Predictors of Placebo Response in Adults With Attention-Deficit/Hyperactivity Disorder: Data From 2 Randomized Trials of Osmotic-Release Oral System Methylphenidate

Department of Cognitive Neuroscience (204), PO Box 9101, 6500 HB Nijmegen, The Netherlands .
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 06/2012; 73(8):1097-102. DOI: 10.4088/JCP.11m07528
Source: PubMed


To find potential correlates of placebo response in adults with attention-deficit/hyperactivity disorder (ADHD) and gain insights into why placebo response may be high in clinical trials.
Post hoc analysis of placebo data from 2 randomized controlled trials of osmotic-release oral system (OROS) methylphenidate in adults with ADHD defined according to the Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition: the Long-Acting Methylphenidate in Adults with ADHD (LAMDA-I) study (2005-2006, 5 weeks, n = 95) and the LAMDA-II study (2008-2009, 13 weeks, n = 97). The primary efficacy measure was the Conners' Adult ADHD Rating Scale-observer rated, short version (CAARS:O-SV). Predictors of CAARS:O-SV change were assessed using a random-intercepts model with demographic and disease-related parameters as independent variables. Sensitivity analyses were conducted using the CAARS self-report (CAARS:S-S) and a categorical response criterion (improvement of > 30% in CAARS:O-SV), and in subjects who completed the study.
In LAMDA-I, mean ± SD change in CAARS:O-SV was -7.6 ± 9.9 with placebo and -11.9 ± 10.6 with OROS methylphenidate. Higher baseline CAARS score (P = .007) and lower educational achievement (P = .014) were significantly associated with greater improvement in placebo-treated subjects. In LAMDA-II, mean ± SD change in CAARS:O-SV was -10.4 ± 11.0 and -14.1 ± 10.7 in subjects receiving placebo and OROS methylphenidate, respectively. Variables significantly associated with greater placebo response were higher baseline CAARS:O-SV (P = .019), shorter time since ADHD diagnosis (P < .045), and younger age (P = .014). None of the sensitivity analyses challenged the outcomes.
Possible predictors of placebo response in adults with ADHD include higher severity of ADHD symptoms, younger age, shorter time since diagnosis, and lower educational level. identifier: NCT00246220 (LAMDA-I) and EudraCT number: 2007-002111-82 (LAMDA-II).

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    • "The OROS-MPH studies were not included in the current analysis, as they were not able to demonstrate maintenance of response (Biederman et al., 2010; Buitelaar et al., 2012). "
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    ABSTRACT: The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD symptoms upon medication discontinuation. The objective of this narrative review and analysis was to better understand the relapse of ADHD symptoms upon discontinuation of medication treatment in children, adolescents, and adults with ADHD who have responded to medication treatment and to explore differences among different medications in maintaining treatment response. Randomized withdrawal studies of dexmethylphenidate hydrochloride (d-MPH), methylphenidate modified-release (MPH-LA), lisdexamphetamine dimesylate (LDX), guanfacine extended-release (GXR), and atomoxetine (ATX) in both children/adolescents and adults with ADHD were reviewed. The percentage of relapse was significantly higher and the time-to-relapse significantly shorter with placebo compared to active treatment in patients who were previously stable on 5 weeks to 1 year of active treatment, suggesting clinically significant benefit with continued long-term pharmacotherapy. However, percentage of relapse at each time point studied after discontinuing stimulants and GXR appears substantially higher than observed when discontinuing ATX, suggesting longer maintenance of response after discontinuing ATX than after stimulants and GXR. Additionally, slope of relapse percentages over time appears to be more rapid with stimulants or GXR than with ATX. These differences in maintenance of response among ATX, GXR, and stimulants may reflect differences in mechanisms of action and persistence of the medication effect. Alternatively, they may be due to methodological differences, including study design and response/relapse definitions. Continued investigation is needed regarding factors that affect risk of symptom relapse upon discontinuation of pharmacotherapy. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; 14(10). DOI:10.1016/j.euroneuro.2015.06.003 · 4.37 Impact Factor
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    ABSTRACT: Objective: The purpose of this study was to find potential variables associated with the difference between subjective and object treatment responses in children with attention-deficit/hyperactivity disorder (ADHD) treated with OROS-methylphenidate (MPH). Methods: We conducted a post-hoc analysis of data from a multicenter, open-label, 12 week trial of OROS-MPH in Korean children with ADHD. The subjective outcome measurement was the parent version of the ADHD Rating Scale-IV (ARS-P), and the objective outcome measurement was the Continuous Performance Test (CPT). We compared the children's demographic and disease-related variables among four groups, classified according to whether they showed subjective or objective improvement after MPH treatment. Results: Higher baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective treatment response among objective nonresponders (p=0.033). Lower baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective nonresponse among objective responders (p=0.045). Lower baseline omission errors (p=0.006) and response time variability scores (p=0.011) on the CPT were associated with a significantly higher probability of both objective and subjective responses, compared with both types of nonresponse to treatment. Conclusions: The baseline severity of parent-perceived inattentive symptoms was predictive of differences in subjective and objective treatment responses, and the baseline severity of neuropsychological deficit (inattention and inconsistency of attention) was predictive of responses, using both subjective and objective measurements.
    Journal of child and adolescent psychopharmacology 08/2013; 23(6):410-4. DOI:10.1089/cap.2013.0031 · 2.93 Impact Factor
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    ABSTRACT: Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P < 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.
    Journal of clinical psychopharmacology 04/2014; 34(2):212-7. DOI:10.1097/JCP.0000000000000091 · 3.24 Impact Factor
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