Skip to main content
SpringerLink
Log in

Treatment Resistance in Anxiety Disorder: Generalized Anxiety Disorder and Social Anxiety Disorder

  • Chapter
  • First Online:
Book cover Treatment Resistance in Psychiatry

  • 1286 Accesses

Abstract

Evidence-based treatments are suggested for generalized anxiety disorder (GAD) and social anxiety disorder (SAD). Pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs) and psychological treatment including cognitive-behavioral treatment (CBT) have been used as first-line treatments. However, many patients do not improve despite successful delivery of standard therapeutic interventions. The definition of treatment resistance is that standard treatments have been effectively delivered, but the results are ineffective. Overcoming treatment resistance requires reevaluation of the diagnosis and optimization of the treatments. Options for treatment-resistant GAD and SAD include augmentation with other antidepressants, atypical antipsychotics, benzodiazepines, and pregabalin. A partial NMDA agonist D-cycloserine was studied as a newer treatment option with exposure therapy in anxiety disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593–602.

    PubMed  Google Scholar 

  2. Ballenger JC. Treatment of anxiety disorders to remission. J Clin Psychiatry. 2001;62:5–9.

    PubMed  Google Scholar 

  3. Barlow DH, Lehman CL. Advances in the psychosocial treatment of anxiety disorders. Implications for national health care. Arch Gen Psychiatry. 1996;53(8):727–35.

    Article  CAS  Google Scholar 

  4. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Bobes J, Beidel DC, et al. Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 1998;59:54–60.

    PubMed  Google Scholar 

  5. Ballenger JC, Davidson JR, Lecrubier Y, Nut DJ, Borkovec TD, Rickels K, et al. Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2001;62:53–8.

    PubMed  Google Scholar 

  6. Ballenger JC. Current treatment of the anxiety disorders in adults. Biol Psychiatry. 1999;46(11):1579–94.

    Article  CAS  Google Scholar 

  7. Roy-Byrne P. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015;17(2):191–206.

    PubMed  PubMed Central  Google Scholar 

  8. Brown C, Schulberg HC, Madonia MJ, Shear MK, Houck PR. Treatment outcomes for primary care patients with major depression and lifetime anxiety disorders. Am J Psychiatry. 1996;153(10):1293–300.

    Article  CAS  Google Scholar 

  9. Bystritsky A. Treatment-resistant anxiety disorders. Mol Psychiatry. 2006;11(9):805–14.

    Article  CAS  Google Scholar 

  10. Pollack MH, Otto MW, Roy-Byrne PP, Coplan JD, Rothbaum BO, Simon NM, et al. Novel treatment approaches for refractory anxiety disorders. Depress Anxiety. 2008;25(6):467–76.

    Article  CAS  Google Scholar 

  11. Klumpp H, Keutmann MK, Fitzgerald DA, Shankman SA, Phan KL. Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder. Biol Mood Anxiety Disord. 2014;4(1):14.

    Article  Google Scholar 

  12. Roy-Whitfield-Gabrieli S, Ghosh SS, Nieto-Castanon A, Saygin Z, Doehrmann O, Chai XJ, et al. Brain connectomics predict response to treatment in social anxiety disorder. Mol Psychiatry. 2016;21(5):680–5.

    Article  Google Scholar 

  13. Byrne P, Cowley DS. Clinical approach to treatment-resistant panic disorder. In: Rosenbaum JF, Pollack MH, editors. Panic disorder and its treatment. New York: Marcel Dekker; 1998. p. 205–27.

    Google Scholar 

  14. Blanco C, Raza MS, Schneier FR, Liebowitz MR. The evidence-based pharmacological treatment of social anxiety disorder. Int J Neuropsychopharmacol. 2003;6(4):427–42.

    Article  CAS  Google Scholar 

  15. Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs. 2003;12(4):663–72.

    Article  CAS  Google Scholar 

  16. McDougle CJ, Barr LC, Goodman WK, Price LH. Possible role of neuropeptides in obsessive compulsive disorder. Psychoneuroendocrinology. 1999;24(1):1–24.

    Article  CAS  Google Scholar 

  17. Nemeroff CB. New vistas in neuropeptide research in neuropsychiatry: focus on corticotrophin releasing factor. Neuropsychopharmacology. 1992;6:69–75.

    CAS  PubMed  Google Scholar 

  18. Herranz R. Cholecystokinin antagonists: pharmacological and therapeutic potential. Med Res Rev. 2003;23(5):559–605.

    Article  CAS  Google Scholar 

  19. Holmes A, Heilig M, Rupniak NMJ, Steckler T, Griebel G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci. 2003;24(11):580–8.

    Article  CAS  Google Scholar 

  20. Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, et al. A double blind, placebo controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder. J Clin Psychopharmacol. 1995;15(6):428–34.

    Article  CAS  Google Scholar 

  21. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry. 2001;62:37–42.

    PubMed  Google Scholar 

  22. Krisanaprakornkit T, Sriraj W, Piyavhatkul N, Laopaiboon M. Meditation therapy for anxiety disorders. Cochrane Database Syst Rev. 2006;1:CD004998.

    Google Scholar 

  23. Hambrick JP, Weeks JW, Harb GC, Heimberg RG. Cognitive behavioral therapy for social anxiety disorder: supporting evidence and future directions. CNS Spectr. 2003;8(5):373–81.

    Article  Google Scholar 

  24. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61(11):1136–44.

    Article  Google Scholar 

  25. Walker DL, Ressler KJ, Lu KT, Davis M. Facilitation of conditioned fear extinction by systemic administration of intraamygdala infusions of D-cycloserine as assessed with fear potentiated startle in rats. J Neurosci. 2002;22(6):2343–51.

    Article  CAS  Google Scholar 

  26. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, et al. Augmentation of exposure therapy for social anxiety disorder with D-Cycloserine. Arch Gen Psychiatry. 2006;63(3):298–304.

    Article  CAS  Google Scholar 

  27. Canadian Psychiatric Association. Clinical practice guidelines: management of anxiety disorders. Can J Psychiatr. 2006;51(8 Suppl 2):9S.

    Google Scholar 

  28. Rubio G, Lopez-Ibor JJ. Generalized anxiety disorder: a 40-year follow-up study. Acta Psychiatr Scand. 2007;115(5):372–9.

    Article  CAS  Google Scholar 

  29. Yonkers KA, Warshaw MG, Massion AO, Keller MB. Phenomenology and course of generalized anxiety disorder. Br J Psychiatry. 1996;168(3):308–13.

    Article  CAS  Google Scholar 

  30. Pollack MH. Refractory generalized anxiety disorder. J Clin Psychiatry. 2009;70(Suppl 2):32–8.

    Article  Google Scholar 

  31. National Institute for Health and Clinical Excellence. Clinical guideline 22 (Amended). Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Available from at: http://www.nice.org.uk/CG022NICEguideline.

  32. Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19(6):567–96.

    Article  CAS  Google Scholar 

  33. Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry. 2008;9(4):248–312.

    Article  Google Scholar 

  34. Ipser JC, Carey P, Dhansay Y, Fakier N, Seedat S, Stein DJ. Pharmacotherapy augmentation strategies in treatment-resistant anxiety disorders. Cochrane Database Syst Rev. 2006;4:CD005473.

    Google Scholar 

  35. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66(10):1321–5.

    Article  CAS  Google Scholar 

  36. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 2006;59:211–5.

    Article  CAS  Google Scholar 

  37. Simon NM, Hoge EA, Fischmann D, Worthington JJ, Christian KM, Kinrys G, et al. An open-label trial of risperidone augmentation for refractory anxiety disorders. J Clin Psychiatry. 2006;67(3):381–5.

    Article  CAS  Google Scholar 

  38. Patterson B, Van Ameringen M. Augmentation strategies for treatment-resistant anxiety disorders: a systematic review and meta-analysis. Depress Anxiety. 2016;33(8):728–36.

    Article  Google Scholar 

  39. Adson DE, Kushner MG, Fahnhorst TA. Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors. J Affect Disord. 2005;86(1):99–104.

    Article  CAS  Google Scholar 

  40. Worthington JJ III, Kinrys G, Wygant LE, Pollack MH. Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol. 2005;20(1):9–11.

    Article  Google Scholar 

  41. Menza MA, Dobkin RD, Marin H. An open label trial of aripiprazole augmentation for treatment-resistant generalized anxiety disorder. J Clin Psychopharmacol. 2007;27(2):207–10.

    Article  Google Scholar 

  42. Hoge EA, Worthington IIIJJ, Kaufman RE, Delong HR, Pollack MH, Simon NM. Aripiprazole as augmentation treatment of refractory generalized anxiety disorder and panic disorder. CNS Spectr. 2008;13(6):522–7.

    Article  Google Scholar 

  43. Snyderman SH, Rynn MA, Rickels K. Open-label pilot study of ziprasidone for refractory generalized anxiety disorder. J Clin Psychopharmacol. 2005;25(5):497–9.

    Article  Google Scholar 

  44. Schwartz TL. The use of tiagabine augmentation for treatment-resistant anxiety disorders: a case series. Psychopharmacol Bull. 2002;36(2):53–7.

    PubMed  Google Scholar 

  45. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry. 1998;155(7):992–3.

    Article  CAS  Google Scholar 

  46. Pollack M. Levetiracetam (Keppra) for anxiety. Curbside Consult. 2002;1(4):4.

    Google Scholar 

  47. Crane D. Tiagabine for the treatment of anxiety. Depress Anxiety. 2003;18(1):51–2.

    Article  Google Scholar 

  48. Feltner DE, Pollack MH, Davidson JR, Stein MB, Fulterer R, Jefferson JW, et al. A placebo-controlled, double-blind study of pregabalin treatment of social phobia: outcome and predictors of response. J Eur Coll Neuropsychopharmacol. 2000;10:344–5.

    Article  Google Scholar 

  49. Rickels K, Pollack MH, Feltner DE, Lydiard RB, Zimbroff DL, Bielski RJ, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry. 2005;62(9):1022–30.

    Article  CAS  Google Scholar 

  50. Montgomery S, Chatamra K, Pauer L, Whalen E, Baldinetti F. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry. 2008;193(5):389–94.

    Article  Google Scholar 

  51. Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, et al. A randomized, double-blind, placebo controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;23(3):240–9.

    CAS  PubMed  Google Scholar 

  52. Pande AC, Crockatt JG, Feltner DE, Janney CA, Smith WT, Weisler R, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):533–40.

    Article  Google Scholar 

  53. Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771–82.

    Article  CAS  Google Scholar 

  54. Stein MB, Stein DJ. Social anxiety disorder. Lancet. 2008;371(9618):1115–25.

    Article  Google Scholar 

  55. Bandelow B, Baldwin DS, Dolberg OT, Andersen HF, Stein DJ. What is the threshold for symptomatic response and remission for major depressive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder. J Clin Psychiatry. 2006;67(9):1428–34.

    Article  Google Scholar 

  56. Stein DJ, Stein MB, Pitts CD, Kumar R, Hunter B. Predictors of response to pharmacotherapy in social anxiety disorder: an analysis of 3 placebo-controlled paroxetine trials. J Clin Psychiatry. 2002;63:152–5.

    Article  CAS  Google Scholar 

  57. Pallanti S, Quercioli L. Resistant social anxiety disorder response to escitalopram. Clin Pract Epidemiol Ment Health. 2006;2(1):35.

    Article  Google Scholar 

  58. Kelsey JE. Venlafaxine in social phobia. Psychopharmacol Bull. 1995;31:767–71.

    CAS  PubMed  Google Scholar 

  59. Altamura AC, Pioli R, Vitto M, Mannu P. Venlafaxine in social phobia: a study in selective serotonin reuptake non-responders. Int Clin Psychopharmacol. 1999;14(4):239–45.

    Article  CAS  Google Scholar 

  60. Aarre TF. Phenelzine efficacy in refractory social anxiety disorder: a case series. Nord J Psychiatry. 2003;57(4):313–5.

    Article  Google Scholar 

  61. Simon NM, Korbly NB, Worthington JJ, Kinrys G, Pollack MH. Citalopram for social anxiety disorder: an open-label pilot study in refractory and nonrefractory patients. CNS Spectr. 2002;7(9):655–7.

    Article  Google Scholar 

  62. Altamura AC, Pioli R, Vitto M, Mannu P. Venlafaxine in social phobia: a study in selective serotonin reuptake inhibitor non-responders. Int Clin Psychopharmacol. 1999;14(4):239–45.

    Article  CAS  Google Scholar 

  63. Barnett SD, Kramer ML, Casat CD, Connor KM, Davidson JR. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol. 2002;16(4):365–8.

    Article  CAS  Google Scholar 

  64. Shaywitz JE, Liebowitz MR. Antiepileptic treatment of anxiety disorders. Prim Psychiatry. 2003:51–6.

    Google Scholar 

  65. Van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M. An open-label trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry. 2004;65(12):1674–8.

    Article  Google Scholar 

  66. Kinrys G, Pollack MH, Simon NM, Worthington JJ, Nardi AE, Versiani M. Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol. 2003;18(3):169–72.

    PubMed  Google Scholar 

  67. Simon NM, Worthington JJ, Doyle AC, Hoge EA, Kinrys G, Fischmann D, et al. An open-label study of levetiracetam for the treatment of social anxiety disorder. J Clin Psychiatry. 2004;65(9):1219–22.

    Article  CAS  Google Scholar 

  68. Van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia. J Affect Disord. 1996;39(2):115–21.

    Article  Google Scholar 

  69. Stein MB, Sareen J, Hami S, Chao J. Pindolol potentiation of paroxetine for generalized social phobia: a double-blind, placebo-controlled, crossover study. Am J Psychiatry. 2001;158(10):1725–7.

    Article  CAS  Google Scholar 

  70. Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clonazepam with paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. J Clin Psychiatry. 2004;65(2):244–8.

    CAS  PubMed  Google Scholar 

  71. Blanco C, Heimberg RG, Schneier FR, Fresco DM, Chen H, Turk CL, et al. A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry. 2010;67(3):286–95.

    Article  CAS  Google Scholar 

  72. Blanco C, Okuda M, Markowitz JC, Liu SM, Grant BF, Hasin DS. The epidemiology of chronic major depressive disorder and dysthymic disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2010;71(12):1645–56.

    Article  Google Scholar 

  73. Guastella AJ, Richardson R, Lovibond PF, et al. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry. 2008;63:544–9.

    Article  CAS  Google Scholar 

  74. Mayo WE, Dias S, Mavranezouli I, Kew K, Clark DM, Ades AE, et al. Psychological and pharmacological interventions for social anxiety disorder in adults: a systematic review and network meta analysis. Lancet Psychiatry. 2014;1(5):368–76.

    Article  Google Scholar 

  75. Craske MG, Golinelli D, Stein MB, Roy-Byrne P, Bystritsky A, Sherbourne C. Does the addition of cognitive behavioral therapy improve panic disorder treatment outcome relative to medication alone in the primary care setting? Psychol Med. 2005;35(11):1645–54.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, CHA University, CHA Bundang Medical Center, Seongnam, South Korea

    Kang Soo Lee & Sang Hyuk Lee

Authors
  1. Kang Soo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Hyuk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Psychiatry, College of Medicine, Korea University, Seoul, Korea (Republic of)

    Yong-Ku Kim

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lee, K.S., Lee, S.H. (2019). Treatment Resistance in Anxiety Disorder: Generalized Anxiety Disorder and Social Anxiety Disorder. In: Kim, YK. (eds) Treatment Resistance in Psychiatry. Springer, Singapore. https://doi.org/10.1007/978-981-10-4358-1_14

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-4358-1_14

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-4357-4

  • Online ISBN: 978-981-10-4358-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation