This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Letter to the Editor

Dr Wang and Colleagues Reply

Liang-Jen Wang, MD, PhD; Sheng-Yu Lee, MD, PhD; and Yu-Chiau Shyu, PhD

Published: March 12, 2019


See letter by Poulton et al

This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Dr Wang and Colleagues Reply

To the Editor: In our recent study,1 we suggested that drug adherence in attention-deficit/hyperactivity disorder (ADHD) patients may be beneficial in the prevention of oppositional defiant disorder (ODD) or conduct disorder (CD). We are grateful for the opportunity to respond to Dr Poulton’s comments about our study.

First, substantial underdiagnosis of ODD and CD in this study population might be due to selection biases and affect our results. The rates of comorbid ODD and CD in ADHD were only 4.1% and 4.0%, respectively, in our study population, which are indeed lower than those reported in previous studies.2,3 The low comorbidity rate in our study may be attributed to the case-recruitment criteria. As such, we excluded patients who had an ODD or CD diagnosis prior to their ADHD diagnosis and whose ODD or CD diagnosis was made within 90 days after medical treatment. In addition, the low comorbidity rate might potentially be related to the lack of a systematic assessment in real-world clinical practice, in contrast to epidemiologic studies that use a structured interview to obtain a comprehensive screen of comorbidity and diagnosis confirmation. However, our sensitivity tests indicated that demographic characteristics may not influence the effect of drug compliance on comorbidity rates; therefore, we believe that drug adherence is an independent factor associated with decreased ODD/CD comorbidity rates.

Second, Dr Poulton questioned whether “a protective effect of medication for subsequent development of both ODD and CD is actually contradicted by the finding that a longer delay in starting medication after a diagnosis of ADHD was also protective.” Our data showed that diagnosis of ADHD at an older age was associated with a lower risk of developing ODD or CD. A possible explanation for this phenomenon is that age of diagnosis/prescription was also associated with patients’ characteristics. For example, patients with greater symptom severity or greater tendency toward disruptive behaviors may seek medical assistance or receive pharmacotherapy earlier than their counterparts with less severity, and this may lead to a lower risk of ODD/CD diagnosis in older patients. Actually, we only reported the results of our sensitivity analyses for drug adherence on the risk of developing ODD or CD, which showed that drug adherence (medication possession ratio ≥ 50% vs < 50%) consistently exerted protective effects on ODD or CD in each stratification (see Table 3 of article). The interval between ADHD diagnosis and medication (comparing < 3 months, 3-12 months, and > 12 months) did not significantly affect ODD/CD risk (see Table 2 of article). Therefore, our results should not be interpreted as showing that “delay in starting medication after a diagnosis of ADHD was also protective.”

Finally, we agree with Dr Poulton’s opinion: “A final warning about the pitfall of database studies: even though the study numbers may be appealingly large, extreme caution should be used in imputing complex clinical causality to limited database data of unknown accuracy.” Indeed, even though we used a large-scale nationwide database to conduct this study, we demonstrated only an association, not necessarily causality, between drug compliance and diagnosis of ODD/CD among youths with ADHD. Randomized controlled design is the gold standard for examining causal inference between these 2 events. However, due to ethical and practical concerns, it is impossible to carry out a longitudinal randomized controlled trial with 2 arms of volunteers (one for good drug compliance and the other for poor drug compliance) to determine the impact of drug adherence on ODD/CD among patients with ADHD. Use of nationwide naturalistic data is the best alternative way to investigate this research topic. We agree that cautious and conservative explanation regarding the causal relationships between persistence of medication treatment and onset of ODD/CD is warranted.


1. Wang LJ, Lee SY, Chou MC, et al. Impact of drug adherence on oppositional defiant disorder and conduct disorder among patients with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2018;79(5):17m11784. PubMed CrossRef

2. Yang LK, Shang CY, Gau SS. Psychiatric comorbidities in adolescents with attention-deficit hyperactivity disorder and their siblings. Can J Psychiatry. 2011;56(5):281-292. PubMed CrossRef

3. Gau SS, Lin YJ, Cheng AT, et al. Psychopathology and symptom remission at adolescence among children with attention-deficit-hyperactivity disorder. Aust N Z J Psychiatry. 2010;44(4):323-332. PubMed CrossRef

Liang-Jen Wang, MD, PhDa

Sheng-Yu Lee, MD, PhDb,c

Yu-Chiau Shyu, PhDd,e,f

aDepartment of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

bDepartment of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

cDepartment of Psychiatry, College of Medicine, Graduate Institute of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

dCommunity Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan

eInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan

fDepartment of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan

Published online: March 12, 2019.

Potential conflicts of interest: None.

Funding/support: None.

J Clin Psychiatry 2019;80(2):19lr12732a

To cite: Wang LJ, Lee SY, Shyu YC. Dr Wang and colleagues reply. J Clin Psychiatry. 2019;80(2):19lr12732a.

To share:

© Copyright 2019 Physicians Postgraduate Press, Inc.

Volume: 80

Quick Links: