Meta-analysis
Systematic Review and Meta-analysis: An Empirical Approach to Defining Treatment Response and Remission in Pediatric Obsessive-Compulsive Disorder

https://doi.org/10.1016/j.jaac.2021.05.027Get rights and content

Objective

A lack of universal definitions for response and remission in pediatric obsessive-compulsive disorder (OCD) has hampered the comparability of results across trials. To address this problem, we conducted an individual participant data diagnostic test accuracy meta-analysis to evaluate the discriminative ability of the Children’s Yale−Brown Obsessive-Compulsive Scale (CY-BOCS) in determining response and remission. We also aimed to generate empirically derived cutoffs on the CY-BOCS for these outcomes.

Method

A systematic review of PubMed, PsycINFO, Embase and CENTRAL identified 5,401 references; 42 randomized controlled clinical trials were considered eligible, and 21 provided data for inclusion (N = 1,234). Scores of ≤2 in the Clinical Global Impressions Improvement and Severity scales were chosen to define response and remission, respectively. A 2-stage, random-effects meta-analysis model was established. The area under the curve (AUC) and the Youden Index were computed to indicate the discriminative ability of the CY-BOCS and to guide for the optimal cutoff, respectively.

Results

The CY-BOCS had sufficient discriminative ability to determine response (AUC = 0.89) and remission (AUC = 0.92). The optimal cutoff for response was a ≥35% reduction from baseline to posttreatment (sensitivity = 83.9, 95% CI = 83.7−84.1; specificity = 81.7, 95% CI = 81.5−81.9). The optimal cutoff for remission was a posttreatment raw score of ≤12 (sensitivity = 82.0, 95% CI = 81.8−82.2; specificity = 84.6, 95% CI = 84.4−84.8).

Conclusion

Meta-analysis identified empirically optimal cutoffs on the CY-BOCS to determine response and remission in pediatric OCD randomized controlled clinical trials. Systematic adoption of standardized operational definitions for response and remission will improve comparability across trials for pediatric OCD.

Section snippets

Eligibility Criteria

References were considered eligible for inclusion in the meta-analysis if the study (a) included individuals ≤18 years of age with a diagnosis of OCD as determined through formal diagnostic criteria (eg, DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, DSM-5, ICD-9, ICD-10); (b) evaluated the efficacy of any pharmacological or psychotherapeutic interventions in comparison to any control condition in the short-term (∼1-4 months) using random allocation procedures to determine the treatment group for

Study Selection and IPD Obtained

Our search identified 5,401 references, of which 42 RCTs were considered eligible for inclusion.6, 7, 8, 9, 10, 11, 12, 13, 14, 15,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 Figure 1 depicts the PRISMA flowchart for the inclusion/exclusion procedures with reasons for exclusion. Of the 42 potentially eligible trials, 4 authors replied that they did not have the CGI-I/CGI-S in their assessments. Of the remaining

Discussion

We performed an IPD meta-analysis to evaluate the discriminative ability of the CY-BOCS in determining positive treatment response and remission in RCTs for pediatric OCD. We also determined the empirically optimal cutoffs corresponding to both of these outcomes. Meta-analyses indicated that the percent (AUC = 0.89) and absolute (AUC = 0.83) reductions from baseline to posttreatment had sufficient discriminative ability to determine positive treatment response as defined by the CGI-I of ≤2; the

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  • Cited by (11)

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      A recent study examining Y-BOCS severity benchmarks for OCD across the lifespan identified subclinical OCD as corresponding to a total score of 0 to 13, mild OCD to 14 to 21, moderate OCD to 22 to 29, and severe OCD to 30 to 40.72 Positive treatment response is defined as a ≥35% score reduction, whereas symptom remission is defined as a raw score of ≤12 posttreatment.73 The CY-BOCS II was recently created to address criticisms of the psychometric properties of the original CY-BOCS.74

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      It is probably too ambitious to include several ratings per follow-up assessments; however, it could be explicitly stated in the instructions for raters doing follow-up assessments that they should rate the severity for the last month or two rather than for the last week. This has also been suggested by Farhat et al. (2021), even for the post-treatment assessment. As regards the reported 'optimal cut-offs', they should be interpreted with caution, especially having concluded that the overall predictive value is low.

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    Drs. Farhat and Vattimo contributed equally to this work.

    The authors have reported no funding for this work.

    Author Contributions

    Conceptualization: Farhat, Mataix-Cols, Bloch

    Data curation: Farhat, Vattimo, Ramakrishnan, Levine, Johnson, Artukoglu, Landeros-Weisenberger, Li, Bloch

    Formal analysis: Farhat, Bloch

    Methodology: Ramakrishnan, Bloch

    Resources: Asbahr, Cepeda, Comer, Fatori, Franklin, Freeman, Geller, Grant, Goodman, Heyman, Ivarsson, Lenhard, Lewin, Li, Merlo, Mohsenabadi, Peris, Piacentini, A.I. Rosa-Alcázar, À. Rosa-Alcázar, Rozenman, Sapyta, Serlachius, Shabani, Shavitt, Small, Skarphedinsson, Swedo, Thomsen, Turner, Weidle, Miguel, Storch, Mataix-Cols

    Supervision: Bloch

    Writing – original draft: Farhat, Mataix-Cols, Bloch

    Writing – review and editing: Farhat, Vattimo, Ramakrishnan, Levine, Johnson, Artukoglu, Landeros-Weisenberger, Asbahr, Cepeda, Comer, Fatori, Franklin, Freeman, Geller, Grant, Goodman, Heyman, Ivarsson, Lenhard, Lewin, Li, Merlo, Mohsenabadi, Peris, Piacentini, A.I. Rosa-Alcázar, À. Rosa-Alcázar, Rozenman, Sapyta, Serlachius, Shabani, Shavitt, Small, Skarphedinsson, Swedo, Thomsen, Turner, Weidle, Miguel, Storch, Mataix-Cols, Bloch

    Disclosure: Dr. Farhat has received salary support from 21/08540-0 by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Dr. Vattimo has reported that he will receive publishing honoraria from Conectfarma on behalf of Aché Laboratórios Farmacêuticos. Dr. Comer has received grant funding from the National Institutes of Health (NIH; R01 HD084497 and R42 MH123368), the Patient-Centered Outcomes Research Institute (PCORI), Boston Medical Center (PCS-2017C2-7588), the National Science Foundation (NSF; 1805645), the Substance Abuse and Mental Health Services Administration (SAMHSA; H79 SM085097), the Andrew Kukes Foundation for Social Anxiety, Alameda Research LLC, and the American Psychological Foundation. He has received royalties from Macmillan Learning and a stipend for editorial duties from the Association for Behavioral and Cognitive Therapies (ABCT). Dr. Fatori has received research support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (grant 2016/13451-9), the Open Society Foundation (grant OR219-62903), and the Grand Challenges Canada & Fundação Maria Cecilia Souto Vidigal (grant SB-POC-1810-20573). Dr. Freeman has received research funding from the National Institute of Mental Health (NIMH) and PCORI. She has received royalties from Oxford University Press and Guilford Press. She has served on the Scientific and Clinical Advisory Board of the International OCD Foundation (IOCDF). Dr. Geller has received grant or research support from Biohaven Pharmaceuticals, Neurocrine Biosciences, and Teva Pharmaceutical Industries. He has served on the editorial boards of Comprehensive Psychiatry and Annals of Clinical Psychiatry. He has received honoraria from the American Academy of Child and Adolescent Psychiatry. He has held stock options/ownership in Assurex Health, Revolutionary Road, and Neurocrine Biosciences. He has a Eunice Kennedy Shriver National Institute of Child Health and Human Development subcontract through the Duke Clinical Research Center. Dr. Goodman has received research funding from NIH, Biohaven Pharmaceuticals, and Mater Foundation. He has received honoraria from Biohaven Pharmaceuticals and Neurocrine. Dr. Lenhard has reported being previously employed by Stockholm Healthcare Services and now is currently employed by WeMind Psykiatri. Dr. Lewin has received research support from the Center for Diseases Control and Prevention, the REAM Foundation, and the Tourette Association of America (TAA), from whom he has received speaker honorarium and travel support. He has served as a consultant for Bracket, LLLC and Columbia University – Data Safety and Monitoring Board. He has served on the scientific advisory board for IOCDF and is a member of the American Psychological Association Commission on Accreditation and the Board of Directors of the American Board of Clinical Child and Adolescent Psychology, from whom he has received travel support. He has acknowledged receiving publishing honorarium and associate editor stipend from Springer and Elsevier. Dr. Peris has received research funding from NIMH and PCORI. She has received royalties from Oxford University Press. Dr. Piacentini has received research support from NIMH, PCORI, the TLC Foundation for BFRBs, and Pfizer Pharmaceuticals; publication royalties from Guilford Press and Oxford University Press; and travel/speaking honoraria from the TAA, IOCDF, and the TLC Foundation for BFRBs. Drs. A I. Rosa-Alcázar and À. Rosa- Alcázar have received research support from the Ministry of Economy and Competitiveness of the Spanish Government (Project PSI2016-78185-P) and the Science Agency and Technology (Seneca Foundation, Region of Murcia, Projet 20902/PI/18). These disclosures are unrelated to the current project. Dr. Rozenman has received funding in the last three years from NIMH (R61MH121552) and the University of Denver to conduct research unrelated to the current project. She will have a book published with Oxford’s Treatments that Work series and may receive royalties later this year. Dr. Shavitt has received research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ-303754/2018-4) and NIMH (RO1MH113250 subcontract). Dr. Small has received funding from the NIH and book royalties from Cambridge University Press. Dr. Thomsen has received royalties from book Publishers Gyldendal and Dansk Psykologisk Forlag for books on OCD and ADHD. He has received speaker fees within the last 3 years from Medicine and Shire. Dr. Weidle has received royalties from book publishers Gyldendal and Universitetsforlaget for co-authorship of books on OCD and Child and Adolescent Psychiatry. Dr. Miguel has received research support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (grants 2014/50917-0; 2020/06172-1; 2020/00851-4), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant CNNPQ-465550/2014-2), NIH (R01MH113250-01), and UNICEF (grant 43316196). Dr. Storch has received grant support from NIH, the Ream Foundation, the Greater Houston Community Foundation, IOCDF, ReBuild Texas, and the Texas Higher Education Coordinating Board. He has received book royalties from Elsevier, Springer, the American Psychological Association, Jessica Kingsley, Oxford, Wiley, and Lawrence Erlbaum. He has reported holding stock in NView, where he serves on the clinical advisory board. He has served as a consultant for Levo Therapeutics in the past 3 years, and currently serves as a consultant for Biohaven. Prof. Mataix-Cols has received personal fees from Elsevier for editorial work and royalties for contributing articles to UpToDate, Inc. Dr. Bloch has received grant or research support from Therapix Biosciences, Emalex Biosciences, Neurocrine Biosciences, Janssen Pharmaceuticals, Biohaven Pharmaceuticals, NIH, National Alliance for Research on Schizophrenia and Depression (NARSAD), Lesbian Health Fund , Yale Foundation for Lesbian and Gay Studies (FLAGS), and Patterson Foundation. He has served on the advisory board/data monitoring and safety board of Therapix Biosciences. He has served as associate editor of Journal of Child Psychology and Psychiatry and on the editorial boards of Journal of Child and Adolescent Psychopharmacology and Depression and Anxiety. He has received royalties from Wolters Kluwer for Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition. He has received moonlighting pay from the Veteran’s Administration. Drs. Artukoglu, Landeros-Weisenberger, Asbahr, Franklin, Grant, Heyman, Ivarsson, Li, Merlo, Mohsenabadi, Sapyta, Serlachius, Shabani, Skarphedinsson, Swedo, Turner, and Mss. Ramakrishnan, Levine, Johnson, Cepeda have reported no biomedical financial interests or potential conflicts of interest.

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