OBJECTIVE: To collect pilot data assessing the safety, tolerability, and efficacy of tomoxetine, a nonstimulant norepinephrine enhancer, in pediatric attention deficit hyperactivity disorder (ADHD).
METHODS: An open-label trial of tomoxetine in pediatric ADHD was conducted as part of a multisite clinical trial. Following a baseline assessment, an ascending dose titration was completed during 10 weekly visits.
RESULTS: Ten subjects were enrolled at baseline, with eight completing the study. Seven of the eight remaining subjects met efficacy criteria. Significant decreases in symptom severity ratings by parents and study investigators were found. The medication was well tolerated, with transient appetite suppression the most frequently reported side effect. However, subjects\u27 weights remained stable across study visits.
DISCUSSION: These preliminary findings suggest that tomoxetine may hold promise as a treatment for pediatric ADHD

Baker, Natalie

Bohac, Daryl

Burke, William J.

Harrington, Martin

Kratochvil, Christopher J.

May, Diane E.

English

University of Nebraska Medical Center Research: DigitalCommons@UNMC

University of Nebraska Medical Center DigitalCommons@UNMC Journal Articles: Psychiatry Psychiatry 6-2001 An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. Christopher J. Kratochvil University of Nebraska Medical Center, ckratoch@unmc.edu Daryl Bohac University of Nebraska Medical Center Martin Harrington University of Nebraska Medical Center Natalie Baker University of Nebraska Medical Center Diane E. May University of Nebraska Medical Center, dmay@unmc.edu See next page for additional authors Follow this and additional works at: https://digitalcommons.unmc.edu/com_psych_articles  Part of the Psychiatry Commons Recommended Citation Kratochvil, Christopher J.; Bohac, Daryl; Harrington, Martin; Baker, Natalie; May, Diane E.; and Burke, William J., "An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder." (2001). Journal Articles: Psychiatry. 13. https://digitalcommons.unmc.edu/com_psych_articles/13 This Article is brought to you for free and open access by the Psychiatry at DigitalCommons@UNMC. It has been accepted for inclusion in Journal Articles: Psychiatry by an authorized administrator of DigitalCommons@UNMC. For more information, please contact digitalcommons@unmc.edu. Authors Christopher J. Kratochvil, Daryl Bohac, Martin Harrington, Natalie Baker, Diane E. May, and William J. Burke This article is available at DigitalCommons@UNMC: https://digitalcommons.unmc.edu/com_psych_articles/13 167JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 11, Number 2, 2001Mary Ann Liebert, Inc.Pp. 167–170An Open-Label Trial of Tomoxetine in Pediatric AttentionDeficit Hyperactivity DisorderCHRISTOPHER J. KRATOCHVIL, M.D., DARYL BOHAC, Ph.D., MARTIN HARRINGTON, M.D., NATALIE BAKER, M.D., DIANE MAY, R.N., M.A.,and WILLIAM J. BURKE, M.D.ABSTRACTObjective: To collect pilot data assessing the safety, tolerability, and efficacy of tomoxetine,a nonstimulant norepinephrine enhancer, in pediatric attention deficit hyperactivity disor-der (ADHD).Methods: An open-label trial of tomoxetine in pediatric ADHD was conducted as part ofa multisite clinical trial. Following a baseline assessment, an ascending dose titration wascompleted during 10 weekly visits.Results: Ten subjects were enrolled at baseline, with eight completing the study. Seven ofthe eight remaining subjects met efficacy criteria. Significant decreases in symptom sever-ity ratings by parents and study investigators were found. The medication was well toler-ated, with transient appetite suppression the most frequently reported side effect. However,subjects’ weights remained stable across study visits.Discussion: These preliminary findings suggest that tomoxetine may hold promise as atreatment for pediatric ADHD.INTRODUCTIONATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) is one of the most common disorders of child-hood, with a prevalence rate of 3–5% (Tannock 1998), yet there are only three primary psychophar-macological interventions for ADHD: methylphenidate, dextroamphetamine, and d,l-amphetamine. Al-though the stimulants are quite effective, some youth do not respond, whereas others are never initiated onstimulants due to concerns regarding treatment with a controlled substance. Additionally, some childrentreated with these stimulants frequently suffer from diminished appetite, weight loss, insomnia, exacerba-tion of tics, stomach aches, headaches, irritability, and mood lability. Thus, there is a clear need for alter-natives to current treatments of ADHD.Recently Spencer and colleagues reported on the use of a novel medication, tomoxetine, in the treatmentof adult ADHD (Spencer et al. 1998). Tomoxetine enhances norepinephrine function through highly selec-tive blockade of the presynaptic norepinephrine transporter and has low affinity for other neuronal trans-Department of Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska.This study was supported in part by a grant from Lilly Research Laboratories.porters or neurotransmitter receptor sites. Spencer et al. found that tomoxetine was well tolerated and ef-fective in the treatment of adult ADHD, with 11 of 21 subjects showing improvement after receiving to-moxetine compared to only 2 of 21 who received placebo. More recently, preliminary results from a pairof double-blind placebo-controlled trials indicated that tomoxetine was well tolerated and effective in treat-ing pediatric ADHD (Heiligenstein et al. 2000). This article reports additional evidence of tomoxetine’s ef-fectiveness based on one site’ s results from the open-label phase of a separate ongoing investigation in-volving 198 subjects at 24 sites.METHODSThe objective of this study was to collect pilot data assessing the safety, tolerability, and efficacy of thisagent in a pediatric population with ADHD. The Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version (ADHDRS-IV-P) was utilized as a primary efficacy measure (DuPaul 1991). The ADHDRS-IV-P is an 18-item scale with 1 item for each of the 18 symptoms contained in the Diagnostic and Statis-tical Manual of Mental Disorders, fourth edition (DSM-IV; American Psychiatric Association 1994)diagnostic criteria for ADHD. It was utilized as a clinician-administered, semistructured parent interviewat each study visit to assess symptom severity for the prior week. The ADHDRS-IV-P Total Score was usedin all statistical analyses. Two secondary measures of efficacy were employed in this study. First, studyphysicians completed the Clinical Global Impressions-ADHD-Improvement (CGI-ADHD-I; Guy 1967) rat-ings at study visits 3 through 12. The CGI-ADHD-I is a single-item clinician rating of the total change inthe patient’ s ADHD symptoms since the beginning of treatment. Second, the Conners’  Parent Rating Scale-Revised: Short Form (CPRS-R:S; Conners et al. 1998), a 27-item scale designed to assess problem behav-iors related to ADHD, was completed by parents at study visits 1, 2, and 12. The ADHD Index score fromthe CPRS-R:S was used as the dependent measure in all statistical analyses.All subjects enrolling in the study met DSM-IV criteria for ADHD (American Psychiatric Association1994). After a complete description of the study to the subjects, written informed consent was obtainedfrom the parents and assent was obtained from the subjects. Following baseline assessment, subjects com-pleted an open-label ascending dose titration of tomoxetine. The titration schedule was based on tolerabil-ity and clinical response.Subjects were defined as treatment responders if they had both a score of 1 or 2 (very much or much im-proved) on the CGI-ADHD-I and at least a 25% decrease in ADHDRS-IV-P total score by visit 12. Onesubject had CGI-ADHD-I scores of 1 for three consecutive visits (i.e., visits 6 through 8). This subject’ sfinal visit data were carried forward into the remaining visits for all statistical analyses.Visits occurred weekly for a total of 10 weeks on medication. Vital signs, weight, EKGs, and chemicaland hematological profiles were repeated serially during the study. Safety monitoring included documen-tation of adverse events at every visit. Adverse events were identified utilizing spontaneous open-endedquestioning. The Barkley Behavior and Adverse Events Questionnaire-Modified (BBAEQ-M) was also usedto review potential untoward effects systematically.RESULTSTen males with ADHD (nine Whites and one Hispanic, 9–14 years of age) were enrolled in the study.The group had an average estimated IQ of 104.4 (SD 5 16.6, range 5 85–130) on a four-subtest short formof the Wechsler Intelligence Scale for Children, third edition (WISC-III; Wechsler 1991). Similarly, sub-jects obtained Wide Range Achievement Test, third edition (Wilkinson 1993), average scores of 100.9(SD 5 15.48, range 5 79–131) for reading, 102.6 (SD 5 18.26, range 5 81–139) for spelling, and 91.6(SD 5 8.93, range 5 81–107) for arithmetic. The average weight of the subjects was 43.2 kg and rangedfrom 30.5 to 65.3 kg. At baseline, all subjects had an ADHDRS-IV-P score at least 1.5 standard deviationsfrom the mean for their age and sex. Of the 10 subjects treated with tomoxetine, one withdrew because ofa rash, one was discontinued due to noncompliance, and eight completed the scheduled visits. Of these eightKRATOCHVIL ET AL.168subjects, seven met criteria for ADHD, combined subtype, and one for inattentive subtype. In addition tothe ADHD diagnoses, one subject met criteria for a simple phobia, one for generalized anxiety disorder,and four for oppositional defiant disorder. At endpoint, seven of eight subjects met efficacy criteria of a25% or greater reduction in the ADHDRS-IV-P total score and a CGI-ADHD-I score of 1 or 2. The onenonresponder met criteria for ADHD, combined subtype, with no comorbid diagnosis.Scores from the efficacy measures were subjected to repeated measures analysis of variance. For ADHDRS-IV-P ratings across study visits, the change in scores was significant, F(9, 63) 5 5.65, p 5 0.0001,and in the expected direction with severity ratings decreasing over the course of the study. Clinician rat-ings of improvement using the CGI-ADHD-I were also significantly different across visits, F(9, 63) 5 5.21,p 5 0.0001. The relationship between mean ADHD severity ratings and mean mg/kg dose levels acrossstudy visits is represented in Fig. 1. A plot of mean CGI-ADHD-I scores by mean dose level resulted incurves nearly paralleling those seen in Fig. 1.CPRS-R:S mean scores across visits were also examined using repeated measures analysis of variance(Table 1). A significant effect was determined across visits 1, 2, and 12, F(2, 14) 5 19.25, p 5 0.0001.Bonferroni-corrected, post-hoc univariate F tests demonstrated that the effect was between visits 2 and 12,F(1, 7) 5 22.64, p 5 0.002. No significant difference was found between rating scale scores on visit 1(screening) and visit 2 (baseline), during which the subjects received no drug.Medication was well tolerated throughout the 10 weeks of treatment. One subject withdrew due to a rash,believed to be medication induced as it reoccurred when the subject was rechallenged with tomoxetine. SixTOMOXETINE AND ADHD169TABLE 1. PRE- AND POSTTREATMENT SCORES FOR EFFICACY MEASURESBaseline PosttreatmentMean SD Mean SD pADHDRS-IV-P 41.6 10.7 20.5 12.6 0.0001CPRS-R;S 60.0 14.0 29.8 18.1 0.0001CGI-ADHD-Ia 3.6 0.9 1.6 0.7 0.0001ADHDRS-IV-P 5 Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version; CGI-ADHD-I 5Clinical Global Impressions-ADHD-Improvement; CPRS-R;S 5 Conners’ Parent Rating Scale-Revised Short Form.aCGI-ADHD-I ratings were first obtained at study visit 3, at which time subjects had been on medication for 1 week.FIG. 1. Dose level by symptom severity across visits. ADHDRS-IV-P 5 Attention Deficit/Hyperactivity DisorderRating Scale-IV-Parent Version.of 10 subjects reported transient appetite suppression of mild to moderate severity. For the 10 subjects whomet entry criteria, weight remained stable across study visits when comparing baseline weight (mean 543.23, SD 5 10.66 kg) to weight at last study visit (mean 5 42.08, SD 5 9.98 kg), using last-observation-carried-forward analysis (t 5 21.75, df 5 9, p 5 0.11). Other transient adverse events included gastro-intestinal symptoms (4 children), irritability (3), fatigue (3), epistasis (1), dizziness (1), dry mouth (1), night-mares (1), headache (1), and heart palpitations (1). There were no spontaneous reports of insomnia. Inves-tigators treated the transient adverse events symptomatically with no further medical intervention required.DISCUSSIONThe initial pilot data suggest that tomoxetine may be a useful intervention for pediatric ADHD. Thesepreliminary findings are important in that they indicate a norepinephrine enhancer may be effective in treat-ing this disorder. Tomoxetine may also represent an alternative for those patients who fail to respond toone of the primary psychopharmacological interventions for ADHD.Despite the limitations of this study, which include a small sample size and an open-label design, theseinitial results are promising. The sample size is currently being addressed in larger multicenter studies. Heili-genstein et al.’ s (2000) preliminary data from two randomized clinical trials in children with ADHD, whichsuggested that tomoxetine is safe, well tolerated, and leads to a significant reduction in ADHD symptoms,are consistent with our findings. Our results and emerging data from other trials suggest that tomoxetinemay hold promise as a treatment for pediatric ADHD.REFERENCESAmerican Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). Wash-ington, DC, American Psychiatric Association, 1994.Conners CK, Sitarenios G, Parker JD, Ebstein JN: The revised Conners’ Parent Rating Scale (CPRS-R): Factor struc-ture, reliability, and criterion validity. J Abnorm Child Psychol 25:257–268, 1998.DuPaul G: Parent and teacher ratings of ADHD symptoms: Psychometric properties in a community-based sample. JClin Child Psychol 20:245–253, 1991.Guy W: CGI, Clinical Global Impression. In: ECDEU Assessment Manual for Psychopharmacology, revised. U.S. De-partment of Health, Education, and Welfare, Washington, D.C. 1967.Heiligenstein JH, Spencer TJ, Faries DE, Biederman J, Kratochvil C, Conners CK: Efficacy of tomoxetine vs. placeboin pediatric outpatients with ADHD. Poster presentation at the 47th Annual Meeting of the American Academy of Childand Adolescent Psychiatry, New York, October 2000.Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone SV, Seidman L: Effectiveness andtolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 155:693–695, 1998.Tannock R: Attention deficit hyperactivity disorder: Advances in cognitive, neurobiological, and genetic research. JChild Psychol Psychiatry 39:65–99, 1998.Wechsler D: Wechsler Intelligence Scale for Children, 3rd ed. San Antonio (Texas), Psychological Corporation, 1991.Wilkinson GS: Wide Range Achievement Test, 3rd ed. Administration Manual. Wilmington (Deleware), Wide Range,Inc., 1993.Address reprint requests to:Christopher J. Kratochvil, M.D.985581 Nebraska Medical CenterOmaha, NE 68191-5581E-mail: ckratoch@unmc.eduKRATOCHVIL ET AL.170

An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder.

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An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder.

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