Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis

Abstract

Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.

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References

  1. Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985). The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. American Journal of Mental Deficiency, 5, 485–491.

    Google Scholar 

  2. Bailey, D. B., Jr., Hatton, D. D., Skinner, M., & Mesibov, G. (2001a). Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndrome. Journal of Autism and Developmental Disorders, 31(2), 165–174.

    Article  Google Scholar 

  3. Bailey, D. B., Jr., Hatton, D. D., Tassone, F., Skinner, M., & Taylor, A. K. (2001b). Variability in FMRP and early development in males with fragile X syndrome. American Journal of Mental Retardation, 106(1), 16–27. https://doi.org/10.1352/0895-8017(2001)106%3c0016:VIFAED%3e2.0.CO;2.

    Article  PubMed  Google Scholar 

  4. Bailey, D. B., Jr., Mesibov, G. B., Hatton, D. D., Clark, R. D., Roberts, J. E., & Mayhew, L. (1998). Autistic behavior in young boys with fragile X syndrome. Journal of Autism and Developmental Disorders, 28(6), 499–508.

    Article  Google Scholar 

  5. Bailey, D. B., Jr., Raspa, M., Bishop, E., Mitra, D., Martin, S., Wheeler, A., et al. (2012a). Health and economic consequences of fragile X syndrome for caregivers. Journal of Developmental and Behavioral Pediatrics, 33(9), 705–712. https://doi.org/10.1097/DBP.0b013e318272dcbc.

    Article  PubMed  Google Scholar 

  6. Bailey, D. B., Jr., Raspa, M., Bishop, E., Olmsted, M., Mallya, U. G., & Berry-Kravis, E. (2012b). Medication utilization for targeted symptoms in children and adults with fragile X syndrome: US survey. Journal of Developmental and Behavioral Pediatrics, 33(1), 62–69. https://doi.org/10.1097/DBP.0b013e318236c0e1.

    Article  PubMed  Google Scholar 

  7. Bailey, D. B., Jr., Raspa, M., Olmsted, M., & Holiday, D. B. (2008). Co-occurring conditions associated with FMR1 gene variations: Findings from a national parent survey. American Journal of Medical Genetics Part A, 146A(16), 2060–2069. https://doi.org/10.1002/ajmg.a.32439.

    Article  PubMed  Google Scholar 

  8. Berry-Kravis, E., & Potanos, K. (2004). Psychopharmacology in fragile X syndrome—Present and future. Mental Retardation and Developmental Disabilities Research Reviews, 10(1), 42–48. https://doi.org/10.1002/mrdd.20007.

    Article  PubMed  Google Scholar 

  9. Berry-Kravis, E., Sumis, A., Hervey, C., & Mathur, S. (2012). Clinic-based retrospective analysis of psychopharmacology for behavior in fragile X syndrome. International Journal of Pediatrics, 2012, 843016. https://doi.org/10.1155/2012/843016.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Budimirovic, D. B., & Kaufmann, W. E. (2011). What can we learn about autism from studying fragile X syndrome? Developmental Neuroscience, 33(5), 379–394. https://doi.org/10.1159/000330213.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chevreul, K., Berg Brigham, K., Brunn, M., des Portes, V., & Network, B.-R. R. (2015). Fragile X syndrome: Economic burden and health-related quality of life of patients and caregivers in France. Journal of Intellectual Disability Research, 59(12), 1108–1120. https://doi.org/10.1111/jir.12215.

    Article  PubMed  Google Scholar 

  12. Chevreul, K., Gandre, C., Brigham, K. B., Lopez-Bastida, J., Linertova, R., Oliva-Moreno, J., et al. (2016). Social/economic costs and health-related quality of life in patients with fragile X syndrome in Europe. The European Journal of Health Economics, 17(Suppl 1), 43–52. https://doi.org/10.1007/s10198-016-0784-3.

    Article  PubMed  Google Scholar 

  13. Constantino, J. N., Davis, S. A., Todd, R. D., Schindler, M. K., Gross, M. M., Brophy, S. L., et al. (2003). Validation of a brief quantitative measure of autistic traits: Comparison of the social responsiveness scale with the autism diagnostic interview-revised. Journal of Autism and Developmental Disorders, 33(4), 427–433.

    Article  Google Scholar 

  14. Cordeiro, L., Ballinger, E., Hagerman, R., & Hessl, D. (2011a). Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: Prevalence and characterization. Journal of Neurodevelopmental Disorders, 3(1), 57–67. https://doi.org/10.1007/s11689-010-9067-y.

    Article  PubMed  Google Scholar 

  15. Cordeiro, L., Ballinger, E., Hagerman, R., & Hessl, D. (2011b). Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: Prevalence and characterization. Journal of Neurodevelopmental Disorders, 3(1), 57–67. https://doi.org/10.1007/s11689-010-9067-y.

    Article  PubMed  Google Scholar 

  16. Erickson, C. A., Davenport, M. H., Schaefer, T. L., Wink, L. K., Pedapati, E. V., Sweeney, J. A., et al. (2017). Fragile X targeted pharmacotherapy: Lessons learned and future directions. Journal of Neurodevelopmental Disorders, 9, 7. https://doi.org/10.1186/s11689-017-9186-9.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Erickson, C. A., Stigler, K. A., Posey, D. J., & McDougle, C. J. (2005). Risperidone in pervasive developmental disorders. Expert Review of Neurotherapeutics, 5(6), 713–719. https://doi.org/10.1586/14737175.5.6.713.

    Article  PubMed  Google Scholar 

  18. Erickson, C. A., Stigler, K. A., Posey, D. J., & McDougle, C. J. (2010). Aripiprazole in autism spectrum disorders and fragile X syndrome. Neurotherapeutics, 7(3), 258–263. https://doi.org/10.1016/j.nurt.2010.04.001.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Erickson, C. A., Stigler, K. A., Wink, L. K., Mullett, J. E., Kohn, A., Posey, D. J., et al. (2011). A prospective open-label study of aripiprazole in fragile X syndrome. Psychopharmacology (Berl), 216(1), 85–90. https://doi.org/10.1007/s00213-011-2194-7.

    Article  Google Scholar 

  20. Guy, W. (1976). ECDEU assessment manual for psychopharmacology. Publication no. 76-338. Washington, DC: U.S. DHEW, NIMH.

  21. Haessler, F., Gaese, F., Huss, M., Kretschmar, C., Brinkman, M., Peters, H., et al. (2016). Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: Final results of the observational EXPLAIN-FXS study. BMC Psychiatry, 16(1), 318. https://doi.org/10.1186/s12888-016-1020-5.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hagerman, R. J., & Hagerman, P. J. (2008). Testing for fragile X gene mutations throughout the life span. JAMA, 300(20), 2419–2421. https://doi.org/10.1001/jama.2008.684.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hagerman, R. J., & Polussa, J. (2015). Treatment of the psychiatric problems associated with fragile X syndrome. Current Opinion in Psychiatry, 28(2), 107–112. https://doi.org/10.1097/YCO.0000000000000131.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hatton, D. D., Bailey, D. B., Jr., Hargett-Beck, M. Q., Skinner, M., & Clark, R. D. (1999). Behavioral style of young boys with fragile X syndrome. Developmental Medicine and Child Neurology, 41(9), 625–632.

    Article  Google Scholar 

  25. Hatton, D. D., Wheeler, A. C., Skinner, M. L., Bailey, D. B., Sullivan, K. M., Roberts, J. E., et al. (2003). Adaptive behavior in children with fragile X syndrome. American Journal of Mental Retardation, 108(6), 373–390. https://doi.org/10.1352/0895-8017(2003)108%3c373:ABICWF%3e2.0.CO;2.

    Article  PubMed  Google Scholar 

  26. Hernandez, R. N., Feinberg, R. L., Vaurio, R., Passanante, N. M., Thompson, R. E., & Kaufmann, W. E. (2009). Autism spectrum disorder in fragile X syndrome: A longitudinal evaluation. American Journal of Medical Genetics Part A, 149A(6), 1125–1137. https://doi.org/10.1002/ajmg.a.32848.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kaufmann, W. E., Abrams, M. T., Chen, W., & Reiss, A. L. (1999). Genotype, molecular phenotype, and cognitive phenotype: Correlations in fragile X syndrome. American Journal of Medical Genetics, 83(4), 286–295.

    Article  Google Scholar 

  28. Kaufmann, W. E., Kidd, S. A., Andrews, H. F., Budimirovic, D. B., Esler, A., Haas-Givler, B., et al. (2017). Autism spectrum disorder in fragile X syndrome: Cooccurring conditions and current treatment. Pediatrics, 139(Suppl 3), S194–S206. https://doi.org/10.1542/peds.2016-1159F.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lewis, P., Abbeduto, L., Murphy, M., Richmond, E., Giles, N., Bruno, L., et al. (2006). Cognitive, language and social-cognitive skills of individuals with fragile X syndrome with and without autism. Journal of Intellectual Disability Research, 50(Pt 7), 532–545. https://doi.org/10.1111/j.1365-2788.2006.00803.x.

    Article  PubMed  Google Scholar 

  30. Loesch, D. Z., Huggins, R. M., & Hagerman, R. J. (2004). Phenotypic variation and FMRP levels in fragile X. Mental Retardation and Developmental Disabilities, 10(1), 31–41. https://doi.org/10.1002/mrdd.20006.

    Article  Google Scholar 

  31. McClellan, L., Pedapati, E., Wink, L., & Erickson, C. (2016). Evidence-based pharmacotherapy for autism spectrum disorders. Current Treatment Options in Psychiatry, 3(2), 161–181. https://doi.org/10.1007/s40501-016-0077-6.

    Article  Google Scholar 

  32. McDougle, C. J., Stigler, K. A., Erickson, C. A., & Posey, D. J. (2008). Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. Journal of Clinical Psychiatry, 69(Suppl 4), 15–20.

    PubMed  Google Scholar 

  33. Posey, D. J., Stigler, K. A., Erickson, C. A., & McDougle, C. J. (2008). Antipsychotics in the treatment of autism. Journal of Clinical Investigation, 118(1), 6–14. https://doi.org/10.1172/JCI32483.

    Article  PubMed  Google Scholar 

  34. Sansone, S. M., Widaman, K. F., Hall, S. S., Reiss, A. L., Lightbody, A., Kaufmann, W. E., et al. (2012). Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment. Journal of Autism and Developmental Disorders, 42(7), 1377–1392. https://doi.org/10.1007/s10803-011-1370-2.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sherman, S. L., Kidd, S. A., Riley, C., Berry-Kravis, E., Andrews, H. F., Miller, R. M., et al. (2017). FORWARD: A registry and longitudinal clinical database to study fragile X syndrome. Pediatrics, 139(Suppl 3), S183–S193. https://doi.org/10.1542/peds.2016-1159E.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Symons, F. J., Byiers, B. J., Raspa, M., Bishop, E., & Bailey, D. B. (2010). Self-injurious behavior and fragile X syndrome: Findings from the national fragile X survey. American Journal on Intellectual and Developmental Disabilities, 115(6), 473–481. https://doi.org/10.1352/1944-7558-115.6.473.

    Article  PubMed  Google Scholar 

  37. Symons, F. J., Clark, R. D., Hatton, D. D., Skinner, M., & Bailey, D. B., Jr. (2003). Self-injurious behavior in young boys with fragile X syndrome. American Journal of Medical Genetics Part A, 118A(2), 115–121. https://doi.org/10.1002/ajmg.a.10078.

    Article  PubMed  Google Scholar 

  38. Tsiouris, J. A., & Brown, W. T. (2004). Neuropsychiatric symptoms of fragile X syndrome: Pathophysiology and pharmacotherapy. CNS Drugs, 18(11), 687–703.

    Article  Google Scholar 

  39. Wheeler, A. C., Raspa, M., Bishop, E., & Bailey, D. B., Jr. (2016). Aggression in fragile X syndrome. Journal of Intellectual Disability Research, 60(2), 113–125. https://doi.org/10.1111/jir.12238.

    Article  PubMed  Google Scholar 

  40. Williams, K., Brignell, A., Randall, M., Silove, N., & Hazell, P. (2013). Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Systematic Review, 8, CD004677. https://doi.org/10.1002/14651858.cd004677.pub3.

    Article  Google Scholar 

  41. Witwer, A. N., & Lecavalier, L. (2007). Autism screening tools: An evaluation of the Social Communication Questionnaire and the Developmental Behaviour Checklist-Autism Screening Algorithm. Journal of Intellectual Developmental Disability, 32(3), 179–187. https://doi.org/10.1080/13668250701604776.

    Article  PubMed  Google Scholar 

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Funding

The FORWARD project is supported by the Cooperative Agreement Numbers 5U01DD000231, 5U19DD000753, and 1U01DD001189 funded by the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. No authors have a conflict financially or otherwise related to the content of this manuscript. The FORWARD database project was local IRB approved at all participating sites. The data reviewed in preparation of this manuscript was deidentified data.

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EME was the primary writer of the manuscript. KCD, EVP, LKW, RCS, and WEK participated in manuscript preparation and edited the manuscript. HA, TWC, and CC conducted the data analysis, participated in manuscript development and edited the manuscript. NT, EMB-K, and CAE participated in manuscript preparation, edited the document, and conceptualized the experiments in the manuscript.

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Correspondence to Craig A. Erickson.

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Eckert, E.M., Dominick, K.C., Pedapati, E.V. et al. Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis. J Autism Dev Disord 49, 4595–4602 (2019). https://doi.org/10.1007/s10803-019-04173-z

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Keywords

  • Fragile X syndrome
  • Irritability
  • Pharmacotherapy