by Leo Bastiaens, MD

Dr. Bastiaens is from Family Services of Western Pennsylvania and is Clinical Associate Professor of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

Funding

No financial support received for this study.

Disclosure

Dr. Bastiaens has received honoraria for participation on the speakers bureaus of Bristol Myers Squibb, Eli Lilly, Forest, Pfizer, and Takeda.

Abstract

Objective: To evaluate the effectiveness of atomoxetine in a real-world attention deficit hyperactivity disorder (ADHD) population.
Design: A retrospective chart review with two nonrandomized samples—patients treated with atomoxetine and patients treated with stimulants.
Setting: One community mental health clinic.
Participants: Over a two-year period, 85 patients treated with atomoxetine and 81 patients treated with stimulants were identified. Many patients had comorbid conditions and were treated concomitantly with other medications.
Measurements: Clinical Global Impression-Improvement scale (CGI-I) and Global Assessment of Functioning scale (GAF).
Results: On average, all patients showed mild improvement, as measured by the CGI, while staying on the same medication for approximately six months. There was no significant difference in GAF, at baseline or at endpoint, or in CGI at endpoint between the two groups. Even though more patients on atomoxetine showed side effects, there was a trend for patients to stay on it longer.
Conclusion: Taking into account the limitations of a retrospective chart review in nonrandomized samples, it appears that patients with (comorbid) ADHD benefit as well from atomoxetine as from stimulants. If replicated in larger, better controlled studies, atomoxetine should be considered a first-line agent for the treatment of ADHD.

Key Words

atomoxetine, stimulants, effectiveness, ADHD

Print Citation

Psychiatry (Edgemont) 2007;4(12):44-48

Introduction

The American Academy of Child and Adolescent Psychiatry identifies stimulants and atomoxetine as first-line agents in the treatment of attention deficit hyperactivity disorder (ADHD).[1] Stimulants have a long track record of good efficacy, effectiveness, and tolerability in numerous studies.[2,3] Atomoxetine, the first nonstimulant approved for the treatment of ADHD, has been available for the past four years. Several placebo-controlled trials showed good efficacy and tolerability of atomoxetine.[4,5] However, more recently, there has been a significant decline in the use of atomoxetine. It has been speculated that the lesser effectiveness of atomoxetine in the real world compared to stimulants is a major cause of this decline.[6] A recent meta-analysis comparing the efficacy of medications for ADHD concluded that stimulant medications tend to be significantly more efficacious than non-stimulant therapy.[7]

Theoretically, atomoxetine has distinct advantages over stimulants. Since it does not affect dopaminergic neurotransmission in certain brain areas, such as the basal ganglia and the nucleus accumbens, it is presumed to cause less anxiety, fewer motor disturbances, and less potential for dependence.[8] As such, it is not a scheduled medication. This also eliminates some practical difficulties in delivering treatment, such as the need for monthly written prescriptions with stimulants. If atomoxetine is as effective in the real world as stimulants, one could argue that because of these advantages, it should be used prior to stimulants in the treatment of ADHD. However, if atomoxetine is indeed less effective in the real world, these advantages would need to be put in this context. Furthermore, atomoxetine recently received a black box warning for increased suicidality in children and adolescents during treatment.[9]

A few head-to-head studies have compared atomoxetine to stimulants.[10,11] In general, these studies showed the superiority of stimulants over atomoxetine in controlling ADHD symptomatology. However, several methodological issues make these comparisons open to criticism, such as the dosing of atomoxetine may have been suboptimal, duration of the studies may have favored stimulants, and an analog classroom setting only evaluates one aspect of ADHD and its improvement.

Because of the lack of real world data, clinicians need to make recommendations for their patients based on research reports. It thus becomes important to evaluate how different medications perform in a particular clinic setting. To this end, in one clinic, a retrospective chart review was performed over a two-year period looking at the effectiveness and tolerability of atomoxetine in patients with ADHD with or without comorbidity. To have some measure of comparison, patients in the same clinic who were treated with stimulants were reviewed as well.

Methods

The retrospective chart review included all patients 5 to 18 years of age who underwent a full psychiatric evaluation in this outpatient clinic between September, 2004, and September, 2006, were diagnosed with ADHD, were started on either stimulants or atomoxetine, and returned for at least one follow-up visit. A full psychiatric evaluation by a board-certified child and adolescent psychiatrist in this clinic includes the administration of the Mini-International Neuropsychiatric Interview for Children and Adolescents[12] to the patient and the completion of the Child/Adolescent Symptom Checklist-Inventory[13] by the parent. In general, patients were started on pharmacotherapy, if indicated, immediately following the assessment, were scheduled for a return visit one month later, and were subsequently seen for follow-up every 2 to 3 months. Follow-up visits included both patient and parents to review progress, side effects, mental status, and the medication regimen. Side effects were elicited by open-ended questioning. No formal rating scales were used. Data were documented in a standardized chart format. As part of every follow-up visit, a Global Assessment of Functioning score (GAF) was determined.[14]

Patients treated with atomoxetine were routinely started with a dose of 0.5mg per kilogram body weight, with a target dose of 1.2mg per kilogram body weight after one week. Initial target dose for stimulants was 1mg per kilogram body weight. Doses were further titrated on clinical grounds. The decision to treat with atomoxetine or stimulants was made with informed consent/assent of the parent and the patient and included individual preference, formulary restrictions, and prior exposure to treatment issues. The chart review included historical information obtained during the initial evaluation and “followed back” the treatment course until either the patient’s initial medication was discontinued or until the last visit within the first year after the initial evaluation. As such, data were only obtained for a maximum of one year of treatment. Information extracted from the records included age at initial evaluation, gender, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) multi-axial diagnoses, previous medication trials, risk factors for suicidality routinely collected in this clinic (e.g., past or present suicidal ideation, past or present suicidal behavior, family history of suicidal behavior, exposure to suicidal behavior, history of physical or sexual abuse if reported by patient or parent, history of psychiatric hospitalization, and substance use disorder diagnosis), name of the medication prescribed after the evaluation, any changes made in the prescription and a reason for the change (e.g., poor response, side effects, other reasons), and symptomatic and/or adverse events reported during the treatment.

A Clinical Global Impression-Improvement Score (CGI) was extracted from the report of the last treatment visit, compared to the initial evaluation.

Statistical comparisons were done with Student’s t-test for continuous variables and Chi-square test for categorical variables. Tests were two-tailed and significance was put at the 0.05 level.

Results

Eighty-five patients were identified as having been diagnosed with ADHD and started on atomoxetine. The average dose of atomoxetine was 40.1±11.4mg per day for patients under age 12 and 61.2±20.6mg for patients ages 12 to 18. Eighty-one patients were diagnosed with ADHD and started on stimulants.

Patients under 12 were treated with an average dose (in methylphenidate equivalents) of 39.4±19.1mg per day, while patients 12 or older received a dose of 54.9±17.1mg per day. Thirty-four patients (40%) started on atomoxetine were previously treated with stimulants, while 26 patients (32%) started on stimulants were previously treated with atomoxetine. Characteristics of both groups are listed in Table 1. Comorbid diagnoses are listed in Table 2. Because of comorbidity, many patients were treated with a variety of medications in conjunction with atomoxetine or stimulants, and these medications are listed in Table 3.

No significant differences were apparent in age, gender distribution, number of diagnoses, number of risk factors for suicidal behavior, GAF score at baseline, GAF score during the last visit on the medication, and CGI score. Both groups showed mild improvement (CGI±3) during approximately six months of treatment with an increase in GAF score of 5.2 in the atomoxetine group and 4.0 in the stimulant group. There was a trend for patients to stay on atomoxetine longer, but this did not reach statistical significance.

During the course of treatment, seven patients (8%) were discontinued from atomoxetine because of ineffectiveness, 15 (18%) because of side effects, and two (2%) because of other reasons. In the stimulant group, 14 (17%) were discontinued because of ineffectiveness, and 13 (16%) were discontinued because of side effects.

Fifty-four (64%) patients on atomoxetine complained of side effects, while 33 patients (41%) on stimulants reported side effects (c2=3.77, p>0.05). Specific side effects in each group are listed in Table 4. Two patients (2.4%) on atomoxetine experienced new onset suicidal thoughts: a 13-year-old white boy with a diagnosis of ADHD, combined type, who was taking atomoxetine 40mg per day for one month, when a depressive episode, including suicidal thoughts, was diagnosed; and an 11-year-old white boy with ADHD, combined type, and oppositional defiant disorder, who was taking atomoxetine 60mg per day for six months, when he voiced suicidal thoughts in response to problems in school. No new onset suicidality was identified in the stimulant group in the one year after the initial evaluation.

Sixteen patients (19%) had suicidality prior to treatment with atomoxetine and did not experience suicidal thoughts while being treated. Eleven (14%) showed a similar improvement while being treated with stimulants.

ADHD-only patients treated with atomoxetine (n=36) improved their GAF score with 6.5 (CGI of 2.6), compared with ADHD-only patients, treated with stimulants (n=32), who improved their GAF score with 3.4 (CGI 3.1; p=0.17).

Comorbid ADHD patients, compared to ADHD only patients, were older, had more risk factors for suicidality, and had lower GAF scores at baseline. Comorbid ADHD patients on atomoxetine (n=49) improved their GAF score with 4.3 (CGI 3.5), compared to the comorbid stimulants (n=49) group with a GAF score improvement of 4.4 (CGI 3; p=0.07).

Discussion

Many limitations apply to this retrospective chart review. Samples were nonrandomized, treatment was uncontrolled, and a limited amount of outcome data was collected retrospectively. Many patients had comorbid conditions, adherence to treatment was unchecked, and some patients were in concomitant psychotherapy. However, this study does shed light on how patients, treated for ADHD in one clinic, fared.

In general, both treatments were beneficial, although some differences appeared. Patients on atomoxetine improved at least as well as patients on stimulants, but experienced more side effects. Despite this, there was a trend for patients to stay on atomoxetine longer. These differences were also apparent in the discontinuation rates where relatively more atomoxetine patients discontinued because of side effects (18% vs. 16% on stimulants), but less because of ineffectiveness (8% vs. 17% on stimulants). No statistical differences in improvement, as measured by the CGI, were found between the atomoxetine and stimulant groups, neither in ADHD-only nor in comorbid ADHD patients.

According to the GAF, ADHD-only patients improved more on atomoxetine.
Side effect profiles were consistent with documented side effects in research studies: Sedation and GI distress were most common in the atomoxetine group, and appetite suppression and insomnia were most common in the stimulant group. Suicidality was rare in this highly comorbid population.

In the experience of this clinic, the assumption that the reduced use of atomoxetine nationwide is related to less effectiveness was not seen. Overall, atomoxetine appeared at least as effective as stimulants, albeit with more side effects, although this did not appear to impact its overall use and tolerability.

Conclusion

The effectiveness and tolerability of atomoxetine in this community clinic was comparable to that of stimulants. If replicated in larger and better controlled studies, atomoxetine should be considered the first line agent in the treatment of ADHD because of several distinct advantages, such as the different chemical profile, duration of action, and unscheduled status.

References

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