children improved, whereas 14 showed adverse effects. It is important to note, however, that no randomized, controlled trials have been published on children with autism. The lack of empirical support for the efficacy of SSRIs in children with autism is compounded by the recent U.S. Food and Drug Administration finding of increased suicidality in children and the FDA directive for drug manufacturers to add a "black-box" warning to labeling of antidepressant medication.

Mood Stabilizers

The comorbidity of epilepsy with autism is well documented, and prevalence findings suggest that 13% of individuals with autism will be treated with anticonvulsants, many of which will stabilize mood (Aman et al., 1995). Survey data, however, suggest that only a small percent of individuals with autism are treated with mood stabilizers, independent of treatment for seizure disorder (Langworthy-Lam et al., 2002). Moreover, there have been few systematic studies on the effects of this class of drugs. In a small open trial, Hollander et al. (2001) found a favorable response to divalproex (Depakote), with improvement in affective stability, impulsivity and aggression. Clinically, there may be a place for drugs such as divalproex as adjunctive treatment for irritability or as a supplement to the atypical antipsychotics.


Hyperactive behavior is often associated with children diagnosed with autism spectrum disorder (ASD), and stimulants are frequently prescribed for this population. Aman and Langworthy (2000) reported that in only 10 of 41 studies were patients prescribed stimulants. However, in clinical practice, it is likely that many more higher-functioning patients received stimulants during treatment. There are few controlled data supporting efficacy of stimulants in ASD, however. Early reports by Campbell et al. (1972) noted little effect on hyperactivity with dextroamphetamine (Adderall) but a worsening of stereotypies and irritability. Two controlled trials of methylphenidate (Ritalin, Concerta, Metadate) both showed improvement in symptoms of hyperactivity, but social withdrawal and irritability were noted as side effects (Handen et al., 2000; Quintana et al., 1995). A multisite, double-blind, placebo-controlled trial of the dopamine agonist amantadine (Symmetrel) was conducted with children with autism and high levels of hyperactivity and irritability (King et al., 2001). Clinician ratings indicated a positive effect for the medication, but this effect was not reflected in parent ratings. Thus, stimulants appear to be only weakly effective and poorly tolerated. Clinically, trials of methylphenidate may prove effective in higher-functioning patients with ASD whose symptoms may represent a true comorbidity with attention-deficit/hyperactivity disorder.

The α2-adrenergic agonists are often used as an adjunct in the treatment of ADHD. Clonidine (Catapres) has been shown to reduce irritability, hyperactivity and impulsivity in two double-blind trials (Fankhauser et al., 1992; Jaselskis et al., 1992). Gradual development of tolerance was noted in these studies. In addition, side effects such as hypotension, rebound hypertension and over-sedation may cause clinical problems. Guanfacine (Tenex) may be less sedating and causes less rebound. In a retrospective, open-label study, Posey et al. (2004) found a CGI response rate of 23.8%, with improvements in insomnia, tics, hyperactivity and inattention.


Survey data suggest a small percentage of individuals are being treated with this class of drugs (Langworthy-Lam et al., 2002). Buspirone (BuSpar) has been shown to reduce aggressive symptoms and anxiety in a small group of adults with mental retardation (Ratey et al., 1991). Realmuto and colleagues (1989) found some improvement in hyperactivity in their small trial study. These few studies suggest that there may be some improvement with these medications, but there are no controlled trials to suggest that buspirone or benzodiazepines have much utility, except for short-term adjunctive treatment of specific periods of high anxiety.

Other Pharmacological Agents

Autism is a disorder associated with many unsubstantiated claims of effective treatment and considerable use of alternative medicine. For example, dimethylglycine has been advanced as a useful treatment of ASD, largely based on anecdotal reports from parents. Little empirical evidence is available to support such claims of efficacy, and at least one small placebo-controlled trial failed to show a drug effect (Bolman and Richmond, 1999). Secretin, initially proffered as a new treatment for ASD, has failed to show efficacy (Sandler et al., 1999). Levy and Hyman (2003), in a review of complementary and alternative treatments for ASD, highlighted the need for scientific scrutiny of new treatments and assessment of the risks and benefits to families. Testimonials concerning the effectiveness of untested treatments may well be due to the high placebo response rate in this population.


There are a number of psychotropic medications being routinely prescribed for individuals with autism with inadequate evidence of efficacy. Indeed, almost half of individuals with autism were receiving psychotropic medication, not including anticonvulsants (Langworthy-Lam et al., 2002). Antidepressants were the most widely prescribed class of psychotropic drugs. Currently, no psychotropic agents are FDA-approved for the treatment of autism, and no medications have been proven to be efficacious in the treatment of the core social or communication impairment seen in this disorder. Open-label and controlled studies conducted with both children and adults have demonstrated the efficacy of various medications in treating repetitive behavior, as well as the associated symptoms of autism (i.e., hyperactivity, inattention, aggression and self-injury).

In addition to atypical antipsychotics, SRIs may be useful in adults with autism but may not be indicated for children and adolescents. Controlled studies of methylphenidate and clonidine suggest the utility of these medications in the treatment of hyperactivity in individuals with high-functioning autism. Little information is available regarding mood stabilizers and anxiolytics. Pharmacotherapy for autism should target associated symptoms of autism (e.g., aggression, anxiety), as well as repetitive behavior that have been demonstrated to respond to medication in controlled treatment studies.

Our review, although admittedly selective, points out the need for well-controlled trials with larger sample sizes. Given the important role of behavioral interventions, there also needs to be systematic examination of the integration of pharmacological and behavioral therapies (Campbell et al., 1978). The need for controlled trials is underscored by the widespread use of alternative therapies, which have not been systematically examined.

As neither genetic nor environmental causes of autism have been identified, it has been difficult to firmly establish molecular mechanisms that would serve as potential targets for pharmacological intervention. Nevertheless, progress is being made in this area including development of relevant animal models. Clearly, a great deal more work in such areas as proteomics and bioinformatics needs to be done before drug targets can be identified with confidence.

Dr. Lewis is professor and associate chair for research in the department of psychiatry at the University of Florida. He has conducted research in developmental disorders, including autism, for over 20 years.

Dr. Lazoritz is associate chair for clinical operations and medical director for the department of psychiatry and Vista Medical Center.


Aman MG, Langworthy K (2000), Pharmacotherapy for hyperactivity in children with autism and other pervasive developmental disorders. J Autism Dev Disord 30(5):451-459.

Aman MG, Van Bourgondien ME, Wolford PL, Sarphare G (1995), Psychotropic and anticonvulsant drugs in subjects with autism: prevalence and patterns of use. J Am Acad Child Adolesc Psychiatry 34(12):1672-1681.

Bolman WM, Richmond JA (1999), A double-blind, placebo-controlled, crossover pilot trial of low dose dimethylglycine in patients with autistic disorder. J Autism Dev Disord 29(3):191-194.

Campbell M, Anderson LT, Meier M et al. (1978), A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Adolesc Psychiatry 17(4):640-655.

Campbell M, Fish B, David R et al. (1972), Response to triiodothyronine and dextroamphetamine: a study of preschool schizophrenic children. J Autism Child Schizophr 2(4):343-358.

Fankhauser MP, Karumanchi VC, German ML et al. (1992), A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry 53(3):77-82.

Gerlai R, Gerlai J (2004), Autism: a target of pharmacotherapies? Drug Discov Today 9(8):366-374 [see comment].

Gordon CT, State RC, Nelson JE et al. (1993), A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 50(6):441-447.

Handen BL, Johnson CR, Lubetsky M (2000), Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord 30(3):245-255.

Hollander E, Dolgott-Kaspar R, Cartwright C et al. (2001), An open trial of divalproex sodium in autism disorders. J Clin Psychiatry 62(7):530-534.

Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL (1992), Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 12(5):322-327.

King BH, Wright DM, Handen BL et al. (2001), Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry 40(6):658-665.

Langworthy-Lam KS, Aman MG, Van Bourgondien ME (2002), Prevalence and patterns of use of psychoactive medicines in individuals with autism in the Autism Society of North Carolina. J Child Adolesc Psychopharmacol 12(4):311-321.

Levy SE, Hyman SL (2003), Use of complementary and alternative treatments for children with autistic spectrum disorder is increasing. Pediatr Ann 32(10):685-691.

Malone RP, Cater J, Sheikh RM et al. (2001), Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 40(8):887-894.

McCracken JT, McGough J, Shah B et al. (2002), Risperidone in children with autism and serious behavioral problems. N Engl J Med 347(5):314-320 [see comments].

McDougle CJ, Holmes JP, Carlson DC et al. (1998), A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 55(7):633-641 [see comments].

McDougle CJ, Kresch LE, Posey DJ (2000), Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors. J Autism Dev Disord 30(5):427-435.

McDougle CJ, Naylor ST, Cohen DJ et al. (1996), A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53(11):1001-1008 [see comments].

Posey DJ, Puntney JI, Sasher TM et al. (2004), Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases. J Child Adolesc Psychopharmacol 14(2):233-241.

Potenza MN, Holmes JP, Kanes SJ, McDougle CJ (1999), Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 19(1):37-44 [see comments].

Quintana H, Birmaher B, Stedge D et al. (1995), Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 25(3):283-294.

Ratey J, Sovner R, Parks A, Rogentine K (1991), Buspirone treatment of aggression and anxiety in mentally retarded patients: a multiple-baseline, placebo lead-in study. J Clin Psychiatry 52(4):159-162.

Realmuto GM, August GJ, Garfinkel BD (1989), Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 9(2):122-125.

Sandler AD, Sutton KA, DeWeese J et al. (1999), Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med 341(24):1801-1806 [see comments].

Related Videos
nicotine use
© 2024 MJH Life Sciences

All rights reserved.