Management of Autism and It's Related Disorders Pharmacologic Treatment of Behavioral Symptoms in Autism and Pervasive Developmental Disorders Robert L. Findling, M.D. “MANAGEMENT OF AUTISM SPECTRUM DISORDERS” EDITED TRANSCRIPT Dr. Robert L. Findling <> I am Robert Findling, M.D. I’m Professor of Psychiatry and Pediatrics at Case Western Reserve University and I’m the Director of Child and Adolescent Psychiatry at University Hospitals of Cleveland. <> There is a role for medications in the treatment of patients with autism and its related conditions, and the American Academy of Child and Adolescent Psychiatry Practice Parameters delineates some key considerations regarding medications that can be useful for the symptoms that can interfere with rehabilitative efforts or can be a source of impairment or distress. It is important to recognize that medications do not lead to a cure for autism, but are targeted to address behavioral manifestations that are dysfunctional and distressing. <> The stimulants are the most common prescribed class of pharmacological agents given to children and adolescents with psychiatric conditions. <> The first studies of stimulants in patients with autism examined the amphetamines. These studies of young children were performed in the 1970s, and suggested that not only were the amphetamines not associated with significant clinical benefit, treatment was associated with some side effects that were disconcerting, including increases in stereotypy as well as irritability. <> Methylphenidate—the most commonly prescribed of those stimulants to young people—surprisingly has not been substantially studied in patients with autism or pervasive developmental disorders. However, there are some smaller trials that generally suggest that there is some potential benefit regarding targeted symptoms of hyperactivity and attention. However, the side effects of irritability and stereotypies have also been reported with methylphenidate in youngsters with pervasive developmental disorders. Unfortunately, there really have been few large-scale methodologically rigorous trials despite the fact that these are commonly prescribed agents, and more research regarding the use of stimulants in this patient population is needed. <> The alpha-2 agonists have been considered for hyperactivity as a target symptom for patients with autism. Although the alpha-2 agonists may have a role in this patient population, methodologically rigorous studies are still lacking. <> Clonidine has been looked at in small controlled studies—either by the oral or the transdermal route—and these reports generally suggest some benefit regarding hyperactivity and agitation. Although the clonidine has been generally well tolerated, sedation appears to be common as a side effect—at least to a transient degree—with some effects on blood pressure regarding hypotension being observed in some subjects. These studies with clonidine have not been methodologically rigorous large-scale clinical trials. <> Similarly, guanfacine—another alpha-2 agonist—has been looked at in a retrospective chart review of 80 young people between the ages of 3 and 18 years with pervasive developmental disorders at an average dose of about 2.5 mg a day. In this report by Posey et al., the responder rate overall was about 25% with benefits noted in hyperactivity, inattention, insomnia and tics. The medicine was generally well tolerated with some transient sedation also noted. <> When we think about other medicines that are commonly prescribed to young people with neuropsychiatric conditions, we think of antidepressants. <> The tricyclic antidepressants were looked at in patients with autism since the 1970s. Imipramine was studied in a small trial with young children, but although some possible benefits have been noted, issues regarding tolerability have been raised. <> In addition, there is a case series of possible benefits noted with nortriptyline. Although these tricyclic antidepressants have been around for a long time, there is really almost no data about these compounds of any methodological rigor for people with autism. <> Clomipramine has at least some degree of methodological stringency. Studies with clomipramine have shown that it is superior to desipramine and placebo in ameliorating compulsive behaviors and rituals, suggesting a role for serotonergic modulation as an underpinning for the beneficial effects. <> Clomipramine was also noted to be associated with benefits equal to that of desipramine for symptoms of hyperactivity. However with clomipramine, tolerability concerns were noted similar to those seen with other tricyclic antidepressants. These include sedation and the need for EKG monitoring, the risk of worsening behavior such as aggression and irritability, and concerns about the lowering of the seizure threshold. <> Because there was some benefit noted with the serotonin-modulating tricyclic, clomipramine, investigators have begun looking at the use of the serotonin reuptake inhibitors—the SSRIs—for patients with autism. Fluoxetine was examined in several case reports and open trials and possible benefits had been noted regarding rituals and stereotypies and repetitive behavior. However, the risks of fluoxetine had also been noted with concerns regarding the development of symptoms of hypomania, agitation and disinhibition. <> Most recently, there’s been a double-blind, placebo-controlled study where 45 young people between the ages of 5 and 17 years were treated with approximately 10 mg a day with fluoxetine or placebo, and the investigators noted that fluoxetine was, in fact, superior to placebo in reducing compulsive and repetitive behaviors, and that the medication was generally well-tolerated. The strength of this study is the fact that it is a placebo-controlled study and a relatively large number of patients. <> The SSRI fluvoxamine has received a substantial amount of consideration in this patient population. Initially, there were several case reports and an open trial that again suggested a potential benefit, similar to the reports that were initially noted with fluoxetine. <> There is a double-blind trial of fluvoxamine in a group of adults with autistic disorder. This is a 12-week placebo-controlled study in which the patients received an average of about 275 mg a day of fluvoxamine. Interestingly enough, about half the patients who received fluvoxamine were considered to be responders; whereas, none of the patients who received placebo were found to be responders. The benefits were similar with fluvoxamine as noted previously with fluoxetine on compulsions and repetitive behaviors. Fluvoxamine is generally well-tolerated in this study with sedation and nausea being the most common side effects that were observed. <> The other SSRIs have been looked at in varying degrees in patients with autism and pervasive developmental disorders. Sertraline has been examined in open-label trials and case reports, paroxetine in case reports, citalopram and escitalopram in case reports and an open trial, and the suggestion is that there are similar benefits with these SSRIs. <> Trazodone is another compound that was commonly given to patients with pervasive developmental disorders. In fact, there is almost no scientific evidence to support its utility, only case reports. <> Another antidepressant that has been examined for patients with autism is venlafaxine. Unfortunately, there is not as much information about venlafaxine as there are with the SSRIs. In a retrospective case series of 10 patients including children, adolescents and adults, hyperactivity and agitation was seen as a common side effect. However, the response rate was 60%. <> Mirtazapine is another antidepressant that has been looked at in patients with pervasive developmental disorders. In an open trial of 26 patients, limited effectiveness was noted with only about one-third of the patients being considered responders. Mirtazapine was generally well-tolerated with the side effects being an increase in appetite and sedation. <> Mood stabilizers have also been looked at in the treatment of patients with pervasive developmental disorders. <> Divalproex sodium has been looked at in a retrospective study of 14 patients—children through adults—with autism and other pervasive developmental disorders. Ten patients were considered to be responders with symptoms that improved including those of affective instability, impulsivity and aggression. It should be noted that not all patients did well with this treatment with two having difficulties during the first 14 days of therapy leading to medication discontinuation. <> Lamotrigine is another anticonvulsant with mood-stabilizing effects. There were some benefits noted in a case series, whereas in a double-blind, placebo-controlled study there was no difference noted between the placebo- and lamotrigine-treated patients. I think the discrepancy between the case series and the double-blind, placebo-controlled study blind study again highlights the importance of performing double-blind, placebo-controlled studies for patients with these conditions. <> Levetiracetam has a single open-label prospective study in a small number of subjects where reductions in hyperactivity and impulsivity as well as aggression were noted. Although promising and generally well-tolerated, the small sample size really precludes definitive conclusions. <> The next group of agents that have received a substantial amount of research for patients with autism is the typical antipsychotics or the neuroleptics. Haloperidol was certainly the best studied of the neuroleptics, but case reports and studies of varying sizes and methodological rigor have described the use of chlorpromazine, fluphenazine, pimozide, thioridazine, trifluoperazine and thiothixene in this patient population. Although efficacy is generally described for irritability, aggression, hyperactivity and tantrums, concerns about neurological side effects, including abnormal involuntary movements and ataxia were consistently noted. <> Because of these concerns about extrapyramidal side effects and neurological side effects, clinicians and scientists have really begun focusing a substantial amount of interest towards the atypical antipsychotics since they reduce propensity for neurological side effects. <> Clozapine has been described in treatment-resistant children, adolescents and adults with potential symptom amelioration in the domains of aggression and hyperactivity. However, clozapine has really limited use in this patient population due to the necessity of hematological monitoring as well as concerns about its lowering of the seizure threshold in a population that has a high rate of seizure disorders. <> Risperidone is the best studied of the atypical antipsychotics in this patient population with benefits suggested from several case reports and open prospective trials, as well as superiority to placebo in three double-blind trials. The first double-blind study that looked at risperidone for patients with autism was done in a group of 31 adults in a 12-week trial where the average dose of risperidone given to the patients was approximately 3 mg a day. It was found that risperidone was, in fact, superior to placebo with benefits for irritability, aggression, as well as anxiety being noted. The authors reported no extrapyramidal side effects in their study population with only mild sedation. <> The next study regarding the use of risperidone in patients with pervasive developmental disorders was published in 2002. 101 patients with autistic disorder were treated for 8 weeks in a parallel study design at a mean dose of 1.8 mg a day. Patients who received risperidone responded at a substantially higher rate than most who received placebo. In this trial, the patients who received risperidone did gain more weight than those who received placebo—about 2.7 kilograms. Also fatigue, dizziness and drooling were noted in the patients treated with risperidone—however, no extrapyramidal side effects were noted in those patient cohorts. <> The next study that examined the use of risperidone in patients with pervasive developmental disorders consisted of 79 children in an 8-week, double-blind, randomized design. The children were treated with an average dose of about 1.2 mg a day. Risperidone-treated patients responded at a substantially higher rate than those who received placebo. Similar to the first double-blind study performed in young people, treatment with risperidone was associated with a greater weight gain than placebo, as well as no substantial extrapyramidal side effects. <> Risperidone is not the only atypical antipsychotic studied in patients with autism and pervasive developmental disorders. There are—for olanzapine—studies and reports of less methodological stringency. Olanzapine is associated with some benefits and a low risk of extrapyramidal side effects, with weight gain and sedation being the most common side effect. In the absence of methodological double-blind, placebo-controlled stringent studies, more controlled studies appear to be indicated with this compound. <> Quetiapine has been described in three separate reports. The first two suggest suboptimal effectiveness. However, a subsequent chart review study noted a possible modest benefit, again indicating that controlled studies may really be warranted for this compound as well. <> The next compound from the atypical antipsychotic class to be examined in patients with autism was ziprasidone. This is a retrospective case series in a group of patients ranging between the ages of 8 and 20 years, given an average dose of 59 mg a day, ranging between 20 and 120 mg a day. The authors reported a response rate of about 50% on the Clinical Global Impression Scale and no significant weight gain, suggesting that this may be a promising compound in this patient population. <> Aripiprazole has been studied in a case series of five patients treated with an average dose of 12 mg a day. The authors report a high response rate with target symptoms of aggression and self-injury and irritability all benefitting from treatment with the compound. The authors reported no difficulty with extrapyramidal side effects. However, some sedation was noted. <> In summary, it appears that there’s a role for the atypical antipsychotics for patients with autism and pervasive developmental disorders. The most methodologically rigorously studied compound is risperidone, and there seems to be promising literature about the other first-line atypical antipsychotics. Based on open-label data and case series, all require double-blind, placebo-controlled studies to confirm or refuse these agents’ efficaciousness in this patient population. <> Other compounds have also been looked at in patients with autism. <> Buspirone has been described as possibly being of benefit for anxiety, irritability and hyperactivity in doses ranging from 10 to 45 mg a day. <> A case series reviewed propranolol for adults with autism with potential beneficial effects for hyperarousal and aggression. Unfortunately, again, what is lacking from this report is a prospective design or substantial methodological rigor. <> A double-blind, placebo-controlled study of amantadine was performed in 39 patients with autism at a dose of 5 mg per kilogram per day. Modest improvement was noted in hyperactivity and it was generally well-tolerated. However, these beneficial effects seem to have been limited in magnitude. <> A small single-blind, placebo-controlled case series in 10 subjects with d-cycloserine noted that there was some improved social responsiveness in the subjects, and it was generally well-tolerated, suggesting that based on these preliminary data, more methodologically rigorous trials appeared to be warranted. <> Some reports describe the potential usefulness of cholinesterase inhibitors in this patient population with potential benefit coming from domains including dysfunctional behaviors and hyperactivity as well as expressive speech. None of these studies were placebo-controlled or of stringent methodological rigor. However, cholinersterase inhibitors seem to have some potential benefit worthy of future study. <> Naltrexone had been extensively studied previously because open trials suggested potential effectiveness and therapeutic benefit. However, the subsequent controlled studies really did not bear out a substantial beneficial effect in this patient population, and perhaps for those reasons, this agent really is not commonly prescribed to patients with pervasive developmental disorders any longer. <> Secretin has received a substantial amount of scientific attention driven by a case series of 3 children that suggested a substantial benefit that was published in the late 1990s. However, subsequently, there have been multiple randomized controlled trials that consistently failed to demonstrate any efficacy for secretin for patients with autism. <> Certainly, many youngsters who have autism are provided with vitamins and nutritional supplements. There are popular beliefs about the use of alternative interventions—including dietary interventions and vitamin-related interventions—for the treatment of patients with autism and its related conditions. However, data suggest that they are not efficacious. Pyridoxamine or high-dose vitamin B6 has been shown not to be superior to placebo. Dimethyl glycine has also been shown not to be superior to placebo, and DMAE hasn’t been studied. <> In conclusion, I’ve been able to highlight medications that may have a beneficial role in the treatment of patients with autism and the pervasive developmental disorders. However, I think many of the agents that may be promising for this patient population hasn’t been adequately studied in double-blind, placebo-controlled trials, and therefore, more research is truly needed in order to best characterize the optimum ways to address the difficulties that many patients with autism have in a way that’s effective, safe and durable.