Pii: s0272-7358(02)00129-0

Clinical Psychology Review 22 (2002) 1107 – 1131 Attention deficit/hyperactivity disorder and methylphenidate A review of height/weight, cardiovascular, and somatic aDepartment of Psychology, University of Central Florida, P.O. Box 161390, Orlando, FL 32816, USA bDepartment of Psychology, University of Hawaii, USA Received 15 February 2002; accepted 7 March 2002 Three classes (height/weight, cardiovascular, and somatic complaints) of treatment emergent symptoms (side effects) associated with methylphenidate (MPH) therapy for children with attentiondeficit/hyperactivity disorder (ADHD) are reviewed. The more easily quantifiable side effects (e.g.,blood pressure [BP], heart rate [HR], height/weight) are mostly transient, dose-dependent, easilyrectified with dosage adjustments, and considered minor from a clinical perspective considering thebreadth and level of improvement in behavior and cognitive functioning observed in most children.
Previously reported somatic complaints associated with psychostimulant therapy may reflectsymptoms occurring prior to initiation of treatment and require additional study.
D 2002 Elsevier Science Ltd. All rights reserved.
The short- and intermediate-term therapeutic efficacy of psychostimulants for treating children with attention deficit/hyperactivity disorder (ADHD) is well-established Cooperative Group, 1999). Beneficial effects are observed across multiple domains offunctioning based on direct observations of children’s attention, behavior, and academic * Corresponding author. Tel.: +1-401-823-2216; fax: +1-401-823-5862.
E-mail address: [email protected] (M.D. Rapport).
0272-7358/02/$ – see front matter D 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 2 7 2 - 7 3 5 8 ( 0 2 ) 0 0 1 2 9 - 0 Ss continued vs. d/c on MPHthrough summer: NSSs continued on stimulants Stimulants: sign decline inheight percentile vs. controls less than normal, for twopatients; sign greater than MPH < BL after1 – 4 years (dose-related) 1 year: MPH d/c forsummer > MPH continuedthrough summer 2 years: NS pharmacologicallytreated ADHD vs.
pharmacologically ADHD < pharmacologicallyuntreated ADHDADHD treated withstimulants in last 2 years 15 and 20 mgwith BL and initialvalues as covariates:HR: 10, 15, and20 mg MPH>PL Decrease in HR 120 min:PL; 180 min: PL, 5 mgWith BL as covariate:decrease in HR 120 and180 min: PL; increase inHR 120 min and 180 mm: stomachache: MPH 0.3,0.5>PL; MPH 0.5>MPH 0.3percent of severe occurrence:decreased appetite andinsomnia: MPH 0.5>PLTeacher ratings: staring and daydreaming,irritability, anxiety, and odds ratios: shown inparenthesisinsomnia: 0.5 mg MPH>Pl MPH>PL (5.29)dizziness: 0.5 mgMPH>PL (7.50); 0.3 mgMPH>PL (4.20) 5 – 10 mg>MPH 10 – 15 mgtics: PL>MPH 10 – 20 mg 4 months vs. MPHat 3 – 4 weeks vs. BL: NS picking at skin:75 mg>PLdecreased appetite:50 and 75 mg>PL, 25 mg Parent Rating Scale; CPT = Continuous Performance Test; CTRS = Conners’ Teachers’ Rating Scale; DBP = diastolic BP; d/c = discontinued;DEX = dextroamphetamine; DICA-P = Diagnostic Interview for Children and Adolescents—Parent Version; DMI = desipramine; HR = heart rate; significant; O = other; P = parent report; PEM = pemoline; Ph = physical or physiological measurement; PICS = Parent Interview for Child Symptoms;PL = placebo; PPVT = Peabody Picture Vocabulary Test; RCMAS = Revised Children’s Manifest Anxiety Scale; RT = reaction time; SEs = side effects;SBP = systolic BP; SE/BMS = Side Effects Behavior Monitoring Scale; SEQ = Side Effects Questionnaire; SNAP = Swanson, Nolan, and Pelham Checklist; SR = self-report; SPPC = Self-Perception Profile for Children; Ss = subjects; T = teacher report; UC-CCBS = University of California—Conners ChildBehavior Scale; WRAT-R = Wide Range Achievement Test—Revised; WWP = Werry – Weiss – Peters Activity Rating Scale.
M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 performance O’Neill, & Britton, 1985; DuPaul & Rapport, 1993; Rapport, Denney, DuPaul, & Gardner,1994), parent/teacher ratings of social deportment Newby, 1991; MTA Cooperative Group, 1999; Musten, Firestone, Pisterman, Bennett, &Mercer, 1997), and objective performance indices associated with a wide range of clinic-based neurocognitive tests, tasks, and paradigms (for reviews, see 2001; Losier, McGrath, & Klein, 1996; Rapport & Kelly, 1991). Peer relationships andinterpersonal behavior & Offord, 1991; Cunningham et al., 1985; Humphries, Kinsbourne, & Swanson, 1978;Smith et al., 1998; Whalen, Henker, Buhrmester, et al., 1989), and even performanceduring extracurricular activities such as playing baseball mayimprove as a function of treatment.
Psychostimulant treatment response rates are equally impressive, with positive effects ascertained in an estimated 50 –96% of children with ADHD, depending on the stringencywith which positive response is defined and the nature of the targeted outcome variable. Forexample, positive treatment response is estimated to occur in 70% of children undergoingpsychostimulant therapy whereas an overall 96% improvement rate inbehavior problems is demonstrated when response is defined as improvement on any one ofseveral alternative psychostimulants Con-versely, others have shown response rates to vary between 53% and 94% for academicefficiency and teacher-rated classroom behavior, respectively, when positive response isevaluated using psychometric indices such as statistically derived normative comparisonscores As with all medications and most other interventions, side effects can and do occur.
These effects warrant consideration because of their relevance to children’s health andpotential impact on treatment continuity. For example, significant cardiovascular effectsLogan, 1989) and reductions in growth velocity areassociated with psychostimulant treatment in children with ADHD. These and morecommonly reported emergent symptoms (e.g., insomnia, reduced appetite, stomachaches)may contribute to poor treatment compliance and are complicated by methodologicalissues that merit discussion. To this end, extant literature investigating both short- andlong-term emergent symptoms associated with methylphenidate (MPH) treatment wasreviewed using front- (e.g., PsycLit, MedScape) and back-search methodology. Articlespublished since 1970 and reporting inferential statistics were selected for review. Earlierstudies included children described as hyperactive, whereas those published after 1980included children meeting DSM criteria for ADHD 1980, 1987, 1994).
A total of 34 studies was located (see As shown in the table, three classes of dependent variables are emphasized in the studies and the focus of this review. Theseinclude effects on height and weight, cardiovascular effects (heart rate [HR] and bloodpressure [BP]), and somatic complaints—the latter of which are assessed using question-naire data derived from parent, teacher, and occasionally self-ratings. Studies are listed M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 under the three classes of dependent variables with additional study details noted underadjoining column headings. These include sample size, basic diagnostic criteria, primaryinstruments used to assess outcome, drug conditions, measurement source (e.g., physio-logical, self-report, parent report), experimental design employed, and a summary ofobtained results.
Eight of 11 studies investigating MPH effects on children’s weight reported significant differences in expected levels of weight gain Cantwell, Schell, & Blashke, 1979), less comparable weight gain between treated anduntreated children between placebo and activemedication conditions Tannock, Cunningham, & Corkum, 1997), or between baseline and active medicationThe remaining studies reported nosignificant MPH effect on children’s weight compared to baseline Hungund, & Young, 1982) or to untreated control children 1995). One of the eight studies reporting reduced weight gain initially found no significantdifference in weight at 2-year follow-up MPH effects on height were examined in 10 studies (see Four reported significant findings. These included reductions in expected levels of height gain less comparable height gain relative to control children lower heightpercentile under active medication contrasted to baseline andgreater expected gains in height percentiles at 2-year follow-up in children discontinued frommedication during summer months The initial reductions in children’sheight reported in two of the four investigations were no longer significant at long-termfollow-up assessment Extant studies of psychostimulant effects on children’s cardiovascular function tradition- ally examine indices of HR and BP. Seven of 14 studies examining MPH on HR reportedsignificant effects (see These include significant differences between placebo andactive drug Garfinkel, Wender, Sloman, & O’Neil, 1983; Kelly et al., 1988; Solanto & Conners, 1982;Sprague & Sleator, 1977; Tannock et al., 1989) and high- vs. low-dose contrast effects et al., 1988; Solanto & Conners, 1982; Tannock et al., 1989). The remaining seven studiesfailed to find HR changes under active drug compared to placebo Brown & Sexson, 1989; Brown, Wynne, & Slimmer, 1984; Conners & Taylor, 1980;Greenberg & Yellin, 1975) or nonmedicated ADHD control children or foundthat initial changes dissipated with time M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 Five of 10 studies examining MPH effects on children’s BP reported significantly elevated systolic BP compared to placebo Tannock et al., 1989; Winsberg et al., 1982) or baseline conditions whereas six reported significantly elevated diastolic BP compared to placebo 1976; Brown & Sexson, 1989; Conners & Taylor, 1980; Garfinkel et al., 1983; Tannocket al., 1989) or baseline conditions Four studies failed to findsignificant elevations in BP between drug and placebo Yellin, 1975; Winsberg et al., 1982) or between treated and untreated children withADHD 4. Somatic complaints (side effects questionnaires/ratings) Eight of 12 studies examining somatic complaints derived from questionnaire data reported significantly more complaints under MPH than placebo conditions. Commoncomplaints associated with MPH therapy included appetite reduction Barkley, McMurray, Edelbrock, & Robbins, 1990; Fine & Johnston, 1993), sleep disturbanceheadaches dizziness andstomachache Two studies failed to find significantdifferences in somatic complaints between MPH and placebo conditions Gaag, Swaab-Barneveld, & Kuiper, 1996; Manos, Short, & Findling, 1999), whereas fourreported paradoxical findings—that is, a significantly greater number of somatic complaintsunder placebo compared to MPH conditions.
Three of the four studies reporting paradoxical findings were based on teacher reports of more severe somatic complaints under placebo than MPH Anastopoulos, Kwasnick, Barkley, & McMurray, 1996; Fischer & Newby, 1991). The fourthstudy relied on parent ratings and reported significantly fewer somatic complaints such asstaring, daydreaming, irritability, anxiety, and nail biting under MPH than placebo et al., 1993).
Our review of potential side effects associated with MPH therapy in children with ADHD focused on the three most frequently reported classes of outcome variables reported in theliterature: weight and height, cardiovascular effects, and somatic complaints.
Studies investigating weight change suggest that MPH is associated with reduced levels of weight gain in some children at least initially and that this association may be dose-dependent. These effects appear to be transient and readily resolved by discontinuation of M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 stimulant therapy during summer months, dosage adjustment, and parent educationconcerning timing of medication (e.g., administration after meals; see Deutsch, & Baren, 1983). With respect to height, extant findings indicate initial reductionsin expected height percentiles in some children treated with psychostimulants. Theseeffects appear to be dose related mitigated in some childrenby discontinuing drug administration during summer months and failto remain significant in longer-term follow-up studies exceeding 4 years Manuzza, 1988).
A review of studies investigating cardiovascular effects indicates that elevated HR occurs in some children undergoing MPH therapy. Increases are generally reported to range from 3to 10 bpm, which are considered minor from a clinical perspective and appearto be linearly related to dose.
Systolic and diastolic BP is also elevated in some children as a function of MPH therapy.
Reported changes for systolic BP ranged from 3.3 to 8 mmHg, while those for diastolicpressure ranged from 1.5 to 14 mmHg.
Explanations offered to account for the paradoxical findings associated with a decreased frequency of somatic complaints as a function of increasing MPH dose include thepossibility that (a) adult raters (parents, teachers) confuse some symptoms of the disordersuch as daydreaming and staring with drug-related side effects and (b) children with ADHD exhibit high rates of somatic complaints without treatmentowing to the disabling nature of the disorder. In the latter case, reductions in somaticcomplaints may coincide with drug-related improved functioning at home and school, butwould require both baseline-placebo and baseline-active drug statistical contrasts todifferentiate everyday complaints from those due to expectancy or drug effects. Despitethe abundance of published MPH side effects studies, only one included both baseline-placebo and baseline-active drug statistical contrasts This study,however, cannot address whether decreased side effects under MPH are associated withhigher baseline rates of somatic complaints because of its design (between group), use of asingle, predetermined target dose, and titration procedure (designed to ‘‘minimize sideeffects,’’ p. 756).
Assessment of physical changes (weight, height) in children is relatively straightforward aside from potential measurement error associated with instrument scales or humanrecording of obtained values. Assessment of physiological functioning (BP and HR), incontrast, is subject to an additional potential confound based on predictions derived from the M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 law of initial value (LIV; The LIV posits that the magnitude of autonomicresponse to a stimulus is related to the prestimulus level of response (i.e., the initial value).
For function raising agents such as psychostimulants, a higher initial level of responding(e.g., a relatively high resting HR or BP recording prior to medication ingestion) should befollowed by a proportionally lower poststimulus response level. Conversely, a lowerprestimulus response level should result in a correspondingly higher poststimulus level ofresponding. At more extreme initial values, the effect should be negligible or even toreverse the direction of response.
The hour-to-hour periodicity in children’s HR and BP under no-medication conditions and the potential contribution of prestimulus response levels (i.e., the initial value of the response)have been virtually ignored in previous investigations. Past reports of significant increases inADHD children’s cardiovascular functioning with increasing dosage may thus be an artifactowing to expected fluctuations in HR and BP across days and even hours, as well as possibledependence on the initial value.
It is equally plausible that physiological effects reported in the literature may underestimate children’s response to psychostimulants (particularly at high doses) if HR or BP normallydecreases over time. For example, if decreases in resting HR normally occur in children overa 3-h interval, then increases associated with MPH may raise HR levels to initial baselinerecording levels and be misinterpreted as showing minimum or no change in HR forrecordings taken later than the initial time interval (e.g., HR assessed initially at 12 noonand again at 3 p.m.). To address these issues, examination of LIV phenomenon as they applyto children’s cardiovascular functioning is warranted and should incorporate multiple,standardized time intervals for recording physiological function under no medication andactive (multiple dose) medication conditions.
Two methodological considerations applicable to studying somatic complaints in children warrant discussion. As noted earlier, additional research involving carefulreplication and inclusion of necessary contrast conditions is needed to clarify whetherthe frequency of somatic complaints reported by children and by adults monitoringchildren exceed baseline levels in both acute and extended trials with psychostimulantsacross a broad range of doses. The importance of this issue is exemplified by studies ofsomatic complaints in the general child population and the interplay between somaticcomplaints and child psychopathology. Past studies, for example, reveal that somaticcomplaints such as headaches, stomachaches, musculoskeletal pain, back pain, dizziness,and fatigue are common in children 1991), with 10 –30% of children reporting weekly or frequent headaches & Costello, l998), 10 –25% reporting recurrent abdominal pain al., 1991), and 5–20% complaining of musculoskeletal pain Kristjansdottir, 1997). Psychiatric disability appears to accentuate the incidence of somaticcomplaints in children with internalizing (depression, anxiety disorders) and externalizingdisorders (oppositional defiant disorder, conduct disorder, ADHD), and stomachaches inparticular in children with ADHD (odds ratio = 3.5) compared to those without the disorderThese findings suggest that the ‘‘paradoxical’’reports of fewer side effects associated with MPH contrasted with placebo reported M.D. Rapport, C. Moffitt / Clinical Psychology Review 22 (2002) 1107–1131 previously may be a function of normally occurring base rates and associated emotional –behavioral problems. For example, children with ADHD are known to experiencesignificant problems and associated distress at home and in school owing to inherentdifficulties associated with the disorder, and may internalize these difficulties as physicalcomplaints. In such cases, improved behavior and school performance associated withMPH therapy may correspond with reductions in somatic complaints consistent withprevious reports of reductions in side effects ratings as a function of MPH therapy et al., 1993; Barkley et al., 1990; DuPaul et al., 1996; Fischer & Newby, 1991). Furtherresearch can elucidate this issue by establishing whether the breadth and severity ofgeneral physical complaints reported by children with ADHD vary as a function of schooland/or home difficulties over time.
A different issue concerns the questions asked on side effect rating scales. Many of the scale items on commonly used side effect questionnaires inquire about internal states (e.g.,stomach discomfort, headaches, mood, anxiety) that are not readily observed by others inthe child’s environment. In these cases, children, as opposed to external observers, mustbe relied upon to accurately report occurrence, severity, and possible changes over time.
Additional study in needed, however, to assess the temporal stability of these ratings (e.g.,by assessing within- and between-day complaints) and to cross-validate their occurrencewith observational data whenever possible. Parent – child agreement on side effectoccurrence must also be addressed to determine whether agreement varies acrossinternal –external states. Calculations using conventional statistics (e.g., correlation coef-ficients) typically rely exclusively on total score agreement but may need to becomplemented by item level analysis. For example, recent investigations reveal nosignificant differences between parent and child side effect total scores across placeboand MPH doses, but minimal agreement on individual scale items Moffitt, 2002).
Extant literature indicates that side effects associated with MPH may include transient weight loss, initial reductions in height velocity, elevated HR, increased BP, and somaticcomplaints (i.e., reduced appetite, sleep disturbance, headaches, dizziness, and stomach-aches). The more easily quantifiable side effects (e.g., BP, HR, and weight) are mostlytransient, dose-dependent, easily rectified with dosage adjustments, and considered minorfrom a clinical perspective considering the breadth and level of improvement in behaviorand cognitive functioning observed in most children. Previously reported somatic com-plaints associated with psychostimulant therapy may reflect symptoms occurring prior tothe initiation of treatment (at least to some degree) and require additional study. Carefulmonitoring of emergent symptoms in children undergoing MPH therapy remains the sinequa non of professional care and should be supplemented with prudent baselineassessment to disentangle normally occurring somatic complaints from changes associatedwith active treatment.
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