Pharmacogenetically Guided Escitalopram Treatment for Pediatric Anxiety Disorders: Protocol for a Double-Blind Randomized Trial

Jeffrey R Strawn, Ethan A Poweleit, Jeffrey A Mills, Heidi K Schroeder, Zoe A Neptune, Ashley M Specht, Jenni E Farrow, Xue Zhang, Lisa J Martin, Laura B Ramsey, Jeffrey R Strawn, Ethan A Poweleit, Jeffrey A Mills, Heidi K Schroeder, Zoe A Neptune, Ashley M Specht, Jenni E Farrow, Xue Zhang, Lisa J Martin, Laura B Ramsey

Abstract

Current pharmacologic treatments for pediatric anxiety disorders (e.g., selective serotonin reuptake inhibitors (SSRIs)) frequently use "one size fits all" dosing strategies based on average responses in clinical trials. However, for some SSRIs, including escitalopram, variation in CYP2C19 activity produces substantial variation in medication exposure (i.e., blood medication concentrations). This raises an important question: would refining current SSRI dosing strategies based on CYP2C19 phenotypes increase response and reduce side effect burden? To answer this question, we designed a randomized, double-blind trial of adolescents 12-17 years of age with generalized, separation, and/or social anxiety disorders (N = 132). Patients are randomized (1:1) to standard escitalopram dosing or dosing based on validated CYP2C19 phenotypes for escitalopram metabolism. Using this approach, we will determine whether pharmacogenetically-guided treatment-compared to standard dosing-produces faster and greater reduction in anxiety symptoms (i.e., response) and improves tolerability (e.g., decreased risk of treatment-related activation and weight gain). Secondarily, we will examine pharmacodynamic variants associated with treatment outcomes, thus enhancing clinicians' ability to predict response and tolerability. Ultimately, developing a strategy to optimize dosing for individual patients could accelerate response while decreasing side effects-an immediate benefit to patients and their families. ClinicalTrials.gov Identifier: NCT04623099.

Keywords: CYP2C19; anxiety disorders; generalized anxiety disorder (GAD); pharmacogenetic; pharmacokinetic; selective serotonin reuptake inhibitor (SSRI); side effects; tolerability.

Conflict of interest statement

Strawn has received research support from NIH (National Institute of Mental Health/National Institute of Environmental Health Sciences/NICHD) and AbbVie. He has received material support from Myriad Genetics and royalties from the publication of two texts (Springer). He has served as an author for UpToDate and as an associate editor for Current Psychiatry and has received honoraria from American Academy of Pediatrics, American Academy of Child & Adolescent Psychiatry, CMEology, and Neuroscience Education Institute. He has provided consultation to the Food and Drug Administration and Intracellular Therapeutics. Ramsey has received research support from NIH (NICHD). She has received an educational grant and provided consultation to BTG Specialty Pharmaceuticals. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The NIH had no role in the design of the study; in planning of the analyses; in the writing of the manuscript; or in the decision to publish this work.

Figures

Figure 1
Figure 1
Multiple factors influence the efficacy and side effect profile of escitalopram in anxious adolescents. 5-HT, serotonin; SLC6A4, serotonin transporter. The current study primarily focuses on pharmacokinetic factors that impact response and tolerability (blue box), although, secondarily, pharmacodynamic influences (green box) are examined. Image created using Biorender.com.
Figure 2
Figure 2
Standard (top) and pharmacogenetically-guided dosing (bottom) in adolescents result in considerable variation and harmonization of the concentration–time curves, respectively. Adapted from Strawn et al., 2017.
Figure 3
Figure 3
Expected response rates and rates of specific adverse events (weight gain and activation) in patients receiving pharmacogenetically-guided and standard escitalopram dosing.

References

    1. Baxter A.J., Vos T., Scott K.M., Ferrari A.J., Whiteford H.A. The global burden of anxiety disorders in 2010. Psychol. Med. 2014;44:2363–2374. doi: 10.1017/S0033291713003243.
    1. Kessler R.C., Berglund P., Demler O., Jin R., Walters E.E. Lifetime prevalence and age-of-onset distributions’ of DSM-IV disorders in the national comorbidity survey replication. Arch. Gen. Psychiatry. 2005;62:593–602. doi: 10.1001/archpsyc.62.6.593.
    1. Costello E.J., Angold A., Burns B.J., Stangl D.K., Tweed D.L., Erkanli A., Worthman C.M. The Great Smoky Mountains Study of Youth. Goals, design, methods, and the prevalence of DSM-III-R disorders. Arch. Gen. Psychiatry. 1996;53:1129–1136. doi: 10.1001/archpsyc.1996.01830120067012.
    1. Asselmann E., Wittchen H.-U., Lieb R., Höfler M., Beesdo-Baum K. Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults. J. Psychiatr. Res. 2014;55:8–14. doi: 10.1016/j.jpsychires.2014.04.001.
    1. Beesdo K., Bittner A., Pine D.S., Stein M.B., Höfler M., Lieb R., Wittchen H.-U. Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life. Arch. Gen. Psychiatry. 2007;64:903–912. doi: 10.1001/archpsyc.64.8.903.
    1. Connolly S.D., Bernstein G.A. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J. Am. Acad. Child Adolesc. Psychiatry. 2007;46:267–283. doi: 10.1097/01.chi.0000246070.23695.06.
    1. Mohatt J., Bennett S.M., Walkup J.T. Treatment of Separation, Generalized, and Social Anxiety Disorders in Youths. Am. J. Psychiatry. 2014;171:741–748. doi: 10.1176/appi.ajp.2014.13101337.
    1. Strawn J.R., Geracioti L., Rajdev N., Clemenza K., Levine A. Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: An evidence-based treatment review. Expert Opin. Pharmacother. 2018;19:1057–1070. doi: 10.1080/14656566.2018.1491966.
    1. Strawn J.R., Mills J.A., Sauley B.A., Welge J.A. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J. Am. Acad. Child Adolesc. Psychiatry. 2018;57:235–244. doi: 10.1016/j.jaac.2018.01.015.
    1. Walkup J.T., Albano A.M., Piacentini J., Birmaher B., Compton S.N., Sherrill J.T., Ginsburg G.S., Rynn M.A., McCracken J., Waslick B., et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N. Engl. J. Med. 2008;359:2753–2766. doi: 10.1056/NEJMoa0804633.
    1. Aldrich S.L., Poweleit E.A., Prows C.A., Martin L.J., Strawn J.R., Ramsey L.B. Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders. Front. Pharmacol. 2019;10:1–12. doi: 10.3389/fphar.2019.00099.
    1. Sakolsky D.J., Perel J.M., Emslie G.J., Clarke G.N., Wagner K.D., Vitiello B., Keller M.B., Birmaher B., Asarnow J.R., Ryan N.D., et al. Antidepressant exposure as a predictor of clinical outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) study. J. Clin. Psychopharmacol. 2011;31:92–97. doi: 10.1097/JCP.0b013e318204b117.
    1. Olesen O.V., Linnet K. Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology. 1999;59:298–309. doi: 10.1159/000028333.
    1. Lloret-Linares C., Bosilkovska M., Daali Y., Gex-Fabry M., Heron K., Bancila V., Michalopoulos G., Perroud N., Richard-Lepouriel H., Aubry J.M., et al. Phenotypic assessment of drug metabolic pathways and P-glycoprotein in patients treated with antidepressants in an ambulatory setting. J. Clin. Psychiatry. 2018;79 doi: 10.4088/JCP.16m11387.
    1. Hicks J.K., Bishop J.R., Sangkuhl K., Muller D.J., Ji Y., Leckband S.G., Leeder J.S., Graham R.L., Chiulli D.L., LLerena A., et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin. Pharmacol. Ther. 2015;98:127–134. doi: 10.1002/cpt.147.
    1. Jukić M.M., Haslemo T., Molden E., Ingelman-Sundberg M. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: A retrospective study based on 2,087 patients. Am. J. Psychiatry. 2018;175:463–470. doi: 10.1176/appi.ajp.2017.17050550.
    1. Steere B., Baker J.A.R., Hall S.D., Guo Y. Prediction of in vivo clearance and associated variability of CYP2C19 substrates by genotypes in populations utilizing a pharmacogenetics-based mechanistic model. Drug Metab. Dispos. 2015;43:870–883. doi: 10.1124/dmd.114.061523.
    1. Ji Y., Schaid D.J., Desta Z., Kubo M., Batzler A.J., Snyder K., Mushiroda T., Kamatani N., Ogburn E., Hall-Flavin D., et al. Citalopram and escitalopram plasma drug and metabolite concentrations: Genome-wide associations. Br. J. Clin. Pharmacol. 2014;78:373–383. doi: 10.1111/bcp.12348.
    1. Uher R., Tansey K.E., Rietschel M., Henigsberg N., Maier W., Mors O., Hauser J., Placentino A., Souery D., Farmer A., et al. Common genetic variation and antidepressant efficacy in major depressive disorder: A meta-analysis of three genome-wide pharmacogenetic studies. Am. J. Psychiatry. 2013;170:207–217. doi: 10.1176/appi.ajp.2012.12020237.
    1. Strawn J.R., Mills J.A., Schroeder H., Mossman S.A., Varney S.T., Ramsey L.B., Poweleit E.A., Desta Z., Cecil K.M., Delbello M.P. Escitalopram in adolescents with generalized anxiety disorder. J. Clin. Psychiatry. 2020;81:e1–e9. doi: 10.4088/JCP.20m13396.
    1. Cipriani A., Zhou X., Del Giovane C., Hetrick S.E., Qin B., Whittington C., Coghill D., Zhang Y., Hazell P., Leucht S., et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: A network meta-analysis. Lancet. 2016;388:881–890. doi: 10.1016/S0140-6736(16)30385-3.
    1. Tulisiak A.K., Klein J.A., Harris E., Luft M.J., Schroeder H.K., Mossman S.A., Varney S.T., Keeshin B.R., Cotton S., Strawn J.R. Antidepressant Prescribing by Pediatricians: A Mixed-Methods Analysis. Curr. Probl. Pediatr. Adolesc. Health Care. 2017;47:15–24. doi: 10.1016/j.cppeds.2016.11.009.
    1. Reinblatt S.P., Dosreis S., Walkup J.T., Riddle M.A. Activation Adverse Events Induced by the Selective Serotonin Reuptake Inhibitor Fluvoxamine in Children and Adolescents. J. Child Adolesc. Psychopharmacol. 2009;19:119–126. doi: 10.1089/cap.2008.040.
    1. Safer D.J., Zito J.M. Treatment-Emergent Adverse Events from Selective Serotonin Reuptake Inhibitors by Age Group: Children versus Adolescents. J. Child Adolesc. Psychopharmacol. 2006;16:159–169. doi: 10.1089/cap.2006.16.159.
    1. Safer D.J. Raising the minimum effective dose of serotonin reuptake inhibitor antidepressants. J. Clin. Psychopharmacol. 2016;36:483–491. doi: 10.1097/JCP.0000000000000564.
    1. Hodgson K., Tansey K.E., Uher R., Dernovšek M.Z., Mors O., Hauser J., Souery D., Maier W., Henigsberg N., Rietschel M., et al. Exploring the role of drug-metabolising enzymes in antidepressant side effects. Psychopharmacology. 2015;232:2609–2617. doi: 10.1007/s00213-015-3898-x.
    1. Tibaldi G., Munizza C., Bollini P., Pampallona S., Kupelnick B. Effectiveness of antidepressants. Meta-analysis of dose-effect relationships in randomised clinical trials. Br. J. Psychiatry. 1999;174:297–303. doi: 10.1192/bjp.174.4.297.
    1. Rynn M.A., Walkup J.T., Compton S.N., Sakolsky D.J., Sherrill J.T., Shen S., Kendall P.C., McCracken J., Albano A.M., Piacentini J., et al. Child/Adolescent anxiety multimodal study: Evaluating safety. J. Am. Acad. Child Adolesc. Psychiatry. 2015;54:180–190. doi: 10.1016/j.jaac.2014.12.015.
    1. Luft M.J., Lamy M., DelBello M.P., McNamara R.K., Strawn J.R. Antidepressant-Induced Activation in Children and Adolescents: Risk, Recognition and Management. Curr. Probl. Pediatr. Adolesc. Health Care. 2018;48:50–62. doi: 10.1016/j.cppeds.2017.12.001.
    1. Zuckerman M.L., Vaughan B.L., Whitney J., Dodds A., Yakhkind A., MacMillan C., Raches D., Pravdova I., DeMaso D.R., Beardslee W.R., et al. Tolerability of selective serotonin reuptake inhibitors in thirty-nine children under age seven: A retrospective chart review. J. Child Adolesc. Psychopharmacol. 2007;17:165–174. doi: 10.1089/cap.2007.0086.
    1. Reid A.M., McNamara J.P.H., Murphy T.K., Guzick A.G., Storch E.A., Geffken G.R., Bussing R. Side-effects of SSRIs disrupt multimodal treatment for pediatric OCD in a randomized-controlled trial. J. Psychiatr. Res. 2015;71:140–147. doi: 10.1016/j.jpsychires.2015.10.006.
    1. Wilens T.E., Biederman J., Kwon A., Chase R., Greenberg L., Mick E., Spencer T.J., Wilens T.E., Biederman J., Kwon A., et al. A systematic chart review of the nature of psychiatric adverse events in children and adolescents treated with selective serotonin reuptake inhibitors. J. Child Adolesc. Psychopharmacol. 2003;13:143–152. doi: 10.1089/104454603322163862.
    1. Calarge C.A., Mills J.A., Janz K.F., Burns T.L., Coryell W.H., Zemel B.S. Body Composition in Adolescents During Treatment With Selective Serotonin Reuptake Inhibitors. Pediatrics. 2017;140:e20163943. doi: 10.1542/peds.2016-3943.
    1. Ramsey L.B., Aldrich S.L., Poweleit E., Prows C.A., Martin L.J., Strawn J.R. Racial Differences in Escitalopram/Citalopram-Related Weight Gain in Children and Adolescents: A Natural Language Processing-Based Electronic Medical Record Study. J. Child Adolesc. Psychopharmacol. 2019;29:162–163. doi: 10.1089/cap.2018.0110.
    1. Isolan L., Pheula G., Salum G.A., Jr., Oswald S., Rohde L.A., Manfro G.G. An open-label trial of escitalopram in children and adolescents with social anxiety disorder. J Child Adolesc Psychopharmacol. 2007;17:751–760. doi: 10.1089/cap.2007.0007.
    1. Emslie G.J., Ventura D., Korotzer A., Tourkodimitris S. Escitalopram in the treatment of adolescent depression: A randomized placebo-controlled multisite trial. J. Am. Acad. Child Adolesc. Psychiatry. 2009;48:721–729. doi: 10.1097/CHI.0b013e3181a2b304.
    1. Green D.J., Mummaneni P., Kim I.W., Oh J.M., Pacanowski M., Burckart G.J. Pharmacogenomics in the assessment of therapeutic risks versus benefits: Inside the United States Food and Drug Administration. Clin. Pharmacol. Ther. 2016;99:622–632. doi: 10.1002/cpt.330.
    1. Maruf A.A., Greenslade A., Arnold P.D., Bousman C. Antidepressant pharmacogenetics in children and young adults: A systematic review. J. Affect. Disord. 2019;254:98–108. doi: 10.1016/j.jad.2019.05.025.
    1. Porcelli S., Fabbri C., Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur. Neuropsychopharmacol. 2012;22:239–258. doi: 10.1016/j.euroneuro.2011.10.003.
    1. Huezo-Diaz P., Uher R., Smith R., Rietschel M., Henigsberg N., Marušič A., Mors O., Maier W., Hauser J., Souery D., et al. Moderation of antidepressant response by the serotonin transporter gene. Br. J. Psychiatry. 2009;195:30–38. doi: 10.1192/bjp.bp.108.062521.
    1. Tomita T., Yasui-Furukori N., Nakagami T., Tsuchimine S., Ishioka M., Kaneda A., Sugawara N., Kaneko S. The influence of 5-HTTLPR genotype on the association between the plasma concentration and therapeutic effect of paroxetine in patients with major depressive disorder. PLoS ONE. 2014;9:1–6. doi: 10.1371/journal.pone.0098099.
    1. Odgerel Z., Talati A., Hamilton S.P., Levinson D.F., Weissman M.M. Genotyping serotonin transporter polymorphisms 5-HTTLPR and rs25531 in European- and African-American subjects from the National Institute of Mental Health’s Collaborative Center for Genomic Studies. Transl. Psychiatry. 2013;3:e307-6. doi: 10.1038/tp.2013.80.
    1. Hu X.-Z., Lipsky R.H., Zhu G., Akhtar L.A., Taubman J., Greenberg B.D., Xu K., Arnold P.D., Richter M.A., Kennedy J.L., et al. Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder. Am. J. Hum. Genet. 2006;78:815–826. doi: 10.1086/503850.
    1. Mrazek D.A., Rush A.J., Biernacka J.M., O’Kane D.J., Cunningham J.M., Wieben E.D., Schaid D.J., Drews M.S., Courson V.L., Snyder K.A., et al. SLC6A4 variation and citalopram response. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2009;150:341–351. doi: 10.1002/ajmg.b.30816.
    1. Biernacka J.M., Sangkuhl K., Jenkins G., Whaley R.M., Barman P., Batzler A., Altman R.B., Arolt V., Brockmöller J., Chen C.H., et al. The International SSRI Pharmacogenomics Consortium (ISPC): A genome-wide association study of antidepressant treatment response. Transl. Psychiatry. 2015;5:1–9. doi: 10.1038/tp.2015.47.
    1. Horstmann S., Lucae S., Menke A., Hennings J.M., Ising M., Roeske D., Müller-Myhsok B., Holsboer F., Binder E.B. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010;35:727–740. doi: 10.1038/npp.2009.180.
    1. Niitsu T., Fabbri C., Bentini F., Serretti A. Pharmacogenetics in major depression: A comprehensive meta-analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2013;45:183–194. doi: 10.1016/j.pnpbp.2013.05.011.
    1. Keeling N.J., Rosenthal M.M., West-Strum D., Patel A.S., Haidar C.E., Hoffman J.M. Preemptive pharmacogenetic testing: Exploring the knowledge and perspectives of US payers. Genet. Med. 2019;21:1224–1232. doi: 10.1038/gim.2017.181.
    1. Czaja A.S., Valuck R.J., Anderson H.D. Comparative safety of selective serotonin reuptake inhibitors among pediatric users with respect to adverse cardiac events. Pharmacoepidemiol. Drug Saf. 2013;22:607–614. doi: 10.1002/pds.3420.
    1. Leeder J.S., Brown J.T., Soden S.E. Individualizing the use of medications in children: Making goldilocks happy. Clin. Pharmacol. Ther. 2014;96:304–306. doi: 10.1038/clpt.2014.130.
    1. Compton S.N., Walkup J.T., Albano A.M., Piacentini J.C., Birmaher B., Sherrill J.T., Ginsburg G.S., Rynn M.A., McCracken J.T., Waslick B.D., et al. Child/Adolescent Anxiety Multimodal Study (CAMS): Rationale, design, and methods. Child Adolesc. Psychiatry Ment. Health. 2010;4:1. doi: 10.1186/1753-2000-4-1.
    1. Sheehan D.V., Sheehan K.H., Shytle R.D., Janavs J., Bannon Y., Rogers J.E., Milo K.M., Stock S.L., Wilkinson B. Reliability and validity of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) J. Clin. Psychiatry. 2010;71:313–326. doi: 10.4088/JCP.09m05305whi.
    1. Caudle K.E., Dunnenberger H.M., Freimuth R.R., Peterson J.F., Burlison J.D., Whirl-Carrillo M., Scott S.A., Rehm H.L., Williams M.S., Klein T.E., et al. Standardizing terms for clinical pharmacogenetic test results: Consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Genet. Med. 2017;19:215–223. doi: 10.1038/gim.2016.87.
    1. Strawn J.R., Lu L., Peris T.S., Levine A., Walkup J.T. Research Review: Peadiatric Anxiety Disorders: What have we learnt in the last 10 years? J. Child Psychol. Psychiatry. 2020 doi: 10.1111/jcpp.13262.
    1. Periclou A., Rao N., Sherman T., Ventura D., Abramowitz W. Single-dose pharmacokinetic study of escitalopram in adolescents and adults; Proceedings of the Annual Meeting of the American College of Clinical Pharmacy; Atlanta, GA, USA. 2–5 November 2003.
    1. Chang M., Tybring G., Dahl M.L., Lindh J.D. Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis. Clin. Pharmacokinet. 2014;53:801–811. doi: 10.1007/s40262-014-0162-1.
    1. Strawn J.R., Poweleit E.A., Ramsey L.B. CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharmacokinetic Modeling Study. J. Child Adolesc. Psychopharmacol. 2019;29:340–347. doi: 10.1089/cap.2018.0160.
    1. Strawn J.R., Poweleit E.A., Uppugunduri C.R.S., Ramsey L.B. Pediatric Therapeutic Drug Monitoring for Selective Serotonin Reuptake Inhibitors. Front. Pharmacol. 2021;12:1–9. doi: 10.3389/fphar.2021.749692.
    1. Riddle M.A., Ginsburg G.S., Walkup J.T., Labelarte M.J., Pine D.S., Davies M., Greenhill L., Sweeney M., Klein R., Abikoff H., et al. The Pediatric Anxiety Rating Scale (PARS): Development and psychometric properties. J. Am. Acad. Child Adolesc. Psychiatry. 2002;41:1061–1069.
    1. Guy W. ECDEU Assessment Manual. U.S. Department of Health, Education, and Welfare; Rockville, MD, USA: 1976. CGI Clinical Global Impressions; pp. 217–222.
    1. Rynn M.A., Riddle M.A., Yeung P.P., Kunz N.R. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: Two placebo-controlled trials. Am. J. Psychiatry. 2007;164:290–300. doi: 10.1176/ajp.2007.164.2.290.
    1. Fluvoxamine for the Treatment of Anxiety Disorders in Children and Adolescents The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. N. Engl. J. Med. 2001;344:1279–1285. doi: 10.1056/nejm200104263441703.
    1. Strawn J.R., Prakash A., Zhang Q., Pangallo B.A., Stroud C.E., Cai N., Findling R.L. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J. Am. Acad. Child Adolesc. Psychiatry. 2015;54:283–293. doi: 10.1016/j.jaac.2015.01.008.
    1. Strawn J.R., Compton S.N., Robertson B., Albano A.M., Hamdani M., Rynn M.A. Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial. J. Child Adolesc. Psychopharmacol. 2017;27:29–37. doi: 10.1089/cap.2016.0132.
    1. Caporino N.E., Sakolsky D., Brodman D.M., McGuire J.F., Piacentini J., Peris T.S., Ginsburg G.S., Walkup J.T., Iyengar S., Kendall P.C., et al. Establishing Clinical Cutoffs for Response and Remission on the Screen for Child Anxiety Related Emotional Disorders (SCARED) J. Am. Acad. Child Adolesc. Psychiatry. 2017;56:696–702. doi: 10.1016/j.jaac.2017.05.018.
    1. Caporino N.E., Brodman D.M., Kendall P.C., Albano A.M., Sherrill J., Piacentini J., Sakolsky D., Birmaher B., Compton S.N., Ginsburg G., et al. Defining Treatment Response and Remission in Child Anxiety: Signal Detection Analysis Using the Pediatric Anxiety Rating Scale. J. Am. Acad. Child Adolesc. Psychiatry. 2013;52:57–67. doi: 10.1016/j.jaac.2012.10.006.
    1. Bussing R., Murphy T.K., Storch E.A., McNamara J.P.H., Reid A.M., Garvan C.W., Goodman W.K. Psychometric properties of the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) in youth with OCD. Psychiatry Res. 2013;205:253–261. doi: 10.1016/j.psychres.2012.09.019.
    1. Posner K., Brown G.K., Stanley B., Brent D.A., Yershova K.V., Oquendo M.A., Currier G.W., Melvin G.A., Greenhill L., Shen S., et al. The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am. J. Psychiatry. 2011;168:1266–1277. doi: 10.1176/appi.ajp.2011.10111704.
    1. Findling R.L., McCusker E., Strawn J.R. A Randomized, Double-Blind, Placebo-Controlled Trial of Vilazodone in Children and Adolescents with Major Depressive Disorder with Twenty-Six-Week Open-Label Follow-Up. J. Child Adolesc. Psychopharmacol. 2020;30:355–365. doi: 10.1089/cap.2019.0176.
    1. Strawn J.R., Welge J.A., Wehry A.M., Keeshin B., Rynn M.A. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: A systematic review and meta-analysis. Depress. Anxiety. 2015;32:149–157. doi: 10.1002/da.22329.
    1. Dobson E.T., Bloch M.H., Strawn J.R. Efficacy and tolerability of pharmacotherapy in pediatric anxiety disorders: A network meta-analysis. J. Clin. Psychiatry. 2019;80:17r12064. doi: 10.4088/JCP.17r12064.
    1. Mansoor B., Rengasamy M., Hilton R., Porta G., He J., Spirito A., Emslie G.J., Mayes T.L., Clarke G., Wagner K.D., et al. The Bidirectional Relationship Between Body Mass Index and Treatment Outcome in Adolescents with Treatment-Resistant Depression. J. Child Adolesc. Psychopharmacol. 2013;23:458–467. doi: 10.1089/cap.2012.0095.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever