Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder

Background: Although many drugs are approved for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), there are few studies and no approved drug treatments for oppositional defiant disorder (ODD).

Objective: To examine the effectiveness of atomoxetine (ATX) for treatment of ODD symptoms in comorbid ADHD/ODD.

Methods:  This prospective, randomized, double-blind, placebo-controlled study took place in 17 clinics across Europe and Australia in 2007.  The study was funded by Eli Lilly, the manufacturers of Straterra (atomoxetine).  Patients aged 6 – 12 who met DSM-IV criteria for ADHD and comorbid ODD, with SNAP-IV ADHD subscore > 4 and ODD subscore > 15 were enrolled.  Patients who suffered from bipolar disorder I or II, psychosis, pervasive developmental disorder, any seizure disorder, alcohol/drug abuse within the past 3 months, major depressive disorder, post-traumatic stress disorder, cardiovascular disease, severe gastrointestinal narrowing were excluded, as well as those at high risk of suicide and those likely to need psychotropic medications at any time during the study.
During study period 1, screening  took place and 226 patients were enrolled and randomized to either ATX 1.2 mg/kg/day (n = 156) or placebo (n = 70) daily for the 8-week-long study period 2.  Patients were tested at baseline for their SNAP-IV ODD and ADHD subscores and CGI-S, CGI-P, SSRS, and AIM scores.  They returned at weeks 2, 5, and 8 to be assessed on these scales, the CGI-I scale, and for adverse effects.  There was 90% power to detect a difference of 2.0 points in score.  For study period 3, patients were randomized to either ATX 1.2 mg/kg/day or ATX 2.4 mg/kg/day.  The primary outcome measure was the change in SNAP-IV ODD subscore after eight weeks.
  
Results:  Repeated-measures analysis of the entire 8-week study period showed that the overall treatment effect of ATX was statistically significantly greater than that of placebo (p = 0.01).  However at the end of 8 weeks, the mean change in SNAP-IV ODD symptom score was -3.7 (±5.3) points in the ATX group and -2.9 (±4.3) points in the placebo group, a nonsignificant difference (p = 0.252).  Analysis of secondary measures showed statistically significant improvements in SNAP-IV inattentive and hyperactivity scales (p = 0.001 and 0.003) as well as in global clinical symptoms of ADHD/ODD (CGI-I, p = 0.37; CGI-S, p = 0.013).  No significant changes in symptoms were found between the two study groups in period 3.  Adverse effects that were more prevalent in the ATX group included decreased appetite (24.4% vs 1.4%, p < .001), nausea (20.5% vs 8.6%, p = 0.033), fatigue (17.3% vs 5.7%, p = 0.021), diastolic BP increase (9.7% vs 1.6%, p = 0.042), and weight loss (39% vs 2.9% lost 3.5% of baseline weight, p < 0.001).  All p-values were 1-tailed.  Authors concluded that patients with comorbid ADHD/ODD show improvement in ADHD symptoms and global clinical functioning when treated with ATX and that it remains uncertain whether it exerts an effect on symptoms of ODD.

Strengths:  The study objective was clearly-defined and the methods used to study the drug were appropriate (double-blind, placebo-controlled, prospective experimental trial).  Study participants did not take other psychotropic medicines or have mood disorders that could affect study results.

Weaknesses:   The extent of compliance to study treatments and confidence intervals were not reported.  There was a possibility for unblinding of both patients and investigators due to the greater incidence of weight loss, appetite loss, and nausea in the ATX group.  Since the rating scales used to assess symptoms were subject to investigator’s assessments, knowing which drug a patient was taking may have influenced results.  Although authors accurately stated all results in their conclusion, statements were somewhat slanted in favor of ATX.  This may have been due to study support from Eli Lilly, where several authors are employed.  Lilly is the manufacturer of Straterra (atomoxetine).

Conclusion:    Although they showed initial improvement, patients taking ATX failed to show a statistically significant improvement in ODD symptoms at the eight-week endpoint.  The authors’ conclusion states their results, but it is misleading and possibly biased due to support from Eli Lilly.  This study does not support atomoxetine’s use in the treatment of ODD even though improvement in some comorbid ADHD/ODD symptoms occurred.

Bangs MD, et al.  Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder.  Pediatrics 2008; 121(2): e314-20.

Keri Del Signore, Doctor of Pharmacy Candidate

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