Atomoxetine for Treating ADHD Symptoms in Autism

Abstract

Objective: This study systematically reviews the current literature on the administration of atomoxetine for treating children and adolescents with comorbidity on autism spectrum disorder (ASD) and ADHD. Method: PubMed/Medline and Google Scholar databases were electronically searched to find the published trials on atomoxetine and ASD. Results: Six articles reported the clinical trials of atomoxetine for treatment of ADHD symptoms in patients with autism or pervasive development disorders. Only one study that was placebo-controlled crossover pilot trial reported that it is effective. Atomoxetine may be effective in high-functioning patients with autism or patients with low severity. Those with high severity of ASD may be more vulnerable to the adverse effects of atomoxetine. Conclusion: There are not enough controlled clinical trials for showing the efficacy of atomoxetine for treatment of ADHD symptoms in autism. Although evidence suggests potential efficacy of atomoxetine, the current evidences are not conclusive.

Keywords

ADHD autism atomoxetine treatment

Autism is a neurodevelopmental disorder whose neurobiology is not clearly known. Autism is one of the autism spectrum disorders (ASD), including the Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder–not otherwise specified. In addition, autism is a long-term disorder that needs long-term management. It also affects different aspects of life, such as interpersonal relationships, family relationships, occupation, and education. Many of the children with autism depend on others in their daily life. Moreover, a spectrum of interventional managements, including educational interventions, behavioral interventions, speech and language therapy, social skills, and medical managements, is applied for these patients.

ADHD and autism are two distinct disorders with different diagnostic criteria (Ghanizadeh, 2010). However, about half of school-age children with ASD have concurrent ADHD symptoms as well (Aman, Farmer, Hollway, & Arnold, 2008; Gadow, DeVincent, & Pomeroy, 2006; Ghanizadeh, 2012). Stimulants are most commonly used for treating ADHD. However, there are contradictory reports about their effects on children with autism and ADHD symptoms. Whereas some studies reported a higher rate of adverse effects and lack of efficacy in children with autism and ADHD (Stigler, Desmond, Posey, Wiegand, & McDougle, 2004), one study reported it to be effective for treating inattention and hyperactivity in ASD (Posey et al., 2007).

Atomoxetine selectively inhibits presynaptic norepinephrine reuptake. It is approved for ADHD treatment in children older than 6 years. Moreover, it is reported to be more effective in older children (Kratochvil, Milton, Vaughan, & Greenhill, 2008). Atomoxetine is an alternative for those with ADHD and anxiety disorders. Its half-life is more than methylphenidate and reaches to 24 hr. Besides, there is no risk of substance use disorders with atomoxetine (Cheng, Chen, Ko, & Ng, 2007).

Atomoxetine increases the release of dopamine and norepinephrine in prefrontal cortex of animals; however, it does not do the same in striatum leading to lower risk of substance use disorders (Bymaster et al., 2002; Koda et al., 2010). It is possible that the efficacy of atomoxetine is gender related; it is more effective in girls than in boys (Cheng et al., 2007). Besides, its efficacy and adverse effects are not related to age in children and adolescents with ADHD (Cheng et al., 2007). However, it is more effective and safer for those with the predominantly inattentive type of ADHD. Hyperactive/impulsive type responds to atomoxetine less than inattentive type (Cheng et al., 2007). In addition, severe forms of ADHD respond to atomoxetine better than those with a milder form of ADHD. Some authors suggested a tolerance to atomoxetine to exist in the children with ADHD. Gastrointestinal problems, such as decreased appetite and abdominal pain, sleep problems, and feeling of fatigue, are common adverse effects of atomoxetine (Cheng et al., 2007). Atomoxetine is associated with increased pulse rate and blood pressure (Kratochvil et al., 2008). Although it is reported that atomoxetine increases suicidal idea, it does not increase suicide rate (Bangs et al., 2008).

The following possible advantages are expected for administration of atomoxetine:

Atomoxetine can be taken once daily, whereas many stimulants need to be used more than once (Garnock-Jones & Keating, 2009).

Atomoxetine can be administered with or without food intake (Garnock-Jones & Keating, 2009).

Atomoxetine does not need to be tapered (Garnock-Jones & Keating, 2009).

Atomoxetine does not increase anxiety in ADHD comorbid with anxiety disorders (Adler et al., 2009).

Atomoxetine is administered for treating tic disorders (Spencer et al., 2008). Many children with ADHD (Ghanizadeh & Mosallaei, 2009) or autism suffer from tic disorders, too. Moreover, stimulants may exacerbate tic disorders.

On the contrary to stimulants, there is no concern for misuse and abuse for atomoxetine (Findling, 2008).

Atomoxetine is the first nonstimulant Food and Drug Administration (FDA)–approved medication for treating ADHD.

Atomoxetine improves ADHD symptoms in adolescents with ADHD and major depressive disorder (Bangs et al., 2007).

In comparison with stimulants, atomoxetine causes less sleep problems which are common in ADHD and autism (Sangal et al., 2006).

Finally, as atomoxetine is a nonstimulant medication and many parents worry about controlled medications, it is expected that atomoxetine be more accepted by the parents in comparison with stimulants.

This study aimed to systematically reviews the current literature regarding the efficacy and safety of atomoxetine in children and adolescents with ASD and ADHD symptoms.

Method

The guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was used for conducting the recent systematic review (Liberati et al., 2009). Published trials on atomoxetine and ASD were electronically searched thorough PubMed/Medline and Google Scholar databases. The reference lists were also checked for possible appropriate clinical trials. The terms atomoxetine AND autism, atomoxetine AND pervasive developmental disorder, tomoxetine AND autism, and tomoxetine AND pervasive developmental disorder were searched. The term AND was used to decrease the overlapping articles.

Inclusion and Exclusion Criteria

The following inclusion criteria were considered: The study design was clinical trial, in which the effect of atomoxetine for treating symptoms of ADHD was investigated; the participants were children, adolescents, and adults; and the efficacy outcomes were assessed through a validated instrument. However, the articles that did not report the results of an experimental trial were excluded.

The Extraction of Data

The used protocol for data extraction includes author, publication year of study, the number of study participants, the duration of trial, the age of study participants, atomoxetine dosages, adverse events, and the rate of dropout due to it. The extracted data were recorded in a data sheet.

Statistical Analysis

Although it was decided to conduct a statistical analysis, it was not practical because only one controlled clinical trial was found.

Results

In the present study, 15 articles were retrieved through an electronic search (Figure 1). However, 11 articles were excluded of which 7 were not experimental studies (Aman, 2004; Hazell, 2007; McCarthy, 2007; Murray, 2010; Myers, 2007; Polanczyk, Bigarella, Hutz, & Rohde, 2010; Rajapakse & Pringsheim, 2010), and 1 article was irrelevant (Academy of Medicine Singapore-Ministry of Health Clinical Practice Guidelines Workgroup on Autism Spectrum Disorders, 2010). One article reported a case repot of a 22-year-old man who took atomoxetine (40 mg/day) for 1 month. The results revealed that atomoxetine had reduced hyperactivity (Niederhofer, Damodharan, Joji, & Corfield, 2006).

Figure 1.

Flowchart of trial selection process.

Moreover, six articles reported clinical trials of atomoxetine for the treatment of ADHD symptoms in patients with autism or pervasive development disorders (Table 1). In addition, none of them included adult patients. One study was a retrospective study (Jou, Handen, & Hardan, 2005), four studies did not have placebo control groups and were open-label studies (Charnsil, 2011; Posey et al., 2006; Troost et al., 2006; Zeiner, Gjevik, & Weidle, 2011), and only one study was a placebo-controlled clinical trial (Arnold et al., 2006).

Table 1.

The Characteristics of Clinical Trials of Atomoxetine for Children and Adolescents With Pervasive Developmental Disorders and ADHD Symptoms.

Reference	DSM-IV diagnosis	Design of study	Sample size	Intervention	Main outcome measure	Main results	Main adverse effects
Arnold et al., 2006	Autism spectrum disorders with ADHD symptoms	Placebo-controlled crossover pilot trial	16 children and adolescents ages 5 to 15 years	Crossover of clinically titrated atomoxetine and placebo, 6 weeks each, separated by 1-week washout	Aberrant Behavior Checklist	Hyperactive/impulsive symptoms improved but without efficacy on nine inattentive symptoms.	One case hospitalized due to violence.
							The most commonly reported adverse effects: dyspepsia, nausea, vomiting, fatigue, decreased appetite, stomach pain, constipation, dry mouth, dizziness, and mood swings
Posey et al., 2006	Pervasive developmental disorders with ADHD symptoms	8-week, open-label, prospective study	16 children and adolescents ages 6 to 14 years. IQ ≥ 70	Atomoxetine 1.2 mg/kg/day	SNAP-IV, Clinical Global Impressions-Improvement, Aberrant Behavior Checklist	75% of children were rated as “much” or “very much improved.”	Two cases dropped due to the adverse effect of irritability.
						No efficacy on the Conners’ Continuous Performance Test	Weight loss (0.8 kg) was reported.
Troost et al., 2006	Pervasive developmental disorders with ADHD symptoms	10-week open-label study	12 children aged 6 to 14 years	Atomoxetine (1.19 ± 0.41 mg/kg/day)	ADHD Rating Scale, Aberrant Behavior Checklist	Atomoxetine reduced ADHD symptoms.	The rate of dropout due to adverse effects: five patients (42%).
							The most common adverse effects: gastrointestinal symptoms, irritability, sleep problems, and fatigue
Zeiner, Gjevik, and Weidle, 2011	High functioning boys with autism spectrum disorders and ADHD	10-week open-label study	14 boys aged 7-17 years	Atomoxetine up to 1.4 mg/kg/day	ADHD Rating Scale	Both parents and teachers reported the reduction of ADHD symptoms.	The most common adverse effects: Nausea, headache
						7 patients were in the range of clinical responders.	Two cases dropped from the study
Charnsil, 2011	Autism with ADHD symptoms	Open-label	12 children and adolescents with the mean age of 10.3 years	Atomoxetine 0.98 mg/kg/day	Aberrant Behavior Checklist	Lack of efficacy	11 out of 12 patients showed side effects.
							Three cases withdraw due to adverse effects.
							Common adverse effects: insomnia (33.3%), decreased appetite (55.5%), and moodiness (33.3%)
Jou, Handen, and Hardan, 2005	Pervasive developmental disorders	Retrospective study	20 patients, (age, 11.5 years, SD = 3.5)	Treatment dose: 43.3 mg (SD = 18.1) for 19.5 weeks (SD = 10.5)	Clinical Global Impressions Scale, Conners’ Parent Rating Scale	Effective to reduce hyperactivity and inattention symptoms	One case dropped due to mood swings.

Note: DSM-IV = Diagnostic and Statistical Manual of Mental Disorders (4th ed.); SNAP-IV = Swanson, Nolan and Pelham (SNAP) Questionnaire

The only randomized controlled study reported the response rate of 43% (Arnold et al., 2006). The response was described as a 25% reduction in the Aberrant Behavior Checklist (ABC)–Hyperactivity subscale score (Table 1). Also, in comparison with placebo, a significant reduction was observed in the score of Hyperactivity/Impulsivity subscale. Mild adverse events were reported, as well. Besides, one fifth of the sample experienced a 4% increase in heart rate and weight loss was more common in the atomoxetine group (Arnold et al., 2006).

The only study that reported that children with autism did not benefit from atomoxetine to treat their ADHD symptoms was conducted by Charnsil (Charnsil, 2011). This study included 12 children with severe autistic disorder comorbid with ADHD and had administered atomoxetine for 10 weeks. They could take concurrent treatments other than systemic catecholaminergic drugs and alpha blockers. Of course, the medication needed to be stable and without any planned changes 1 month before the onset of the study. The dosage of atomoxetine was not more than 1.2 mg/kg/day. However, the rate of drop due to adverse effects was 25%. These adverse effects were abdominal discomfort and irritable mood occurring during the first 2 weeks of the study. Adverse effects were reported in 11 out of 12 patients and the most common ones were decreased appetite as well as hypersomnia. According to the results, atomoxetine did not significantly decrease the score of Hyperactivity subscale from ABC measurement (Charnsil, 2011).

Discussion

This is the first systematic review of the efficacy and safety of atomoxetine in children and adolescents with ASD and ADHD symptoms. Few studies, however, have investigated the efficacy of atomoxetine in such populations.

Except one open-label case series study (Charnsil, 2011), all the three other case series (Zeiner et al., 2011; Posey et al., 2006; Troost et al., 2006) as well as the only one controlled trial (Arnold et al., 2006) reported atomoxetine to be effective in reducing the ADHD symptoms. In fact, parents, teachers, and clinicians rated it as effective. In addition, the response rate was reported up to 75% (Posey et al., 2006). Nevertheless, atomoxetine did not improve their function measured using continuous performance test.

In addition, there are some limitations that should be taken into account regarding the only published controlled clinical trial. This study included only 13 participants, and maximum dosage per day was 100 mg/day. Also, 1 patient stopped atomoxetine due to the adverse effect of irritability. Moreover, taking concomitant medication was allowed and 4 patients were concurrently taking atypical antipsychotics, which is a marked covariant factor (Arnold et al., 2006). Nearly all the studies reported gastrointestinal problems, somnolence, irritability, and weight loss as the most commonly reported adverse effects. The rate of severe adverse effects was very low in most studies and most of the adverse effects were mild. Of course, gastrointestinal problems were very common in children with autism and reached up to 70% (Valicenti-McDermott et al., 2006). Therefore, it cannot be concluded that these high rates of gastrointestinal problems are certainly associated with atomoxetine. Thus, more well-controlled studies are needed to be conducted on the issue.

In addition to the lack of efficacy of atomoxetine, there is a speculation that the children with severe autism and ADHD symptoms taking atomoxetine may show a higher rate of adverse effects (Troost et al., 2006). Those uncontrolled studies which had reported atomoxetine to be effective for treating ADHD symptoms in autism included high functioning autism (Posey et al., 2006; Zeiner et al., 2011) or included ASD, such as Asperger’s disorder (Arnold et al., 2006; Posey et al., 2006). The study that showed the lack of efficacy included autistic disorders, as well. Moreover, it did not include ASD (Charnsil, 2011). Meanwhile, the sample size of this study was very low. These may suggest that atomoxetine can decrease ADHD symptoms in the children with high functioning autism or those with low severity of autism.

Moreover, no published study was found including participants more than 22 years old and children less than 5 years old. Therefore, these results cannot be generalized to other age groups. Furthermore, all of these studies reported the short-term efficacy and adverse effects of atomoxetine (no more than 10 weeks). Thus, these findings cannot be generalized to the long-term administration of atomoxetine in autism. Of course, the full effect of atomoxetine in children with ADHD is expected to be achieved after 6 to 8 weeks, and there is no long-term efficacy (Cheng et al., 2007). Moreover, age is a protective factor for adverse effects of atomoxetine (Cheng et al., 2007). In many of the studies, the children with autism were not naïve patients (Arnold et al., 2006; Charnsil, 2011). At least regarding the children with ADHD, those who are naïve patients respond to atomoxetine better than those who have already received medications (Perwien et al., 2004).

In conclusion, there is no enough evidence-based knowledge regarding the efficacy of atomoxetine. Although, some uncontrolled studies suggested its efficacy, it was not shown in another uncontrolled study (Charnsil, 2011). Therefore, well-controlled clinical trials considering all the limitations of the current literature are needed to be conducted to reach a firm conclusion.

Footnotes

Acknowledgements

Research improvement center of Shiraz University of Medical Sciences and Ms. A. Keivanshekouh are appreciated for improving the use of English in the manuscript.

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

Author Biography

Ahmad Ghanizadeh, MD, is associate professor of child and adolescent psychiatry in the Department of Psychiatry at Shiraz University of Medical Sciences, Iran. Also, he is the director of the Research Center of Psychiatry and Behavioral Sciences. His research area is mainly focused on ADHD and autism.

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