Sage Journals: Discover world-class research

Abstract

Objective: Pervasive developmental disorder (PDD) is associated with emotional and behavioural problems. There is no pharmacological cure for PDD, but some comorbidities and dysfunctional behaviours in PDD can be managed pharmacologically. The aim of the present study was to provide a better understanding of the efficacy and limitations in the currently available agents.

Methods: Electronic literature searches were conducted from the following sources: MEDLINE, Cochrane Library, PSYARTICLES and PsycINFO. Search terms included, but were not limited to, ‘autism’, ‘PDD’, ‘autism spectrum disorder’ (‘ASD’), and ‘pharmacological management’.

Results: A range of pharmacological agents are available for the management of various dysfunctional symptoms in PDD. Broadly speaking, these agents help in the management of repetitive stereotyped behaviours, anxiety, aggression/irritability/self-injurious behaviour, hyperactivity/inattention and in sleep.

Conclusions: There is a paucity of systemic, well-conducted trials on the use of pharmacological agents in the management of PDD, and more research in this area is warranted.

Keywords

Asperger's syndrome autism autism spectrum disorder pervasive developmental disorder pharmacological management

Pervasive developmental disorder (PDD) consists of a group of childhood-onset developmental difficulties that include autism, Asperger's syndrome, PDD not otherwise specified (PDDNOS), Rett's disorder and childhood disintegrative disorder. PDD is a spectrum of disorders encompassing children with a wide range of abilities. There is thus gradation in the level of presentation. Children with Asperger's syndrome would not have significant communication difficulties and children with PDDNOS may not present with the full picture of the classical triad. Children and adolescents with autism will present with a triad of difficulties consisting of impairments in social interaction, impairments in communication and a restricted repetitive and stereotyped pattern of behaviours, interests and activities. Difficulties in social interaction manifest as impairments in non-verbal behaviours, failure to develop age-appropriate peer relationships, a lack of spontaneous sharing of enjoyment and a lack of social and emotional reciprocity. Communication difficulties present as a delay or lack in development of spoken language without compensatory modes of communication, impairment in initiating and sustaining conversation with others when language is adequately developed, stereotyped language and a lack of spontaneous make-belief or social imitative play. Restricted repetitive and stereotyped behaviours include encompassing preoccupations or interests that are abnormal in intensity or focus, inflexible adherence to specific, nonfunctional routines or rituals, stereotyped and repetitive motor mannerisms and persistent preoccupation with parts of objects.

The most well-replicated neurochemical finding is a 25–50% increase in blood serotonin levels in subjects with autism. Studies on the dopamine neurotransmitter system, glutamate, γ-aminobutyric acid (GABA) and neuropeptides have not produced significant findings [1–3]. Serotonin dysfunction may thus form a basis for the use of some pharmacological interventions of behavioural issues in PDD. Although pharmacological agents will not cure PDD, they may be efficacious in treating dysfunctional behavioural symptoms that interfere with rehabilitative efforts and cause impairment or distress [4]. Such behavioural symptoms may include aggression, irritability, stereotyped behaviours, anxiety, hyperactivity and sleep difficulties.

It should be noted that management of mental health and behavioural difficulties in people with learning disabilities should be based on multidisciplinary and multimodal approaches. Such treatment should follow a contextual and functional analysis of behaviour and pay careful attention to the language abilities and developmental level of the child or adult that possibly underlies their medical disorders and life events. Pharmacological intervention is only one component of the therapeutic package [5]. Children and adolescents on medications for behavioural and mental health issues should thus have their condition and need for medication periodically reviewed.

Pharmacological management in children and adolescents with PDD is an area of much interest. Many studies on various pharmacological agents have been done. Much of the current research, however, consists of case reports, open-label studies or small clinical trials. Very few well-conducted randomized controlled trials of good sample sizes are available. Studies were also conducted on different types of sample groups, such as differing age groups or on individuals in different ranges of the spectrum. This scenario limits understanding, interpretation and clinical application of the findings.

This article reviews the available research on pharmacological agents used in managing behavioural symptoms associated with PDD. The aim was to provide a better understanding of the efficacy and limitations in the currently available agents. Agents included were those commonly used in clinical practice in the authors’ setting and agents of specific interest for children and adolescents with PDD. Electronic literature searches were conducted from the following sources: MEDLINE, Cochrane Library, PSYARTICLES and PsycINFO. Search terms included, but were not limited to, ‘autism’, ‘PDD’, ‘autism spectrum disorder’ (‘ASD’), and ‘pharmacological management’. Searches were limited to English-language materials from 1975 to 2008 inclusive. Article abstracts obtained from the search strategy were perused and eligible articles were then retrieved as full text. Articles were then classified according to the Ministry of Health (Singapore) levels of evidence (Table 1). Studies included in this review used various terminologies, making standardization of terminology difficult. Hence, the ‘terms pervasive developmental disorder’ (PDD) and ‘autism spectrum disorder’ (ASD) are used in accordance with the terminologies used by the individual authors.

Table 1.

Grades of recommendation

Grade	Recommendation
A	At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++ and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+; directly applicable to the target population, and demonstrating overall consistency of results.
B	A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+.
C	A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++.
D	Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+.
GPP	Recommended best practice based on the clinical experience of the guideline development group.

Tricyclic antidepressants

Tricyclic antidepressants block presynaptic re-uptake of norepinephrine and serotonin to varying degrees. Although the tricyclic antidepressants were the drugs of choice for management of depression in the 1980s, their non-selective action on cholinergic, histaminergic, and presynaptic adrenergic receptors resulted in adverse effects, thus resulting in reduced use of these drugs in recent years.

Clomipramine

Clomipramine is a tricyclic antidepressant that has serotonin re-uptake inhibitor properties. In a double-blind, comparison study of 12 autistic subjects aged 6–18 years, Gordon et al. found that clomipramine was superior to desipramine and placebo in improving autistic symptoms, anger, compulsive and ritualized behaviours, with no differences between desipramine and placebo [6]. Clomipramine was equal to desipramine and both drugs superior to placebo in reducing hyperactivity.

Remington et al. conducted a double-blind, placebo-controlled cross-over trial comparing clomipramine (mean dose 128.4 mg), haloperidol (mean dose 1.3 mg) and placebo in 36 subjects (age 10–36 years) with autistic disorder [7]. They found that clomipramine was comparable to haloperidol in terms of improvement from baseline based on before–after measurements on the Childhood Autism Rating Scale and the Irritability subscale of the Aberrant Behaviour Checklist (ABC). Significantly fewer, however, receiving clomipramine (37.5%) versus haloperidol (69.7%) were able to complete the trial due to side-effects and behaviour problems (lethargy, tremors, tachycardia, insomnia, diaphoresis, nausea and decreased appetite).

In an open-label pilot study conducted by Sanchez et al., eight young autistic children (aged 3.5–8.7 years) were rated using the Children's Psychiatric Rating Scale, Clinical Global Impressions (CGI), Conner's Parent Teacher Questionnaire and the Clinical Global Consensus Ratings [8]. Clomipramine was found to be not therapeutic and was associated with serious, untoward effects, such as acute urinary retention, severe constipation, insomnia, behavioural problems and drowsiness. Young children seemed more prone to experience untoward effects.

While clomipramine may reduce irritability and stereotypical behaviour in autism, it may be associated with more frequent side-effects.

Selective serotonin re-uptake inhibitors

Selective serotonin re-uptake inhibitors (SSRIs) increase the extracellular level of the neurotransmitter serotonin by inhibiting its re-uptake into the presynaptic cell, increasing the level of serotonin available to bind to the postsynaptic receptor. Serotonin dysfunction has been postulated to be one of the underlying causes of autism. Persons with autism display repetitive thoughts and behaviours that are very similar to the presentation of obsessive– compulsive disorders. It is thus that SSRIs are considered as a pharmacological intervention for autism.

Fluvoxamine

McDougle et al. conducted a 12 week, double-blind, placebo-controlled trial of fluvoxamine in 30 adults with autistic disorder [9]. Eight (53%) of the 15 subjects who received fluvoxamine were rated as responders compared to 0 of the 15 placebo-treated subjects. Improvements were seen in repetitive thoughts and behaviour, maladaptive behaviours, repetitive language and aggression. Adverse effects included nausea and sedation, which were transient and of minor severity.

McDougle et al. conducted another 12 week, double-blind, placebo-controlled trial of fluvoxamine with 34 children and adolescents (5–18 years) with PDD [10]. The study found the medication to be poorly tolerated and ‘with limited efficacy at best’. Only one of the fluvoxamine-treated children demonstrated significant clinical improvement with the drug. Fourteen of the children demonstrated adverse effects, including insomnia, hyperactivity, agitation, aggression, increased rituals, anxiety, anorexia, increased appetite, irritability, decreased concentration and impulsivity.

In a 10 week, prospective open-label trial with fluvoxamine in 18 children and adolescents (7–18 years) with PDD, Martin et al. found that there was no response to fluvoxamine as a group [11]. Current research findings suggest that fluvoxamine is more efficacious in adults with autism and seems to be poorly tolerated with limited efficacy in children.

Fluoxetine

In 2005 Hollander et al. conducted an 8 week placebo-controlled cross-over trial of liquid fluoxetine in 45 child and adolescent patients with ASD [12]. Liquid fluoxetine in low doses was found to be more effective than placebo in the treatment of repetitive behaviours, and did not differ from placebo on treatment-emergent side-effects. In a retrospective chart review, Fatemi et al. observed the effects of fluoxetine on seven adolescents and young adults with autistic disorder [13]. There was a reduction in the subscales of irritability, lethargy, stereotypy and inappropriate speech as measured on the ABC. Side-effects reported included transient appetite suppression, vivid dreams and increase in hyperactivity.

DeLong et al. followed up 129 children (aged 2–8 years) with ASD on fluoxetine between 5 and 76 months [14]. They reported that 22 (17%) had an excellent response, 67 (52%) demonstrated good response, 10 (8%) had fair response and 30 (23%) had a poor response. In an open trial, Cook et al. examined the effect of fluoxetine treatment on children and adults (aged 7–28 years) with autism and mental retardation [15]. Fifteen (65%) of the 23 autistic subjects and 10 (63%) of the 16 mentally retarded subjects had improvement in overall clinical severity. Side-effects consisted primarily of restlessness, hyperactivity, agitation, decreased appetite or insomnia. Fluoxetine may be considered as an option in management of ASD.

Citalopram

Namerow et al. studied the effects of citalopram in a retrospective review of 15 children and adolescents (aged 6–16 years) with PDD [16]. They reported that 11 (73%) exhibited significant improvement in PDD symptoms, or anxiety and mood scores on the Clinical Global Improvement Scale. A total of 66% of patients improved significantly on anxiety symptoms associated with PDD while 47% improved on mood symptoms. Mild side-effects were reported by five patients.

Escitalopram

Owley et al. reported a 10 week, open-label, prospective study of escitalopram on 28 subjects with PDD [17]. A total of 17 (61%) were rated as responders based on the irritability subscale on the ABC. Dose-related side-effects included hyperactivity and aggression.

Sertraline

Three open-label trials have been conducted on the effects of sertraline on PDD. McDougle et al. conducted a 12 week, prospective, open-label study in 42 adults with PDD [18]. Twenty-four (57%) of the subjects were treatment responders with improvements primarily in the aggressive and repetitive behaviour symptoms. Sertraline was generally well-tolerated with no adverse cardiovascular effects, extra-pyramidal symptoms or seizures identified.

Hellings et al. conducted an open-label trial of sertraline in nine adults with mental retardation and autistic disorder presenting with target symptoms of self-injury and/ or aggression [19]. Eight subjects (89%) demonstrated significant reduction in aggression and self-injurious behaviour. In another open-label study of nine children (aged 6–12 years), Steingard et al. administered sertraline to children with autism and transition-associated anxiety and agitation [20]. Eight of the nine children (89%) demonstrated ‘some degree of response to sertraline treatment’.

Typical antipsychotics

The therapeutic actions of typical antipsychotics lie in their antagonism of dopamine receptors, particularly the D₂ receptors. These antipsychotics produce extra-pyramidal symptoms, such as parkinsonism, dystonia, and tardive dyskinesia. In addition, typical antipsychotics also increase serum prolactin concentration.

Haloperidol

Campbell et al. conducted a double-blind, placebo-controlled, cross-over trial of haloperidol in 33 children (aged 2.3–7.9 years) with autism and mental retardation [21]. They reported a significant reduction in maladaptive behaviours and that it facilitated learning. Above the optimal range of dosage, however, increased irritability and dystonic reactions emerged. Campbell et al. also conducted a 15 year, prospective, longitudinal evaluation of haloperidol in 118 children (aged 2.3–8.2 years) with autism [22]. A significant proportion of the children developed dyskinesias.

Anderson et al. demonstrated that haloperidol decreased maladaptive behaviours such as temper tantrums, hyper-activity and stereotypies in 45 autistic children aged 2.02–7.58 years (double-blind, placebo-controlled) [23]. With careful regulation of dosage, none of the children had adverse effects at therapeutic dosages.

Haloperidol reduces maladaptive behaviours in children with PDD. At therapeutic doses with careful monitoring, side-effects may be minimized. Above therapeutic doses, the probability of developing extrapyramidal side-effects increases. There is a risk of developing tardive dyskinesia with the use of haloperidol.

Atypical antipsychotics

The therapeutic action of atypical antipsychotics is characterized by a broader spectrum of pharmacological properties because they work on serotonin receptors as well as dopamine receptors. Thus, the atypical antipsychotics have a reduced propensity to produce extrapyramidal symptoms and may have less prolactin elevation. Atypical antipsychotic medications, however, have recently been associated with potential adverse metabolic effects, such as weight gain, insulin resistance, dyslipidemia and hyperglycemia [24]. Hence, taking of a good medical history, and regular weight, blood pressure, fasting blood glucose and lipid profile monitoring are recommended.

Risperidone

Risperidone is an antagonist of both dopamine (D₂) and serotonin (5HT₂ and others) receptors. Because conventional antipsychotics have been shown to improve behaviour in children with autism, and because serotonin dysfunction has been postulated to be a possible underlying mechanism of autism, interest has developed in investigating the efficacy of risperidone in ASD. Risperidone is currently the only medication that the US Food and Drug Administration (US FDA) has approved for the treatment of irritability and concomitant aggressive behaviours in autism.

In 2002 McCracken et al. at the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network conducted a multisite, randomized, double-blind trial of risperidone compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behaviour in 101 children aged 5–17 years old [25]. The rate of positive response, as defined by >25% decrease in irritability score and a rating of much improved or very much improved on the Clinical Global Improvement Scale, was 69% in the risperidone group and 12% in the placebo group. They concluded that risperidone was effective and well-tolerated for the treatment of tantrums, aggression or self-injurious behaviour in children with autistic disorder.

In the same cohort of children, McDougle et al. investigated whether risperidone improved the core symptoms of autism [26]. They reported that risperidone led to significant improvements in restricted, repetitive and stereotyped patterns of behaviour, interests, and activities in autistic children but did not significantly change their deficit in social interaction and communication.

To investigate longer-term benefits of risperidone in the group of children who showed a positive effect in the RUPP [27] trial, the children were followed up in a two-part study. Part 1 consisted of a 4 month open-label treatment with risperidone. Part 2 was an 8 week randomized, double-blind, placebo-substitution study of risperidone withdrawal. The authors concluded that risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behaviour. Discontinuation after 6 months was associated with rapid return of disruptive and aggressive behaviour in most subjects.

A second multi-centre, placebo-controlled study of risperidone in 79 children (aged 5–12 years) with PDD was conducted by Shea et al. [28]. Risperidone was associated with 64% reduction in ABC Irritability subscale scores as compared to 31% in placebo. More risperidone-treated subjects (87%) had global improvement in their condition compared to the placebo group (40%). Adverse events included somnolence, increases in weight, pulse rate and systemic blood pressure. Side-effects were manageable.

Olanzapine

Two case series and two randomized control trials have been done with olanzapine. Potenza et al. reported a case series of response to olanzapine in seven children, adolescents and adults with PDD [29]. Six of the seven subjects were responders, with significant improvement in overall symptoms of autism, motor restlessness, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behaviour, aggression, irritability or anger, anxiety and depressive symptoms. Adverse events were increased appetite and weight gain.

Kemner et al. conducted an open-label trial of olanzapine in 25 children with PDD (aged 6–16 years) [30]. In that study olanzapine was found to be effective in only three subjects (12%) in terms of improvement on CGI ratings. This low response may have been related to the young age of the children and the level of cognitive functioning. There were positive changes found on the sub-scales Hyperactivity, Excessive Speech and Irritability of the ABC. In a parallel group design comparing olanzapine and haloperidol in 12 children with autism, Malone et al. reported that five of six subjects in the olanzapine group and three of six in the haloperidol group were rated as responders [31]. Weight gain was significantly higher in the olanzapine group.

A small double-blind placebo-controlled study of olanzapine in the treatment of 11 children and adolescents with PDD was conducted by Hollander et al. in 2005 [32]. A total of 50% on olanzapine versus 20% on placebo were responders. Olanzapine was associated with significant weight gain.

Current research suggests that olanzapine leads to improvement in motor restlessness, self-injurious behaviour, aggression and irritability. The risk of significant weight gain is a concern. More randomized controlled trials are indicated.

Quetiapine

Two reports on open-label trials and two case series on quetiapine have been published. Findings have been inconsistent. Martin et al. conducted an open-label study involving six children and adolescents (aged 6–15 years) with autism and mental retardation [33]. Overall, there was no significant improvement. Two of the six subjects were reported to be responders. Adverse effects reported included sedation, possible seizures, increased appetite and weight gain. The investigators concluded that quetiapine was poorly tolerated and generally ineffective.

Findling et al. reported a 12 week open-label trial of quetiapine in nine autistic adolescents (aged 10–17 years) [34]. Two of the nine were judged as responders. Adverse events reported were sedation, weight gain, agitation and aggression. They concluded that quetiapine may not be a particularly effective agent in the treatment of adolescent patients with autistic disorder.

A retrospective case series reported by Corson et al. found that eight of the 20 subjects (aged 5–28 years) were responders to quetiapine [35]. Adverse events were reported in 50% of the subjects and led to drug discontinuation. The authors concluded that quetiapine was modestly effective for maladaptive behaviour in patients with a PDD. In a second case series, Hardan et al. reported clinically significant improvement in symptoms of hyper-activity and inattention in six of 10 patients treated with quetiapine [36]. Adverse events were mild.

Ziprasidone

McDougle et al. published a report of an open-label trial of ziprasidone in 12 autistic subjects (aged 8–20 years) [37]. Six of the 12 were judged as treatment responders with improvements in symptoms of aggression, agitation and irritability. Adverse effects were minimal. They concluded that ziprasidone appeared to have potential for improving symptoms of aggression, agitation and irritability in autism. Cohen et al., in their retrospective chart review of 10 adults, noted that seven of the 10 patients had an improvement or no change in their maladaptive behaviour [38]. There were no significant adverse events associated with ziprasidone.

The US FDA has raised concerns about the potential for QTc interval prolongation with ziprasidone on electrocardiogram [39], so the drug should not be given to individuals with cardiac disease or those who are taking other medications that can prolong QTc interval without careful monitoring.

Aripiprazole

Stigler et al. conducted a prospective, open-label case series of five children with autism treated with aripiprazole [40]. All five children were reported to be responders with clinically significant improvements in aggression, self-injurious behaviour and irritability. Stigler et al. further reported a 14 week prospective, open-label study of aripiprazole in 25 children and adolescents with PDD [41]. A total of 22 of the 25 children were considered responders, with improvements in aggression, self-injurious behaviour and severe tantrums.

In a retrospective chart review, Valicenti-McDermott and Demb treated 32 children and adolescents with developmental disabilities with aripiprazole [42]. Aripiprazole was effective in 56% of the subjects and in 37% of the autistic subjects. Side-effects were reported in 50% of the subjects.

Clozapine

Clozapine blocks 5-HT_2A, 5-HT_2C, 5-HT₃ and DA D₁-D₄ receptors. There is a paucity of reports on the use of clozapine in persons with autism, with only three case reports to date. Zuddas et al. described three children with hyperactivity, fidgetiness and aggression treated with clozapine [43]. Two of the three showed sustained improvement. Chen et al. reported on a 17-year-old boy with autism and severe mental retardation who was treated with clozapine [44]. He showed marked reduction of signs of ‘overt tension’, hyperactivity and repetitive movements. Gobbi and Pulvirenti described long-term treatment with clozapine in an adult with autistic disorder and aggression [45]. Clinical improvement was evident in aggressiveness and social responsiveness. Although clozapine could possibly be useful in the management of ASD, it is rarely considered because it has the potential to cause life-threatening agranulocytosis and requires regular blood count monitoring.

Stimulants

Stimulant medication has been found to be an effective treatment strategy in attention-deficit–hyperactivity disorder (ADHD). Methylphenidate is a potent stimulant derived from amphetamine, and it exerts its effect by enhancing dopaminergic transmission in the brain.

Conventional diagnostic guidelines (such as the DSM IV-TR and the ICD-10) exclude the diagnosis of ADHD in PDD. Symptoms of hyperactivity and inattention, however, are frequently found in children with PDD, and practical management strategies useful in ADHD, including pharmacological intervention, may be considered.

Methylphenidate

Quintana et al. conducted a double-blind cross-over study of methylphenidate in 10 autistic children, aged 7–11 years [46]. They reported improvement in irritability and hyperactivity. No significant side-effects, including worsening of stereotypic movements, were observed. In another double-blind, placebo-controlled cross-over trial, Handen et al. observed 13 autistic children with symptoms of ADHD (aged 5.6–11.2 years) on methylphenidate [47]. Eight subjects responded positively, based on a minimum 50% decrease on the Conner's Hyperactivity Index. Significant adverse effects observed included social withdrawal and irritability.

In a multisite, double-blind, placebo-controlled, crossover trial conducted by the RUPP Autism Network, 72 children with PDD (aged 5–14 years) were given a 1 week test-dose phase of low, medium and high doses of methylphenidate, followed by a randomized, double-blind, cross-over phase [48]. Methylphenidate was found to be superior to placebo on improvement of the hyper-activity subscale of the ABC, with 49% of subjects classified as methylphenidate responders. Adverse effects (primarily irritability) led to discontinuation of the study medication in 18% of the patients. The authors concluded that methylphenidate was often efficacious in treating hyperactivity associated with PDD, but the magnitude of response was less than that seen in typically developing children with ADHD. Adverse effects were more frequent.

Selective norepinephrine re-uptake inhibitors

Atomoxetine

Atomoxetine is non-stimulant drug used as a second-line treatment in the treatment of children with ADHD. Jou et al. conducted a retrospective assessment of atomoxetine in 20 children and adolescents with PDD [49]. Improvements were observed in the Conners Parent Rating Scale subscales of conduct, hyperactivity, inattention and learning.

Posey et al. described an open-label study of the use of atomoxetine for ADHD symptoms associated with high-functioning PDD [50]. Twelve of the 16 participants (75%), were rated as ‘much’ or ‘very much improved’ on the CGI–Improvement scale. The most significant improvements were in the area of ADHD symptoms.

In another open-label trial, Troost et al. examined the effects of atomoxetine on ADHD symptoms and autistic features in 12 children with PDD [51]. They found a reduction of 21% for changes in the subscale Hyperactivity of the ABC. Gastrointestinal symptoms, irritability, sleep problems and fatigue were the most frequent side-effects.

In a small placebo-controlled cross-over trial with 16 children and adolescents with ASD, Arnold et al. reported that atomoxetine was superior to placebo on the primary outcomes of the Hyperactivity subscale of the ABC [52], but it did not reach statistical significance on inattentive symptoms. Adverse events were tolerable. They concluded that the effects appeared as large as with methylphenidate with fewer side-effects.

Atomoxetine may be a promising agent in the treatment of ADHD symptoms in children with ASD.

Anti-convulsants

Anti-convulsants are usually indicated for the treatment of epilepsy. They may also be used as mood stabilizers and in the management of impulsivity and aggression.

Lithium carbonate

Limited studies have been done on lithium carbonate. Kebeshian et al. described two patients with infantile autism and atypical bipolar symptomatology treated with lithium carbonate [53]. Both children demonstrated a significant response at levels >1.0 mEq L⁻¹. Steingard et al. reported on the treatment of two patients with infantile autism and mental retardation who developed acute manic-like symptoms [54].

Oxcarbazepine

Oxcarbazepine is a structural derivative of carbamazepine. It has a reduced impact on the liver, and reduced frequency of agranulocytosis occasionally associated with carbamazepine. It generally has the same mechanism as carbamazepine and is used to treat the same conditions.

Kapetanovic reported the use of oxcarbazepine in managing disruptive behaviours in three youths with autistic disorder [55]. Improvements with oxcarbazepine included decreased aggression and improved compliance. The author suggested that oxcarbazepine has a favourable side-effect profile and may be more convenient for administration in view of an available liquid formulation.

Divalproex sodium

Divalproex sodium consists of a compound of sodium valproate and valproic acid in a 1:1 molar relationship in an enteric coated form. Hollander et al. reported an open trial of divalproex sodium in 14 children with ASD [56]. A total of 71% of the subjects were rated as having sustained response to treatment. It was generally well tolerated. The authors concluded that divalproex sodium may be beneficial to patients with ASD, particularly those with associated features of affective instability, impulsivity, and aggression as well as those with a history of electroencephalography abnormalities or seizures.

Hollander et al. then conducted an 8 week, double-blind, placebo-controlled trial of divalproex sodium versus placebo in 13 children with ASD [57]. There was a significant group difference on improvement of repetitive behaviours as measured on the Children's Yale–Brown Obsessive–Compulsive Scale. Hellings et al., however, also conducted another randomized, double-blind, placebo-controlled study of valproate in 30 subjects with PDD [58]. They found that no treatment difference was observed statistically between valproate and placebo groups in the ABC–Community scale (ABC-C) Irritability Subscale. In view of the inconsistent findings, more studies on divalproex sodium are indicated.

Opiate antagonist

Naltrexone

Naltrexone is an opiate antagonist. In the 1980s it was postulated that abnormalities of the endogenous opioid system led to maladaptive behaviours, cognitive deviances and other problems associated with autism. As such, naltrexone was considered a promising pharmacological treatment for autism. In 1989 an open-dose trial by Campbell et al. was conducted on 10 autistic children [59]. They reported promising results, with increased verbal production and reduced stereotypies, but a subsequent parallel group study by Campbell et al. suggested that although naltrexone significantly reduced hyperactivity, no effect on discrimination learning was observed [60].

Subsequent studies have failed to show any improvement in the core symptoms of autism with naltrexone. Kolmen et al. conducted a double-blind, placebo-controlled cross-over study of naltrexone in 13 young autistic children [61, 62]. They found significant improvement in impulsivity, hyperactivity and restlessness. Feldman et al. reported a randomized, double-blind, placebo-controlled, cross-over trial of naltrexone on 24 children with autism [63]. They found that the medication did not lead to improvement in communication. WillemsenSwinkels et al. conducted a double-blind, placebo crossover study of naltrexone treatment in 23 young children [64]. They reported a decrease in hyperactivity and irritability but no effects on social and stereotypic behaviour. As such, naltrexone has limited effect on reducing irritability and hyperactivity. It does not lead to improvements in the core symptoms of autism.

α₂-Adrenergic agonists

α₂-Adrenergic agonists have been used as anti-hypertensive agents. They have also been used in the management of ADHD.

Clonidine

Clonidine is an α ₂-adrenergic receptor partial agonist. It is commonly used as an anti-hypertensive agent. Two small double-blind, placebo-controlled studies have been conducted on the use of clonidine in autism. Jaselskis et al. conducted a placebo-controlled, double-blind cross-over trial of clonidine on eight autistic boys [65]. The subjects had symptoms of inattention, impulsivity and hyperactivity. Irritability, stereotypy, hyperactivity and inappropriate speech were lower during treatment with clonidine than during treatment with placebo. Clonidine led to increased ratings of the side-effects of drowsiness and decreased activity.

Fankhauser et al. investigated the efficacy of transdermal clonidine in autism in a double-blind, placebo-controlled study involving nine autistic male subjects (aged 5–33 years) [66]. Significant improvement was seen on the CGI scale and in abnormal sensory responses, affectual reactions and social relationships. The most common adverse effects were sedation and fatigue.

Clonidine has demonstrated modest improvements in hyperactivity, aggression and irritability, but side-effects such as drowsiness may occur. There is a risk of hypertensive crises on withdrawal.

Guanfacine

Guanfacine is a newer α ₂-adrenergic agonist than clonidine and appears to be less sedating and better tolerated. It has a longer duration of action than cloni-dine, thus requiring less frequent dosing and thereby protecting against rebound hypertension on abrupt discontinuation. Posey et al. retrospectively reviewed 80 subjects with PDD (aged 3–18 years) treated with guanfacine [67]. They reported that subjects with PDDNOS and Asperger's syndrome had a greater rate of global response than those with autistic disorder. Symptom improvement was seen in hyperactivity, inattention, insomnia and tics.

Scahill et al. conducted an open-label trial of guanfacine involving 25 children with PDD accompanied by hyperactivity [68]. They concluded that guanfacine may be useful in the treatment of hyperactivity in children with PDDs. Common adverse effects included irritability, sedation, sleep disturbances and constipation. Preliminary studies suggest that guanfacine may be useful in treating hyperactivity in children with PDD.

Glutamatergic antagonist

Amantadine

Amantadine hydrochloride is a non-competitive N-methyl-D-aspartate antagonist. It is routinely used for treatment of influenza, herpes zoster and Parkinson disease. There is only one clinical trial on amantadine and hence there is insufficient evidence to make any recommendation. King et al. conducted a double-blind, placebo-controlled study of amantadine in the treatment of children with ASD in 39 subjects [69]. Parents did not report statistically significant behavioural change with amantadine, but modest clinician-rated improvements in hyperactivity and inappropriate speech were observed.

Memantine

Memantine works as a glutamatergic antagonist and is used in the treatment of Alzheimer's disease. In a retrospective study of memantine in 18 children and adolescents with PDD, Erickson et al. found that there was improvement primarily in social withdrawal and inattention [70]. A total of 61% of patients were judged to be responders to memantine based on a rating of ‘much improved’ or ‘very much improved’ on the CGI scale.

Owley et al. conducted a prospective, 8 week open-label trial of memantine in improving cognitive functioning and behavioural symptoms in 14 children with PDD [71]. The study suggested that memantine improved hyperactivity, lethargy and irritability. There was significant improvement from baseline on the Children's Memory Scale Dot Learning Subtest. Chez et al. observed 151 patients with autism and PDDNOS in an open-label trial of memantine [72]. They found significant improvements in language function, social behaviour and self-stimulatory behaviour.

Memantine may be a promising agent in improving hyperactivity, inattention, social behaviour, language function, self-stimulatory behaviour and memory. Because current findings are based only on case series and open-label trials, randomized controlled trials are indicated.

Melatonin

Melatonin is an endogenous neurohormone secreted by the pineal gland that causes drowsiness. Melatonin levels increase rapidly after nightfall, peak in the middle of the night and decrease towards dawn. Melatonin has been increasingly used to manage sleep disorders in children with neurodevelopmental disorders. Wasdell et al. reported a randomized, placebo-controlled trial of melatonin treatment in delayed sleep phase syndrome and impaired sleep maintenance in 50 children with neu-rodevelopmental disabilities [73]. Overall, the therapy improved sleep of 47 children and was effective in reducing family stress.

Three open-label trials and one small randomized control trial of melatonin in the treatment of sleep disturbances in children with ASD have been reported. Paavonen et al. conducted an open clinical trial of melatonin in 15 children with Asperger's disorder [74]. The sleep patterns of all the children improved, and half of them had an excellent response to melatonin. Giannotti et al. conducted an open-label study of controlled-release melatonin in the treatment of sleep disorders in children with autism [75]. During treatment the sleep patterns of all 25 children improved. After discontinuation, 16 children returned to pre-treatment sleep patterns and read-ministration of melatonin was again effective. Treatment gains were maintained at 24 month follow up and no adverse effects were reported.

Andersen et al. conducted a large retrospective review of the use of melatonin for insomnia in 107 children with ASD [76]. After initiation of melatonin, parents of 25% of the children no longer reported sleep concerns and 60% reported improved sleep. Only thee children had mild side-effects, including morning sleepiness and increased enuresis. Garstang and Wallis conducted a small randomized controlled trial of melatonin in 11 children with ASD [77]. They reported that sleep latency, waking per night and total sleep duration improved in children receiving melatonin as compared to those receiving placebo. The use of melatonin may be considered in children with PDD with sleep disorders.

Secretin

Secretin is a gastrointestinal hormone produced in the duodenum. In 1998 Hovath first reported a case series of three children with positive responses to the administration of porcine secretin during endoscopy [78]. Interest in secretin as a possible treatment for autism resulted in several controlled studies of the effectiveness of i.v. secretin. Williams et al. conducted a Cochrane review of 13 randomized studies and found no evidence that single- or multiple-dose i.v. secretin is effective across a range of outcomes [79]. It was concluded that secretin should not be recommended or administered as a treatment for autism.

Conclusion

Pharmacological management does not address the core symptomatology of PDD. When dysfunctional behaviours or comorbid mental health disorders are present, behavioural management strategies should be considered together with the implementation of pharmacological intervention. There is a range of available pharmacological agents for the management of various dysfunctional symptoms in PDD. Broadly speaking, these agents help in the management of repetitive stereotyped behaviours, anxiety, aggression/irritability/self-injurious behaviour, hyperactivity/inattention and in sleep (see Tables 2–5 for selected studies). There is a paucity of systemic, well-conducted trials on the use of pharmacological agents in the management of PDD. More research in this area is warranted.

Table 2.

Pharmacological management for anxiety and repetitive behaviours

Agent	Drug name	Sample	Study design	Duration/dose	Main outcomes	Grading/recommendation
SSRI	Fluvoxamine McDougle et al. [9]	n=30; autistic disorder Adults	Double blind, placebo controlled	12 weeks Mean dose 276.7 mg day⁻¹	53% responded to treatment. Improvements also seen in maladaptive behaviours.	Recommended for use among adults Grade D
	McDougle et al. [10]	n = 34; PDD Age = 5–18 years	Double blind, placebo controlled	12 weeks Mean dose 106.9 mg day⁻¹	Fluvoxamine was poorly tolerated and ‘with limited efficacy at best’ One out of 15 responded to treatment. A total of 93% demonstrated adverse effects.
	Martin et al. [11]	n = 18; PDD Age = 7–18 years	Open label	10 weeks 1.5 mg kg⁻¹ per day	0% responded to treatment.
	Fluoxetine Hollander et al. [12]	n = 45; ASD Age = 5–17 years	Placebo-controlled cross-over study	8 week Mean dose 9.9 ± 4.35 mg day⁻¹	Effect size of 0.76 (medium-large effect) on reducing repetitive behaviours on CY-BOCS. Effective in treating repetitive behaviours.	Recommended Grade B
	Fatemi et al. [13]	n=7; autistic disorder Age= 9–20 years	Retrospective chart view	1.3–32 months 20–80 mg day⁻¹	Reduction in irritability (21%), lethargy (37%), stereotypy (27%) and inappropriate speech (21%).
	Delong et al. [14]	n = 129; ASD Age = 2–8 years	Open-label trial	5-76 months 0.15–0.5 mg kg⁻¹	17% showed an excellent response, 52% demonstrated good response, 8% had fair response and 23% had a poor response.
	Cook et al. [15]	n=39; autism, mental retardation Age=7-28 years	Open label	11–426 days 20 mg every other day to 80 mgday^∼1	65% of the 23 autistic subjects and 63% of the 16 mentally retarded subjects showed improvement in overall clinical severity.
	Citalopram Namerow et al. [16]	n = 15; PDD Age = 6–16 years	Retrospective review	218.8 ± 167.2 days 16.9 ± 12.1 mg day⁻¹	66% improved significantly on anxiety symptoms associated with PDD while 47% improved on mood symptoms.	Insufficient evidence to make recommendations
	Escitalopram Owley et al. [17]	n = 28; PDD Mean Age = 125. 1 ± 33.5 months	Open label	10 weeks Max dose 20 mg	61% improved on irritability. Dose-related side-effects included hyperactivity and aggression.	Insufficient evidence to make recommendations
	SertralineMc Dougle et al. [18]	n = 42; PDD Adults	Open label	12 weeks	57% responded to treatment. Improvements in the aggressive and repetitive behaviour symptoms.	Insufficient evidence to make recommendations
	Hellings et al. [19]	n = 9; autistic disorder, mental retardation Adults	Open label	At least 28 days 25–150 mg daily	89% demonstrated significant reduction in aggression and self-injurious behaviour
	Steingard et al. [20]	n = 9; autism Age=6–12 years	Open label	2–8 weeks 25–50 mg daily	89% demonstrated some degree of response to treatment.
Tricyclic Antidepressant	Clomipramine Gordon et al. [6]	n=12; autistic disorder Age=6–18 years	Double-blind, comparison study	10 weeks	Improvements in autistic symptoms, anger, compulsive and ritualized behaviours.	Recommended Grade B
	Remington et al. [7]	n = 36; autistic disorder Age = 10–36 years	Double-blind, placebo-controlled cross-over trial	7 weeks Mean dose 128.4 mg	Improvements in autistic symptoms and irritability. Fewer individuals (compared to haloperidol) completed the trial in view of side-effects or behaviour problems.
	Sanchez et al. [8]	n = 8; autistic disorder Age=3.5–8.7 years	Open-label study	5 weeks 25–250 mg day⁻¹	Not therapeutic, side-effects included acute urinary retention, severe constipation, insomnia, behavioural problems and drowsiness

ASD, autism spectrum disorder; CY-BOCS, Children's Yale–Brown Obsessive–Compulsive Scale; PDD, pervasive developmental disorder; SSRI, selective serotonin re-uptake inhibitor.

Table 3.

Pharmacological management for ADHD symptoms

Agent	Drug Name	Sample	Study Design	Duration/Dose	Main Outcomes	Grading/Recommendation
Stimulant	Methylphenidate Quintana et al. [46]	N = 10; Autistic Disorder Age = 7–11 years	Double-blind, cross-over	6 weeks 10mg or 20mg bid	Improvements in irritability and hyperactivity	Recommended Grade A
	Handen et al. [47]	N = 13; Autistic Disorder Age = 5.6–11.2 years	Double-blind, placebo-controlled cross-over	21 days 0.3mg/kg and 0.6mg/kg	62% responded to treatment. Significant improvements in hyperactivity.
	RUPP [48]	N = 72;PDD Age = 5–14 years	Double-blind, placebo-controlled cross-over, open-label, multisite	1-week test-dose; 4-week crossover; 8-week Continuation; 75–50.0 mg/day	49% responded to treatment.
Selective Norepinephrine Reuptake Inhibitors	Atomoxetine Jou et al. [48]	N = 20; PDD Age = 11.5 years, SD 3.5	Retrospective	12 months Dose 43.3mg, SD 18.1	Improvements in conduct, hyperactivity, inattention, and learning.	Recommended Grade D
	Posey et al. [50]	N = 16; PDD Age = 6–14 years	Open-label	8 weeks Mean dose 1.2 +/− 0.3 mg/kg/day	75% were rated as “much” or “very much improved” on attention problems.
	Troost et al. [51]	N = 12; PDD Age = 6-14 years	Open-label	10 week 1.19+/− 0.41 mg/kg/day	21% improved on hyperactivity.
	Arnold et al. [52]	N = 16;ASD Age = 5–15 years	Placebo-controlled cross-over	6-week 0.25 mg/kg/day to 1.4 mg/kg/day	Improvements in hyperactivity.
Glutamatergic Antagonist	Amantadine King et al. [69]	N = 39; ASD Age = 5–19 years	Double-blind, placebo-controlled	5 week 5.0 mg/kg per day	Parents did not report significant behavioral change. Clinicians reported modest improvements in hyperactivity and inappropriate speech.	Insufficient evidence to make recommendations
	Memantine Erikson et al. [70]	N = 18; PDD Age = 6–19 years	Retrospective study	Mean duration 19.3 weeks Mean dose 10.1mg/day	61% responded to treatment. Improvements in inattention and social withdrawal.	Recommended Grade D
	Owley etal. [71]	N = 14; PDD Age = 3-12 years	Open-label trial	8-week; 0.4mg/day	Improvements in hyperactivity lethargy, and irritability.
	Chez et al. [72]	N = 151; Autism, PDDNOS	Open-label trial	4 to 8 weeks	Significant improvements in language function, social behavior and self-stimulatory behavior.
Alpha2 adrenergic agonists	Clonidine Jaselskis et al. [65]	N = 8; Autistic Disorder Age = 5–10 years	Double-blind, placebo-controlled cross-over trial	13-week; 0.15–.20 mg/day	Improvements in irritability, stereotypy, hyperactivity and inappropriate speech.	Insufficient evidence to make recommendations.
	Fankhauser et al. [66]	N = 9; Autistic Disorder Age = 5–33 years	Double-blind, placebo-controlled cross-over trial	12-week; 0.0036 mg/kg/day	Significant improvements in abnormal sensory responses, affectual reactions and social relationships.
	Guanfacine Posy et al. [67]	N = 80; PDD Age = 3–18 years	Retrospective study	Mean duration 334 +/− 374 days Mean dose 2.6 +/− 1.7 mg daily	Improvements in hyperactivity, inattention, insomnia and tics.	Recommended Grade D
	Scahilletal.[68]	N = 25; PDD Age = 5–14 years	Open-label trial	8-week; 1.0–3.0 mg/day	Useful in the treatment of hyperactivity.

ASD = Autistic Spectrum Disorder, PDD = Pervasive Developmental Disorder.

Table 4.

Pharmacological management for aggression, irritability, and self-injurious behaviours

Agent	Drug name	Sample	Study design	Duration/Dose	Main outcomes	Grading/recommendation
Typical Antipsychotics	Haloperidol Campbell et al. [22]	n=33; autism, mental retardation Age=2.3–7.9 years	Double-blind, placebo-controlled, cross-over trial	14 weeks 0.5–4.0 mg day⁻¹	Significant reduction in maladaptive behaviour and facilitates learning	Recommended Grade B
	Campbell et al. [21]	n = 118; autism Age=2.3–8.2 years	Longitudinal evaluation	15 years Mean dose 1.75 mg day⁻¹	A significant proportion developed dyskinesias.
	Anderson et al. [23]	n = 45; Age = 2.02–758 years	Double-blind, placebo-controlled	4 weeks 0.25–4.0 mg day⁻¹	Decreased maladaptive behaviours such as temper tantrums, hyperactivity and stereotypies
Atypical antipsychotics	Risperidone McCracken et al. [25]	n = 101; autistic disorder Age=5–17 years	Multisite, randomized, double-blind, placebo-controlled	8 weeks 0.5–3.5 mg day⁻¹	Improvements in tantrums, aggression and self-injurious.	Recommended Grade A
	RUPP [27]	n = 63 (part 1) n = 32 (part 2) Age=5-17 years	Open-label (part 1); Randomized, double-blind, placebo-substitution (part 2)	4 month open-label; 8 week randomized Mean dose 1.96 mg day⁻¹	Effective for intermediate length treatment of tantrums, aggression, and/ or self-injurious behaviour.
	Shea et al. [28]	n=79; Age=5–12 years	Multi-centre, placebo-controlled	8 weeks Mean dose 1.17 mg day⁻¹	64% showed improvement in irritability.
	Olanzapine Potenza et al. [29]	n=7; PDDs children, adolescents, adults	Case series	12 weeks Mean dose 7.8 ± 4.7 mg day⁻¹	86% responded to treatment. Significant improvements in overall symptoms of autism, self-injurious behaviour, aggression, irritability or anger, anxiety and depressive symptoms.	Recommended Grade D
	Kemner et al. [30]	n = 25; PDD Age = 6–16 years	Open-label trial	3 months Mean dose 10.7 mg day⁻¹	12% showed improvements in hyperactivity, excessive speech and irritability.
	Malone et al. [31]	n = 12; autism Mean Age=7.8 ± 2.1 years	Parallel group study	6 weeks Mean dose 7.9 ± 2.5 mg day⁻¹	83% responded to olanzapine while 50% responded to haloperidol.
	Hollander et al. [32]	n = 11; PDD Age 6-14 years	Double-blind, placebo-controlled trial	8 week Up to 20 mg day⁻¹	50% responded to treatment.
	Quetiapine Martin et al. [33]	n=6; autism, mental retardation Age=6–15 years	Open-label trial	16 weeks 100–350 mg day⁻¹	Poor toleration and generally ineffective. Only 33% responded to treatment.	Insufficient evidence to make recommendations.
	Findling et al. [34]	n=9; autistic disorder Age = 10–17 years	Open-label trial	12 weeks 300–750 mg day⁻¹	Ineffective. Only 22% responded to treatment.
	Corson et al. [35]	n = 20; PDD Age = 5–28 years	Retrospective case series	4–180 weeks 25–600 mg day⁻¹	40% responded to treatment. Adverse events were reported in 50% of the subjects.
	Hardan et al. [36]	n = 10, PDD Age = 12.0 ± 5.1 years	Retrospective case series	22.0 ±10.1 weeks Dose 477 ± 212 mg	60% showed improvements in hyperactivity and inattention.
	Ziprasidone McDougle et al. [37]	n = 12; autistic disorder Age=8–20 years	Open-label trial	At least 6 weeks 20–120 mg	50% showed improvements in symptoms of aggression, agitation and irritability.	Insufficient evidence to make recommendations.
	Cohen et al. [38]	n = 10; autistic disorder Adults, 43.8 ± 6.0 years	Retrospective chart review	At least 6 months 128 ± 41 mg	70% responded to treatment.
	Aripiprazole Stigler et al. [40]	n=5; autism Age=5–18 years	Open-label case series	12.8 weeks 10–15 mg day⁻¹	100% showed improvements in aggression, self-injurious behaviour and irritability.	Insufficient evidence to make recommendations.
	Stigler et al. [41]	n = 25; PDD Age = 5–17 years	Open-label trial	14 weeks 2.5–15 mg day⁻¹	88% showed improvements in aggression, self-injurious behaviour and severe tantrums.
	Valicenti-McDermott and Demb [42]	n=32; developmental disabilities Age=5–19 years	Retrospective chart review	6–15 months 10.55 ± 6.9 mg	37% of the autistic subjects showed improvements.
	Clozapine Zuddas et al. [43]	n=3; children	Case report	8 months 200–450 mg day⁻¹	66% showed improvements in hyperactivity, fidgetiness and aggression.	Insufficient evidence to make recommendations.
	Chen et al. [44]	n = 1; autism, mental retardation Age = 17 years	Case report	15 days 275 mg day⁻¹	Significant reductions in ‘overt tension’, hyperactivity and repetitive movements.
	Gobbi and Pulvirenti [45]	n = 1; autistic disorder Age=32 years	Case report	5 years 300 mg day⁻¹	Clinical improvement in aggression and social responsiveness.
Anti-convulsants	Lithium carbonate Kebeshian et al. [53]	n=2; infantile autism Children	Case report	Serum level >1.0 mEq L⁻¹	Significant response in bipolar symptomatology	Insufficient evidence to make recommendations.
	Steingard et al. [54]	n=2; infantile autism Age=7 years and 20 years	Case report		Treatment of acute episode of manic-like symptoms
	Oxcarbazepine Kapetanovic [55]	n = 3; autistic disorder Age=3¹/2 years, 13 years and 19 years	Case report	3¹/2–6 months 450–1200 mg	Decreased aggression and improved compliance.	Insufficient evidence to make recommendations.
	Divalproex sodium Hollander et al. [56]	n=14; ASD	Open label	Mean dose 768 mg day⁻¹	71% showed improvements in affective instability, impulsivity, and aggression.	Insufficient evidence to make recommendations.
	Hollander et al. [57]	n = 13; ASD Age = 5–17 years	Double-blind, placebo-controlle	8 weeks Up to 30 mg d kg∼¹ per day	Signifcant improvement in repetitive behaviours
	Hellings et al. [58]	n = 30; PDD Age = 6–20 years	Randomized, double-blind, placebo-controlle trial	8 week Mean VPA trough blood levels d 77.8 mg μL⁻¹ at 8 weeks	No signifcant improvements found.

ASD, autism spectrum disorder; PDD, pervasive developmental disorder; VPA, valproate

Table 5.

Pharmacological management for sleep

Agent	Drug name	Sample	Study design	Duration/Dose	Main outcomes	Grading/recommendation
Hormones	Melatonin Wasdell et al. [73]	n = 51 (neurodevelopmental) n = 16 (autistic) Age 52–18 years	Randomized controlled trial	3–4 months 5 mg	Improved sleep in 47 children and reduced family stress	Recommended Grade B
	Paavonen et al. [74]	n = 15; Asperger's syndrome Age = 6–17 years	Open label	14 days 3 mg day⁻¹	The sleep patterns of all children improved, half displayed excellent response.
	Giannotti et al. [75]	n = 25; autism Age = 2.6–9.6 years	Open label	24 months 3–6 mg daily	Sleep patterns of all children improved. Treatment gains maintained at 12 and 24 months follow up.
	Andersen et al. [76]	n = 107; ASD Age = 2–18 years	Retrospective case review	0.75–6 mg	25% no longer reported sleep concerns, 60% reported improved sleep.
	Garstang and Wallis [77]	n = 11, ASD Age = 4–16 years	Randomized controlled trial	4 weeks 5 mg	Melatonin was benefcial

ASD, autism spectrum disorder.

Footnotes

Acknowledgements

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

Lam

Aman

Arnold

. Neurochemical correlates of autistic disorder: a review of literature. Res Dev Disabil 2006; 27:254–289.

McDougle

Erickson

Stigler

Posey

. Neurochemistry in the pathophysiology of autism. J Clin Psychiatry 2005; 66:9–18.

Fatemi

Halt

Stary

Kanodia

Schulz

Realmuto

. Glutamic acid decarboxylase 65 and 67kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 2002; 52:805–810.

Volkmar

Cook

Jr Pomeroy

Realmuto

Tanguay

. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38 (Suppl 12):32–54.

Santosh

Baird

. Psychopharmacotherapy in children and adults with intellectual disability. Lancet 1999; 354:233–242.

Gordon

State

Nelson

. A double-blind comparison of clomipramine, desipramine and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50:441–447.

Remington

Sloman

Konstantareas

. Clomipramine vs haloperidol in the treatment of autistic disorder: a double-blind, placebo-controlled crossover study. J Clin Psychopharmacol 2001; 21:440–444.

Sanchez

Campbell

Small

Cueva

Armenteros

Adams

. A pilot study of clomipramine in young autistic children. J Am Acad Child Adolesc Psychiatry 1996; 35:537–544.

McDougle

Naylor

Cohen

. Double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorders. Arch Gen Psychiatry 1996; 53:1001–1008.

10.

McDougle

Kresch

Posey

. Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors. J Autism Dev Disabil 2000; 30:427–435.

11.

Martin

Koenig

Anderson

. Low-dose fluvoxamine treatment of children and adolescents with pervasive developmental disorders: a prospective, open-label study. J Autism Dev Disord 2003; 33:77–85.

12.

Hollander

Phillips

Chaplin

. A placebo-controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005; 30:582–589.

13.

Fatemi

Realmuto

Khan

Thuras

. Fluoxetine in the treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord 1998; 28:303–307.

14.

DeLong

Ritch

Burch

. Fluoxetine response in children with autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement. Dev Med Child Neurol 2002; 44:652–659.

15.

Cook

Rowlett

Jaselinkis

. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739–745.

16.

Namerow

Thomas

Bostic

Prince

Monuteaux

. Use of citalopram in pervasive developmental disorders. J Dev Behav Pediatr 2003; 24:104–108.

17.

Owley

Walton

Salt

. An open-label trial of escitalopram in pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 2005; 44:343–348.

18.

McDougle

Brodkin

Naylor

Carlson

Cohen

Price

. Sertraline in adults with pervasive developmental disorders: a prospective, open-label investigation. J Clin Psychopharmacol 1998; 18:62–66.

19.

Hellings

Kelley

Gabrielli

Kilgore

Shah

. Sertraline response in adults with mental retardation and autistic disorder. J Clin Psychiatry 1996; 57:333–336.

20.

Steingard

Zimnitzky

DeMaso

Bauman

Bucci

. Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. J Child Adolesc Psychopharmacol 1997; 7:9–15.

21.

Campbell

Armenteros

Malone

Adams

Eisenberg

Overall

. Neuroleptic related dyskinesias in autistic children: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 1997; 36:835–843.

22.

Campbell

Anderson

Small

Perry

Green

Caplan

. The effects of haloperidol on learning and behavior in autistic children. J Autism Dev Disord 1982; 12:167–175.

23.

Anderson

Campbell

Adams

Small

Perry

Shell

. The effects of haloperidol on discrimination learning and behavioral symptoms on autistic children. J Autism Dev Disord 1989; 19:227–239.

24.

Newcomer

. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 (Suppl):1–93.

25.

McCracken

McGough

Shah

. Risperidone in children with autism and serious behavioral problems. New Engl J Med 2002; 347:314–321.

26.

McDougle

Scahill

Aman

. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005; 162:1142–1148.

27.

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months. Am J Psychiatry 2005; 162:1361–1369.

28.

Shea

Turgay

Carroll

. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatr 2004; 114:634–641.

29.

Potenza

Holmes

Kanes

. Olanzapine treatment of children, adolescents and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999; 19:37–44.

30.

Kemner

Wilemsen-Swinkels

de Jonge

. Open-label study of olanzapine in children with pervasive developmental disorder. J Clin Psychopharmacol 2002; 22:455–460.

31.

Malone

Cate

Sheikh

. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 2001; 40:887–894.

32.

Hollander

Wasserman

Swanson

. A double-blind placebo-controlled pilot study of olanzapine in childhood adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol 2006; 16:541–548.

33.

Martin

Koenig

Scahill

. Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 1999; 9:99–107.

34.

Findling

McNamara

Gracious

. Quetiapine in nine youths with autistic disorder. J Child Adolesc Psychopharmacol 2004; 14:287–294.

35.

Corson

Barkenbus

Posey

. A retrospective analysis of quetiapine in the treatment of pervasive developmental disorders. J Clin Psychiatry 2004; 65:1531–1536.

36.

Hardan

Jou

Handan

. Retrospective study of quetiapine in children and adolescents with pervasive developmental disorders. J Autism Dev Disord 2005; 35:387–391.

37.

McDougle

Kem

Posey

. Case series: use of ziprasidone for maladaptive symptoms in youths with autism. J Am Acad Child Adolesc Psychiatry 2002; 41:921–927.

38.

Cohen

Fitzgerald

Khan

. The effect of a switch to ziprasidone in an adult population with autistic disorder: chart review of naturalistic, open-label treatment. J Clin Psychiatry 2004; 65:110–113.

39.

Food and Drug Administration. (FDA) Psychopharmacological Drugs Advisory Committee background document on Zeldox (PDAC 0700.M01). Rockville, MD: Food and Drug Administration; 2000.

40.

Stigler

Posey

McDougle

. Aripiprazole for maladaptive behavior in pervasive developmental disorders. J Child Adolesc Psychiatry 2002; 41:921–927.

41.

Stigler

Diener

Kohn

Erickson

Posey

McDougle

. A prospective, open-label study of aripiprazole in youth with pervasive developmental disorder not otherwise specified and Asperger's disorder. J Child Adolesc Psychopharmacol 2009 Jun; 19 (3):265–74.

42.

Valicenti-McDermott

Demb

. Clinical effects and adverse reactions of off-label use of aripiprazole in children and adolescents with developmental disabilities. J Child Adolesc Psychopharmacol 2006; 16:549–560.

43.

Zuddas

Ledda

Fratta

Muglia

Cianchetti

. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153:738.

44.

Chen

Bedair

McKay

Bowers

Jr Mazure

. Clozapine in the treatment of aggression in an adolescent with autistic disorder. J Clin Psychiatry 2001; 62:479–480.

45.

Gobbi

Pulvirenti

. Long-term treatment with clozapine in an adult with autistic disorder accompanied by aggressive behavior. J Psychiatry Neurosci 2001; 26:340–341.

46.

Quintana

Birmaher

Stedge

. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995; 25:283–294.

47.

Handen

Johnson

Lubetsky

. Efficacy of methylpheni-date among children with autism and symptoms of attention deficit hyperactivity disorder. J Autism Dev Disord 2000; 30: 245–255.

48.

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Randomized controlled crossover trial of methylpheni-date in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005; 62:1266–1274.

49.

Jou

Handen

Harda

. Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2005; 15: 325–330.

50.

Posey

Wiegand

Wilkerson

Maynard

Stigler

McDougle

. Open-label atomoxetine for attention-deficit/ hyper-activity disorder symptoms associated with high-functioning pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006; 16:599–610.

51.

Troost

Steenhuis

Tuynman-Qua

. Atomoxetine for attention-deficit hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. J Child Adolesc Psychopharmacol 2006; 16:611–619.

52.

Arnold

Aman

Cook

. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled cross-over pilot trial. J Am Acad Child Adolesc Psychopharmacol 2006; 45:1196–1205.

53.

Kerbeshian

Burd

Fisher

. Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. J Clin Psychopharmacol 1987; 7:401–405.

54.

Steingard

Biederman

. Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1987; 26:932–935.

55.

Kapetanovic

. Oxcarbazepine in youths with autistic disorder and significant disruptive behaviors. Am J Psychiatry 2007; 164:832–833.

56.

Hollander

Soorya

Wasserman

Esposito

Chaplin

Anagnostou

. Divalproex sodium vs placebo in the treatment of repetitive behaviors in autistic spectrum disorder. Int J Neuropsychopharmacol 2006; 9:209–213.

57.

Hollander

Dolgoff-Kaspar

Cartwright

Rawitt

Novotny

. An open trial of divalproex sodium in autistic spectrum disorders. J Clin Psychiatry 2001; 62:530–534.

58.

Hellings

Weckbaugh

Nickel

. A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2005; 15:682–692.

59.

Campbell

Overall

Small

. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989; 28:200–206.

60.

Campbell

Anderson

Small

Adams

Gonzalez

Ernst

. Naltrexone in autistic children: behavioral symptoms and attentional learning. J Am Acad Child and Adolesc Psychiatry 1993; 32:1283–1291.

61.

Kolmen

Feldman

Handen

. Naltrexone in young autistic children: a double-blind placebo-controlled crossover-study. J Am Acad Child Adolesc Psychiatry 1995; 34:223–231.

62.

Kolmen

Feldman

Handen

Janosky

. Naltrexone in young autistic children: replication study and learning measures. J Am Acad Child Adolesc Psychiatry 1997; 36:1570–1578.

63.

Feldman

Kolmen

Gonzaga

. Naltrexone and communication skills in young children with autism. J Am Acad Child Adolesc Psychiatry 1999; 38:587–593.

64.

Willemsen-Swinkels

SHN

Buitelaar

van Engeland

. The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Biol Psychiatry 1996; 39:1023–1031.

65.

Jaselskis

Cook

Fletcher

Leventhal

. Clonidine treatment of hyperactive and impulsive children with autistic Disorder. J Clin Psychopharmacol 1992; 12:322–327.

66.

Fankhauser

Karamanchi

German

MLEA

. A double blind placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry 1992; 53:77–82.

67.

Posey

Puntney

Sasher

Kem

McDougle

. Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases. J Child Adolesc Psychopharmacol 2004; 14:233–241.

68.

Scahill

Aman

McDougle

. A prospective open trial of guanfacine in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006; 16:589–598.

69.

King

Wright

Handen

. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry 2001; 40:658–665.

70.

Erickson

Posey

Stigler

Mullett

Katschke

McDougle

. A retrospective study of memantine in children and adolescents with pervasive developmental disorder. Psychopharmacol 2007; 191:141–147.

71.

Owley

Salt

Guter

. A prospective open-label trial of memantine in the treatment of cognitive, behavioral and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006; 16:517–524.

72.

Chez

Burton

Dowling

Chang

Khanna

Kramer

. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: An observation of initial clinical response and maintenance tolerability. J Child Neurol 2007; 22:574–579.

73.

Wasdell

Jan

Bomben

. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008; 44:57–64.

74.

Paavonen

Nieminen-von Wendt

Vanhala

Aronen

von Wendt

. Effectiveness of melatonin in the treatment of sleep disturbance in children with asperger disorder. J Child Adolesc Psychopharmacol 2003; 13:38–95.

75.

Giannotti

Cortesi

Cerquiglini

Bernabei

. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006; 36:741–752.

76.

Andersen

Kaczmarska

McGrew

Malow

. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol 2008; 23:482–485.

77.

Garstang

Wallis

. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev 2006; 32:585–589.

78.

Hovath

Stefanatos

Sokolski

Wachtel

Nabors

Tildon

. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minority Physicians 1998; 9: 9–15.

79.

Williams

Wray

Wheeler

. Intravenous secretin for autism spectrum disorder. Cochrane Database Syst Rev 2005; (3):CD003495.

Pharmacological Management in Children and Adolescents with Pervasive Developmental Disorder

Abstract

Keywords

Tricyclic antidepressants

Clomipramine

Selective serotonin re-uptake inhibitors

Fluvoxamine

Fluoxetine

Citalopram

Escitalopram

Sertraline

Typical antipsychotics

Haloperidol

Atypical antipsychotics

Risperidone

Olanzapine

Quetiapine

Ziprasidone

Aripiprazole

Clozapine

Stimulants

Methylphenidate

Selective norepinephrine re-uptake inhibitors

Atomoxetine

Anti-convulsants

Lithium carbonate

Oxcarbazepine

Divalproex sodium

Opiate antagonist

Naltrexone

α2-Adrenergic agonists

Clonidine

Guanfacine

Glutamatergic antagonist

Amantadine

Memantine

Melatonin

Secretin

Conclusion

Footnotes

Acknowledgements

References

α₂-Adrenergic agonists