Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Feature Review
  • Published:

Treatment-resistant anxiety disorders

Abstract

Several epidemiological studies confirmed that Anxiety Disorders as a group are the most prevalent psychiatric conditions in the United States. The importance of these conditions is underlined by the fact that they cause significant disability, poor quality of life, alcohol and drug abuse. Anxiety disorders are treatable conditions and respond to the front-line interventions such as serotonin reuptake inhibitors and cognitive behavioral therapy. However, only about 60% of patients respond to those treatments to any significant degree. Many still have residual symptoms or stay treatment refractory. The group of anxiety patients that is resistant to the treatment has been shown to have very poor quality of life and have highest rate of suicidal attempts than any other disorders. Many biological, treatment specific and social factors are affecting treatment resistance. In this paper, we are attempting to review reasons for the treatment resistance. In addition, we would like to review current strategies that could be helpful in reducing treatment resistance and aiding people chronically suffering from these severe and disabling conditions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.

    Article  CAS  PubMed  Google Scholar 

  2. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med 2005; 352: 2515–2523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE . Prevalence severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 617–627.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Leon AC, Portera L, Weissman MM . The social costs of anxiety disorders. Br J Psychiatry Suppl 1995; 27: 19–22.

    Article  Google Scholar 

  5. Wittchen HU, Fehm L . Epidemiology, patterns of comorbidity, and associated disabilities of social phobia. Psychiatr Clin N Am 2001; 24: 617–641.

    Article  CAS  Google Scholar 

  6. Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J . Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry 2002; 63: 24–34.

    PubMed  Google Scholar 

  7. Diagnostic and Statistical Manual for Mental Disorders (DSM-IV). American Psychiatric Association: Washington, DC, 2000.

  8. Olfson M, Broadhead WE, Weissman MM, Leon AC, Farber L, Hoven C et al. Subthreshold psychiatric symptoms in a primary care group practice. Arch Gen Psychiatry 1996; 53: 880–886.

    Article  CAS  PubMed  Google Scholar 

  9. Pini S, Dell'Osso L, Mastrocinque C, Marcacci G, Papasogli A, Vignoli S et al. Prevalence and 12-month outcome of threshold and subthreshold mental disorders in primary care. J Affect Disord 1999; 56: 37–48.

    Article  CAS  PubMed  Google Scholar 

  10. Lochner C, Mogotsi M, du Toit PL, Kaminer D, Niehaus DJ, Stein D . Quality of life in anxiety disorders: a comparison of obsessive-compulsive disorder, social anxiety disorder, and panic disorder. Psychopathology 2003; 36: 255–262.

    Article  PubMed  Google Scholar 

  11. Bystritsky A, Saxena S, Maidment K, Vapnik T, Tarlow G, Rosen R . Quality-of-life changes among patients with obsessive-compulsive disorder in a partial hospitalization program. Psychiatr Serv 1999; 50: 412–414.

    Article  CAS  PubMed  Google Scholar 

  12. ADAA. Anxiety Disorders Association of America Website (ADAA.org). 2005.

  13. Barlow DH, Lehman CL . Advances in the psychosocial treatment of anxiety disorders. Implications for national health care. Arch Gen Psychiatry 1996; 53: 727–735.

    Article  CAS  PubMed  Google Scholar 

  14. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Baldwin DS, den Boer JA et al. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 1998; 59: 47–54.

    Article  PubMed  Google Scholar 

  15. 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 

  16. Ballenger JC, Davidson JR, Lecrubier Y, Nutt 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: 53–58.

    PubMed  Google Scholar 

  17. 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 2002; 3: 171–199.

    Article  PubMed  Google Scholar 

  18. Roy-Byrne P, Stein M, Bystrisky A, Katon W . Pharmacotherapy of panic disorder: proposed guidelines for the family physician. J Am Board Fam Pract 1998; 11: 282–290.

    Article  CAS  PubMed  Google Scholar 

  19. Klein E . The role of extended-release benzodiazepines in the treatment of anxiety: a risk–benefit evaluation with a focus on extended-release alprazolam. J Clin Psychiatry 2002; 63: 27–33.

    CAS  PubMed  Google Scholar 

  20. Otto MW, Pollack MH, Sachs GS, Reiter SR, Meltzer-Brody S, Rosenbaum JF . Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Am J Psychiatry 1993; 150: 1485–1490.

    Article  CAS  PubMed  Google Scholar 

  21. Barlow DH, Gorman JM, Shear MK, Woods SW . Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial. JAMA 2000; 283: 2529–2536.

    Article  CAS  PubMed  Google Scholar 

  22. Cowley DS, Ha DE, Roy-Byrne PP . Determinants of pharmacologic treatment failure in panic disorder. J Clin Psychiatry 1997; 58: 555–561.

    Article  CAS  PubMed  Google Scholar 

  23. Bakish D . New standard of depression treatment: remission and full recovery. J Clin Psychiatry 2001; 62: 5–9.

    PubMed  Google Scholar 

  24. Cuffel BJ, Azocar F, Tomlin M, Greenfield SF, Busch AB, Croghan TW . Remission, residual symptoms, and nonresponse in the usual treatment of major depression in managed clinical practice. J Clin Psychiatry 2003; 64: 397–402.

    Article  PubMed  Google Scholar 

  25. Nemeroff CB . Remission: today's target in the treatment of mood and anxiety disorders. Psychopharmacol Bull 2002; 36: 5.

    Google Scholar 

  26. Pollack MH, Meoni P, Otto MW, Simon N, Hackett D . Predictors of outcome following venlafaxine extended-release treatment of DSM-IV generalized anxiety disorder: a pooled analysis of short- and long-term studies. J Clin Psychopharmacol 2003; 23: 250–259.

    CAS  PubMed  Google Scholar 

  27. 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: 1293–1300.

    Article  CAS  PubMed  Google Scholar 

  28. 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: 1293–1300.

    Article  CAS  PubMed  Google Scholar 

  29. Kessler RC, Wittchen HU . Anxiety and depression: the impact of shared characteristics on diagnosis and treatment. Introduction. Acta Psychiatr Scand Suppl 2000; 406: 5–6.

    Article  Google Scholar 

  30. Bystritsky A . Diagnosis and treatment of anxiety. Focus 2004; 2: 333–342.

    Article  Google Scholar 

  31. Hollander E, Kwon JH, Stein DJ, Broatch J, Rowland CT, Himelein CA . Obsessive-compulsive and spectrum disorders: overview and quality of life issues. J Clin Psychiatry 1996; 57: 3–6.

    PubMed  Google Scholar 

  32. Gorman JM, Kent JM, Sullivan GM, Coplan JD . Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000; 157: 493–505.

    Article  CAS  PubMed  Google Scholar 

  33. LeDoux J . The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 2003; 23: 727–738.

    Article  PubMed  Google Scholar 

  34. Rauch SL . Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatment of psychiatric disorders. Neurosurg Clin N Am 2003; 14: 213–223.

    Article  PubMed  Google Scholar 

  35. Baxter LR . Neuroimaging studies of obsessive compulsive disorder. Psychiatr Clin North Am 1992; 15: 871–884.

    Article  PubMed  Google Scholar 

  36. Saxena S, Brody AL, Schwartz JM, Baxter LR . Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998; 35: 26–37.

    Article  Google Scholar 

  37. Craske MG, Barlow DH (eds). Contributions of Cognitive Psychology To Assessment and Treatment of Anxiety. In: Handbook of behavior therapy and psychological science: an integrative approach. Pergamon Press, Inc.: Elmsford, NY, US, 1991, pp 151–168.

    Google Scholar 

  38. Connor KM, Hidalgo RB, Crockett B, Malik M, Katz RJ, Davidson JR . Predictors of treatment response in patients with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 337–345.

    Article  CAS  PubMed  Google Scholar 

  39. Pollack MH, Meoni P, Otto MW, Simon N, Hackett D . Predictors of outcome following venlafaxine extended-release treatment of DSM-IV generalized anxiety disorder: a pooled analysis of short- and long term studies. J Clin Psychopharmacol 2003; 23: 250–259.

    CAS  PubMed  Google Scholar 

  40. Katerndahl DA . Predictors and outcomes in people told that they have panic attacks. Depress Anxiety 2003; 17: 98–100.

    Article  PubMed  Google Scholar 

  41. Roy-Byrne PP, Craske MG, Stein MB, Sullivan G, Bystritsky A, Katon W et al. A randomized effectiveness trial of collaborative care for patients with panic disorder in primary care. Arch Gen Psychiatry 2001; 58: 869–876.

    Article  CAS  PubMed  Google Scholar 

  42. Katon W . Panic disorder: epidemiology, diagnosis, and treatment in primary care. J Clin Psychiatry 1986; 47: 21–30.

    PubMed  Google Scholar 

  43. Craske MG, Edlund MJ, Sullivan G, Roy-Byrne P, Sherbourne C, Bystritsky A et al. Perceived unmet need for mental health treatment and barriers to care among patients with panic disorder. Psychiatr Serv 2005; 56: 988–994.

    Article  PubMed  Google Scholar 

  44. Craske MG, Roy-Byrne P, Stein MB, Donald-Sherbourne C, Bystritsky A, Katon W et al. Treating panic disorder in primary care: a collaborative care intervention. Gen Hosp Psychiatry 2002; 24: 148–155.

    Article  PubMed  Google Scholar 

  45. Nickel C, Tritt K, Kettler C, Lahmann C, Loew T, Rother W et al. Motivation for therapy and the results of inpatient treatment of patients with a generalized anxiety disorder: a prospective study. Wien Klin Wochenschr 2005; 117: 359–363.

    Article  PubMed  Google Scholar 

  46. Barlow DH, Gorman JM, Shear MK, Woods SW . Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA 2000; 283: 2529–2536.

    Article  CAS  PubMed  Google Scholar 

  47. 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: 1645–1654.

    Article  PubMed  Google Scholar 

  48. Foa EB, Kozak MJ, Steketee GS, McCarthy PR . Treatment of depressive and obsessive-compulsive symptoms in OCD by imipramine and behavior therapy. Br J Clin Psychol 1992; 31: 279–292.

    Article  PubMed  Google Scholar 

  49. Hambrick JP, Weeks JW, Harb GC, Heimberg RG . Cognitive-behavioral therapy for social anxiety disorder: supporting evidence and future directions. CNS Spectr 2003; 8: 373–381.

    Article  PubMed  Google Scholar 

  50. Ackerman DL, Greenland S . Multivariate meta-analysis of controlled drug studies for obessive-compulsive disorder. J Clin Psychopharmacol 2002; 22: 309–317.

    Article  CAS  PubMed  Google Scholar 

  51. Roy-Byrne PP, Bystritsky A, Russo J, Craske MG, Sherbourne CD, Stein MB . Use of herbal medicine in primary care patients with mood and anxiety disorders. Psychosomatics 2005; 46: 117–122.

    Article  PubMed  Google Scholar 

  52. Hollander E, Bienstock CA, Koran LM, Pallanti S, Marazziti D, Rasmussen SA et al. Refractory obsessive-compulsive disorder: state-of-the-art treatment. J Clin Psychiatry 2002; 63: 20–29.

    PubMed  Google Scholar 

  53. Blanco C, Raza MS, Schneier FR, Liebowitz MR . The evidence-based pharmacological treatment of social anxiety disorder. Int J Neuropsychopharmacol 2003; 6: 427–442.

    Article  CAS  PubMed  Google Scholar 

  54. Lauria-Horner BA, Pohl RB . Pregabalin: a new anxiolytic. Expert Opin Invest Drugs 2003; 12: 663–672.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  57. Pollack MH, Smoller JW . The longitudinal course and outcome of panic disorder. Psychiatr Clin N Am 1995; 18: 785–801.

    Article  CAS  Google Scholar 

  58. Goodman WK . Obsessive-compulsive disorder: diagnosis and treatment. J Clin Psychiatry 1999; 60: 27–32.

    PubMed  Google Scholar 

  59. Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M . Double-blind treatment with oral morphine in treatment-resistant obsessive compulsive disorder. J Clin Psychiatry 2005; 66: 353–359.

    Article  CAS  PubMed  Google Scholar 

  60. Pallanti S, Hollander E, Goodman WK . A qualitative analysis of nonresponse: management of treatment-refractory obsessive-compulsive disorder. J Clin Psychiatry 2004; 65: 6–10.

    Article  CAS  PubMed  Google Scholar 

  61. Fallon BA, Mathew SJ . Biological therapies for obsessive-compulsive disorder. J Psychiatr Pract 2000; 6: 113–128.

    CAS  PubMed  Google Scholar 

  62. Saxena S, Maidment KM, Vapnik T, Golden G, Rishwain T, Rosen RM et al. Obsessive-compulsive hoarding: symptom severity and response to multimodal treatment. J Clin Psychiatry 2002; 63: 21–27.

    Article  PubMed  Google Scholar 

  63. Bystritsky A, Liberman RP, Hwang S, Wallace CJ, Vapnik T, Maindment K et al. Social functioning and quality of life comparisons between obsessive-compulsive and schizophrenic disorders. Depress Anxiety 2001; 14: 214–218.

    Article  CAS  PubMed  Google Scholar 

  64. Shear MK, Houck P, Greeno C, Masters S . Emotion-focused psychotherapy for patients with panic disorder. Am J Psychiatry 2001; 158: 1993–1998.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    Google Scholar 

  67. Hughes JR . A review of the usefulness of the standard EEG in psychiatry. Clin Electroencephalogr 1996; 27: 35–39.

    Article  CAS  PubMed  Google Scholar 

  68. Jenike MA . An update on obsessive-compulsive disorder. Bull Menninger Clin 2001; 65: 4–25.

    Article  CAS  PubMed  Google Scholar 

  69. Beale MD, Kellner CH, Pritchett JT, Burns CM . ECT for OCD. J Clin Psychiatry 1995; 56: 81–82.

    CAS  PubMed  Google Scholar 

  70. Benabid AL, Pollak P, Gross C, Hoffmann D, Benazzouz A, Gao DM et al. Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease. Stereotact Funct Neurosurg 1994; 62: 76–84.

    Article  CAS  PubMed  Google Scholar 

  71. Gross RE, Lozano AM . Advances in neurostimulation for movement disorders. Neurol Res 2000; 22: 247–258.

    Article  CAS  PubMed  Google Scholar 

  72. Nuttin BJ, Gabriels L, van Kuyck K, Cosyns P . Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports. Neurosurg Clin N Am 2003; 14: 267–274.

    Article  PubMed  Google Scholar 

  73. Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, Taylor SF et al. Deep brain stimulation for refractory obsessive-compulsive disorder. Biol Psychiatry 2005; 57: 510–516.

    Article  PubMed  Google Scholar 

  74. Morris GL, Mueller WM . Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 1999; 53: 1731–1735.

    Article  PubMed  Google Scholar 

  75. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005; 58: 347–354.

    Article  PubMed  Google Scholar 

  76. Groves DA, Brown VJ . Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev 2005; 29: 493–500.

    Article  PubMed  Google Scholar 

  77. Martin JL, Barbanoj MJ, Schlaepfer TE, Clos S, Perez V, Kulisevsky J et al. Transcranial magnetic stimulation for treating depression. Cochrane Database System Rev 2002; 2: CD003493.

    Google Scholar 

  78. Greenberg BD, Ziemann U, Cora-Locatelli G, Harmon A, Murphy DL, Keel JC et al. Altered cortical excitability in obsessive-compulsive disorder. Neurology 2000; 54: 142–147.

    Article  CAS  PubMed  Google Scholar 

  79. Alonso P, Menchon JM, Pifarre J, Mataix-Cols D, Torres L, Salgado P et al. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2001; 158: 1143–1145.

    Article  CAS  PubMed  Google Scholar 

  80. Martin JL, Barbanoj MJ, Perez V, Sacristan M . Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder. Cochrane Database System Rev 2003; 3: CD003387.

    Google Scholar 

  81. Mantovani A, Lisanby SH, Pieraccini F, Ulivelli M, Castrogiovanni P, Rossi S . Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Int J Neuropsychopharmacol 2006; 9: 95–100.

    Article  PubMed  Google Scholar 

  82. Greenberg BD, Price LH, Rauch SL, Friehs G, Noren G, Malone D et al. Neurosurgery for intractable obsessive compulsive disorder and depression: critical issues. Neurosurg Clin N Am 2003; 14: 199–212.

    Article  PubMed  Google Scholar 

  83. Cosgrove GR, Rauch SL . Stereotactic cingulotomy. Neurosurg Clin N Am 2003; 14: 225–235.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

I like to thank Lauren Kerwin and Mary Grace Savella for their help with the preparation of this manuscript. This work was supported in part by Saban Family Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Bystritsky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bystritsky, A. Treatment-resistant anxiety disorders. Mol Psychiatry 11, 805–814 (2006). https://doi.org/10.1038/sj.mp.4001852

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001852

Keywords

This article is cited by

Search

Quick links