Abstract
Objective:
The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10–18 years of age.
Methods:
Eleven subjects ages 10–18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS).
Results:
The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period.
Conclusions:
These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period.
Introduction
Given that second-generation antipsychotics (SGAs) have been shown to be effective in reducing aggression in several pediatric disorders (Connor et al. 2000; Aman et al. 2002, 2004; Buitelear et al. 2003; Stephens et al. 2004; Barzman et al. 2006; Masi et al. 2006), the current study investigated whether the combination treatment of the nonstimulant, atomoxetine, and the SGA, olanzapine, would result in significant improvement of ADHD symptoms as well as in aggression in a 10 week open- label trial. To our knowledge, clinical trials have yet to study this combination treatment in children and adolescents with ADHD and comorbid DBDs. We hypothesized that 10 week combination treatment of atomoxetine and olanzapine would be well tolerated and result in statistically significant pre-to posttreatment reductions in ADHD symptoms and overt aggression, as evidenced by score reduction on the ADHD Rating Scale (ADHD-RS) and Modified Overt Aggression Scale (MOAS), respectively.
Methods
Participants
Eleven participants were enrolled into this study. Patients were 10–18 years of age, and met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for ADHD (any subtype) and comorbid ODD or conduct disorder (CD) as determined by the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS), a structured clinical assessment (American Psychiatric Association 1994). Patients also scored above the 93rd percentile on any subtype of the ADHD-Rating Scale, Investigator (ADHD-RS-I) (DuPaul et al 1998).
Patients were excluded if they had a history of bipolar disorder, psychosis, pervasive developmental disorder, major depressive disorder, anxiety disorders, or mental retardation. Patients were also excluded if they had histories of an unstable medical condition, epilepsy, drug or alcohol abuse, allergic reaction to or intolerance of atomoxetine, or any prior treatment with olanzapine. Patients were prohibited from certain concomitant medications during the study. Antidepressants required discontinuation 1 week prior to commencing study medications (fluoxetine required a 4 week withdrawal; monoamine oxidase inhibitors [MAOIs] required 2 weeks). Benzodiazapines and other anxiolytics were required to be discontinued within 4 days of commencing study medications. Antipsychotics were required to be discontinued 2 weeks prior to commencing study medications.
This research study was in compliance with Western Institutional Review Board (WIRB) (protocol number: BH-001).
Measures
Patients were initially assessed with the K-SADS. An experienced child and adolescent psychiatrist and trained graduate student administered the clinical interviews with parents and children to determine eligibility.
ADHD-RS-IV
The ADHD-RS (DuPaul et al. 1998) was a primary outcome measure. The ADHD-RS–IV is a DSM-IV-based symptom checklist composed of 18 items, which yields three clusters of scores: Inattention, Hyperactivity/Impulsivity, and Total ADHD score. Internal consistency for the ADHD-RS Home version is 0.92 for the Total score, 0.86 for Inattention, and 0.88 for Hyperactivity/Impulsivity.
MOAS
The MOAS (Yudofsky et al. 1986) was also considered a primary efficacy measure. The MOAS is a clinician interview-based scale that measures instances of overt aggression that occurred over the previous 7 days.
Global Assessment of Functioning (GAF)
The GAF is a single item assessment of level of global functioning, based on a scale ranging from 1 to 100.
Study design
The primary objective of this study was to test the hypothesis that the combination use of atomoxetine and olanzapine for a 10 week treatment period would produce significant improvement in ADHD and aggressive behavior from baseline to posttreatment in an open-label design. There was no control or placebo group in our design. Patients were considered treatment responders if they showed significant improvement in both ADHD symptoms and overt aggression, as assessed by our primarily outcome measures, the ADHD-RS and MOAS, respectively.
Patients received a telephone screening and initial comprehensive evaluation (visit 1) to determine eligibility for the study. Patients were then given a 7–21 day period prior to visit 2 to allow for medication washout. All study measures were administered at visit 2. The same procedures were repeated for visits 3–6. Patient visits were scheduled every 2 weeks, except for visit 6, which was 4 weeks following visit 5, making for a 10 week treatment period.
Patients were started on an initial dose of atomoxetine and olanzapine at visit 2. Atomoxetine treatment followed standard dosing procedures, commencing at 40 mg and titrating up to 80 mg within 7 days (mean mg/kg=0.8). Patients were scheduled to reach maximum dosage in week 6 (visit 5) and remain on that dose through posttreatment (visit 6). Olanzapine treatment followed standard dosing procedure, commencing at 2.5 mg daily for patients who weighed 25–50 kg; 5 mg daily for those weighing 50–70 kg; and 7.5 mg daily for those weighing > 70 kg. Starting olanzapine dosage remained steady throughout treatment with adjustments made at the investigator's clinical judgment.
Patients also received a comprehensive physical examination during visit 1, including hematology, clinical chemistry, urinalysis, urine drug screen, and electrocardiogram. This procedure was repeated at 10 weeks posttreatment (visit 6).
Statistical methods
The primary outcome measures were the ADHD-RS-I and the MOAS. Analyses were also computed for the GAF and weight gain. Analyses were conducted using paired samples t test comparing mean scores at baseline to scores at posttreatment. As patients only commenced study treatment after visit 2, data collected from the first two visits were averaged to obtain a baseline score. We used last observation carried forward (LOCF) in our analyses of missing data. t test analyses were also rerun after detecting and removing outliers in our data. Outliers were replaced with the mean score for that variable with the outlier removed. Only MOAS scores required removal of outliers. We also determined the percentage of responders to treatment from analyzing the primary measures. Treatment response was defined as showing 33% reduction in both ADHD-RS-I and MOAS scores from baseline to posttreatment.
Results
Of 16 patients initially assessed, 11 met criteria for the study. As this was an open-label design, all 11 patients received medication, and there was no placebo or control group. Of the 11 patients, 10 were male (90.9%) and 1 was female (9.1%). Ages ranged from 10 to 17 with a mean age of 13.1. Regarding race, six patients were Caucasian (54.5%), two were Hispanic (16.7%), two were Asian (16.7%), and one was African American (8.3%).
Diagnostically, all 11 patients met criteria for ADHD, 10 met criteria for ODD, and 1 patient met criteria for CD. As other common comorbidities were exclusionary, no other comorbid disorders were found in these patients. Within the ADHD diagnosis, 81.8% (9/11) met criteria for combined type, whereas 18.2% met criteria for primarily inattentive type. According to the ADHD-RS-I rating, all patients scored in the 97.5th percentile or higher in total ADHD symptoms at visit 1.
ADHD-RS-I
Results yielded a mean ADHD-RS-I total baseline score (mean of visits 1 and 2) of 41.95 (SD=3.69). Posttreatment (week 10) scores reduced to a mean of 26 (SD=11.99) (See Table 1). Paired samples t test for total ADHD score from baseline (mean of visits 1 and 2) to posttreatment (visit 6) revealed a significant two tailed difference, t(10)=4.23, p=0.002. ADHD-RS Inattention mean score was 21.77 (SD=3.2) at baseline and 13.73 (SD=5.3) at posttreatment. ADHDR-RS Hyperactivity mean score was 20.2 (SD=3.7) at baseline and 12.3 (SD=7.2) at posttreatment. Paired sample t test revealed a significant difference (two tailed) from baseline to posttreatment for both ADHD-RS Inattention, t(10)=4.0, p=0.01, and Hyperactivity t(10)=3.6, p=0.005.
Significantly different from baseline at the 0.01 level.
Significantly different from baseline at the 0.05 level.
ADHD-RS-I, Attention-Deficit/Hyperactivity Disorder Rating Scale, Investigator; MOAS, Modified Overt Aggression Scale; GAF, Global Assessment of Functioning.
MOAS
Reduction in aggression was measured through the MOAS. Mean MOAS score was 20.45 at baseline and 12.64 (SD=8.04) at posttreatment (week 10). Paired sample t tests revealed a statistically significant difference (two tailed) from baseline to posttreatment on the MOAS, t(10)=2.6, p=0.024.
Response to treatment
Seven of 11 (63.6%) of patients were considered treatment responders, as demonstrated by 33% improvement in both ADHD-RS-I and MOAS from baseline to posttreatment. Results yielded that 72.7% (8/11) showed at least a 33% reduction in total ADHD symptoms alone and 54.5% (6/11) showed a 33% improvement in aggression, according to the MOAS.
Global functioning
Mean GAF score was 48.81 (SD=3.19) at baseline (visit 2) and 57.09 (SD=4.87) at Visit 6. Paired sample t tests revealed a statistically significant difference (two tailed) in GAF scores from visit 2 to visit 6, t(10)=−7.0, p<0.001.
Dosage
Dosing for atomoxetine was titrated over time following a specific protocol. Mean dosage at visit 2 was 0.81 mg/kg (range from 0.46 to 0.99 mg/kg) and titrated up to 1.51 mg/kg by visit 6 (range from 1.17 to 1.8 mg/kg). Mean olanzapine dosing remained steady throughout treatment, commencing at visit 2 with a mean dose of 0.06 mg/kg and reducing slightly to 0.05 mg/kg by visit 6. See Table 2 for atomoxetine and olanzapine dosage means and ranges per study visit.
Adverse events
With the exception of weight gain, patients experienced few and minor adverse events. One patient (10%) experienced mild fasciculation (muscle twitching) in the leg. Two patients (18.2%) experienced significant somnolence.
Weight gain
From baseline to post-treatment, patients' mean weight gain was 3.9 kg, which is a 6% increase in body weight from baseline to posttreatment. Weight gain was statistically significant (two tailed) from baseline to posttreatment t(10)=−5.4, p<0.001. Most (81.8%) patients increased at least one BMI point during the 10 week period, whereas 54.5% increased two or three BMI points.
Discussion
The current study investigated the combined use of atomoxetine and olanzapine in a 10 week open-label trial for children and adolescents ages 10–18 diagnosed with ADHD and disruptive behaviors. Our hypotheses were confirmed: That combined use of the atomoxetine and olanzapine resulted in significant improvement in ADHD symptoms and aggressive behavior from baseline to posttreatment. These findings have significant implications, especially given that previous research using atomoxetine alone did not improve aggression in children with ADHD and disruptive behavior (Bangs et al. 2008). Both medications were generally well tolerated with few adverse events. Weight gain associated with olanzapine treatment was common, however. Within the 10 week treatment period, patients gained, on average, 3.9 kg. which may limit olanzapine's viability as a long-term treatment option for children with ADHD and DBD, despite its positive treatment effects.
Limitations
As this was an open-label design, positive results demonstrated may have resulted from placebo effects as well as clinician expectation for patient improvement as a result of treatment. Also, as this pilot study did not compare combination use of atomoxetine/olanzapine with either of these medications alone, we cannot state with confidence that atomoxetine/olanzapine in combination are more effective that either treatment in isolation. This study was also limited in its number of patients enrolled. The generalizability of these findings may also be limited, as subjects with comorbid mood and anxiety disorders were excluded from treatment.
Conclusion
Given the significant weight gain observed in this 10 week treatment period, combination treatment with olanzapine may not be a suitable long-term intervention, and parents may be reluctant to have their children on this medication despite its positive effects. As such, future research should study the effectiveness of atomoxetine in combination with another SGA that does not produce as much weight gain. Given that there is little research in this area, randomized controlled trials are warranted.
Clinical Significance
To the knowledge of the authors, this is the first clinical trial to investigate combination pharmacological treatment for children with ADHD and comorbid disruptive behaviors. Results from this study provide initial evidence for the efficacy of combination use of atomoxetine and olanzapine in treating this challenging population of children.
Footnotes
Disclosures
This study was an investigator-initiated clinical trial. This research was supported by an unrestricted grant funded by Eli Lilly and Company. All research procedures, statistical analyses, and manuscript preparation were completed by the study investigators. The authors, did not receive any monetary incentives for completing this research. Drs. Lopes and Holzer do not have any affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Lehman is a principal investigator in clinical trials for Merck, Pfizer, Eli Lilly, Shire, Forest, Otsuka, BMS, Naurex, Cephalon/Teva, Cyberonics, and Takeda. He is on the Speaker's Bureau for Shionogi, Merck, and Forest.