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Hyperactivity and Anxiety Disorders
Sequential Pharmacotherapy for Children With Comorbid Attention-Deficit/Hyperactivity and Anxiety Disorders HOWARD ABIKOFF, PH.D., JAMES MCGOUGH, M.D., BENEDETTO VITIELLO, M.D., JAMES MCCRACKEN, M.D., MARK DAVIES, M.P.H., JOHN WALKUP, M.D., MARK RIDDLE, M.D., MELVIN OATIS, M.D., LAURENCE GREENHILL, M.D., ANNE SKROBALA, M.A., JOHN MARCH, M.D., M.P.H., PAT GAMMON, PH.D., JAMES ROBINSON, M.ED., ROBERT LAZELL, B.S., DONALD J. MCMAHON, M.S., LOUISE RITZ, M.B.A., AND THE RUPP ADHD/ANXIETY STUDY GROUP
ABSTRACT Objective: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by clinically significant anxiety, but few empirical data guide treatment of children meeting full DSM-IV criteria for ADHD and anxiety disorders (ADHD/ANX). This study examined the efficacy of sequential pharmacotherapy for ADHD/ANX children. Method: Children, age 6 to 17 years, with ADHD/ANX were titrated to optimal methylphenidate dose and assessed along with children who entered the study on a previously optimized stimulant. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine (STIM/FLV) or stimulant + placebo (STIM/PL). Primary efficacy measures were the Swanson, Nolan, Atkins, and Pelham IV Parent and Teacher Rating Scale ADHD score and the Pediatric Anxiety Rating Scale total score. ADHD, ANX, and overall Clinical Global Impressions-Improvement scores were also obtained. Results: Of the 32 medication-naı¨ve children openly treated with methylphenidate, 26 (81%) improved as to ADHD. Twenty-five children entered the randomized trial. Intent-to-treat analysis indicated no differences between the STIM/FLV (n = 15) and STIM/PL groups on the Pediatric Anxiety Rating Scale or Clinical Global Impressions-Improvement–defined responder rate. Medications in both arms were well tolerated. Conclusions: Children with ADHD/ANX have a response rate to stimulants for ADHD that is comparable with that of children with general ADHD. The benefit of adding FLV to stimulants for ANX remains unproven. J. Am. Acad. Child Adolesc. Psychiatry, 2005;44(5):418–427. Key Words: attention-deficit/hyperactivity, anxiety, comorbidity, combination pharmacotherapy.
The co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (ANX) in children is common, with estimated comorbidity rates of 20% to 45% (Biederman et al., 1991). Pharmacotherapy guidelines for ADHD/ANX are not well established, and sparse treatment studies are inconsistent. Accepted November 16, 2004. From Columbia University at the New York State Psychiatric Institute, New York (M.D., L.G., A.S.); Duke University Medical Center, Durham, NC (J.M., P.G.); Johns Hopkins University, Baltimore, MD (J.W., M.R.); Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (J.R., R.L., D.M.); National Institute of Mental Health, Bethesda, MD (B.V., L.R.); New York University Child Study Center, New York (H.A, M.O.); University of California Los Angeles (J.Mc., J.Mc.). The RUPP (Research Units of Pediatric Psychopharmacology) ADHD/Anxiety Study is a multisite clinical trial supported by contracts from the National Institute of Mental Health to Johns Hopkins University (N01MH60016:
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Several short-term trials report that psychostimulants may be associated with more side effects and a less robust response in ADHD/ANX than in ADHD alone (Pliszka, 1989; Tannock et al., 1995; Taylor et al., 1987; Urman et al., 1995). However, two long-term studies suggest that children with ADHD with and P.I. Mark Riddle, M.D.), the Research Foundation for Mental Hygiene (N01MH60005: P.I. Laurence Greenhill, M.D.), and the University of California Los Angeles (K23MH01966: P.I. James McGough, M.D., N01MH70010 and MH01805: P.I. James McCracken, M.D.). The authors are indebted to Solvay Pharmaceuticals for supplying study drug and to the NIMH Data Safety and Monitoring Board. Correspondence to Dr. Abikoff, NYU Child Study Center, 215 Lexington Avenue, 14th Floor, New York, NY 10016; e-mail: [email protected]. 0890-8567/05/4405–0418Ó2005 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000155320.52322.37
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without ANX show comparable improvements in ADHD symptoms with stimulants, with some concomitant improvements in internalizing symptoms (Diamond et al., 1999; MTA Cooperative Group, 1999a,b). In the multisite MTA study, children with and without comorbid ANX improved similarly in the medication management arm, although anxiety was a significant moderator of response to behavioral therapy (MTA Cooperative Group, 1999b). Unlike earlier studies, most of which relied on ratings or reports of emotional problems to ascertain anxiety, these trials used systematic clinical assessment. However, diagnostic and outcome measures were not representative of those used in clinical trials of pediatric ANX. Medication combinations, particularly stimulants with selective serotonin reuptake inhibitors (SSRIs), are increasingly prevalent in the clinical treatment of ADHD/ANX (Pliszka et al., 2000; Rushton and Whitmire, 2001). Although the efficacy of SSRI treatment of pediatric ANX has been demonstrated in randomized clinical trials (Birmaher et al., 2003; RUPP Anxiety Study Group, 2001), evidence supporting the adjunctive use of SSRIs in children with ADHD/ANX is limited to one open study (Barrickman et al., 1991). Moreover, the percentage of children with ADHD/ ANX who require polypharmacy after systematic, flexible stimulant titration and maintenance is unknown. Currently, the Texas Medication Algorithm Consensus Panel, acknowledging the lack of controlled evidence, recommends an initial trial of stimulant monotherapy followed by additional SSRI treatment in children with ADHD and ongoing ANX (Pliszka et al., 2000). No study prototype has been developed for controlled polypharmacy trials in comorbid ADHD. Treatment research in comorbid psychiatric disorders is complex, involving two or more treatment targets and potential use of multiple medications. The specific aims of this study were to (a) test the feasibility of a multisite, sequential treatment design for ADHD/ANX using both global and disorder-specific outcomes; (b) estimate whether the efficacy and tolerability of methylphenidate (MPH) in children with ADHD/ANX is comparable with that reported for nonanxious ADHD; (c) explore whether ADHD improvement during MPH treatment is accompanied by improvement in ANX; and (d) explore whether adding fluvoxamine (FLV) to psychostimulants increases ANX response compared with psychostimulant monotherapy. Because of the
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small sample size, this study was intended to be a pilot, exploratory investigation whose results could inform future definitive trials. METHOD Study Participants Inclusion Criteria. Subjects were boys and girls, ages 6 to 17, of normal intelligence, who met DSM-IV criteria for both ADHD (combined or inattentive type) and ANX (separation anxiety disorder, generalized anxiety disorder, and/or social phobia). Inclusion criteria for ADHD and ANX closely paralleled those used in the MTA Cooperative Group study (1999a) and the FLV anxiety study of the RUPP Anxiety Study Group (2001). Children presenting on stimulants had a minimum 5-day washout at the time of screening to evaluate baseline symptomatology. Diagnosis of ADHD. Diagnosis of ADHD was based on the Diagnostic Interview Schedule for Children-Parent, version 4.0 (Shaffer et al., 1996). For cases falling just below this scale’s threshold, the diagnosis could be supplemented with up to two symptoms with elevated scores on the Swanson, Nolan, Atkins, and Pelham (SNAP-IV) teacher rating scale (Swanson, 1992). ADHD was confirmed by clinician interview of the parent and child supplemented by the research measures. Severity of ADHD. Subjects were rated (a) at least 1 SD above age and gender norms on the hyperactivity factor (combined subtype) or inattentive factor (inattentive subtype) of the Conners Parent Rating Scale (Conners et al., 1998a), and (b) at least 1.5 SD above age and gender norms on the hyperactivity factor (combined subtype) or inattentive factor (inattentive subtype) of the Conners Teacher Rating Scale (Conners et al., 1998b). If teacher ratings were unobtainable due to the academic calendar, then the previous year’s report card and other corroborating information were reviewed by a cross-site panel to determine whether school functioning was commensurate with an ADHD diagnosis. Diagnosis of ANX. Diagnoses of ANX were based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) (Kaufman et al., 1997) administered to both parent and child. Severity of Anxiety. Children were required to exhibit anxiety symptoms of at least moderate severity, as indicated by a minimum score of 3 on the item ‘‘overall severity of anxiety feelings’’ or ‘‘overall avoidance of anxiety provoking situations’’ of the Pediatric Anxiety Rating scale (PARS) (RUPP Anxiety Study Group, 2002) and a minimum score of 3 on one of the two interference items (at home, out of home). Clinician-rated PARS scores were derived from both parent and child reports. Exclusion Criteria. Children were excluded if they (a) were taking other (nonstimulant) medications with CNS effects; (b) had medical conditions that precluded MPH or FLV treatment; (c) had current evidence of autism, major depression, substance abuse, obsessivecompulsive disorder, posttraumatic stress disorder, panic disorder, chronic tic disorders, or Tourette’s syndrome, significant suicidality, lifetime history of psychosis or mania; (d) had a current history of sexual or physical abuse or a past history of sexual or physical abuse with ongoing Department of Social Services involvement; (e) had failed a previous trial of FLV judged adequate in dose (50 mg) and duration (6 weeks), had a history of intolerance to FLV, or had failed two previous SSRI trials judged adequate in dose and duration; or (f) had failed an adequate trial of MPH (30 mg/day for at least 4 weeks).
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Procedures
Study Measures
Prospective participants were recruited at six academic child and adolescent psychiatry clinics through clinical referral or community advertisements. After receiving a full verbal explanation of all study requirements and procedures, parents and children provided written informed consent and assent, respectively, and participants were approved by each respective study site’s Institutional Review Board. Overview of Study Protocol. The study comprised four phases. Phase I comprised subject screening. Subjects who entered the study on previously stabilized stimulants underwent a 5-day washout to assess symptom baselines off medication. Phase II assessed stimulant response and optimal stimulant dose. Procedures differed for stimulant-naı¨ve children and those presenting on a stimulant. Stimulant-naı¨ve youngsters underwent a 4-week, open-label titration with immediate-release MPH using a fixed-flexible t.i.d.-dosing schedule. Subjects were titrated with weekly adjustments, based on clinical response and side effect profiles, to a maximum of 40 mg/day for children weighing less than 25 kg, or 50 mg/day if weighing more than 25 kg. Children currently on stimulant medication (e.g., other MPH or amphetamine preparations) were assessed at baseline and, if eligible, immediately entered phase III stimulant stabilization on their current medication, where their dose was optimized, if necessary. Children receiving a clinician Clinical Global Impressions-Improvement (CGI-I) (Guy, 1976) rating for ADHD of at least ‘‘improved’’ (score of 3) without clinically significant side effects on at least one regimen during dose titration were designated MPH responders. A rating of improved required significant improvement in ADHD-related problems at school and/or at home and a reduction in impairment. The CGI-I ADHD ratings were based on clinical observation and review of teacher and parent ratings on the Conners hyperactivity and inattentive factor items and on the Conners, Loney, and Milich rating scale (Swanson et al., 1998). Nonresponders were discontinued and referred for clinical treatment. Optimal doses were chosen based on the best CGI-I rating and lowest report of side effects and affirmed by consensus of two clinicians at the treating site. The lower dose was selected when CGI and side effects ratings were equivalent. Clinicians at a collaborating site blindly reviewed CGI and side effects ratings to maintain consistency across sites. Phase III was a 2-week stabilization on optimal stimulant dose (either phase II titrated MPH or patients’ stimulant at study entry) to assess improvement in ADHD and ANX. Children moved to phase IV if (a) they demonstrated sufficient improvements in ADHD (ADHD responders) and (b) they continued to show clinically significant and impairing anxiety symptoms (ANX nonresponders). ANX nonresponse was defined as (a) CGI-I Anxiety ratings of ‘‘slightly improved’’ (score of 4) or worse and (b) PARS scores of >2 on a severity item and an impairment item. Youngsters who showed clinical improvement in both ADHD and ANX were followed openly on stimulant monotherapy. Phase IV was an 8-week, double-blind, placebo-controlled trial. Phase III subjects with stimulant-stabilized ADHD and ANX nonresponse continued optimal stimulant therapy plus randomized, double-blind FLV or placebo (PL). Randomization was done within site and was based on age, gender, and diagnosis. FLV or PL titration followed procedures used in the previous FLV anxiety trial (RUPP Anxiety Study Group, 2001). Drug was initiated at 25 mg/day and increased approximately 50 mg/wk to a maximum of 300 mg in adolescents and 250 mg in children younger than 13 years of age. Dose escalation was delayed or halted in children who developed clinically significant side effects or ANX remission.
Study measures were collected at baseline and throughout the study to assess changes in ADHD and ANX symptoms, severity, improvement, and side effects. ADHD Measures. Parents and teachers completed the SNAP-IV and the Conners, Loney, and Milich rating scales. A composite score derived from the mean of parent and teacher ratings on the 18-item SNAP scale served as the primary index of ADHD severity. Anxiety Measures. The clinician-completed PARS contained five items that assess the severity of distress due to anxiety, the frequency of anxiety, avoidance of anxiety-provoking situations, and the degree of interference from anxiety at home and elsewhere. The PARS total score, a sum of these five items, was the primary continuous outcome measure of change in anxiety. Global Measures. Clinician-rated CGI-Severity (Guy, 1976) and CGI-I scores, generated separately for ADHD, ANX, and overall functioning, were obtained weekly. The CGI-I Anxiety score using a modified 8-point CGI-I scale (Klein et al., 1992) was the primary categorical outcome measure in the double-blind trial. Children were responders when they had scores of 1 (free of symptoms), 2 (much improved), or 3 (improved). Safety Assessments. Adverse events (AEs) were elicited through clinician inquiry of the child and parent during each study visit. Additionally, at each visit, parents completed the Physical Symptom Checklist, which was reviewed and discussed by the clinician. The Physical Symptom Checklist assessed side effects common to SSRIs and stimulants, including activation, disinhibition, and overactivity. Positive items on the Physical Symptom Checklist deemed to be both clinically relevant and related to study medications were recorded as AEs.
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Data Analyses The following analyses were conducted: 1. To examine improvement with initial stimulant treatment in ADHD/ANX, the percentage of stimulant-naı¨ve children who were ADHD and ANX stimulant responders was calculated. 2. To explore the efficacy of ANX improvement with the addition of FLV to ongoing stimulant treatment, mixed-effects linear regression analyses (fixed effects were treatment status and site and random effects were the child-specific parameters [intercept and slope] of the regression of the outcome measure on week of the study, and error) were used to compare the change in total PARS scores from the end of phase III to the end of the phase IV in the FLV and PL groups. Analyses of phase IV data followed intent-to-treat principles, including all subjects randomized. Response rates on CGI-I Anxiety criteria at the end of phase IV were compared using a x2 test. Additionally, the percentage of children in the FLV and PL groups who met criteria for ANX response by attaining improvement on both the PARS and CGI-I Anxiety were compared using a x2 test. Finally, to explore the impact on ADHD after the addition of FLV to ongoing stimulant treatment, changes in composite SNAP scores from the end of phase III to the end of phase IV were analyzed with a mixed-effects linear regression. 3. To ascertain AEs associated with stimulant treatment alone, McNemar’s test for correlated proportions was used to determine the emergence of clinically relevant AEs in stimulant-naı¨ve subjects who participated in the phase II titration. 4. To identify differences in clinically relevant AEs with the addition of an SSRI, change in SE rates from the end of phase III stabilization to the end of phase IV were tested using a x2 test. Given the exploratory nature of this study and its special attention to tolerability and safety, it was considered important to minimize
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type II error (i.e., false-negative results) due to the small sample size. To this effect, p values <.20 are reported for heuristic purposes. RESULTS Subjects
An overview of subject flow and disposition is depicted in Figure 1. Phase I: Screening. Of 100 children screened, 42 met the entry criteria. Table 1 summarizes subject characteristics. Thirty-two subjects were stimulant naı¨ve and underwent medication titration. Ten additional subjects entered the study on preexisting stimulant regimens including mixed amphetamine salts extended release (MAS-XR) (n = 2),
OROS-MPH (n = 3), MPH immediate release (IR) (n = 3), other MPH extended release (n = 1), and OROS-MPH + MPH-IR (n = 1). These subjects underwent baseline assessment after a 5-day medication washout and immediately entered phase III. There were no significant clinical or demographic differences between stimulant-naı¨ve and previously treated subjects. Phase II: Open-Label MPH Titration. Of the 32 stimulant-naı¨ve youths who entered titration, 26 (81%) had a positive ADHD response, one had no response, two withdrew due to side effects, and three withdrew for other reasons. Commonly reported AEs included trouble sleeping (50% of subjects), appetite loss (40%), sleeplessness,
Fig. 1 Study design and subject flow.
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Variable
TABLE 1 Subject Profile, Demographic, and Descriptive Variables at Baseline Totals Across Enrolled in Titration Groups (n = 12) (n = 32)
Age, yr, mean (SD) [range] Male, no. (%) Weight, kg, mean (SD) [range] Ethnicity, no. (%) White, not of Hispanic origin Black, not of Hispanic origin Native American Hispanic Other Conners Parent Rating Scale, mean (SD) Hyperactivity factor Inattentive factor Conners Teacher Rating Scale, mean (SD) Hyperactivity factor Inattentive factor SNAP-IV Parent and Teacher ADHD, mean (SD) ADHD subtype (DISC diagnoses), no. (%) Combined type Inattentive type Clinical Global Impressions-ADHD-Severity, no. (%) Minimally ill Moderately ill Markedly ill Severely ill Clinical Impressions-Anxiety-Severity, no. (%) Mildly ill Moderately ill Markedly ill Severely ill PARS total score, mean (SD) Comorbidity (K-SADS-PL diagnoses), no. (%) Generalized anxiety disorder Seperation anxiety disorder Social phobia Specific phobia Oppositional defiant disorder Enuresis Encopresis Depressive disorder* Obsessive-compulsive disorder**
10.0 (2.8) [6.0–17.4] 24 (57) 38.5 (16.1) [18.8–88.2] 33 (79) 4 (10) 1 (2) 2 (5) 2 (5) 35/34 15.49 (7.90) 22.03 (4.21) 25 9.40 (6.40) 17.28 (5.83) 2.00 (0.55)
10.7 (3.1) [7.4–17.4] 18 (56) 38.1 (16.9) [18.8–88.2] 24 3 1 2 2
(75) (9) (3) (6) (6)
Enrolled Directly in Stabilization (n = 10) 9.8 (2.7) [6.0–16.0] 6 (60) 39.7 (14.0) [24.3–64.9] 9 (90) 1 (10) 0 (0) 0 (0) 0 (0)
16.32 (7.50) 22.46 (4.29)
13.40 (8.87) 21.00 (4.03)
9.61 (6.58) 17.78 (5.34) 2.03 (0.55)
8.86 (6.38) 16.00 (7.26) 1.90 (0.55)
29 (69) 12 (29)
24 (75) 8 (25)
5 (50) 4 (40)
1 15 18 8
0 (0) 10 (31) 15 (47) 7 (22)
1 5 3 1
(2) (36) (43) (19)
2 14 19 7 16.71
(5) (33) (45) (17) (3.20)
32/41 24 12 12 6/22 4/41 1/41 2 1
(78) (57) (29) (29) (27) (10) (2) (5) (2)
2 12 13 5 16.59
(6) (37) (41) (16) (3.30)
23 (72) 16 (50) 9 (28) 9 (28) 4 (29) 2 (6) 0 (0) 2 (6) 1 (3)
(10) (50) (30) (10)
0 (0) 2 (20) 6 (60) 2 (20) 17.10 (3.00) 9 (100) 8 (80) 3 (30) 3 (30) 2 (25) 2 (20) 1 (10) 0 (0) 0 (0)
Note: Groups did not differ significantly on any variable. DISC ¼ Diagnostic Interview Schedule for Children; K-SADS-PL ¼ Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Versions; SNAP = Swanson, Nolar, Atkins, and Pelham; PARS = Pediatric Anxiety Rating Scale; ADHD = attention-deficit/hyperactivity disorder. *One subject met non-exclusionary diagnosis; one subject’s specific depressive disorder was unknown. **Protocol violation.
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prone to crying, emotional lability, biting fingernails, and headache (30%). There were few significant differences between complaints at baseline and after initiation of treatment. Appetite loss increased with MPH (x 21 = 2.67, p = .10). Complaints of restlessness (x 21 = 8.00, p = .005) and headache (x 21 = 2.00, p = .16) decreased. Phase III: 2-Week Stabilization. Of 36 children who entered stabilization, 34 received some form of MPH. The mean (SD) [range] of total daily MPH in milligrams during the last week of stabilization was 39.63 (15.29) [10–87]. Total daily doses for subjects taking once-daily stimulant preparations, including two each on 36 mg and 72 mg OROS-MPH, and one on 40 mg MPH extended release, were considered roughly comparable with t.i.d MPH used in our titration. One child on MAS-XR received 20 mg and a second child received 30 mg. Among the 36 children entering phase III, 7 (19%) were ANX responders, whereas 25 (69%) were nonresponders. All 10 children who entered this phase on preexisting stimulant regimens were ANX nonresponders. Four subjects did not complete stabilization. The total rate of stimulant failure for any reason was 24%. For the 26 stimulant-naı¨ve subjects who were MPH responders,
composite SNAP scores were significantly reduced from baseline to end of stabilization (2.04 ± 0.58 versus 0.80 ± 0.61, paired t test = 9.35, df = 24, p < .001). Baseline and end of phase III SNAP scores were available for six of 10 subjects who entered stabilization on previously prescribed stimulants and did not change significantly (2.26 ± 0.20 versus 1.54 ± 1.09; paired t test = 1.78, df = 5, no significance). Most AE frequencies were unchanged over the 2-week period. Trouble sleeping (40% of subjects) was the most frequently occurring AE but evidenced a significant reduction from the 50% rate seen at the beginning of stabilization (x 21 = 4.00, p = .05). Fingernail biting also decreased (x 21 = 4.00, p = .05). Phase IV: 8-Week, Placebo-Controlled, Double-Blind Trial. Twenty-five children entered this phase, and 20 completed it (FLV, n = 12, mean [SD] age = 10.4 [2.7]; PL, n = 8, age = 10.8 [2.6]). Results are summarized in Table 2. FLV and PL groups did not differ significantly in baseline PARS total and SNAP composite scores. Mean daily doses (SD, ranges) of FLV and PL at end of the 8-week trial were 145.4 mg (91.2, 25–300 mg) and 202.4 mg (84.4, 0–278.57 mg), respectively. Random regression analysis indicated no significant treatment by time interaction in PARS total score
TABLE 2 Double-Blind Treatment Results SSRI and Stimulant End of Stabilization SNAP-IV Parent and Teacher ADHD, mean (SD) [no.] PARS Total score, mean (SD) [no.]
Clinical Global Impressions - AnxietyImprovement, no. (%) Responder Non-responder Joint PARS and Clinical Global Impressions-I Anxiety criteria, no. (%) Responder Non-responder
Placebo and Stimulant
End of Double-Blind
End of Stabilization
End of Double-Blind
Random Regression Results: Comparison of Responder Rates at End of Double-Blind Phase
F (1, 22) treatment x time = 0.67; p = .42 F (1, 22) time = .07; p = .79 15.73 (3.41) [15] 10.20 (7.37) [15] 15.00 (2.31) [10] 12.10 (4.25) [10] F (1, 146) treatment x time = 1.46; p = .23 F (1, 146) time = 9.25; p = .006 0.96 (0.65) [15]
0.87 (0.53) [14]
1.09 (0.70) [10]
1.24 (0.74) [10]
1 (7) 14 (93)
10 (67) 5 (33)
2 (20) 8 (80)
5 (50) 5 (50)
x21 = .03; p = .87
0 (0) 15 (100)
7 (47) 8 (53)
0 (0) 10 (100)
5 (50) 5 (50)
x21 = .69; p = .40
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(p = .23). Both groups showed significant decreases in PARS scores, as reflected in the significant main effect for time (p < .01) (Table 2). Comparisons of responder rates yielded no significant differences based on CGI-I Anxiety scores (FLV, 10/15 versus PL, 5/10; Fisher’s exact test, p = .44) or on those who met joint improvement thresholds on the PARS and CGI-I Anxiety (FLV, 7/15 versus PL, 5/10; Fisher’s exact test, p = 1.00). FLV and PL groups did not differ significantly in mean composite SNAP scores at the end of the double-blind phase (0.87 and 1.24, respectively, p = .42). SNAP scores in both groups remained stable, as indicated by the nonsignificant main effect for time. Physical symptoms occurring in at least 20% of subjects or at rates that differentiated the groups at p < .20 are summarized in Table 3. Side effects occurring more frequently with FLV were stomachache and muscle pain. Crying, biting nails, rash, and dry mouth were reported more frequently with PL. Frequencies of side ef-
fects in the FLV group remained unchanged between the end of stimulant stabilization and the end of the double-blind trial, whereas late afternoon emotional lability and dry skin decreased in the PL group. There were no differences in restlessness, behavioral activation, or mood lability between FLV and PL groups. DISCUSSION
Clinicians frequently prescribe medication combinations to address coexisting psychopathology. However, most published ADHD medication trials routinely exclude comorbid subjects, and there are no standards to inform design of sequential medication studies. The current study is the first systematic investigation of a dualmedication strategy in ADHD/ANX and provides a basis for the design of future sequential medication trials. Consistent with previous reports (Diamond et al., 1999; MTA Cooperative Group, 1999b), our findings suggest that stimulant treatment of children with
TABLE 3 Adverse Events Reported at Any Time During Double-Blind Phasea Placebo and Stimulant SSRI and Stimulant (n = 10) No. (%)b Physical Symptom (n = 15) No. (%)b Total (%) Headache Stomach pain or ache Trouble sleeping Decreased appetite Head cold or sniffles Prone to crying Bites fingernails Sore throat Sleeplessness Restlessness or uncomfortable urge to move Abnormal behavioral activation Late afternoon/early evening increase in emotional lability Allergies Skin rash Late afternoon/early evening increase in ADHD symptoms Dry skin Nightmares or very strange dreams Dry mouth
9 9 8 7 6 4 4 4 6
(60) (60) (53) (47) (40) (27) (27) (27) (40)
(40) (30) (40) (50) (50) (70) (60) (50) (20)
52 48 48 48 44 44 40 36 32
.28 .14 .40 .60 .47 .04 .11 .22 .27
5 (33) 5 (33) 3 (20)
2 (20) 2 (20) 4 (40)
28 28 28
.39 .39 .26
4 (27) 2 (13)
2 (20) 4 (40)
24 24
.54 .15
3 2 2 1
3 3 3 3
24 20 20 16
.46 .30 .30 .16
(20) (13) (13) (7)
4 3 4 5 5 7 6 5 2
P valuec
(30) (30) (30) (30)
a
Physical symptoms occurring in at least 20% of subjects or at rates that differentiated the groups at p < .20. Number of subjects who reported symptoms at the ‘‘pretty much’’ and ‘‘very much’’ severity levels. If a subject reported more than one physical symptom during the phase, the report at the highest severity was analyzed. c Fisher’s exact test for small samples. b
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ADHD/ANX is associated with reduced ADHD. Eighty-one percent of children were ADHD responders to MPH during open-label titration, a response rate typical, if not slightly higher, than that found in most pediatric ADHD clinical trials (Spencer et al., 1996). This contrasts with earlier views that ADHD/ANX has a differentially poorer stimulant response (Pliszka, 1989; Tannock et al., 1995). Although 19% of subjects failed MPH titration due to lack of efficacy, side effects, or other reasons, this was well within the 30% failure rate seen in most stimulant trials. MPH was not associated with increased anxiety or clinically meaningful AEs. Similar to the MTA Cooperative Group trial, some patients had meaningful reductions in anxiety with MPH alone. Most subjects, however, exhibited ongoing anxietyrelated impairment that warranted additional pharmacotherapy. Improvements in ADHD remained stable for both FLV and PL groups during the double-blind trial. The substantially less benefit of FLV versus PL in the current study (PARS effect size = –0.30) than in the 2001 RUPP trial (PARS effect size = –1.11) is likely due to a combination of factors. Overall PARS symptom reduction with FLV was less than in the RUPP anxiety study (35% versus 52%, respectively), whereas subjects receiving PL showed comparable decreases (19% versus 16%). Conversely, global ratings of improvement showed a similar response rate to FLV as in the RUPP study (67% versus 76%), but PL response rates were higher (50% versus 29%). Whether these differences suggest a negative impact on SSRI response due to ADHD, as reported in adolescent depression (Birmaher et al., 2003), the confounding of global ratings in the presence of comorbidity, a greater tendency for placebo response in ADHD/ANX (a high placebo response rate in children with ADHD/ANX has also been reported by Pliszka [1989]), or some combination of these factors is unclear. Although the mean doses of FLV, controlled for body weight, in the RUPP anxiety study and the current study were very similar (average dose [mg/kg of body weight]: RUPP ANX = 2.9 ± 1.3, ADHD/ANX = 3.0 ± 1.5; last dose: RUPP ANX = 4.0 ± 2.2, ADHD/ANX = 4.0 ± 2.7), it is also possible that differences in patient characteristics, i.e., lower mean level of anxiety on the PARS at the start of the double-blind trial in the current compared with the RUPP anxiety study (15.44 versus 18.70), and/or differences in study design contributed to the disparate findings.
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Perceived medication side effects are a major impediment to treatment adherence (Fine and Johnston, 1992). Although polypharmacy is commonplace in clinical ADHD treatment, there is a dearth of scientific data on the tolerability or safety of combination pharmacotherapies. Clinical studies of stimulant monotherapy provide qualitative descriptions of AEs but rarely address time course effects of medication on side effects. Two previous studies (Barkley et al., 1990; Fine and Johnston, 1992) demonstrated that side effects often attributed to MPH occur equally in subjects randomized to placebo and might represent symptoms of ADHD. These conclusions are supported by the current study. Baseline rates of physical symptoms were high, with noticeable reductions after initiation of MPH treatment. The position that stimulant treatment of ADHD/ANX leads to exacerbations in anxiety and physical symptoms was not supported in this study. Use of PL during combination treatment provided a basis for assessing the tolerability of stimulants in combination with SSRI therapy. Subjects assigned to active and PL groups had distinct side effect profiles, but physical symptoms were fairly well tolerated. As during stimulant titration, the frequency of most side effects decreased over time. Limitations
This pilot study was conducted to inform design of future research efforts and was not a definitive clinical trial. The small sample size limits the applicability of study findings to clinical practice and precluded moderator and mediator analyses that might better inform treatment planning for individual patients. There are few precedents to guide design of combination treatments for coexisting psychiatric disorders (Tourette Syndrome Study Group, 2002). The study did not assess alternative clinical approaches such as initial SSRI treatment followed by stimulant titration. Study recruitment was more difficult than expected. Evidence from the MTA Cooperative Group study suggested that more than 25% of patients with ADHD have ANX, and on initial phone screen, all subjects exhibited ADHD and anxiety symptoms. Nonetheless, more than 40% of screened potential subjects failed inclusion or exclusion criteria, including many who failed to meet specified impairment thresholds during comprehensive evaluation. Diagnosis of anxiety in the MTA study was based
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on structured parent Diagnostic Interview Schedule for Children interviews as opposed to more stringent parent/child K-SADS and PARS interview criteria in the current study. It is unknown whether parentreported anxiety in the MTA study would have met the DSM threshold for ANX. Similarly, it is unclear whether our assessment strategies and diagnostic thresholds adequately identified the type of patients with ADHD/ANX typically seen in clinical practice. Inclusion/exclusion criteria representative of those used by practitioners who treat youngsters with stimulants + SSRIs should be incorporated into future effectiveness studies. Clinical Implications
The results indicate that stimulant treatment in children with ADHD/ANX leads to ADHD symptom reductions similar to those seen in noncomorbid ADHD and that stimulants are tolerated without significant exacerbation of anxiety or development of untoward side effects. Consistent with the MTA study, a small but significant minority of children exhibited clinically meaningful reductions in anxiety with stimulant monotherapy. The mechanism underlying this reduction is unclear. Similar results in the MTA were postulated as resulting from decreased social conflicts, fewer failures, and more success experiences (MTA Cooperative Group, 1999b). Current consensus recommendations on treatment of ADHD/ANX suggest stimulant titration followed by SSRI therapy (Pliszka et al., 2000). Although this study provides the first evidence from a controlled trial suggesting that this medication combination is well tolerated and not associated with development of untoward side effects, the reductions in anxiety with added SSRI did not differ significantly from those obtained with PL. However, the absolute degree of improvement in anxiety symptom ratings was greater with FLV than with PL (effect size, Cohen’s d = 0.35), suggesting that a study with a larger sample size might be better powered to detect significant treatment differences. Disclosure: Dr. Abikoff has received support from McNeil (research support, consulting fees), Shire (research support, consulting fees), Eli Lilly (research support), and Celltech (consulting fees). Dr. McGough has received support from Eli Lilly (grant/research support, consulting fees, speaker’s bureau), McNeil (grant/research support, consulting fees, speaker’s bureau), Novartis (grant/research support, consulting fees, speaker’s bureau), Shire (grant/research support, consulting fees, speaker’s bureau), and Pfizer (consulting fees). Dr. McCracken has received sup-
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port from Eli Lilly (research support, consulting fees, speaker fees), Shire (research support, speaker fees), Pfizer (research support, consulting fees), Solvay (research support), Gliatech (research support), Bristol-Myers Squibb (consulting fees), McNeil (consulting fees), Noven (consulting fees), and Janssen (consulting fees). Dr. Walkup has received support from Abbott (grant support), Pfizer (grant support, honoraria), Janssen (honoraria), and Lilly (grant support, honoraria, consulting fees). Dr. Riddle has received support from Forest (speaker fees), Janssen (speaker fees, scientific advisor), Lilly (consulting fees), Pfizer (research support, consulting fees), Sanofi (consulting fees), AstraZeneca (scientific advisor), Shire (scientific advisor), Mallinckrodt, and Bristol-Myers Squibb (consulting fees). Dr. Oatis has received support (consulting fees and speaker fees) from Lilly, McNeil, and Shire. Dr. Greenhill has received support (honoraria or grants to do research) from Celltech, Shire, Lilly, McNeil, Alza, Janssen-Cilag, and Novartis. Dr. March has received support from Pfizer (consulting fees, speaker fees, scientific advisor), Solvay (speaker fee, consulting fee), Wyeth (research support, consulting fees), Shire (scientific advisor), and GSK (consulting fee). The other authors have no financial relationships to disclose.
REFERENCES Barkley RA, McMurray MB, Edelbrock CS, Robbins K (1990), Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systematic, placebo-controlled evaluation. Pediatrics 86: 184–192 Barrickman L, Noyes R, Kuperman S (1991), Treatment of ADHD with fluoxetine: a preliminary trial. J Am Acad Child Adolesc Psychiatry 30:762–767 Biederman J, Newcorn J, Sprich S (1991), Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:565–577 Birmaher B, Axelson DA, Monk K et al. (2003), Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 42:415–423 Conners CK, Sitarenios G, Parker J, Epstein J (1998a), The revised Conners Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 26:257–268 Conners CK, Sitarenios G, Parker J, Epstein J (1998b), Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability and criterion validity. J Abnorm Child Psychol 26:279– 293 Diamond I, Tannock R, Schachar R (1999), Response to methylphenidate in children with ADHD and comorbid anxiety. J Am Acad Child Adolesc Psychiatry 38:402–409 Fine S, Johnston C (1992), Drug and placebo side effects in methylphenidateplacebo trial for attention deficit hyperactivity disorder. Child Psychiatry Hum Dev 24:25–30 Guy W (ed) (1976), ECDEU Assessment Manuel for Psychopharmacology (Revised). Washington, DC: U.S. Department of Health, Education and Welfare (DHEW) Kaufman J, Birmaher B, Brent D et al. (1997), The Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:444–454 Klein RG, Koplewicz HS, Kanner A (1992), Imipramine treatment of children with separation anxiety disorder. J Am Acad Child Adolesc Psychiatry 31:21–28 MTA Cooperative Group (1999a), A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086 MTA Cooperative Group (1999b), Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1088–1096
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Pliszka SR (1989), Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 28:882–887 Pliszka SR, Greenhill LL, Crismon ML et al. (2000), The Texas Children’s Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Childhood AttentionDeficit/Hyperactivity Disorder. Part I. Attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 39:903–919 Research Unit on Pediatric Psychopharmacology (RUPP) Anxiety Study Group (2001), Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 344:1279–1285 Research Unit on Pediatric Psychopharmacology (RUPP) Anxiety Study Group (2002), The pediatric anxiety rating scale (PARS): development and psychometric properties. J Am Acad Child Adolesc Psychiatry 41:1061–1069 Rushton JL, Whitmire JT (2001), Pediatric stimulant and selective serotonin reuptake inhibitor prescription trends: 1992–1998. Arch Pediatr Adolesc Med 155:560–565 Shaffer D, Fisher P, Dulcan M et al. (1996), The NIMH Diagnostic Interview Schedule for Children Version 2.3 (DISC-2.3): description, acceptability, prevalence rates, and performance in the MECA Study. J Am Acad Child Adolesc Psychiatry 35:865–877
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Spencer T, Biederman J, Wilens T, Harding M, O’Donnel D, Griffen S (1996), Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 35:409– 432 Swanson JM (1992), School-based Assessment and Interventions for ADD Students Irvine, CA: K.C. Press Swanson J, Wigal S, Greenhill L et al. (1998), Analog classroom assessment of Adderall in children with ADHD. J Am Acad Child Adolesc Psychiatry 37:1–8 Tannock R, Ickowicz A, Schachar R (1995), Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–899 Tourette Syndrome Study Group (2002), Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 58:527–536 Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M (1987), Which boys respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behavior. Psychol Med 17: 121–143 Urman R, Ickowicz A, Fulford P, Tannock R (1995), An exaggerated cardiovascular response to methylphenidate in ADHD children with anxiety. J Child Adolesc Psychopharmacol 5:29–37
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ABSTRACT Objective: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by clinically significant anxiety, but few empirical data guide treatment of children meeting full DSM-IV criteria for ADHD and anxiety disorders (ADHD/ANX). This study examined the efficacy of sequential pharmacotherapy for ADHD/ANX children. Method: Children, age 6 to 17 years, with ADHD/ANX were titrated to optimal methylphenidate dose and assessed along with children who entered the study on a previously optimized stimulant. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine (STIM/FLV) or stimulant + placebo (STIM/PL). Primary efficacy measures were the Swanson, Nolan, Atkins, and Pelham IV Parent and Teacher Rating Scale ADHD score and the Pediatric Anxiety Rating Scale total score. ADHD, ANX, and overall Clinical Global Impressions-Improvement scores were also obtained. Results: Of the 32 medication-naı¨ve children openly treated with methylphenidate, 26 (81%) improved as to ADHD. Twenty-five children entered the randomized trial. Intent-to-treat analysis indicated no differences between the STIM/FLV (n = 15) and STIM/PL groups on the Pediatric Anxiety Rating Scale or Clinical Global Impressions-Improvement–defined responder rate. Medications in both arms were well tolerated. Conclusions: Children with ADHD/ANX have a response rate to stimulants for ADHD that is comparable with that of children with general ADHD. The benefit of adding FLV to stimulants for ANX remains unproven. J. Am. Acad. Child Adolesc. Psychiatry, 2005;44(5):418–427. Key Words: attention-deficit/hyperactivity, anxiety, comorbidity, combination pharmacotherapy.
The co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (ANX) in children is common, with estimated comorbidity rates of 20% to 45% (Biederman et al., 1991). Pharmacotherapy guidelines for ADHD/ANX are not well established, and sparse treatment studies are inconsistent. Accepted November 16, 2004. From Columbia University at the New York State Psychiatric Institute, New York (M.D., L.G., A.S.); Duke University Medical Center, Durham, NC (J.M., P.G.); Johns Hopkins University, Baltimore, MD (J.W., M.R.); Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (J.R., R.L., D.M.); National Institute of Mental Health, Bethesda, MD (B.V., L.R.); New York University Child Study Center, New York (H.A, M.O.); University of California Los Angeles (J.Mc., J.Mc.). The RUPP (Research Units of Pediatric Psychopharmacology) ADHD/Anxiety Study is a multisite clinical trial supported by contracts from the National Institute of Mental Health to Johns Hopkins University (N01MH60016:
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Several short-term trials report that psychostimulants may be associated with more side effects and a less robust response in ADHD/ANX than in ADHD alone (Pliszka, 1989; Tannock et al., 1995; Taylor et al., 1987; Urman et al., 1995). However, two long-term studies suggest that children with ADHD with and P.I. Mark Riddle, M.D.), the Research Foundation for Mental Hygiene (N01MH60005: P.I. Laurence Greenhill, M.D.), and the University of California Los Angeles (K23MH01966: P.I. James McGough, M.D., N01MH70010 and MH01805: P.I. James McCracken, M.D.). The authors are indebted to Solvay Pharmaceuticals for supplying study drug and to the NIMH Data Safety and Monitoring Board. Correspondence to Dr. Abikoff, NYU Child Study Center, 215 Lexington Avenue, 14th Floor, New York, NY 10016; e-mail: [email protected]. 0890-8567/05/4405–0418Ó2005 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000155320.52322.37
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without ANX show comparable improvements in ADHD symptoms with stimulants, with some concomitant improvements in internalizing symptoms (Diamond et al., 1999; MTA Cooperative Group, 1999a,b). In the multisite MTA study, children with and without comorbid ANX improved similarly in the medication management arm, although anxiety was a significant moderator of response to behavioral therapy (MTA Cooperative Group, 1999b). Unlike earlier studies, most of which relied on ratings or reports of emotional problems to ascertain anxiety, these trials used systematic clinical assessment. However, diagnostic and outcome measures were not representative of those used in clinical trials of pediatric ANX. Medication combinations, particularly stimulants with selective serotonin reuptake inhibitors (SSRIs), are increasingly prevalent in the clinical treatment of ADHD/ANX (Pliszka et al., 2000; Rushton and Whitmire, 2001). Although the efficacy of SSRI treatment of pediatric ANX has been demonstrated in randomized clinical trials (Birmaher et al., 2003; RUPP Anxiety Study Group, 2001), evidence supporting the adjunctive use of SSRIs in children with ADHD/ANX is limited to one open study (Barrickman et al., 1991). Moreover, the percentage of children with ADHD/ ANX who require polypharmacy after systematic, flexible stimulant titration and maintenance is unknown. Currently, the Texas Medication Algorithm Consensus Panel, acknowledging the lack of controlled evidence, recommends an initial trial of stimulant monotherapy followed by additional SSRI treatment in children with ADHD and ongoing ANX (Pliszka et al., 2000). No study prototype has been developed for controlled polypharmacy trials in comorbid ADHD. Treatment research in comorbid psychiatric disorders is complex, involving two or more treatment targets and potential use of multiple medications. The specific aims of this study were to (a) test the feasibility of a multisite, sequential treatment design for ADHD/ANX using both global and disorder-specific outcomes; (b) estimate whether the efficacy and tolerability of methylphenidate (MPH) in children with ADHD/ANX is comparable with that reported for nonanxious ADHD; (c) explore whether ADHD improvement during MPH treatment is accompanied by improvement in ANX; and (d) explore whether adding fluvoxamine (FLV) to psychostimulants increases ANX response compared with psychostimulant monotherapy. Because of the
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small sample size, this study was intended to be a pilot, exploratory investigation whose results could inform future definitive trials. METHOD Study Participants Inclusion Criteria. Subjects were boys and girls, ages 6 to 17, of normal intelligence, who met DSM-IV criteria for both ADHD (combined or inattentive type) and ANX (separation anxiety disorder, generalized anxiety disorder, and/or social phobia). Inclusion criteria for ADHD and ANX closely paralleled those used in the MTA Cooperative Group study (1999a) and the FLV anxiety study of the RUPP Anxiety Study Group (2001). Children presenting on stimulants had a minimum 5-day washout at the time of screening to evaluate baseline symptomatology. Diagnosis of ADHD. Diagnosis of ADHD was based on the Diagnostic Interview Schedule for Children-Parent, version 4.0 (Shaffer et al., 1996). For cases falling just below this scale’s threshold, the diagnosis could be supplemented with up to two symptoms with elevated scores on the Swanson, Nolan, Atkins, and Pelham (SNAP-IV) teacher rating scale (Swanson, 1992). ADHD was confirmed by clinician interview of the parent and child supplemented by the research measures. Severity of ADHD. Subjects were rated (a) at least 1 SD above age and gender norms on the hyperactivity factor (combined subtype) or inattentive factor (inattentive subtype) of the Conners Parent Rating Scale (Conners et al., 1998a), and (b) at least 1.5 SD above age and gender norms on the hyperactivity factor (combined subtype) or inattentive factor (inattentive subtype) of the Conners Teacher Rating Scale (Conners et al., 1998b). If teacher ratings were unobtainable due to the academic calendar, then the previous year’s report card and other corroborating information were reviewed by a cross-site panel to determine whether school functioning was commensurate with an ADHD diagnosis. Diagnosis of ANX. Diagnoses of ANX were based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) (Kaufman et al., 1997) administered to both parent and child. Severity of Anxiety. Children were required to exhibit anxiety symptoms of at least moderate severity, as indicated by a minimum score of 3 on the item ‘‘overall severity of anxiety feelings’’ or ‘‘overall avoidance of anxiety provoking situations’’ of the Pediatric Anxiety Rating scale (PARS) (RUPP Anxiety Study Group, 2002) and a minimum score of 3 on one of the two interference items (at home, out of home). Clinician-rated PARS scores were derived from both parent and child reports. Exclusion Criteria. Children were excluded if they (a) were taking other (nonstimulant) medications with CNS effects; (b) had medical conditions that precluded MPH or FLV treatment; (c) had current evidence of autism, major depression, substance abuse, obsessivecompulsive disorder, posttraumatic stress disorder, panic disorder, chronic tic disorders, or Tourette’s syndrome, significant suicidality, lifetime history of psychosis or mania; (d) had a current history of sexual or physical abuse or a past history of sexual or physical abuse with ongoing Department of Social Services involvement; (e) had failed a previous trial of FLV judged adequate in dose (50 mg) and duration (6 weeks), had a history of intolerance to FLV, or had failed two previous SSRI trials judged adequate in dose and duration; or (f) had failed an adequate trial of MPH (30 mg/day for at least 4 weeks).
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Procedures
Study Measures
Prospective participants were recruited at six academic child and adolescent psychiatry clinics through clinical referral or community advertisements. After receiving a full verbal explanation of all study requirements and procedures, parents and children provided written informed consent and assent, respectively, and participants were approved by each respective study site’s Institutional Review Board. Overview of Study Protocol. The study comprised four phases. Phase I comprised subject screening. Subjects who entered the study on previously stabilized stimulants underwent a 5-day washout to assess symptom baselines off medication. Phase II assessed stimulant response and optimal stimulant dose. Procedures differed for stimulant-naı¨ve children and those presenting on a stimulant. Stimulant-naı¨ve youngsters underwent a 4-week, open-label titration with immediate-release MPH using a fixed-flexible t.i.d.-dosing schedule. Subjects were titrated with weekly adjustments, based on clinical response and side effect profiles, to a maximum of 40 mg/day for children weighing less than 25 kg, or 50 mg/day if weighing more than 25 kg. Children currently on stimulant medication (e.g., other MPH or amphetamine preparations) were assessed at baseline and, if eligible, immediately entered phase III stimulant stabilization on their current medication, where their dose was optimized, if necessary. Children receiving a clinician Clinical Global Impressions-Improvement (CGI-I) (Guy, 1976) rating for ADHD of at least ‘‘improved’’ (score of 3) without clinically significant side effects on at least one regimen during dose titration were designated MPH responders. A rating of improved required significant improvement in ADHD-related problems at school and/or at home and a reduction in impairment. The CGI-I ADHD ratings were based on clinical observation and review of teacher and parent ratings on the Conners hyperactivity and inattentive factor items and on the Conners, Loney, and Milich rating scale (Swanson et al., 1998). Nonresponders were discontinued and referred for clinical treatment. Optimal doses were chosen based on the best CGI-I rating and lowest report of side effects and affirmed by consensus of two clinicians at the treating site. The lower dose was selected when CGI and side effects ratings were equivalent. Clinicians at a collaborating site blindly reviewed CGI and side effects ratings to maintain consistency across sites. Phase III was a 2-week stabilization on optimal stimulant dose (either phase II titrated MPH or patients’ stimulant at study entry) to assess improvement in ADHD and ANX. Children moved to phase IV if (a) they demonstrated sufficient improvements in ADHD (ADHD responders) and (b) they continued to show clinically significant and impairing anxiety symptoms (ANX nonresponders). ANX nonresponse was defined as (a) CGI-I Anxiety ratings of ‘‘slightly improved’’ (score of 4) or worse and (b) PARS scores of >2 on a severity item and an impairment item. Youngsters who showed clinical improvement in both ADHD and ANX were followed openly on stimulant monotherapy. Phase IV was an 8-week, double-blind, placebo-controlled trial. Phase III subjects with stimulant-stabilized ADHD and ANX nonresponse continued optimal stimulant therapy plus randomized, double-blind FLV or placebo (PL). Randomization was done within site and was based on age, gender, and diagnosis. FLV or PL titration followed procedures used in the previous FLV anxiety trial (RUPP Anxiety Study Group, 2001). Drug was initiated at 25 mg/day and increased approximately 50 mg/wk to a maximum of 300 mg in adolescents and 250 mg in children younger than 13 years of age. Dose escalation was delayed or halted in children who developed clinically significant side effects or ANX remission.
Study measures were collected at baseline and throughout the study to assess changes in ADHD and ANX symptoms, severity, improvement, and side effects. ADHD Measures. Parents and teachers completed the SNAP-IV and the Conners, Loney, and Milich rating scales. A composite score derived from the mean of parent and teacher ratings on the 18-item SNAP scale served as the primary index of ADHD severity. Anxiety Measures. The clinician-completed PARS contained five items that assess the severity of distress due to anxiety, the frequency of anxiety, avoidance of anxiety-provoking situations, and the degree of interference from anxiety at home and elsewhere. The PARS total score, a sum of these five items, was the primary continuous outcome measure of change in anxiety. Global Measures. Clinician-rated CGI-Severity (Guy, 1976) and CGI-I scores, generated separately for ADHD, ANX, and overall functioning, were obtained weekly. The CGI-I Anxiety score using a modified 8-point CGI-I scale (Klein et al., 1992) was the primary categorical outcome measure in the double-blind trial. Children were responders when they had scores of 1 (free of symptoms), 2 (much improved), or 3 (improved). Safety Assessments. Adverse events (AEs) were elicited through clinician inquiry of the child and parent during each study visit. Additionally, at each visit, parents completed the Physical Symptom Checklist, which was reviewed and discussed by the clinician. The Physical Symptom Checklist assessed side effects common to SSRIs and stimulants, including activation, disinhibition, and overactivity. Positive items on the Physical Symptom Checklist deemed to be both clinically relevant and related to study medications were recorded as AEs.
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Data Analyses The following analyses were conducted: 1. To examine improvement with initial stimulant treatment in ADHD/ANX, the percentage of stimulant-naı¨ve children who were ADHD and ANX stimulant responders was calculated. 2. To explore the efficacy of ANX improvement with the addition of FLV to ongoing stimulant treatment, mixed-effects linear regression analyses (fixed effects were treatment status and site and random effects were the child-specific parameters [intercept and slope] of the regression of the outcome measure on week of the study, and error) were used to compare the change in total PARS scores from the end of phase III to the end of the phase IV in the FLV and PL groups. Analyses of phase IV data followed intent-to-treat principles, including all subjects randomized. Response rates on CGI-I Anxiety criteria at the end of phase IV were compared using a x2 test. Additionally, the percentage of children in the FLV and PL groups who met criteria for ANX response by attaining improvement on both the PARS and CGI-I Anxiety were compared using a x2 test. Finally, to explore the impact on ADHD after the addition of FLV to ongoing stimulant treatment, changes in composite SNAP scores from the end of phase III to the end of phase IV were analyzed with a mixed-effects linear regression. 3. To ascertain AEs associated with stimulant treatment alone, McNemar’s test for correlated proportions was used to determine the emergence of clinically relevant AEs in stimulant-naı¨ve subjects who participated in the phase II titration. 4. To identify differences in clinically relevant AEs with the addition of an SSRI, change in SE rates from the end of phase III stabilization to the end of phase IV were tested using a x2 test. Given the exploratory nature of this study and its special attention to tolerability and safety, it was considered important to minimize
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type II error (i.e., false-negative results) due to the small sample size. To this effect, p values <.20 are reported for heuristic purposes. RESULTS Subjects
An overview of subject flow and disposition is depicted in Figure 1. Phase I: Screening. Of 100 children screened, 42 met the entry criteria. Table 1 summarizes subject characteristics. Thirty-two subjects were stimulant naı¨ve and underwent medication titration. Ten additional subjects entered the study on preexisting stimulant regimens including mixed amphetamine salts extended release (MAS-XR) (n = 2),
OROS-MPH (n = 3), MPH immediate release (IR) (n = 3), other MPH extended release (n = 1), and OROS-MPH + MPH-IR (n = 1). These subjects underwent baseline assessment after a 5-day medication washout and immediately entered phase III. There were no significant clinical or demographic differences between stimulant-naı¨ve and previously treated subjects. Phase II: Open-Label MPH Titration. Of the 32 stimulant-naı¨ve youths who entered titration, 26 (81%) had a positive ADHD response, one had no response, two withdrew due to side effects, and three withdrew for other reasons. Commonly reported AEs included trouble sleeping (50% of subjects), appetite loss (40%), sleeplessness,
Fig. 1 Study design and subject flow.
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Variable
TABLE 1 Subject Profile, Demographic, and Descriptive Variables at Baseline Totals Across Enrolled in Titration Groups (n = 12) (n = 32)
Age, yr, mean (SD) [range] Male, no. (%) Weight, kg, mean (SD) [range] Ethnicity, no. (%) White, not of Hispanic origin Black, not of Hispanic origin Native American Hispanic Other Conners Parent Rating Scale, mean (SD) Hyperactivity factor Inattentive factor Conners Teacher Rating Scale, mean (SD) Hyperactivity factor Inattentive factor SNAP-IV Parent and Teacher ADHD, mean (SD) ADHD subtype (DISC diagnoses), no. (%) Combined type Inattentive type Clinical Global Impressions-ADHD-Severity, no. (%) Minimally ill Moderately ill Markedly ill Severely ill Clinical Impressions-Anxiety-Severity, no. (%) Mildly ill Moderately ill Markedly ill Severely ill PARS total score, mean (SD) Comorbidity (K-SADS-PL diagnoses), no. (%) Generalized anxiety disorder Seperation anxiety disorder Social phobia Specific phobia Oppositional defiant disorder Enuresis Encopresis Depressive disorder* Obsessive-compulsive disorder**
10.0 (2.8) [6.0–17.4] 24 (57) 38.5 (16.1) [18.8–88.2] 33 (79) 4 (10) 1 (2) 2 (5) 2 (5) 35/34 15.49 (7.90) 22.03 (4.21) 25 9.40 (6.40) 17.28 (5.83) 2.00 (0.55)
10.7 (3.1) [7.4–17.4] 18 (56) 38.1 (16.9) [18.8–88.2] 24 3 1 2 2
(75) (9) (3) (6) (6)
Enrolled Directly in Stabilization (n = 10) 9.8 (2.7) [6.0–16.0] 6 (60) 39.7 (14.0) [24.3–64.9] 9 (90) 1 (10) 0 (0) 0 (0) 0 (0)
16.32 (7.50) 22.46 (4.29)
13.40 (8.87) 21.00 (4.03)
9.61 (6.58) 17.78 (5.34) 2.03 (0.55)
8.86 (6.38) 16.00 (7.26) 1.90 (0.55)
29 (69) 12 (29)
24 (75) 8 (25)
5 (50) 4 (40)
1 15 18 8
0 (0) 10 (31) 15 (47) 7 (22)
1 5 3 1
(2) (36) (43) (19)
2 14 19 7 16.71
(5) (33) (45) (17) (3.20)
32/41 24 12 12 6/22 4/41 1/41 2 1
(78) (57) (29) (29) (27) (10) (2) (5) (2)
2 12 13 5 16.59
(6) (37) (41) (16) (3.30)
23 (72) 16 (50) 9 (28) 9 (28) 4 (29) 2 (6) 0 (0) 2 (6) 1 (3)
(10) (50) (30) (10)
0 (0) 2 (20) 6 (60) 2 (20) 17.10 (3.00) 9 (100) 8 (80) 3 (30) 3 (30) 2 (25) 2 (20) 1 (10) 0 (0) 0 (0)
Note: Groups did not differ significantly on any variable. DISC ¼ Diagnostic Interview Schedule for Children; K-SADS-PL ¼ Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Versions; SNAP = Swanson, Nolar, Atkins, and Pelham; PARS = Pediatric Anxiety Rating Scale; ADHD = attention-deficit/hyperactivity disorder. *One subject met non-exclusionary diagnosis; one subject’s specific depressive disorder was unknown. **Protocol violation.
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prone to crying, emotional lability, biting fingernails, and headache (30%). There were few significant differences between complaints at baseline and after initiation of treatment. Appetite loss increased with MPH (x 21 = 2.67, p = .10). Complaints of restlessness (x 21 = 8.00, p = .005) and headache (x 21 = 2.00, p = .16) decreased. Phase III: 2-Week Stabilization. Of 36 children who entered stabilization, 34 received some form of MPH. The mean (SD) [range] of total daily MPH in milligrams during the last week of stabilization was 39.63 (15.29) [10–87]. Total daily doses for subjects taking once-daily stimulant preparations, including two each on 36 mg and 72 mg OROS-MPH, and one on 40 mg MPH extended release, were considered roughly comparable with t.i.d MPH used in our titration. One child on MAS-XR received 20 mg and a second child received 30 mg. Among the 36 children entering phase III, 7 (19%) were ANX responders, whereas 25 (69%) were nonresponders. All 10 children who entered this phase on preexisting stimulant regimens were ANX nonresponders. Four subjects did not complete stabilization. The total rate of stimulant failure for any reason was 24%. For the 26 stimulant-naı¨ve subjects who were MPH responders,
composite SNAP scores were significantly reduced from baseline to end of stabilization (2.04 ± 0.58 versus 0.80 ± 0.61, paired t test = 9.35, df = 24, p < .001). Baseline and end of phase III SNAP scores were available for six of 10 subjects who entered stabilization on previously prescribed stimulants and did not change significantly (2.26 ± 0.20 versus 1.54 ± 1.09; paired t test = 1.78, df = 5, no significance). Most AE frequencies were unchanged over the 2-week period. Trouble sleeping (40% of subjects) was the most frequently occurring AE but evidenced a significant reduction from the 50% rate seen at the beginning of stabilization (x 21 = 4.00, p = .05). Fingernail biting also decreased (x 21 = 4.00, p = .05). Phase IV: 8-Week, Placebo-Controlled, Double-Blind Trial. Twenty-five children entered this phase, and 20 completed it (FLV, n = 12, mean [SD] age = 10.4 [2.7]; PL, n = 8, age = 10.8 [2.6]). Results are summarized in Table 2. FLV and PL groups did not differ significantly in baseline PARS total and SNAP composite scores. Mean daily doses (SD, ranges) of FLV and PL at end of the 8-week trial were 145.4 mg (91.2, 25–300 mg) and 202.4 mg (84.4, 0–278.57 mg), respectively. Random regression analysis indicated no significant treatment by time interaction in PARS total score
TABLE 2 Double-Blind Treatment Results SSRI and Stimulant End of Stabilization SNAP-IV Parent and Teacher ADHD, mean (SD) [no.] PARS Total score, mean (SD) [no.]
Clinical Global Impressions - AnxietyImprovement, no. (%) Responder Non-responder Joint PARS and Clinical Global Impressions-I Anxiety criteria, no. (%) Responder Non-responder
Placebo and Stimulant
End of Double-Blind
End of Stabilization
End of Double-Blind
Random Regression Results: Comparison of Responder Rates at End of Double-Blind Phase
F (1, 22) treatment x time = 0.67; p = .42 F (1, 22) time = .07; p = .79 15.73 (3.41) [15] 10.20 (7.37) [15] 15.00 (2.31) [10] 12.10 (4.25) [10] F (1, 146) treatment x time = 1.46; p = .23 F (1, 146) time = 9.25; p = .006 0.96 (0.65) [15]
0.87 (0.53) [14]
1.09 (0.70) [10]
1.24 (0.74) [10]
1 (7) 14 (93)
10 (67) 5 (33)
2 (20) 8 (80)
5 (50) 5 (50)
x21 = .03; p = .87
0 (0) 15 (100)
7 (47) 8 (53)
0 (0) 10 (100)
5 (50) 5 (50)
x21 = .69; p = .40
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(p = .23). Both groups showed significant decreases in PARS scores, as reflected in the significant main effect for time (p < .01) (Table 2). Comparisons of responder rates yielded no significant differences based on CGI-I Anxiety scores (FLV, 10/15 versus PL, 5/10; Fisher’s exact test, p = .44) or on those who met joint improvement thresholds on the PARS and CGI-I Anxiety (FLV, 7/15 versus PL, 5/10; Fisher’s exact test, p = 1.00). FLV and PL groups did not differ significantly in mean composite SNAP scores at the end of the double-blind phase (0.87 and 1.24, respectively, p = .42). SNAP scores in both groups remained stable, as indicated by the nonsignificant main effect for time. Physical symptoms occurring in at least 20% of subjects or at rates that differentiated the groups at p < .20 are summarized in Table 3. Side effects occurring more frequently with FLV were stomachache and muscle pain. Crying, biting nails, rash, and dry mouth were reported more frequently with PL. Frequencies of side ef-
fects in the FLV group remained unchanged between the end of stimulant stabilization and the end of the double-blind trial, whereas late afternoon emotional lability and dry skin decreased in the PL group. There were no differences in restlessness, behavioral activation, or mood lability between FLV and PL groups. DISCUSSION
Clinicians frequently prescribe medication combinations to address coexisting psychopathology. However, most published ADHD medication trials routinely exclude comorbid subjects, and there are no standards to inform design of sequential medication studies. The current study is the first systematic investigation of a dualmedication strategy in ADHD/ANX and provides a basis for the design of future sequential medication trials. Consistent with previous reports (Diamond et al., 1999; MTA Cooperative Group, 1999b), our findings suggest that stimulant treatment of children with
TABLE 3 Adverse Events Reported at Any Time During Double-Blind Phasea Placebo and Stimulant SSRI and Stimulant (n = 10) No. (%)b Physical Symptom (n = 15) No. (%)b Total (%) Headache Stomach pain or ache Trouble sleeping Decreased appetite Head cold or sniffles Prone to crying Bites fingernails Sore throat Sleeplessness Restlessness or uncomfortable urge to move Abnormal behavioral activation Late afternoon/early evening increase in emotional lability Allergies Skin rash Late afternoon/early evening increase in ADHD symptoms Dry skin Nightmares or very strange dreams Dry mouth
9 9 8 7 6 4 4 4 6
(60) (60) (53) (47) (40) (27) (27) (27) (40)
(40) (30) (40) (50) (50) (70) (60) (50) (20)
52 48 48 48 44 44 40 36 32
.28 .14 .40 .60 .47 .04 .11 .22 .27
5 (33) 5 (33) 3 (20)
2 (20) 2 (20) 4 (40)
28 28 28
.39 .39 .26
4 (27) 2 (13)
2 (20) 4 (40)
24 24
.54 .15
3 2 2 1
3 3 3 3
24 20 20 16
.46 .30 .30 .16
(20) (13) (13) (7)
4 3 4 5 5 7 6 5 2
P valuec
(30) (30) (30) (30)
a
Physical symptoms occurring in at least 20% of subjects or at rates that differentiated the groups at p < .20. Number of subjects who reported symptoms at the ‘‘pretty much’’ and ‘‘very much’’ severity levels. If a subject reported more than one physical symptom during the phase, the report at the highest severity was analyzed. c Fisher’s exact test for small samples. b
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ADHD/ANX is associated with reduced ADHD. Eighty-one percent of children were ADHD responders to MPH during open-label titration, a response rate typical, if not slightly higher, than that found in most pediatric ADHD clinical trials (Spencer et al., 1996). This contrasts with earlier views that ADHD/ANX has a differentially poorer stimulant response (Pliszka, 1989; Tannock et al., 1995). Although 19% of subjects failed MPH titration due to lack of efficacy, side effects, or other reasons, this was well within the 30% failure rate seen in most stimulant trials. MPH was not associated with increased anxiety or clinically meaningful AEs. Similar to the MTA Cooperative Group trial, some patients had meaningful reductions in anxiety with MPH alone. Most subjects, however, exhibited ongoing anxietyrelated impairment that warranted additional pharmacotherapy. Improvements in ADHD remained stable for both FLV and PL groups during the double-blind trial. The substantially less benefit of FLV versus PL in the current study (PARS effect size = –0.30) than in the 2001 RUPP trial (PARS effect size = –1.11) is likely due to a combination of factors. Overall PARS symptom reduction with FLV was less than in the RUPP anxiety study (35% versus 52%, respectively), whereas subjects receiving PL showed comparable decreases (19% versus 16%). Conversely, global ratings of improvement showed a similar response rate to FLV as in the RUPP study (67% versus 76%), but PL response rates were higher (50% versus 29%). Whether these differences suggest a negative impact on SSRI response due to ADHD, as reported in adolescent depression (Birmaher et al., 2003), the confounding of global ratings in the presence of comorbidity, a greater tendency for placebo response in ADHD/ANX (a high placebo response rate in children with ADHD/ANX has also been reported by Pliszka [1989]), or some combination of these factors is unclear. Although the mean doses of FLV, controlled for body weight, in the RUPP anxiety study and the current study were very similar (average dose [mg/kg of body weight]: RUPP ANX = 2.9 ± 1.3, ADHD/ANX = 3.0 ± 1.5; last dose: RUPP ANX = 4.0 ± 2.2, ADHD/ANX = 4.0 ± 2.7), it is also possible that differences in patient characteristics, i.e., lower mean level of anxiety on the PARS at the start of the double-blind trial in the current compared with the RUPP anxiety study (15.44 versus 18.70), and/or differences in study design contributed to the disparate findings.
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Perceived medication side effects are a major impediment to treatment adherence (Fine and Johnston, 1992). Although polypharmacy is commonplace in clinical ADHD treatment, there is a dearth of scientific data on the tolerability or safety of combination pharmacotherapies. Clinical studies of stimulant monotherapy provide qualitative descriptions of AEs but rarely address time course effects of medication on side effects. Two previous studies (Barkley et al., 1990; Fine and Johnston, 1992) demonstrated that side effects often attributed to MPH occur equally in subjects randomized to placebo and might represent symptoms of ADHD. These conclusions are supported by the current study. Baseline rates of physical symptoms were high, with noticeable reductions after initiation of MPH treatment. The position that stimulant treatment of ADHD/ANX leads to exacerbations in anxiety and physical symptoms was not supported in this study. Use of PL during combination treatment provided a basis for assessing the tolerability of stimulants in combination with SSRI therapy. Subjects assigned to active and PL groups had distinct side effect profiles, but physical symptoms were fairly well tolerated. As during stimulant titration, the frequency of most side effects decreased over time. Limitations
This pilot study was conducted to inform design of future research efforts and was not a definitive clinical trial. The small sample size limits the applicability of study findings to clinical practice and precluded moderator and mediator analyses that might better inform treatment planning for individual patients. There are few precedents to guide design of combination treatments for coexisting psychiatric disorders (Tourette Syndrome Study Group, 2002). The study did not assess alternative clinical approaches such as initial SSRI treatment followed by stimulant titration. Study recruitment was more difficult than expected. Evidence from the MTA Cooperative Group study suggested that more than 25% of patients with ADHD have ANX, and on initial phone screen, all subjects exhibited ADHD and anxiety symptoms. Nonetheless, more than 40% of screened potential subjects failed inclusion or exclusion criteria, including many who failed to meet specified impairment thresholds during comprehensive evaluation. Diagnosis of anxiety in the MTA study was based
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on structured parent Diagnostic Interview Schedule for Children interviews as opposed to more stringent parent/child K-SADS and PARS interview criteria in the current study. It is unknown whether parentreported anxiety in the MTA study would have met the DSM threshold for ANX. Similarly, it is unclear whether our assessment strategies and diagnostic thresholds adequately identified the type of patients with ADHD/ANX typically seen in clinical practice. Inclusion/exclusion criteria representative of those used by practitioners who treat youngsters with stimulants + SSRIs should be incorporated into future effectiveness studies. Clinical Implications
The results indicate that stimulant treatment in children with ADHD/ANX leads to ADHD symptom reductions similar to those seen in noncomorbid ADHD and that stimulants are tolerated without significant exacerbation of anxiety or development of untoward side effects. Consistent with the MTA study, a small but significant minority of children exhibited clinically meaningful reductions in anxiety with stimulant monotherapy. The mechanism underlying this reduction is unclear. Similar results in the MTA were postulated as resulting from decreased social conflicts, fewer failures, and more success experiences (MTA Cooperative Group, 1999b). Current consensus recommendations on treatment of ADHD/ANX suggest stimulant titration followed by SSRI therapy (Pliszka et al., 2000). Although this study provides the first evidence from a controlled trial suggesting that this medication combination is well tolerated and not associated with development of untoward side effects, the reductions in anxiety with added SSRI did not differ significantly from those obtained with PL. However, the absolute degree of improvement in anxiety symptom ratings was greater with FLV than with PL (effect size, Cohen’s d = 0.35), suggesting that a study with a larger sample size might be better powered to detect significant treatment differences. Disclosure: Dr. Abikoff has received support from McNeil (research support, consulting fees), Shire (research support, consulting fees), Eli Lilly (research support), and Celltech (consulting fees). Dr. McGough has received support from Eli Lilly (grant/research support, consulting fees, speaker’s bureau), McNeil (grant/research support, consulting fees, speaker’s bureau), Novartis (grant/research support, consulting fees, speaker’s bureau), Shire (grant/research support, consulting fees, speaker’s bureau), and Pfizer (consulting fees). Dr. McCracken has received sup-
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port from Eli Lilly (research support, consulting fees, speaker fees), Shire (research support, speaker fees), Pfizer (research support, consulting fees), Solvay (research support), Gliatech (research support), Bristol-Myers Squibb (consulting fees), McNeil (consulting fees), Noven (consulting fees), and Janssen (consulting fees). Dr. Walkup has received support from Abbott (grant support), Pfizer (grant support, honoraria), Janssen (honoraria), and Lilly (grant support, honoraria, consulting fees). Dr. Riddle has received support from Forest (speaker fees), Janssen (speaker fees, scientific advisor), Lilly (consulting fees), Pfizer (research support, consulting fees), Sanofi (consulting fees), AstraZeneca (scientific advisor), Shire (scientific advisor), Mallinckrodt, and Bristol-Myers Squibb (consulting fees). Dr. Oatis has received support (consulting fees and speaker fees) from Lilly, McNeil, and Shire. Dr. Greenhill has received support (honoraria or grants to do research) from Celltech, Shire, Lilly, McNeil, Alza, Janssen-Cilag, and Novartis. Dr. March has received support from Pfizer (consulting fees, speaker fees, scientific advisor), Solvay (speaker fee, consulting fee), Wyeth (research support, consulting fees), Shire (scientific advisor), and GSK (consulting fee). The other authors have no financial relationships to disclose.
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