Efficacy of Atomoxetine for Symptoms of Attention-Deficit/Hyperactivity Disorder in Children with a History of Child Abuse

Introduction

Recent studies suggest that the severity or drug response of mental symptoms is related to childhood abuse experiences. Nanni et al. (2012) meta-analyzed 16 epidemiological studies and found that childhood maltreatment was associated with an elevated risk of depression and of persistent depressive episodes. Additionally, they meta-analyzed 10 clinical trials and reported that childhood maltreatment was associated with a lack of response or remission during treatment for depression. Bruce et al. (2012) reported that childhood physical neglect, emotional neglect, and emotional abuse were related to increased social anxiety, and that individuals who reported emotional abuse were more likely to drop out of pharmacotherapy. Attention-deficit/hyperactivity disorder (ADHD) is observed in 14–46% of abused children (Endo et al. 2006), suggesting that ADHD is more common in abused children than in the general population. However, the relationship between the severity or drug response of ADHD symptoms and child maltreatment is unclear. Atomoxetine is the most common nonstimulant drug prescribed for the treatment of ADHD, and it has been placed in the first or second line in the drug guidelines of many countries (Taylor et al. 2004; Pliszka et al. 2006; Weiss et al. 2011; Wolraich et al. 2011). We conducted a retrospective study to assess the efficacy of atomoxetine for children with a history of child abuse.

Methods

We conducted a retrospective chart review for 41 cases of children treated with atomoxetine at the Department of Psychiatry, Niigata University Medical and Dental Hospital, or the Department of Psychiatry, Aichi Children's Health and Medical Center. The authors confirmed that all participants met the criteria A–D for ADHD based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (American Psychiatric Association 2000), although the samples included 24 patients who had been diagnosed as having pervasive developmental disorders (PDD), and 17 patients who had been diagnosed as having ADHD (χ² test revealed that there were no differences in the existence of child abuse between the PDD group and the ADHD group). Each attending physician had determined the dose of atomoxetine according to the dosage described in the package insert (start at 0.5 mg/kg/day, increase to 0.8 mg/kg/day after 2 weeks, maintain at 1.2–1.8 mg/kg/day).

We investigated the medical charts of the patients and retrospectively assessed their ADHD symptoms using the ADHD Rating Scale (ADHD-RS) before and 8 weeks after atomoxetine administration. The ADHD-RS comprises 18 questions (9 assessing inattention, and 9 assessing hyperactivity/impulsivity), and an observer gives a score of 0–3 points for each question. Trauma is known to lead to dissociative symptoms, such as impaired memory, depersonalization, and daydreaming (Olsen and Beck 2012; Brewin et al. 2013). These dissociative symptoms may overlap the symptoms of ADHD (Endo et al. 2006). To assess the influence of child maltreatment on the development and severity of attention-deficit/hyperactivity symptoms, we defined the sum of the three subscores of the ADHD-RS; Q5 (Does not seem to listen when spoken to directly), Q13 (Loses things necessary for tasks or activities), and Q17 (Is forgetful in daily activities) as “dissociation associating symptoms (DAS: 9 points maximum),” and the sum of the other 15 subscores as “ the other symptoms (OS: 45 points maximum).”

We used t tests and paired t tests with the Bonferroni correction for statistical analyses. We corrected the significance levels to 0.016 for the t tests and to 0.0056 for the paired t tests. All statistical analyses were performed using IBM SPSS Statistics 19 (IBM Japan).

This study was approved by the Institutional Review Board of Niigata University Graduate School of Medical and Dental Sciences and the Aichi Children's Health and Medical Center.

Results

A total of 41 children (37 were male and 4 were female) participated in this study. The mean age and standard deviation of the participants was 9.5±2.6 years, and the mean dose of atomoxetine was 33.4±13.9 mg. No obvious adverse reactions to the medication were observed.

At baseline, the abused children had higher total scores (38.7±9.3 vs. 30.5±9.4, t=−2.67, p=0.011), and greater levels of hyperactivity/impulsivity (17.3±5.8 vs. 11.3±6.0, t=−3.11, p=0.004) as measured by the ADHD-RS than the nonabused children, whereas the inattention scores were similar between the groups (21.4±4.8 vs. 19.2±4.6). In the nonabused group, three scores significantly decreased after atomoxetine treatment (total: 30.5±9.4 vs. 21.3±7.8, t=5.89, p<0.001; inattention: 19.2±4.6 vs. 14.1±4.8, t=5.45, p<0.001; hyperactivity/impulsivity: 11.3±6.0 vs. 7.2±4.1, t=5.61, p<0.001). In the abused group, the same three scores significantly decreased after atomoxetine treatment (total: 38.7±9.3 vs. 30.8±8.0, t=4.05, p=0.001; inattention: 21.4±4.7 vs. 17.7±4.0, t=4.68, p<0.001; hyperactivity/impulsivity: 17.3±5.8 vs. 13.1±5.3, t=3.30, p=0.006). In the nonabused group, both DAS (5.5±2.3 vs. 3.9±1.7, t=4.54, p<0.001) and OS (25.0±8.1 vs. 17.4±6.7, t=5.88, p<0.001) significantly decreased after atomoxetine treatment. However, although there was a significant reduction in OS in the abused group (32.8±7.6 vs. 25.7±7.2, t=3.89, p=0.002), DAS were unaffected by atomoxetine treatment (5.9±2.3 vs. 5.1±1.8).

Discussion

Our findings suggest that atomoxetine is less efficacious in treating DAS, which are symptoms associated with maltreatment, in abused children. Although recent studies suggest that the severity and drug response of depression and anxiety symptoms is related to experiences of childhood abuse (Bruce et al. 2012; Nanni et al. 2012), to the best of our knowledge, no studies have shown that a history of child abuse influences the severity or drug response of ADHD. Therefore, ours is the first study to describe a relationship between experiences of child abuse and an altered response to anti-ADHD medication.

There are several potential explanations for the observed difference between abused and nonabused children in terms of DAS response to atomoxetine treatment, likely related to a difference in the nature of DAS between these groups. It is difficult to distinguish DAS symptoms (such as “forgetfulness,” “being blurred,” or “seeming like they do not hear when someone is talking to them directly”) from the dissociation symptoms of abuse in children (such as “impairment of memory,” “depersonalization,” or “daydreaming”). Therefore, both original ADHD symptoms and similar symptoms resulting from child maltreatment might be assessed as DAS in abused children. Atomoxetine exerts its anti-ADHD effect by inhibition of the norepinephrine transporter in the prefrontal cortex, which increases the dopamine concentration in the synaptic cleft. Although the etiology of the dissociation symptoms related to child abuse is still unclear, one report suggested that childhood sexual abuse causes impaired visual memory through reduction of the volume of the bilateral visual cortex (Tomoda et al. 2009). These different natures of the two similar sets of symptoms might explain why we observed a reduction in OS of the abused group, whereas DAS remained unchanged. If DAS were caused from traumatic experiences, trauma treatment tools other than pharmacotherapy, such as eye movement desensitization and reprocessing and trauma-focused cognitive behavioral therapy might be useful to treat DAS.

Conclusions

Compared with nonabused ADHD children, abused children might have more severe ADHD symptoms, and their DAS could resist anti-ADHD pharmacotherapy. A combination of the techniques, such as a focus on trauma treatments other than pharmacotherapy, might be useful in the treatment of DAS.

Clinical Significance

To the best of our knowledge, this is the first study to investigate the efficacy of atomoxetine for the treatment of ADHD symptoms in abused children.