**4. Psychopharmacological treatment of ASD patients**

Since to date there is no specific medication developed to autism itself, the psychopharmaco‐ logic approach is addressed to some core symptoms, such as hyperactivity, anxiety, depres‐ sion, etc. Actually, medication is frequently required to decrease the "noise" surrounding autism, including a wide range of maladaptive behaviors and/or associated problems (Benvenuto et al. 2012). To our knowledge, psychopharmacotherapy can eventually improve adhesion to non-medical treatment of ASD patients (Gottfried and Riesgo 2011).

In our experience, we usually identify 2-5 ASD associated symptoms and/or diagnosis, including epilepsy. We have found disruptive behavior more frequently in ASD patients with cognitive impairment, as well as symptoms related with depression and/or anxiety in pre‐ served intelligence ASD children (Gottfried and Riesgo 2011). Other related symptoms are: aggression, self-injury, impulsivity, decreased attention, anxiety, depression, and sleep disruption, among others.

Because ASD are chronic and markedly impairing situations in many cases, there is justifiably a high desire for effective treatments. By the other side, it is important to mention that there is a paucity of well conducted evidence-based studies of medications used in ASD patients. Not infrequently, this desire leads to premature enthusiasm for agents and interventions that appear promising in early reports but later do not withstand the rigor of randomized controlled trial (RTC).

Another critical issue is the co-occurrence of epilepsy in ASD patients which is almost twenty times more frequent when ASD patients are compared with children with typical develop‐ ment. The management of combined epilepsy can represent a challenge for clinicians. Several anti-epileptic drugs can determine an exacerbation of behavioral symptoms, and some psychotropic medications used in ASD patients may lower the seizure threshold (Benvenuto et al. 2012). In our experience, risperidone can be safely used up to 3mg/Kg/day, and higher doses can lead to seizures in susceptible patients. That is the reason why we prefer to perform an electroencephalogram before using psychoactive drugs in ASD children (Gottfried and Riesgo 2011). Therefore, it's mandatory to search a treatment strategy with the minor negative impact on this subgroup of patients

It should be noted that most psychotropic use in ASD is actually off-label, as currently there are only two medications approved for use in ASD children by the FDA (Food and Drug Administration). These drugs are risperidone and aripiprazole, which are effective to associated behaviors, but not to autism itself. The general principles for the pharmaco‐ therapy in ASD are similar to the used in other neuropsychiatric conditions (Weinssman and Bridgemohan 2012).

In summary, the use of psychotropic medications, alone or in combination, should follow some guidelines, such as: be focused on specific targets, be used at the minimum effective dosage, as well as be used for short period of time (Benvenuto et al. 2012). Ideally, medications should be initiated only after behavioral and educational interventions are in place.

#### **4.1. Disruptive behaviors**

The second more frequent psychiatric disorder in ASD patients is probably bipolar disorder (Howlin, Mawhood, and Rutter 2000). Young ASD children experience more difficulties in mood stabilization. In addition, mood's changes occur more rapidly in children when com‐ pared with adults. As a result, in very young ASD children the humor can change almost

The prevalence of bipolar disorders as a whole can reach up to 33% in ASD patients (Abramson et al. 1992). Obsessive and compulsive symptoms are frequently identified in ASD, although is difficult to distinguish the pure obsessive-compulsive disorder from bizarre concerns

Adults with Asperger disorder can experience occasional episodes of psychosis, such as persecutory ideas, auditory hallucinations, paranoid idea or delusional thoughts. But schizo‐ phrenia is not common and must remain as a differential diagnosis (Howlin, Mawhood, and Rutter 2000). The abovementioned episodes of psychosis can be identified in up to 15% of

Hyperactivity is a frequent symptom in children with ASD, is more prevalent in boys than in girls, and can decrease as time passes. Although the concomitant aggressiveness itself usually decrease with aging, the consequences of aggressiveness can be worse with age increasing in patients with autism because of their increase of muscle strength. An overlap between ADHD and ASD is relatively common in childhood, but this association is rarely described in

Although there are no doubts regarding a substantial improvement in the management of autism in the last three decades, unfortunately even nowadays a minority of adults with autism is able to work, to live independently, as well to develop appropriate social skills. Most of these

It is known by far that the most important prognostic value is defined by the cognitive functioning in childhood. In this sense, the clinical problem eventually is to access intelligence in non-verbal ASD children. According with literature, children with autism and IQ above 70

The ability to acquire functional language until the age of six years is also another prognostic landmark (Howlin et al. 2004). Better language and more preserved cognition are the two probably reasons to explain the best prognosis in Asperger disorder when compared with

Since to date there is no specific medication developed to autism itself, the psychopharmaco‐ logic approach is addressed to some core symptoms, such as hyperactivity, anxiety, depres‐

patients still live with their parents or other caregivers (Howlin et al. 2004).

had better global prognosis in adulthood (Howlin et al. 2004).

**4. Psychopharmacological treatment of ASD patients**

common in patients with autism (Howlin, Mawhood, and Rutter 2000).

Asperger patients after adolescence (Hofvander et al. 2009).

manuscripts with ASD adults (Stahlberg et al. 2004).

**3.3. Prognosis for ASD patients in adulthood**

classical forms of autism.

instantaneously.

638 Recent Advances in Autism Spectrum Disorders - Volume I

Disruptive behaviors in ASD children may include irritability, aggression, explosive outbursts (tantrums), and/or self-injury. These symptoms can be identified in almost two thirds of ASD patients and certainly have the biggest impact on the care of affected individuals, as well as marked distress for their families (Benvenuto et al. 2012; Kanne and Mazurek 2011). Although behavioral and environmental approaches are recommended as the initial treatment, more severe or even dangerous behaviors usually result in requests for urgent pharmacologic intervention (Kaplan and McCracken 2012; Weinssman and Bridgemohan 2012). In our experience, this type of symptoms is more frequently found in intelligence disabled ASD patients (Gottfried and Riesgo 2011).

events rarely led to treatment discontinuation (Marcus et al. 2009; Owen et al. 2009). Aripi‐ prazole dosing and response can vary considerably; the usual recommended clinical dose for

Clinical Approach in Autism: Management and Treatment

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641

Other atypical antipsychotics lack large-scale controlled studies. Small open-label reports suggest variable benefits of olanzapine (Potenza et al. 1999), clozapine (Beherec et al. 2011), and ziprasidone (Malone et al. 2007), which have possible support, versus quetiapine, which has not appeared to be beneficial. Other medications of different classes have been used, such as alpha-2 agonists, mood stabilizers, beta blockers, SSRI (selective serotonin reuptake inhibitors), all of them without evidence-based studies of efficacy in disruptive behavior to

Probably due the co-occurrence of epilepsy in ASD, the use of some antiepileptic drugs has been used in the management of maladaptive behaviors (Gottfried and Riesgo 2011). Dival‐ proex sodium has been demonstrated to be efficient not only in decreasing irritability/ aggression, but also in improving of repetitive behaviors, social relatedness and mood

Adjunctive topiramate therapies can decrease irritability, hyperactivity and inattention (Hardan, Jou, and Handen 2004; Mazzone and Ruta 2006). Moreover, the combination of topiramate with risperidone has been proved superior to risperidone monotherapy in reducing irritability and severe disruptive symptoms (Rezaei et al. 2010). In our experience, this specific combination would be helpful in preventing or at least decreasing the weight gain

Although preliminary data of open-label studies showed that levetiracetam may reduce hyperactivity, impulsivity, mood instability and aggression in autistic children, a RCT suggest that levetiracetam does not improve behavioral disturbances of ASD (Weinssman and

These symptoms are frequently identified in ASD patients. Inattention, hyperactivity and impulsivity may be related to comorbid ADHD (attention deficit hyperactivity disorder) and/ or to baseline anxiety of these children (Murray 2010; Rommelse et al. 2010; Benvenuto et al. 2012) Weinssman & Bridgemohan, 2012). It is known that children with ASD and ADHD have more clinical impairments than children with ASD alone (Gadow, DeVincent, and Pomeroy

The potentially useful drugs for inattention and hyperactivity in ASD could be stimulants, alpha-2 adrenergic agonists, atypical antipsychotics as well as anticonvulsant mood stabilizers. To date, there is strong evidence that both stimulants and risperidone are effective for hyperactivity. If the inattention and/or hyperactivity behaviors are due to anxiety, SSRI may

Psychoestimulants and other medications used in typically developing children with ADHD have been evaluated as a therapeutic option for treatment of ADHD symptoms

maintenance is between 5 and 15 mg/d (Kaplan and McCracken 2012).

date (Weinssman and Bridgemohan 2012).

due to risperidone usage in ASD patients.

**4.2. Hyperactivity and inattention symptoms**

2006; Kaplan and McCracken 2012).

instability (Hollander et al. 2006; Hollander et al. 2010).

Bridgemohan 2012), as well lamotrigine (Belsito et al. 2001).

be a useful choice (Weinssman and Bridgemohan 2012).

In the past, conventional neuroleptic agents such as haloperidol have been used in disruptive behaviors of autistic patients (Benvenuto et al. 2012; Miral et al. 2008; Kaplan and McCracken 2012). Our group showed that risperidone is superior when compared with haloperidol in one experimental research using hippocampal cells (Quincozes-Santos et al. 2010). Additionally, in the clinical research, at least one study proved that risperidone is more effective than haloperidol in ASD patients (Miral et al. 2008). There are two RTC suggesting that haloperidol is effective in disruptive behaviors of ASD children (Campbell et al. 1982; Miral et al. 2008), but sedation and other side effects including dyskinesia and extrapyramidal symptoms limits its use (Weinssman and Bridgemohan 2012).

As a result, to date atypical antipsychotic seem to be more helpful in treatment of disruptive behaviors. Currently, risperidone and aripiprazole are the only second-generation antipsy‐ chotic drugs that have shown to decrease disruptive behaviors in large-scale, controlled, double-blind studies (Benvenuto et al. 2012; Kaplan and McCracken 2012; Weinssman and Bridgemohan 2012).

Before the approval by FDA in 2006, risperidone was carefully studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. A multiphasic trial comparing risperidone with placebo was performed by RUPP for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week RCT study (McCracken et al. 2002).

The studies found that risperidone, in mean doses of 2,08mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. There wasn't evidence of side effects such as dyskinesia or dystonia. However, the observed weight gain of 5,6kg for the risperidone group was more than twice the expected weight gain over a 6-month period (McCracken et al. 2002; Kaplan and McCracken 2012).

Risperidone was approved by the FDA in 2006 for the treatment of disruptive symptoms in children and adolescents aged from 5 to 16 years with autism, with a maximum recommended dose of 3 mg/d. In our experience, risperidone was initially used in dose up to 6 mg/d. As time pass, we noted that if no response was obtained with 3mg/d, no more increments were useful. Coincidentally, this daily regimen seems to be the seizure threshold in susceptible patients (Gottfried and Riesgo 2011).

Aripiprazole was approved by the FDA for the treatment of disruptive behavior in ASD patients aged 6 to 17 years in 2009. Two large controlled studies documented the short-term efficacy of aripiprazole at 5, 10 or 15 mg/d for severe aggression and irritability in young subjects with autistic disorder. The most commonly reported adverse events were drowsiness and weight gain, with extrapyramidal symptoms mostly in the fixed-dose study, but these events rarely led to treatment discontinuation (Marcus et al. 2009; Owen et al. 2009). Aripi‐ prazole dosing and response can vary considerably; the usual recommended clinical dose for maintenance is between 5 and 15 mg/d (Kaplan and McCracken 2012).

Other atypical antipsychotics lack large-scale controlled studies. Small open-label reports suggest variable benefits of olanzapine (Potenza et al. 1999), clozapine (Beherec et al. 2011), and ziprasidone (Malone et al. 2007), which have possible support, versus quetiapine, which has not appeared to be beneficial. Other medications of different classes have been used, such as alpha-2 agonists, mood stabilizers, beta blockers, SSRI (selective serotonin reuptake inhibitors), all of them without evidence-based studies of efficacy in disruptive behavior to date (Weinssman and Bridgemohan 2012).

Probably due the co-occurrence of epilepsy in ASD, the use of some antiepileptic drugs has been used in the management of maladaptive behaviors (Gottfried and Riesgo 2011). Dival‐ proex sodium has been demonstrated to be efficient not only in decreasing irritability/ aggression, but also in improving of repetitive behaviors, social relatedness and mood instability (Hollander et al. 2006; Hollander et al. 2010).

Adjunctive topiramate therapies can decrease irritability, hyperactivity and inattention (Hardan, Jou, and Handen 2004; Mazzone and Ruta 2006). Moreover, the combination of topiramate with risperidone has been proved superior to risperidone monotherapy in reducing irritability and severe disruptive symptoms (Rezaei et al. 2010). In our experience, this specific combination would be helpful in preventing or at least decreasing the weight gain due to risperidone usage in ASD patients.

Although preliminary data of open-label studies showed that levetiracetam may reduce hyperactivity, impulsivity, mood instability and aggression in autistic children, a RCT suggest that levetiracetam does not improve behavioral disturbances of ASD (Weinssman and Bridgemohan 2012), as well lamotrigine (Belsito et al. 2001).

#### **4.2. Hyperactivity and inattention symptoms**

marked distress for their families (Benvenuto et al. 2012; Kanne and Mazurek 2011). Although behavioral and environmental approaches are recommended as the initial treatment, more severe or even dangerous behaviors usually result in requests for urgent pharmacologic intervention (Kaplan and McCracken 2012; Weinssman and Bridgemohan 2012). In our experience, this type of symptoms is more frequently found in intelligence disabled ASD

In the past, conventional neuroleptic agents such as haloperidol have been used in disruptive behaviors of autistic patients (Benvenuto et al. 2012; Miral et al. 2008; Kaplan and McCracken 2012). Our group showed that risperidone is superior when compared with haloperidol in one experimental research using hippocampal cells (Quincozes-Santos et al. 2010). Additionally, in the clinical research, at least one study proved that risperidone is more effective than haloperidol in ASD patients (Miral et al. 2008). There are two RTC suggesting that haloperidol is effective in disruptive behaviors of ASD children (Campbell et al. 1982; Miral et al. 2008), but sedation and other side effects including dyskinesia and extrapyramidal symptoms limits

As a result, to date atypical antipsychotic seem to be more helpful in treatment of disruptive behaviors. Currently, risperidone and aripiprazole are the only second-generation antipsy‐ chotic drugs that have shown to decrease disruptive behaviors in large-scale, controlled, double-blind studies (Benvenuto et al. 2012; Kaplan and McCracken 2012; Weinssman and

Before the approval by FDA in 2006, risperidone was carefully studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. A multiphasic trial comparing risperidone with placebo was performed by RUPP for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week

The studies found that risperidone, in mean doses of 2,08mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. There wasn't evidence of side effects such as dyskinesia or dystonia. However, the observed weight gain of 5,6kg for the risperidone group was more than twice the expected weight gain

Risperidone was approved by the FDA in 2006 for the treatment of disruptive symptoms in children and adolescents aged from 5 to 16 years with autism, with a maximum recommended dose of 3 mg/d. In our experience, risperidone was initially used in dose up to 6 mg/d. As time pass, we noted that if no response was obtained with 3mg/d, no more increments were useful. Coincidentally, this daily regimen seems to be the seizure threshold in susceptible patients

Aripiprazole was approved by the FDA for the treatment of disruptive behavior in ASD patients aged 6 to 17 years in 2009. Two large controlled studies documented the short-term efficacy of aripiprazole at 5, 10 or 15 mg/d for severe aggression and irritability in young subjects with autistic disorder. The most commonly reported adverse events were drowsiness and weight gain, with extrapyramidal symptoms mostly in the fixed-dose study, but these

over a 6-month period (McCracken et al. 2002; Kaplan and McCracken 2012).

patients (Gottfried and Riesgo 2011).

640 Recent Advances in Autism Spectrum Disorders - Volume I

its use (Weinssman and Bridgemohan 2012).

Bridgemohan 2012).

RCT study (McCracken et al. 2002).

(Gottfried and Riesgo 2011).

These symptoms are frequently identified in ASD patients. Inattention, hyperactivity and impulsivity may be related to comorbid ADHD (attention deficit hyperactivity disorder) and/ or to baseline anxiety of these children (Murray 2010; Rommelse et al. 2010; Benvenuto et al. 2012) Weinssman & Bridgemohan, 2012). It is known that children with ASD and ADHD have more clinical impairments than children with ASD alone (Gadow, DeVincent, and Pomeroy 2006; Kaplan and McCracken 2012).

The potentially useful drugs for inattention and hyperactivity in ASD could be stimulants, alpha-2 adrenergic agonists, atypical antipsychotics as well as anticonvulsant mood stabilizers. To date, there is strong evidence that both stimulants and risperidone are effective for hyperactivity. If the inattention and/or hyperactivity behaviors are due to anxiety, SSRI may be a useful choice (Weinssman and Bridgemohan 2012).

Psychoestimulants and other medications used in typically developing children with ADHD have been evaluated as a therapeutic option for treatment of ADHD symptoms in patients with ASD. The largest trial undertaken by RUPP Autism Network has dem‐ onstrated that methylphenidate (MPH) was reasonably efficacious in patient with both ASD and ADHD (RUPP 2005). Convergent evidence from different studies confirms a positive effect on social behaviors (joint attention, response to bids for joint attention, self-regulation, and regulated affective sate), hyperactivity, inattention and impulsiveness (Di Martino et al. 2004; Jahromi et al. 2009). However, response rate to MPH is lower in ASD children compared with children with ADHD without ASD (Weinssman and Bridgemohan 2012). In ASD children, MPH should be started at the lowest dosage ant ti‐ trated slowly because of these patients are more prone to experience side effects.

Because of the similarity of this cluster of autistic symptoms to anxiety as well as other serotonin-related disorders such as obsessive compulsive disorder has led clinicians to use and researchers to investigate the efficacy of SSRI in the treatment of repetitive behaviors and rigidity. Other possibilities in terms of medication include clomipramine, atypical antipsy‐

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643

To date, although the lack of high quality evidence that SSRI are effective to stereotypy and repetitive behaviors, we still use this class of medication in clinical practice. In a meta-analysis of published trials with different classes of antidepressants, including SSRI and tricyclic antidepressants, the small benefit of these drugs on repetitive behavior disappeared after

Other types of SSRI were tested in ASD children with stereotypy and repetitive behaviors, for example: fluvoxamine, sertraline, paroxetine, citalopram and escitalopram. There is one unpublished trial of fluvoxamine, which was poorly tolerated by children (McDougle et al., 1996). There are no RCT of sertraline and paroxetine in ASD children (Weinssman & Bridge‐ mohan, 2012). The largest published trial of citalopram (mean dose 16mg/d) found no effect at all on repetitive or compulsive behavior but found a possible effect on challenging behaviors (King et al., 2009). Others RCT didn't show strengths of evidence for effect of citalopram or

Concerning antipsychotic drugs, in the RUPP studies, stereotypies and repetitive behaviors were examined as secondary outcomes and then risperidone achieved levels of statistical significance in reduction of repetitive behavior (McDougle et al., 2005). Similarly, aripiprazole studies showed that the agent significantly improved repetitive behaviors over placebo

There is only one small RCT which shows the efficacy of valproate in repetitive behaviors of ASD children (Hollander et al., 2006). Our group avoids the usage of valproate in such symptoms. In summary, from the clinical point of view, it is hard to improve stereotypy and repetitive behaviors with pharmacotherapy. As a matter of fact, sometimes these symptoms

In clinical practice, mood instability is more difficult to control in ASD patients compared with typically developed children (Gottfried & Riesgo, 2011). Different drugs have been used, including antipsychotics, SSRI, and lithium. The problem is that none of these medications have been studied with RCT specifically for mood regulation in ASD pediatric patients

If mood lability is associated with disruptive behavior, the best choice could be atypical antipsychotics. If this symptom is associated with depression and or anxiety, the use of SSRI could be considered. It is important to remember the higher possibilities of behavio‐ ral activation in ASD patients after SSRI use, leading to hypomaniac states in susceptible

escitalopram to reduce repetitive or challenging behavior (McPheeters et al., 2011).

chotics and valproate (Weinssman & Bridgemohan, 2012).

statistical adjustment (Carrasco et al., 2012).

(Marcus et al., 2009; Owen et al., 2009).

(Weinssman & Bridgemohan, 2012).

**4.4. Mood instability**

children.

can be more uncomfortable to parents than patients.

As the same observed with MPH, atomoxetine has initially demonstrated a lower efficacy in ASD patients with ADHD than in ADHD children without autism (Posey et al. 2007; Charnsil 2011). Nevertheless, more recent studies showed significant reductions in ADHD symptoms in high-functioning ASD boys (Zeiner, Gjevik, and Weidle 2011).

Regarding the use of antipsychotic drugs in inattentive/hyperactive ASD patients, secondary analyses from large RTCs demonstrated that risperidone and aripiprazole are associated with large reduction of hyperactivity in children with ASD (McCracken et al. 2002; Owen et al. 2009; Weinssman and Bridgemohan 2012).

Despite the small number of RCT, another option is the use of alpha-2 agonists drugs in ASD children with inattention, hyperactivity, and impulsivity. The use of guanfacine in autistic children has showed modest improvement in the domains of hyperactivity, inat‐ tention, insomnia, and tics (Scahill et al. 2006; Handen, Sahl, and Hardan 2008; Weinss‐ man and Bridgemohan 2012). Clonidine is effective in reducing sleep disorders of children with ASD, with a consequent daily improvement of attention deficits, hyperac‐ tivity, mood instability and aggressiveness (Jaselskis et al. 1992; Ming et al. 2008). How‐ ever, only two RCT have been conducted for this class of agent (Weinssman and Bridgemohan 2012).

#### **4.3. Stereotypy and repetitive behaviors**

One of the core symptoms in ASD children is perseverative or repetitive behaviors usually associated with difficulties in change interests, which can interfere in the quality of life of patients and parents. Stereotypies and repetitive behaviors are not unique to ASD and can be found in other developmental disorders, although clinicians and researchers agree that these tend to be more frequent in ASD (Kaplan & McCracken, 2012; Leekam et al., 2011). By the other hand, difficulties in changing interests, in the context of a developmental disorder, is one of the hallmarks of autism.

Before use of medication, behavioral therapies should be performed. In our experience, poor cognitive performance can be one of the limitations to behavioral therapy. If the child is mentally disabled, the non-medical approach can be unsuccessful. In this situation, when these symptoms are intense enough to cause impairments to academic performance and/or inter‐ personal relationships, pharmacologic treatment is often considered.

Because of the similarity of this cluster of autistic symptoms to anxiety as well as other serotonin-related disorders such as obsessive compulsive disorder has led clinicians to use and researchers to investigate the efficacy of SSRI in the treatment of repetitive behaviors and rigidity. Other possibilities in terms of medication include clomipramine, atypical antipsy‐ chotics and valproate (Weinssman & Bridgemohan, 2012).

To date, although the lack of high quality evidence that SSRI are effective to stereotypy and repetitive behaviors, we still use this class of medication in clinical practice. In a meta-analysis of published trials with different classes of antidepressants, including SSRI and tricyclic antidepressants, the small benefit of these drugs on repetitive behavior disappeared after statistical adjustment (Carrasco et al., 2012).

Other types of SSRI were tested in ASD children with stereotypy and repetitive behaviors, for example: fluvoxamine, sertraline, paroxetine, citalopram and escitalopram. There is one unpublished trial of fluvoxamine, which was poorly tolerated by children (McDougle et al., 1996). There are no RCT of sertraline and paroxetine in ASD children (Weinssman & Bridge‐ mohan, 2012). The largest published trial of citalopram (mean dose 16mg/d) found no effect at all on repetitive or compulsive behavior but found a possible effect on challenging behaviors (King et al., 2009). Others RCT didn't show strengths of evidence for effect of citalopram or escitalopram to reduce repetitive or challenging behavior (McPheeters et al., 2011).

Concerning antipsychotic drugs, in the RUPP studies, stereotypies and repetitive behaviors were examined as secondary outcomes and then risperidone achieved levels of statistical significance in reduction of repetitive behavior (McDougle et al., 2005). Similarly, aripiprazole studies showed that the agent significantly improved repetitive behaviors over placebo (Marcus et al., 2009; Owen et al., 2009).

There is only one small RCT which shows the efficacy of valproate in repetitive behaviors of ASD children (Hollander et al., 2006). Our group avoids the usage of valproate in such symptoms. In summary, from the clinical point of view, it is hard to improve stereotypy and repetitive behaviors with pharmacotherapy. As a matter of fact, sometimes these symptoms can be more uncomfortable to parents than patients.

#### **4.4. Mood instability**

in patients with ASD. The largest trial undertaken by RUPP Autism Network has dem‐ onstrated that methylphenidate (MPH) was reasonably efficacious in patient with both ASD and ADHD (RUPP 2005). Convergent evidence from different studies confirms a positive effect on social behaviors (joint attention, response to bids for joint attention, self-regulation, and regulated affective sate), hyperactivity, inattention and impulsiveness (Di Martino et al. 2004; Jahromi et al. 2009). However, response rate to MPH is lower in ASD children compared with children with ADHD without ASD (Weinssman and Bridgemohan 2012). In ASD children, MPH should be started at the lowest dosage ant ti‐

trated slowly because of these patients are more prone to experience side effects.

in high-functioning ASD boys (Zeiner, Gjevik, and Weidle 2011).

2009; Weinssman and Bridgemohan 2012).

642 Recent Advances in Autism Spectrum Disorders - Volume I

**4.3. Stereotypy and repetitive behaviors**

Bridgemohan 2012).

the hallmarks of autism.

As the same observed with MPH, atomoxetine has initially demonstrated a lower efficacy in ASD patients with ADHD than in ADHD children without autism (Posey et al. 2007; Charnsil 2011). Nevertheless, more recent studies showed significant reductions in ADHD symptoms

Regarding the use of antipsychotic drugs in inattentive/hyperactive ASD patients, secondary analyses from large RTCs demonstrated that risperidone and aripiprazole are associated with large reduction of hyperactivity in children with ASD (McCracken et al. 2002; Owen et al.

Despite the small number of RCT, another option is the use of alpha-2 agonists drugs in ASD children with inattention, hyperactivity, and impulsivity. The use of guanfacine in autistic children has showed modest improvement in the domains of hyperactivity, inat‐ tention, insomnia, and tics (Scahill et al. 2006; Handen, Sahl, and Hardan 2008; Weinss‐ man and Bridgemohan 2012). Clonidine is effective in reducing sleep disorders of children with ASD, with a consequent daily improvement of attention deficits, hyperac‐ tivity, mood instability and aggressiveness (Jaselskis et al. 1992; Ming et al. 2008). How‐ ever, only two RCT have been conducted for this class of agent (Weinssman and

One of the core symptoms in ASD children is perseverative or repetitive behaviors usually associated with difficulties in change interests, which can interfere in the quality of life of patients and parents. Stereotypies and repetitive behaviors are not unique to ASD and can be found in other developmental disorders, although clinicians and researchers agree that these tend to be more frequent in ASD (Kaplan & McCracken, 2012; Leekam et al., 2011). By the other hand, difficulties in changing interests, in the context of a developmental disorder, is one of

Before use of medication, behavioral therapies should be performed. In our experience, poor cognitive performance can be one of the limitations to behavioral therapy. If the child is mentally disabled, the non-medical approach can be unsuccessful. In this situation, when these symptoms are intense enough to cause impairments to academic performance and/or inter‐

personal relationships, pharmacologic treatment is often considered.

In clinical practice, mood instability is more difficult to control in ASD patients compared with typically developed children (Gottfried & Riesgo, 2011). Different drugs have been used, including antipsychotics, SSRI, and lithium. The problem is that none of these medications have been studied with RCT specifically for mood regulation in ASD pediatric patients (Weinssman & Bridgemohan, 2012).

If mood lability is associated with disruptive behavior, the best choice could be atypical antipsychotics. If this symptom is associated with depression and or anxiety, the use of SSRI could be considered. It is important to remember the higher possibilities of behavio‐ ral activation in ASD patients after SSRI use, leading to hypomaniac states in susceptible children.

#### **4.5. Sleep disorders**

Sleep disorders can be identified years before an unequivocal diagnosis of autism. Not infrequently, we face with sleep complaints in very young babies who lately will develop the whole clinical picture compatible with ASD. By the other hand, sleep disorders occur more frequently in ASD patients compared with developing children (Benvenuto et al., 2012; Miano & Ferri, 2010).

**5. Non-medical treatment of ASD patients**

(LeBlanc & Gillis, 2012).

(Gottfried & Riesgo, 2011).

2011; LeBlanc & Gillis, 2012).

in the outcome measures, etc.

**5.1. Behavioral treatment**

& Johnson, 2007).

The treatment of ASD evolves professionals coming from different area and usually is characterized by comprehensive and intense programs encompassing both patients and families. Early identification is critically important to ensure that families have the op‐ portunity to reap the many unique benefits that may arise from early intervention ef‐ forts. For example, intervention efforts that occur early during a child's development may have the advantage of increasing brain plasticity, which may enhance outcomes

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In our experience, children with low intensity ASD treats, when early-treated can eventually get out from de ASD diagnosis when accessed by CARS, a rating scale of autism symptoms

The non-medical intervention programs are directed to the core social, communication and cognitive issues in autism. The objectives of each one program are selected according with the specific abilities and difficulties as well as the actual neurodevelopmental phase of the ASD patient. As a result, this kind of intervention needs to be customized (Dawson & Burner,

In general, the following types of therapy can be used both isolate or in different combi‐ nations: behavioral, occupational, speech therapy as well as psychopedagogic therapy. Although the non-medical treatments for ASD patients can be different from each other, they usually had the same goals, such as to give the child the best degree of independ‐ ent functioning as well as to improve quality of life from the patient and family (Myers

There is a consensus that facing a suspicious case of ASD in children the treatment must be promptly initiated, independently of the type of non-medical treatment, because of the brain

Besides the large number of non-medical type of treatment, there are some of them with good level of evidence. According with the National Autism Center's Standard Report, after a systematic review of literature available from 1957 to 2007, at least 11 treatment methods for

Additionally, there are some problems in evaluating the efficacy of non-medical treatments in ASD patients. For example, the small sample sizes, the different methodologies, the difficulty

The therapies involving behavioral and educational strategies are the main components of the non-medical treatments of ASD children. The only psychoeducational treatment that meets the criteria as well-established and efficacious intervention for ASD to date is the behavior

plasticity in the developing child (LeBlanc & Gillis, 2012; Lord & McGee, 2001).

ASD were considered with good level of evidence.

treatment (Dawson & Burner, 2011; LeBlanc & Gillis, 2012).

Sleep disorders tend to be under-recognized valued in the ASD patient group, probably because they can be considered less disabling than aggression and repetitive behaviors; however, ongoing abnormal sleep patterns are very disruptive to the overall quality of family life and interfere with patient daytime functioning. Parents frequently ask for medication and then physicians are confronted with the lack of FAD-approved treatments for this problem (Kaplan & McCracken, 2012; Weinssman & Bridgemohan, 2012).

Before use of medication, is important to ensure appropriate sleep hygiene as well as to use behavioral intervention. Pharmacology is recommended only when psychosocial treatments fail. Melatonin administration in ASDs is reported to be safe, well tolerated and efficient in improving sleep parameters and daytime behavior, and in decreasing of parental stress (Malow et al., 2011; Rossignol & Frye, 2011).


\*FDA-approved medications for ASD children; \*\*Secondary analysis; RCT = randomized controlled trials

**Table 2.** Psychopharmacological treatment in ASD patients
