Comparative Effectiveness Review Number 192 Anxiety in Children e Comparative Effectiveness Review Number 192 Anxiety in Children Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. 290-2015-00013-I Prepared by: Mayo Clinic Evidence-based Practice Center Rochester, MN Investigators: Zhen Wang, Ph.D. Stephen Whiteside, Ph.D., L.P. Leslie Sim, Ph.D., L.P. Wigdan Farah, M.B.B.S. Allison Morrow, B.A. Mouaz Alsawas, M.D., M.Sc. Patricia Barrionuevo Moreno, M.D. Mouaffaa Tello, M.D. Noor Asi, M.D. Bradley Beuschel, B.S.P.H. Lubna Daraz, Ph.D. Jehad Almasri, M.D. Feras Zaiem, M.D. Shalak Gunjal, M.S. Laura Larrea Mantilla, M.D. Oscar Ponce Ponte, M.D. Annie LeBlanc, Ph.D. Larry J. Prokop, M.L.S. M. Hassan Murad, M.D., M.P.H. AHRQ Publication No. 17-EHC023-EF August 2017 This report is based on research conducted by the Mayo Clinic Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2015-00013-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report is made available to the public under the terms of a licensing agreement between the author and the Agency for Healthcare Research and Quality. This report may be used and reprinted without permission except those copyrighted materials that are clearly noted in the report. Further reproduction of those copyrighted materials is prohibited without the express permission of copyright holders. AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied. This report may periodically be assessed for the currency of conclusions. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the title of the report. Persons using assistive technology may not be able to fully access information in this report. For assistance contact [email protected]. Suggested citation: Wang Z, Whiteside S, Sim L, Farah W, Morrow A, Alsawas M, Barrionuevo Moreno P, Tello M, Asi N, Beuschel B, Daraz L, Almasri J, Zaiem F, Gunjal S, Larrea Mantilla L, Ponce Ponte O, LeBlanc A, Prokop LJ, Murad MH. Anxiety in Children. Comparative Effectiveness Review No. 192. (Prepared by the Mayo Clinic Evidence-based Practice Center under Contract No. 290-2015-00013-I.) AHRQ Publication No. 17-EHC023-EF. Rockville, MD: Agency for Healthcare Research and Quality; August 2017. www.effectivehealthcare.ahrq.gov/reports/final.cfm. DOI: https://doi.org/10.23970/AHRQEPCCER192. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about AHRQ EPC systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm. AHRQ expects that these systematic reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an email list to learn about new program products and opportunities for input. If you have comments on this systematic review, they may be sent by mail to the Task Order Officers named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane, Rockville, MD 20857, or by email to [email protected]. Gopal Khanna, M.B.A. Arlene S. Bierman, M.D., M.S. Director Director Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Director Evidence-based Practice Center Program Suchitra Iyer, Ph.D. Center for Evidence and Practice Task Order Officer Improvement Center for Evidence and Practice Agency for Healthcare Research and Quality Improvement Agency for Healthcare Research and Quality David W. Niebuhr, M.D., M.P.H., M.Sc. Task Order Officer Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality iii Key Informants In designing the study questions, the EPC consulted several Key Informants who represent the end-users of research. The EPC sought the Key Informant input on the priority areas for research and synthesis. Key Informants are not involved in the analysis of the evidence or the writing of the report. Therefore, in the end, study questions, design, methodological approaches, and/or conclusions do not necessarily represent the views of individual Key Informants. Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any conflicts of interest. The list of Key Informants who provided input to this report follows: Lynn F. Bufka, Ph.D. Judith L. Rapoport, M.D. American Psychological Association National Institute of Mental Health Washington, DC Bethesda, MD Lauren G. Caldwell, J.D., Ph.D. Moira A. Rynn, M.D.* American Psychological Association Chair of Department of Psychiatry & Washington, DC Behavioral Sciences Duke University Medical Center Elizabeth Edgerton, M.D. Durham, NC Health Resources and Services Administration Joel Sherrill, Ph.D. Rockville, MD National Institute of Mental Health Bethesda, MD Stephanie C. Eken, M.D., FAAP Rogers Behavioral Health Elizabeth Sweet, M.Ed. Tampa, FL Substance Abuse and Mental Health Services Administration Raquel Halfond, Ph.D.* Rockville, MD American Psychological Association Washington, DC Jing Zhang, M.D., Ph.D. Food and Drug Administration Adrienne Kennedy, M.A. Silver Spring, MD National Alliance on Mental Illness Austin, TX Anna E. Ordóñez, M.D., M.A.S. National Institute of Mental Health Bethesda, MD *Provided input on Draft Report. iv Technical Expert Panel In designing the study questions and methodology at the outset of this report, the EPC consulted several technical and content experts. Broad expertise and perspectives were sought. Divergent and conflicted opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, methodologic approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified. The list of Technical Experts who provided input to this report follows: Jonathan Comer, Ph.D. Florida International University Jill Ehrenreich May, Ph.D. Miami, FL University of Miami Coral Gables, FL Stephanie C. Eken, M.D., FAAP Rogers Behavioral Health Tampa, FL Moira A. Rynn, M.D.* Abbe Garcia, Ph.D.* Chair of Department of Psychiatry & The Warren Alpert Medical School of Behavioral Sciences Brown University Duke University Medical Center East Providence, RI Durham, NC Amie E. Grills, Ph.D.* Boston University Boston, MA *Provided input on Draft Report. v Peer Reviewers Prior to publication of the final evidence report, EPCs sought input from independent Peer Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the scientific literature presented in this report do not necessarily represent the views of individual reviewers. Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified. The list of Peer Reviewers follows: Jennie M. Kuckertz, M.S. Karen T. G. Schwartz, M.S. SDSU/UC San Diego Joint Doctoral SDSU/UC San Diego Joint Doctoral Program in Clinical Psychology Program in Clinical Psychology San Diego, CA San Diego, CA Eli Lebowitz, Ph.D. John T. Walkup, M.D. Yale School of Medicine Weill Cornell Medicine and New York- New Haven, CT Presbyterian New York, NY David Rettew, M.D. University of Vermont Larner College of V. Robin Weersing, Ph.D. Medicine SDSU/UC San Diego Joint Doctoral Burlington, VT Program in Clinical Psychology San Diego, CA vi Anxiety in Children Structured Abstract Objectives. To evaluate the comparative effectiveness and safety of treatments for childhood anxiety disorders, including panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, and separation anxiety. Data sources. We searched MEDLINE®, Embase®, PsycINFO®, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus through February 1, 2017, and reviewed bibliographies and the gray literature. Review methods. We included randomized and non-randomized comparative studies that compared psychotherapy, pharmacotherapy, or a combination in children ages 3 to 18 years with panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, or separation anxiety. Pairs of independent reviewers selected studies using pre-specified inclusion and exclusion criteria. Results. We included 206 studies. Compared with pill placebo, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors improved primary anxiety symptoms (moderate to high strength of evidence [SOE]). Tricyclic antidepressants marginally improved clinical response (low SOE). Benzodiazepines did not show significant improvement in primary anxiety symptoms (low SOE). Data on head-to-head comparisons across drugs were sparse (only 2 RCTs; low SOE). Compared with waitlisting or no treatment, cognitive behavioral therapy (CBT) improved primary anxiety symptoms (clinician, child, and parent report), function, remission, and clinical response (low to moderate SOE). Compared with other therapies (attention control or treatment as usual), CBT reduced primary anxiety symptoms (child report; moderate SOE). Compared with CBT alone, the combination of imipramine and CBT reduced primary anxiety symptoms (child report) and function (moderate SOE). The combination of sertraline and CBT reduced primary anxiety symptoms (clinician report), improved function, and increased clinical response compared with CBT alone or sertraline alone (moderate SOE). CBT reduced primary anxiety symptoms and improved function more than fluoxetine, and was more likely to increase remission than sertraline. Medications increased short-term adverse events that were mostly not serious (low or moderate SOE). Studies were too small or too short to assess suicidality with SSRI or SNRI. One trial showed a statistically nonsignificant increase in suicidal ideation with venlafaxine (low SOE). Conclusions. CBT is effective in reducing anxiety symptoms and improving function. Medications, primarily those targeting serotonin, are also effective and were associated with various short-term adverse events, which were mostly not serious, but studies were too small or too short to assess suicidality with SSRI or SNRI. The combination of medications and CBT is likely more effective than either treatment alone. Comparative effectiveness evidence between various medications and comparing CBT versus medications, or the combination, is limited and represents a need for research in this field. Future research is needed to evaluate components of CBT, effect modifiers of treatment, and long-term safety of drugs, and needs to be more inclusive of underserved populations and minorities. vii Contents Introduction ................................................................................................................................... 1 Background ................................................................................................................................. 1 Scope and Key Questions ........................................................................................................... 2 Scope of the Review ............................................................................................................... 2 Key Questions ......................................................................................................................... 3 Methods .......................................................................................................................................... 5 Literature Search Strategy........................................................................................................... 5 Search Strategy ....................................................................................................................... 5 Inclusion and Exclusion Criteria ............................................................................................. 6 Study Selection ....................................................................................................................... 6 Data Extraction ....................................................................................................................... 6 Assessment of Methodological Risk of Bias of Individual Studies ........................................ 6 Data Synthesis ......................................................................................................................... 7 Grading the Strength of Evidence ........................................................................................... 8 Assessing Applicability .......................................................................................................... 9 Results .......................................................................................................................................... 10 Literature Searches and Evidence Base .................................................................................... 10 Analysis Results ........................................................................................................................ 10 KQ 1: What is the comparative effectiveness of the available treatments for childhood anxiety disorders, including panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, and separation anxiety? ......................................................... 10 KQ 2: What are the comparative harms and safety concerns regarding the available treatments for childhood anxiety disorders, including panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, and separation anxiety? .............................. 24 Discussion..................................................................................................................................... 40 Findings in Relation to What Is Known ................................................................................... 40 Limitations ................................................................................................................................ 42 Applicability ............................................................................................................................. 42 A Guide To Aid in Applicability .......................................................................................... 42 Future Research Needs ............................................................................................................. 43 Conclusion ................................................................................................................................ 44 References .................................................................................................................................... 45 Abbreviations .............................................................................................................................. 57 Tables Table 1. Psychotherapy used to treat childhood anxiety ..................................................................2 viii Table 2. Medications used to treat childhood anxiety .....................................................................2 Table 3. PICOTS (population, interventions, comparisons, outcomes, timing, and setting) ...........4 Table 4. Categories of standardized outcome measures ..................................................................8 Table 5. Strength of evidence for drug classes versus pill placebo ...............................................11 Table 6. Strength of evidence for individual drugs versus pill placebo.........................................12 Table 7. Strength of evidence for drugs versus drugs ....................................................................15 Table 8. Strength of evidence for drugs versus CBT .....................................................................16 Table 9. Strength of evidence for CBT versus pill placebo, waitlisting/no treatment, or attention control/treatment as usual ..............................................................................................................18 Table 10. Strength of evidence for CBT combined with drugs .....................................................21 Table 11. Strength of evidence for adverse events of drugs versus pill placebo ...........................24 Table 12. Strength of evidence for adverse events reported in other comparisons, including combination treatments ..................................................................................................................33 Table 13. Average standard deviations for commonly used scales that can be multiplied by SMD for conversion ................................................................................................................................40 Figure Figure 1. Analytic framework……………………………………………………………………... 5 Appendixes Appendix A. Flow Chart Appendix B. Search Strategy Appendix C. Criteria for Inclusion/Exclusion of Studies Appendix D. Excluded Studies Appendix E. Description of Included Studies Appendix F. Risk of Bias Appendix G. Subgroup Analysis Appendix H. Figures Appendix I. References for Appendixes ix