Atomoxetine in Adults with ADHD
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Therapy Article: Atomoxetine in Adults with ADHD
Background:
- Many children with ADHD will continue to suffer from the condition as adults, resulting in significant comorbidity and distress.
- Medications effective in children with ADHD appear to be effective in adults, but the literature is limited, and the few studies available all have small sample sizes.
- Treatments for ADHD include amphetamines and methylphenidate, but they can be addictive. Desipramine has shown to be effective in small studies with adults. However, desipramine has a low therapeutic index and can have dangerous cardiac side effects.
- Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter, with little affinity for other systems. It is not associated with adverse effects on cardiac conduction and does not appear to be addictive.
- Atomoxetine has been shown to be effective in treating children and adolescents with ADHD. Because of its limited spectrum of adverse effects and low abuse potential, atomoxetine might also be beneficial in adults.
Clinical Question: A 45 year old male comes to your office because of attention problems that have been present since childhood and are now affecting him at work. After a full evaluation, you diagnose him with ADHD. He does not want to take methylphenidate or amphetamines, because he has read that these can be addictive. He does not want to take bupropion or desipramine because he has a family history of seizures and heart problems. What therapy can be offered to him as an alternative?
Methods:
Design- Two identically designed, 10-week long, multicenter, double-blind, placebo-controlled, parallel design studies comparing atomoxetine (with flexible dosing from 60mg-120mg/day) vs. placebo. 2-week double-blind placebo lead-in phase.
Setting- Study I involved 17 outpatient sites in North America, while study II involved 14 outpatient sites.
Patient Population- All patients met criteria for ADHD clinically and confirmed by the CAAR-D. They were recruited from clinics and by advertisement. Diagnosis had to be corroborated by a second reporter. Exclusion criteria: Current major depression, anxiety disorder, current or past bipolar or psychotic disorder, serious medical illness, alcohol dependence, actively using drugs of abuse, no second reporter to corroborate diagnosis.
Study I. 448 patients signed consent, 280 were randomized, 141 to atomoxetine, 139 to placebo (see figure 1).
Study II. 388 patients signed consent, 256 were randomized, 129 to atomoxetine, 127 to placebo (see figure 2).
Blinding- Raters were blind to all the details of the study design and were not allowed to evaluate or ask about side effects.
Analysis- Intention-to treat basis. Primary analysis: MIXED procedure in SAS. For the CAARS, if more than one item of a subscale was missing, the whole score for the subscale was also considered missing. If only a single item was missing, the mean score for all other items in the subscale was given as the missing score. Self-reported CAARS values were given as t scores. Secondary analysis: Included all patients with at least one postbaseline measurements. Safety analysis- all patients who took at least 1 dose. LOCF using ANOVA. Treatment differences in binary measures assess by Fisher’s Exact Test. Two-sided significance level= 0.05.
Outcomes- Primary: Sum of the Inattention and Hyperactivity/Impulsivity subscales of the investigator-rated CAARS( Conners’ Adult ADHD Rating Scales). Other: CGI-S, self-reported CAARS, WRAADDS (Wender-Reimherr Adult Attention Deficit Disorder Scale), Sheehan Disability scale. They also measured anxiety and depressive symptoms through the HAM-A and HAM-D 17. Safety and tolerability were assessed at each visit by open ended questions and monitoring of vital signs and labs.
Dosing- Atomoxetine was administered in evenly divided doses in the AM and early PM, beginning at a total of 60mg. Afterwards, dose could be titrated up if residual symptoms remained and if dose was well tolerated: after 2 weeks, increase to 90mg/day, after 4 weeks increase to 120mg/day.
Follow-up: 10-week study. Patients had visits q2weeks. If pt dropped out, LOCF was used for the purpose of analysis.
Validity:
Randomization? Yes. Concealed list? Yes. Treatment groups similar at baseline? Yes. Patients starting trial accounted for at conclusion? Yes (see figure 1 and figure 2). Patients and clinicians blinded to treatment? Patients and raters were blinded, not clear whether PI’s were blinded. Groups treated similarly outside of intervention? Hard to tell, it was a multicenter trial and possible differences between raters and between centers could have been present. Do the study characteristics describe our patients? Yes and no. Although demographically the patients were similar to our pt population, most patients had had previous stimulant exposure, which is not always the case. Pts with comorbidities such as depression, anxiety disorders and substance abuse, common for ADHD patients, were excluded.
Results: Patient characteristics (table 1): Mean age in all groups was 40-43 y/o (with SD’s ranging from 10.3-11.7). The majority of pts were male (83-91%). Baseline ADHD severity scores based on the CARRS-inv, CARRS-self, CGI-ADHD-S and WRAADDS were not significantly different between groups. Dose: Most common dose was 90mg/day, followed by 120mg and 60mg. Primary outcome: CAARS-inv scores were significantly reduced from baseline in the atomoxetine group (Study I: -9.5 (SD=10.1, %dec=28%) atomoxetine vs. –6.0 (SD=9.3, %dec=18%,)placebo, p= .005; Study II: -10.5 (SD=10.9, %dec=30%) atomoxetine vs. –6.7 (SD=9.3, %dec=19%) placebo, p= .002.
Effect size for primary outcome: 0.35 in study I and 0.40 in study II (medium effect). Atomoxetine showed significantly separated from placebo as early as the first post-randomization visit, but scores continued to decline through the study.
Statistically significant change in secondary outcome measures (CAARS-self, CGI-S and WRAADS) were also observed, but the effect sizes for these variables were small. RRR,ARR, NNT- N/A, cannot be calculated because outcome is point reduction in a severity scale. Please see table 2 for CI’s, and other outcome variables.
Compliance with therapy: A greater proportion of pts taking atomoxetine discontinued from study II but not study I due to adverse events. Completers: Study I- 103 (73%) in the atomoxetine group vs. 107 (77%) of the placebo group; Study II- 94(73%) of the atomoxetine group vs. 104 (81.9%) of the placebo group. See table 3 for patient disposition. Safety and Tolerability: The most common side effects with atomoxetine were dry mouth (57%) and insomnia (56%). Others include nausea, decreased appetite, constipation, decreased libido, dizziness, erectile difficulties and sweating, all significantly more common in the atomoxetine group. Atomoxetine was associated with clinically insignificant increases in blood pressure and heart rate.
Comments: These two studies, overall were well designed. Limitations include recall bias by the patients, since the diagnosis of ADHD requires the onset of symptoms before age 7. Patients don’t necessarily represent the adult population with ADHD, since common comorbidities were excluded. Strengths include good design, large sample size, separate safety and efficacy raters who were blinded to treatment and study design and double-blind placebo-lead in. The end-point dose (90mg/day, corresponding to 1.3mg/kg/day in a 70kg adult) is similar to that one that has been found effective in children (1.2mg/kg/day). Although atomoxetine significantly differentiated from placebo early on, longer periods of time seemed to be required to obtain maximum response. Alhough not described in this article, at the end of the 10-week trial 384 of the patients, elected to enter an open-label extension study for 34 weeks [described in Spencer TJ, ADHD Treatment Across the Life Cycle, Journal of Clinical Psychiatry 2004;65(suppl 3)], where CAARS:inv scores decreased by 43.5%. At present, atomoxetine is the only FDA approved medication for adult ADHD.
Bottom Line: This article describes two identically designed multicenter, double-blind, randomized, placebo-controlled studies looking at the efficacy and tolerability of atomoxetine when used to treat adults suffering from ADHD, using larger sample sizes studied than previous studies in this population. Atomoxetine showed superiority to placebo and was generally well tolerated, but it is questionable whether the study subjects are representative of the general adult population with ADHD.
Presented by Georgette De Jesus, M.D. on 11-29-04
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