Methylphenidate for Preschoolers with ADHD
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Clinical Question: What’s the evidence out there for treating 4yo’s with ADHD?
Clinical Case or Background Info: 4yo WM is brought to an outpatient private practice clinic by his parents who are “desperate.” “John” has always been a much more active kid than any of his 3 brothers and sisters, his parents “can’t keep up” with him at home or wherever they take him, has just been kicked out of 2 preschools in the last month for aggressive behaviors towards his peers.
Question Type: Therapy
Validity Criteria for Therapy:
Follow-up: Follow-up was complete and all patients who entered the trial were properly accounted for and attributed at its conclusion.
Randomization: Computerized stratified randomization, 1:1:1:1 starting allocation ratio, using a randomized, balanced, crossover protocol designed to avoid order effects. Second randomization to active MPH or to placebo was performed before entering the parallel-design, placebo-controlled phase.
Intention to treat: Pts were analyzed in the groups to which they were randomized and all randomized patient data was analyzed.
Similar groups: Pts in treatment and control groups are similar with respect to known prognostic factors.
Blinding: Clinicians remained blind to the dose sequences except in emergencies and blinding was maintained for primary dependent measures until after the best dose was determined or as needed. Patent & teacher dose-response rating scale graphs prepared & blindly evaluated by 2 study clinicians who determined child’s best response by id’ing week with optimally minimized ADHD sx’s and medication SE’s. Parents & child blinded throughout. Active drug of different strengths and placebos all in same type of capsule.
Equal treatment: Aside from the intervention, groups were treated equally.
Study Design Type: Randomized Controlled Trial
Relevant Criteria for Randomized Controlled Trial:
Blinding: see above
Duration:5-week crossover-titration phase; 1 day washout; 4-week parallel-design within an 8-phase, 70 week trial.
Setting: Academic clinics at Columbia, Duke, John Hopkins, NYU, UC-Irvine & LA
Patients/Population: 303 Preschoolers (mean age 4.4, 73% male) recruited from communities surrounding Columbia, Duke, John Hopkins, NYU, UC-Irvine & LA diagnosed with ADHD-combined or hyperactive type (DISC) with moderate impairment (CGAS-I <55) w/ IQ>70, participating in out of home structured setting, with same primary caregiver >6mos prior. No other significant Axis I pathology requiring medication in child, cocaine/ stim. abuse in home, or h/o bipolar in both parents. ODD most common comorbidity,(1915 screened1272 eligible553 consented303 met criteria303 enrolled165 randomized into crossover-titration phase114 randomized into parallel trial). Those eligible for crossover-titration phase continued to meet ADHD severity criteria after 10wks parents training & completed 1 week sequential, open-label, safety lead-in phase.
Intervention/exposure: MPH-IR 1.25, 2.5, 5.0, or 7.5mg or placebo on TID schedule.
Outcomes:Primary outcome for titration phase (set a priori)-composite formed by standardizing & combining parent & teacher CLAM and SKAMP rating scales to reflect overall medication response for each dose across settings. Primary efficacy measure for parallel phase-met “excellent responder”criterion using combination of parent and teacher SNAP rating scales.
Main Results: Crossover phase-Sig linear trend w/ dose on SKAMP/CLAM scores and statistically sig reduced ADHD symptom scores for TID doses of 2.5, 5.0, and 7.5mg compared to placebo. No significant correlation b/w age and MPH absolute dose or MPH dose by weight. Effect sizes relative to placebo for scalar composite SKAMP/CLAM ratings during titration w/ doses 1.25, 2.5, 5, & 7.5 TID were 0.16, 0.34, 0.43, & 0.72. Parallel phase- Only22% on best dose MPH and 13% placebo met “excellent responder” criteria (non-sig diff). Effect sizes for composite ratings were 0.22, 0.48, 0.52, & 0.87 (same respective dose order). Safety & Tolerability Data: 92% tolerated MPH in open safety lead-in phase. 14 left d/t AE’s (9-emotionality/irritability). % AE’s more common at higher doses (appetite loss, trouble sleeping, stomach aches, social w/d, lethargy). Some elevated BP & tachycardia during crossover-titration phase. Weight velocity decreases seen in kids who completed titration & parallel phases. 8 serious AE’s during entire study, but only one (seizure) thought to be d/t medication. No mania, hypomania, depression or suidicality.
Conclusions: Preschoolers with severe ADHD respond to 7.5 to 30mg MPH, with mean optimal dose around 14+/-8mg/d. Although degree of response by effect size was less than that seen in MTA trial, this may have been d/t limitations on dose range imposed by regulatory agency, difficulty in assessing attention in preschoolers, and increased length and complexity of the whole PATS trial which required multiple reconsenting, “skip out” option for direct path to maintenance trt, and increased attrition during controlled phases.
Synopsis:
This NIMH-funded, 6-center, randomized, controlled 70 week trial that included 2 double-blind, controlled phases (crossover titration trial followed by placebo-controlled parallel trial) of 165 preschoolers with severe ADHD, MPH-IR was effective in the treatment of severe ADHD, but somewhat less so than previous studies investigating school-age children. Replication of this finding with a study design that includes higher doses is needed.
Presented by Kerry Landry MD, on 12/04/06
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