1) Interactions between SSRIs and Stimulants

Craig B.H. Surman, MD

Medscape Psychiatry & Mental Health

Little formal study of coadministration of antidepressant and stimulant treatments has been conducted. However, there are no prominent drug-drug interactions between stimulants and SSRIs and no known contraindication to simultaneous treatments when both are beneficial and well tolerated. SSRIs do not improve ADHD symptoms, which may make agents that do have proven ADHD efficacy, such as bupropion and desipramine, appropriate alternatives in some cases of comorbid ADHD and depression.

Although it is considered relatively safe to combine SSRI and stimulant treatments when both are indicated, individual patients should be closely monitored for their individual responses. It is worth noting that atomoxetine, a nonstimulant used to treat ADHD, is metabolized through the 2D6 cytochrome P450 pathway, so SSRIs like paroxetine and fluoxetine may affect atomoxetine levels.

It is fortunate that SSRIs are compatible with ADHD treatment, given high rates of mood and anxiety disorder comorbidity among individuals with ADHD. The recent replication of the National Comorbidity Survey reported rates of mental health comorbidity in the last year for participants.[1] It suggested that among subjects with ADHD, 18.6% had experienced major depression and 47.1% had experienced an anxiety disorder in the previous year, compared with 7.8% (major depression) and 19.5% (anxiety disorder) of subjects without ADHD.

In clinical practice, anecdotal evidence suggests that outcomes may be optimized in patients with comorbid presentations by treating prominent mood and anxiety distress before addressing ADHD treatment. However, patients with mild depression or anxiety symptoms often experience improvements in ADHD symptoms with standard ADHD pharmacotherapy, and with relief of ADHD burden many patients report less mood and anxiety distress.

2. Cerebellar Development and Clinical Outcome in Attention Deficit Hyperactivity Disorder

Susan Mackie, B.S., Philip Shaw, M.D., Ph.D., Rhoshel Lenroot, M.D., Ron Pierson, M.D., Deanna K. Greenstein, Ph.D., Tom F. Nugent III, B.S., Wendy S. Sharp, M.S.W., Jay N. Giedd, M.D. and Judith L. Rapoport, M.D.

Am J Psychiatry 164:647-655, April 2007

OBJECTIVE: Anatomic magnetic resonance imaging (MRI) studies have detected smaller cerebellar volumes in children with attention deficit hyperactivity disorder (ADHD) than in comparison subjects. However, the regional specificity and longitudinal progression of these differences remain to be determined. The authors compared the volumes of each lobe of the cerebellar hemispheres and vermis in children with ADHD and comparison subjects and used a new regional cerebellar volume measurement to characterize the developmental trajectory of these differences.

METHOD: In a longitudinal case-control study, 36 children with ADHD were divided into a group of 18 with better outcomes and a group of 18 with worse outcomes and were compared with 36 matched healthy comparison subjects. The volumes of six cerebellar hemispheric lobes, the central white matter, and three vermal subdivisions were determined from MR images acquired at baseline and two or more follow-up scans conducted at 2-year intervals. A measure of global clinical outcome and DSM-IV criteria were used to define clinical outcome.

RESULTS: In the ADHD groups, a nonprogressive loss of volume was observed in the superior cerebellar vermis; the volume loss persisted regardless of clinical outcome. ADHD subjects with a worse clinical outcome exhibited a downward trajectory in volumes of the right and left inferior-posterior cerebellar lobes, which became progressively smaller during adolescence relative to both comparison subjects and ADHD subjects with a better outcome.

CONCLUSIONS: Decreased volume of the superior cerebellar vermis appears to represent an important substrate of the fixed, nonprogressive anatomical changes that underlie ADHD. The cerebellar hemispheres constitute a more plastic, state-specific marker that may prove to be a target for clinical intervention.

3. Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial.

J Clin Psychiatry. 2007 Mar; 68(3):390-8

McElroy SL, Guerdjikova A, Kotwal R, Welge JA, Nelson EB, Lake KA, Keck PE Jr, Hudson JI.

Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267-0559, USA. susan.mcelroy@uc.edu

OBJECTIVE: Binge-eating disorder (BED) is associated with obesity. Atomoxetine is a highly selective norepinephrine reuptake inhibitor associated with weight loss. The purpose of this study was to evaluate atomoxetine in the treatment of BED.

METHOD: In this 10-week, single-center, randomized, double-blind, placebo-controlled, flexible dose (40-120 mg/day) trial, outpatients with DSM-IV-TR BED received atomoxetine or placebo. The primary outcome measure was binge-eating episode frequency. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 2004 through October 2005.

RESULTS: Compared with placebo (N = 20), atomoxetine (N = 20) was associated with a significantly greater rate of reduction in binge-eating episode frequency, as well as in binge day frequency, weight, body mass index, and scores on the Clinical Global Impressions-Severity of Illness scale, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating obsession sub-scale, and Three Factor Eating Questionnaire hunger subscale. The mean (SD) atomoxetine daily dose at endpoint evaluation was 106 (21) mg/day. Four patients (N = 3 receiving atomoxetine, N = 1 receiving placebo) discontinued because of adverse events. The reasons for atomoxetine discontinuation were increased depressive symptoms (N = 1), constipation (N = 1), and nervousness (N = 1).

CONCLUSION: Atomoxetine was efficacious and fairly well tolerated in the short-term treatment of BED.

4. Effects of methylphenidate in auditory processing evaluation of children and adolescents with attention deficit hyperactivity disorder

Arq Neuropsiquiatr. 2007 Mar; 65(1): 138-43.

Cavadas M, Pereira LD, Mattos P.
Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rua Domingos Mondim 165, 21920-160 Rio de Janeiro, RJ, Brazil.

PURPOSE: To compare the performance of a group of children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD) pre and post-methylphenidate use in a behavioral auditory processing test battery (AP).

METHOD: Twenty-nine subjects, male and female, ranging from 7 to 15 years old have undergone different behavioral auditory processing tests. A control group composed of 29 subjects with and without learning disabilities was also evaluated.

RESULTS: The group with ADHD had a performance similar to the control group without learning disabilities which improved after medication. The group with learning disabilities and without ADHD had the worst performance in tests while the group without learning disabilities and without ADHD exhibited the best ones.

CONCLUSION: The AP battery was unable to distinguish ADHD patients from paired controls; the use of methylphenidate improved the performance on AP tests of ADHD group in the post-medication evaluation.

5. Effect of two different methods of initiating atomoxetine on the adverse event profile of atomoxetine.

J Am Acad Child Adolesc Psychiatry. 2007 May; 46(5):566-72

Greenhill LL, Newcorn JH, Gao H, Feldman PD.
The New York State Psychiatric Institute/Columbia University, New York 10032, USA.

OBJECTIVE: To compare the effects of two different methods for initiating atomoxetine in terms of the incidence of early adverse events.

METHOD: Data on atomoxetine treatment-emergent adverse events in youths, ages 6 to 18 years, were analyzed from five randomized, double-blind, placebo-controlled, acute-phase studies. Two studies involve once-daily dosing and titration to 1.2 mg/kg/day over 3 days (fast/once daily, n = 234) and three involve twice-daily dosing and titration to a dose of 1.2 mg/kg/day over at least 2 weeks (slow/twice daily, n = 213).

RESULTS: During the first 2 weeks of treatment, fast/once daily titration patients showed higher rates of spontaneously reported adverse events than patients in the slow/twice daily titration group. This included decreased appetite (14.3% versus 8.0%, p = .036) and somnolence (14.3% versus 4.2%, p < .001). Patients in the slow/twice daily group showed higher rates of headache (7.4% versus 16.9%, p = .003). Analysis of the studies' overall acute treatment phases revealed significantly higher rates in the fast/once daily group only for somnolence. No significant differences were seen in completion rates or reasons for discontinuation.

CONCLUSIONS: When starting atomoxetine, the risk of adverse events within the first few weeks of treatment may be lower if patients are dosed twice daily and titrated to the 1.2 mg/kg/day total daily dose over the first week.