SpringerLink
Log in

Predicting and Managing Treatment Non-response in Posttraumatic Stress Disorder

  • PTSD (S Creech and L Sippel, Section Editors)
  • Published:
Current Treatment Options in Psychiatry Aims and scope Submit manuscript

Abstract

Purpose of review

This review aims to synthesize existing research regarding the definition of treatment resistance in posttraumatic stress disorder (PTSD), predictors of treatment non-response to first-line interventions, and emerging second-line PTSD treatment options into an accessible resource for the practicing clinician.

Recent findings

The concept of treatment resistance in PTSD is currently poorly defined and operationalized. There are no well-established predictors of treatment non-response utilized in routine clinical care, but existing research identifies several potential candidate markers, including male gender, low social support, chronic and early life trauma exposure, comorbid psychiatric disorders, severe PTSD symptoms, and poor physical health. The most promising available treatment options for PTSD patients non-responsive to first-line psychotherapies and antidepressants include transcranial magnetic stimulation and ketamine infusion. Methylenedioxymethamphetamine-assisted psychotherapy also appears promising but is only available in a research context. These options require careful consideration of risks and benefits for a particular patient.

Summary

More research is required to develop a robust, clinically useful definition of treatment resistance in PTSD; identify reliable, readily assessable, and generalizable predictors of PTSD treatment non-response; and implement measurement and prediction in clinical settings to identify individuals unlikely to respond to first-line treatments and direct them to appropriate second-line treatments.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Seal KH, Metzler TJ, Gima KS, Bertenthal D, Maguen S, Marmar CR. Trends and risk factors for mental health diagnoses among Iraq and Afghanistan veterans using Department of Veterans Affairs health care, 2002-2008. Am J Public Health. 2009;99(9):1651–8. https://doi.org/10.2105/ajph.2008.150284.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Marmar CR, Schlenger W, Henn-Haase C, Qian M, Purchia E, Li M, et al. Course of posttraumatic stress disorder 40 years after the Vietnam war: findings from the National Vietnam Veterans Longitudinal Study. JAMA Psychiatry. 2015;72(9):875–81. https://doi.org/10.1001/jamapsychiatry.2015.0803.

    Article  PubMed  Google Scholar 

  3. Schnurr PP, Lunney CA, Bovin MJ, Marx BP. Posttraumatic stress disorder and quality of life: extension of findings to veterans of the wars in Iraq and Afghanistan. Clin Psychol Rev. 2009;29(8):727–35. https://doi.org/10.1016/j.cpr.2009.08.006.

    Article  PubMed  Google Scholar 

  4. • Cusack K, Jonas DE, Forneris CA, Wines C, Sonis J, Middleton JC, et al. Psychological treatments for adults with posttraumatic stress disorder: a systematic review and meta-analysis. Clin Psychol Rev. 2016;43:128–41. https://doi.org/10.1016/j.cpr.2015.10.003.Large meta-analysis of psychological treatments for PTSD.

    Article  PubMed  Google Scholar 

  5. Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006; (1):Cd002795. doi:https://doi.org/10.1002/14651858.CD002795.pub2.

  6. • Koek RJ, Schwartz HN, Scully S, Langevin J-P, Spangler S, Korotinsky A, et al. Treatment-refractory posttraumatic stress disorder (TRPTSD): a review and framework for the future. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;70:170–218. https://doi.org/10.1016/j.pnpbp.2016.01.015.A very comprehensive literature review on treatment-refractory PTSD.

    Article  Google Scholar 

  7. Schottenbauer MA, Glass CR, Arnkoff DB, Tendick V, Gray SH. Nonresponse and dropout rates in outcome studies on PTSD: review and methodological considerations. Psychiatry. 2008;71(2):134–68. https://doi.org/10.1521/psyc.2008.71.2.134.

    Article  PubMed  Google Scholar 

  8. • VA/DOD. Clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. Washington: Department of Veterans Affairs; 2017.One of the major evidence-based guidelines for treatment of PTSD.

    Google Scholar 

  9. • American Psychological Association clinical practice guideline for the treatment of posttraumatic stress disorder. 2017.A second major evidence-based guideline for the treatment of PTSD.

  10. Foa EB, Hembree EA, Rothbaum BO, Rauch SA. Prolonged exposure therapy for PTSD: emotional processing of traumatic experiences. Second ed. treatments that work. Oxford: Oxford University Press; 2019.

    Book  Google Scholar 

  11. Resick PA, Monson CM, Chard KM. Cognitive processing therapy for PTSD: a comprehensive manual. New York: The Guilford Press; 2017.

    Google Scholar 

  12. • Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507–17. https://doi.org/10.1056/NEJMoa1507598.This trial called into question the apparent efficacy of prazosin for treating nightmares in PTSD.

  13. Foa EB, Gillihan SJ, Bryant RA. Challenges and successes in dissemination of evidence-based treatments for posttraumatic stress: lessons learned from prolonged exposure therapy for PTSD. Psychol Sci Public Interest : a journal of the American Psychological Society. 2013;14(2):65–111. https://doi.org/10.1177/1529100612468841.

    Article  Google Scholar 

  14. • Merz J, Schwarzer G, Gerger H. Comparative efficacy and acceptability of pharmacological, psychotherapeutic, and combination treatments in adults with posttraumatic stress disorder: a network meta-analysis. JAMA Psychiatry. 2019. https://doi.org/10.1001/jamapsychiatry.2019.0951.A controversial meta-analysis that yielded some evidence that psychotherapeutic interventions are superior to pharmacological interventions for treating PTSD.

  15. • Sippel LM, Holtzheimer PE, Friedman MJ, Schnurr PP. Defining treatment-resistant posttraumatic stress disorder: a framework for future research. Biol Psychiatry. 2018;84(5):e37–41. https://doi.org/10.1016/j.biopsych.2018.03.011.This article outlines a proposal and framework for measuring and defining treatment resistance in PTSD.

  16. Hinton DE, Hofmann SG, Rivera E, Otto MW, Pollack MH. Culturally adapted CBT (CA-CBT) for Latino women with treatment-resistant PTSD: a pilot study comparing CA-CBT to applied muscle relaxation. Behav Res Ther. 2011;49(4):275–80. https://doi.org/10.1016/j.brat.2011.01.005.

    Article  PubMed  Google Scholar 

  17. Schnurr PP, Lunney CA. Symptom benchmarks of improved quality of life in PTSD. Depress Anxiety. 2016;33(3):247–55. https://doi.org/10.1002/da.22477.

    Article  PubMed  Google Scholar 

  18. Scherrer JF, Salas J, Norman SB, Schnurr PP, Chard KM, Tuerk P, et al. Association between clinically meaningful posttraumatic stress disorder improvement and risk of type 2 diabetes. JAMA Psychiatry. 2019. https://doi.org/10.1001/jamapsychiatry.2019.2096.

  19. • Wade D, Varker T, Kartal D, Hetrick S, O'Donnell M, Forbes D. Gender difference in outcomes following trauma-focused interventions for posttraumatic stress disorder: systematic review and meta-analysis. Psychol Trauma : theory, research, practice and policy. 2016;8(3):356–64. https://doi.org/10.1037/tra0000110.A novel meta-analysis that examines gender differences in PTSD treatment outcomes.

    Article  Google Scholar 

  20. Tarrier N, Sommerfield C, Pilgrim H, Faragher B. Factors associated with outcome of cognitive-behavioural treatment of chronic post-traumatic stress disorder. Behav Res Ther. 2000;38(2):191–202. https://doi.org/10.1016/s0005-7967(99)00030-3.

    Article  CAS  PubMed  Google Scholar 

  21. Karatzias A, Power K, McGoldrick T, Brown K, Buchanan R, Sharp D, et al. Predicting treatment outcome on three measures for post-traumatic stress disorder. Eur Arch Psychiatry Clin Neurosci. 2007;257(1):40–6. https://doi.org/10.1007/s00406-006-0682-2.

    Article  PubMed  Google Scholar 

  22. Fletcher S, Elklit A, Shevlin M, Armour C. Predictors of PTSD treatment response trajectories in a sample of childhood sexual abuse survivors: the roles of social support, co**, and PTSD symptom clusters. J Interpers Violence. 2017;886260517741212. https://doi.org/10.1177/0886260517741212.

  23. Maguen S, Madden E, Neylan TC, Cohen BE, Bertenthal D, Seal KH. Timing of mental health treatment and PTSD symptom improvement among Iraq and Afghanistan veterans. Psychiatric Serv (Washington, DC). 2014;65(12):1414–9. https://doi.org/10.1176/appi.ps.201300453.

    Article  Google Scholar 

  24. Sripada RK, Blow FC, Rauch SAM, Ganoczy D, Hoff R, Harpaz-Rotem I, et al. Examining the nonresponse phenomenon: factors associated with treatment response in a national sample of veterans undergoing residential PTSD treatment. J Anxiety Disord. 2019;63:18–25. https://doi.org/10.1016/j.janxdis.2019.02.001.

    Article  PubMed  Google Scholar 

  25. Bekes V, Beaulieu-Prevost D, Guay S, Belleville G, Marchand A. Women with PTSD benefit more from psychotherapy than men. Psychol Trauma : theory, research, practice and policy. 2016;8(6):720–7. https://doi.org/10.1037/tra0000122.

    Article  Google Scholar 

  26. Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull. 2006;132(6):959–92. https://doi.org/10.1037/0033-2909.132.6.959.

    Article  PubMed  Google Scholar 

  27. Smith HL, Summers BJ, Dillon KH, Cougle JR. Is worst-event trauma type related to PTSD symptom presentation and associated features? J Anxiety Disord. 2016;38:55–61. https://doi.org/10.1016/j.janxdis.2016.01.007.

    Article  PubMed  Google Scholar 

  28. van Minnen A, Arntz A, Keijsers GPJ. Prolonged exposure in patients with chronic PTSD: predictors of treatment outcome and dropout. Behav Res Ther. 2002;40(4):439–57. https://doi.org/10.1016/S0005-7967(01)00024-9.

    Article  PubMed  Google Scholar 

  29. Litz BT, Berke DS, Kline NK, Grimm K, Rusowicz-Orazem L, Resick PA, et al. Patterns and predictors of change in trauma-focused treatments for war-related posttraumatic stress disorder. J Consult Clin Psychol. 2019;87(11):1019–29. https://doi.org/10.1037/ccp0000426.

    Article  PubMed  Google Scholar 

  30. Murphy D, Smith KV. Treatment efficacy for veterans with posttraumatic stress disorder: latent class trajectories of treatment response and their predictors. J Trauma Stress. 2018;31(5):753–63. https://doi.org/10.1002/jts.22333.

    Article  PubMed  PubMed Central  Google Scholar 

  31. • Sripada RK, Pfeiffer PN, Rampton J, Ganoczy D, Rauch SA, Polusny MA, et al. Predictors of PTSD symptom change among outpatients in the U.S. Department of Veterans Affairs Health Care system. J Trauma Stress. 2017;30(1):45–53. https://doi.org/10.1002/jts.22156.A large study on predictors of treatment outcomes for veterans in PTSD treatment.

  32. Hale AC, Rodriguez JL, Wright TP, Driesenga SA, Spates CR. Predictors of change in cognitive processing therapy for veterans in a residential PTSD treatment program. J Clin Psychol. 2019;75(3):364–79. https://doi.org/10.1002/jclp.22711.

    Article  PubMed  Google Scholar 

  33. Price M, Gros DF, Strachan M, Ruggiero KJ, Acierno R. The role of social support in exposure therapy for operation Iraqi freedom/operation enduring freedom veterans: a preliminary investigation. Psychol Trauma : theory, research, practice and policy. 2013;5(1):93–100. https://doi.org/10.1037/a0026244.

    Article  Google Scholar 

  34. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry. 2005;162(2):214–27. https://doi.org/10.1176/appi.ajp.162.2.214.

    Article  PubMed  Google Scholar 

  35. Watts BV, Schnurr PP, Mayo L, Young-Xu Y, Weeks WB, Friedman MJ. Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. J Clin Psychiatry. 2013;74(6):e541–50. https://doi.org/10.4088/JCP.12r08225.

    Article  PubMed  Google Scholar 

  36. Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy for military-related PTSD: a review of randomized clinical trials. Jama. 2015;314(5):489–500. https://doi.org/10.1001/jama.2015.8370.

    Article  CAS  PubMed  Google Scholar 

  37. Magruder KM, Frueh BC, Knapp RG, Davis L, Hamner MB, Martin RH, et al. Prevalence of posttraumatic stress disorder in veterans affairs primary care clinics. Gen Hosp Psychiatry. 2005;27(3):169–79. https://doi.org/10.1016/j.genhosppsych.2004.11.001.

    Article  PubMed  Google Scholar 

  38. Belsher BE, Tiet QQ, Garvert DW, Rosen CS. Compensation and treatment: disability benefits and outcomes of U.S. veterans receiving residential PTSD treatment. J Trauma Stress. 2012;25(5):494–502. https://doi.org/10.1002/jts.21747.

    Article  PubMed  Google Scholar 

  39. Goodson JT, Helstrom AW, Marino EJ, Smith RV. The impact of service-connected disability and therapist experience on outcomes from prolonged exposure therapy with veterans. Psychol Trauma : theory, research, practice and policy. 2017;9(6):647–54. https://doi.org/10.1037/tra0000260.

    Article  Google Scholar 

  40. Hembree EA, Street GP, Riggs DS, Foa EB. Do assault-related variables predict response to cognitive behavioral treatment for PTSD? J Consult Clin Psychol. 2004;72(3):531–4. https://doi.org/10.1037/0022-006x.72.3.531.

    Article  PubMed  Google Scholar 

  41. Currier JM, Holland JM, Drescher KD. Residential treatment for combat-related posttraumatic stress disorder: identifying trajectories of change and predictors of treatment response. PLoS One. 2014;9(7):e101741. https://doi.org/10.1371/journal.pone.0101741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zang Y, Su YJ, McLean CP, Foa EB. Predictors for excellent versus partial response to prolonged exposure therapy: who needs additional sessions? J Trauma Stress. 2019;32(4):577–85. https://doi.org/10.1002/jts.22412.

    Article  PubMed  Google Scholar 

  43. Zandberg LJ, Rosenfield D, McLean CP, Powers MB, Asnaani A, Foa EB. Concurrent treatment of posttraumatic stress disorder and alcohol dependence: predictors and moderators of outcome. J Consult Clin Psychol. 2016;84(1):43–56. https://doi.org/10.1037/ccp0000052.

    Article  PubMed  Google Scholar 

  44. Combs HL, Berry DTR, Pape T, Babcock-Parziale J, Smith B, Schleenbaker R, et al. The effects of mild traumatic brain injury, post-traumatic stress disorder, and combined mild traumatic brain injury/Post-traumatic stress disorder on returning veterans. J Neurotrauma. 2015;32(13):956–66. https://doi.org/10.1089/neu.2014.3585.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dikmen SS, Corrigan JD, Levin HS, Machamer J, Stiers W, Weisskopf MG. Cognitive outcome following traumatic brain injury. J Head Trauma Rehabil. 2009;24(6):430–8. https://doi.org/10.1097/HTR.0b013e3181c133e9.

    Article  Google Scholar 

  46. Vasterling JJ, Brailey K, Proctor SP, Kane R, Heeren T, Franz M. Neuropsychological outcomes of mild traumatic brain injury, post-traumatic stress disorder and depression in Iraq-deployed US Army soldiers. Br J Psychiatry. 2018;201(3):186–92. https://doi.org/10.1192/bjp.bp.111.096461.

    Article  Google Scholar 

  47. Mikolic A, Polinder S, Retel Helmrich IRA, Haagsma JA, Cnossen MC. Treatment for posttraumatic stress disorder in patients with a history of traumatic brain injury: a systematic review. Clin Psychol Rev. 2019;73:101776. https://doi.org/10.1016/j.cpr.2019.101776.

    Article  PubMed  Google Scholar 

  48. McCrea M, Guskiewicz KM, Marshall SW, Barr W, Randolph C, Cantu RC, et al. Acute effects and recovery time following concussion in collegiate football players: the NCAA concussion study. Jama. 2003;290(19):2556–63. https://doi.org/10.1001/jama.290.19.2556.

    Article  CAS  PubMed  Google Scholar 

  49. Stein NR, Dickstein BD, Schuster J, Litz BT, Resick PA. Trajectories of response to treatment for posttraumatic stress disorder. Behav Ther. 2012;43(4):790–800. https://doi.org/10.1016/j.beth.2012.04.003.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Haagen JF, Ter Heide FJ, Mooren TM, Knipscheer JW, Kleber RJ. Predicting post-traumatic stress disorder treatment response in refugees: multilevel analysis. Br J Clin Psychol. 2017;56(1):69–83. https://doi.org/10.1111/bjc.12121.

    Article  PubMed  Google Scholar 

  51. Richardson JD, Contractor AA, Armour C, St Cyr K, Elhai JD, Sareen J. Predictors of long-term treatment outcome in combat and peacekee** veterans with military-related PTSD. J Clin Psychiatry. 2014;75(11):e1299–305. https://doi.org/10.4088/JCP.13m08796.

    Article  PubMed  Google Scholar 

  52. Phelps AJ, Steel Z, Metcalf O, Alkemade N, Kerr K, O'Donnell M, et al. Key patterns and predictors of response to treatment for military veterans with post-traumatic stress disorder: a growth mixture modelling approach. Psychol Med. 2018;48(1):95–103. https://doi.org/10.1017/s0033291717001404.

    Article  CAS  PubMed  Google Scholar 

  53. Taylor S, Fedoroff IC, Koch WJ, Thordarson DS, Fecteau G, Nicki RM. Posttraumatic stress disorder arising after road traffic collisions: patterns of response to cognitive-behavior therapy. J Consult Clin Psychol. 2001;69(3):541–51.

    Article  CAS  Google Scholar 

  54. Rizvi SL, Vogt DS, Resick PA. Cognitive and affective predictors of treatment outcome in cognitive processing therapy and prolonged exposure for posttraumatic stress disorder. Behav Res Ther. 2009;47(9):737–43. https://doi.org/10.1016/j.brat.2009.06.003.

    Article  PubMed  PubMed Central  Google Scholar 

  55. APA. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Publishing; 2013.

    Google Scholar 

  56. Cloitre M, Garvert DW, Weiss BJ. Depression as a moderator of STAIR narrative therapy for women with post-traumatic stress disorder related to childhood abuse. Eur J Psychotraumatol. 2017;8(1):1377028. https://doi.org/10.1080/20008198.2017.1377028.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hagenaars MA, van Minnen A, Hoogduin KA. The impact of dissociation and depression on the efficacy of prolonged exposure treatment for PTSD. Behav Res Ther. 2010;48(1):19–27. https://doi.org/10.1016/j.brat.2009.09.001.

    Article  PubMed  Google Scholar 

  58. van Minnen A, Hagenaars M. Fear activation and habituation patterns as early process predictors of response to prolonged exposure treatment in PTSD. J Trauma Stress. 2002;15(5):359–67. https://doi.org/10.1023/a:1020177023209.

    Article  PubMed  Google Scholar 

  59. Wilkinson ST, Stefanovics E, Rosenheck RA. Marijuana use is associated with worse outcomes in symptom severity and violent behavior in patients with posttraumatic stress disorder. J Clin Psychiatry. 2015;76(9):1174–80. https://doi.org/10.4088/JCP.14m09475.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Feeny NC, Zoellner LA, Foa EB. Treatment outcome for chronic PTSD among female assault victims with borderline personality characteristics: a preliminary examination. J Personal Disord. 2002;16(1):30–40. https://doi.org/10.1521/pedi.16.1.30.22555.

    Article  Google Scholar 

  61. Clarke SB, Rizvi SL, Resick PA. Borderline personality characteristics and treatment outcome in cognitive-behavioral treatments for PTSD in female rape victims. Behav Ther. 2008;39(1):72–8. https://doi.org/10.1016/j.beth.2007.05.002.

    Article  PubMed  Google Scholar 

  62. Lloyd D, Nixon RD, Varker T, Elliott P, Perry D, Bryant RA, et al. Comorbidity in the prediction of cognitive processing therapy treatment outcomes for combat-related posttraumatic stress disorder. J Anxiety Disord. 2014;28(2):237–40. https://doi.org/10.1016/j.janxdis.2013.12.002.

    Article  CAS  PubMed  Google Scholar 

  63. Forbes D, Parslow R, Creamer M, Allen N, McHugh T, Hopwood M. Mechanisms of anger and treatment outcome in combat veterans with posttraumatic stress disorder. J Trauma Stress. 2008;21(2):142–9. https://doi.org/10.1002/jts.20315.

    Article  PubMed  Google Scholar 

  64. Forbes D, Creamer M, Hawthorne G, Allen N, McHugh T. Comorbidity as a predictor of symptom change after treatment in combat-related posttraumatic stress disorder. J Nerv Ment Dis. 2003;191(2):93–9. https://doi.org/10.1097/01.nmd.0000051903.60517.98.

    Article  PubMed  Google Scholar 

  65. Foa EB, Riggs DS, Massie ED, Yarczower M. The impact of fear activation and anger on the efficacy of exposure treatment for posttraumatic stress disorder. Behav Ther. 1995;26(3):487–99. https://doi.org/10.1016/S0005-7894(05)80096-6.

    Article  Google Scholar 

  66. Vasterling JJ, Brailey K, Constans JI, Sutker PB. Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology. 1998;12(1):125–33. https://doi.org/10.1037//0894-4105.12.1.125.

    Article  CAS  PubMed  Google Scholar 

  67. Schuitevoerder S, Rosen JW, Twamley EW, Ayers CR, Sones H, Lohr JB, et al. A meta-analysis of cognitive functioning in older adults with PTSD. J Anxiety Disord. 2013;27(6):550–8. https://doi.org/10.1016/j.janxdis.2013.01.001.

    Article  PubMed  Google Scholar 

  68. Parslow RA, Jorm AF. Pretrauma and posttrauma neurocognitive functioning and PTSD symptoms in a community sample of young adults. Am J Psychiatry. 2007;164(3):509–15. https://doi.org/10.1176/ajp.2007.164.3.509.

    Article  PubMed  Google Scholar 

  69. • Nijdam MJ, de Vries GJ, Gersons BP, Olff M. Response to psychotherapy for posttraumatic stress disorder: the role of pretreatment verbal memory performance. J Clin Psychiatry. 2015;76(8):e1023–8. https://doi.org/10.4088/JCP.14m09438.One of the first reports to identify a cognitive capacity (verbal memory) as a predictor of PTSD psychotherapy outcomes.

    Article  PubMed  Google Scholar 

  70. • Etkin A, Maron-Katz A, Wu W, Fonzo GA, Huemer J, Vertes PE, et al. Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder. Sci Transl Med. 2019;11(486):eaal3236. https://doi.org/10.1126/scitranslmed.aal3236.This study reports the first evidence for an objective subtype of PTSD, rooted both in neurobiology and cognition, that is treatment-resistant.

  71. Lanius RA, Vermetten E, Loewenstein RJ, Brand B, Schmahl C, Bremner JD, et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry. 2010;167(6):640–7. https://doi.org/10.1176/appi.ajp.2009.09081168.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Sofko CA, Currier JM, Drescher KD. Prospective associations between changes in mental health symptoms and health-related quality of life in veterans seeking posttraumatic stress disorder residential treatment. Anxiety Stress Co**. 2016;29(6):630–43. https://doi.org/10.1080/10615806.2016.1157171.

    Article  PubMed  Google Scholar 

  73. Bartoszek G, Hannan SM, Kamm J, Pamp B, Maieritsch KP. Trauma-related pain, reexperiencing symptoms, and treatment of posttraumatic stress disorder: a longitudinal study of veterans. J Trauma Stress. 2017;30(3):288–95. https://doi.org/10.1002/jts.22183.

    Article  PubMed  Google Scholar 

  74. Berlim MT, Van Den Eynde F. Repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for treating posttraumatic stress disorder: an exploratory meta-analysis of randomized, double-blind and sham-controlled trials. Can J Psychiatr. 2014;59(9):487–96.

    Article  Google Scholar 

  75. George MS, Post RM. Daily left prefrontal repetitive transcranial magnetic stimulation for acute treatment of medication-resistant depression. Am J Psychiatry. 2011;168(4):356–64. https://doi.org/10.1176/appi.ajp.2010.10060864.

    Article  PubMed  Google Scholar 

  76. Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N. Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry. 2004;161(3):515–24. https://doi.org/10.1176/appi.ajp.161.3.515.

    Article  PubMed  Google Scholar 

  77. Kozel FA, Van Trees K, Larson V, Phillips S, Hashimie J, Gadbois B, et al. One hertz versus ten hertz repetitive TMS treatment of PTSD: a randomized clinical trial. Psychiatry Res. 2019;273:153–62. https://doi.org/10.1016/j.psychres.2019.01.004.

    Article  PubMed  Google Scholar 

  78. Watts BV, Landon B, Groft A, Young-Xu Y. A sham controlled study of repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Brain Stimul. 2012;5(1):38–43. https://doi.org/10.1016/j.brs.2011.02.002.

    Article  PubMed  Google Scholar 

  79. Carpenter LL, Conelea C, Tyrka AR, Welch ES, Greenberg BD, Price LH, et al. 5Hz repetitive transcranial magnetic stimulation for posttraumatic stress disorder comorbid with major depressive disorder. J Affect Disord. 2018;235:414–20. https://doi.org/10.1016/j.jad.2018.04.009.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Yan T, **e Q, Zheng Z, Zou K, Wang L. Different frequency repetitive transcranial magnetic stimulation (rTMS) for posttraumatic stress disorder (PTSD): a systematic review and meta-analysis. J Psychiatr Res. 2017;89:125–35. https://doi.org/10.1016/j.jpsychires.2017.02.021.

    Article  PubMed  Google Scholar 

  81. Philip NS, Barredo J, Aiken E, Larson V, Jones RN, Shea MT et al. Theta-burst transcranial magnetic stimulation for posttraumatic stress disorder. Am J Psychiatry. 2019:appi.ajp.2019.18101160. doi:https://doi.org/10.1176/appi.ajp.2019.18101160.

  82. • Kozel FA, Motes MA, Didehbani N, DeLaRosa B, Bass C, Schraufnagel CD, et al. Repetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: a randomized clinical trial. J Affect Disord. 2018;229:506–14. https://doi.org/10.1016/j.jad.2017.12.046.One of the first studies to demonstrate that brain modulation can enhance psychotherapy outcomes for PTSD.

  83. Fryml LD, Pelic CG, Acierno R, Tuerk P, Yoder M, Borckardt JJ, et al. Exposure therapy and simultaneous repetitive transcranial magnetic stimulation: a controlled pilot trial for the treatment of posttraumatic stress disorder. The journal of ECT. 2019;35(1):53–60. https://doi.org/10.1097/yct.0000000000000505.

    Article  PubMed  Google Scholar 

  84. Karsen EF, Watts BV, Holtzheimer PE. Review of the effectiveness of transcranial magnetic stimulation for post-traumatic stress disorder. Brain Stimul: Basic, Translational, and Clinical Research in Neuromodulation. 2014;7(2):151–7. https://doi.org/10.1016/j.brs.2013.10.006.

    Article  Google Scholar 

  85. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety of TMSCG. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol : official journal of the International Federation of Clinical Neurophysiology. 2009;120(12):2008–39. https://doi.org/10.1016/j.clinph.2009.08.016.

    Article  Google Scholar 

  86. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–66. https://doi.org/10.1176/appi.ajp.2015.15040465.

    Article  PubMed  Google Scholar 

  87. • Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205–15. https://doi.org/10.1176/appi.ajp.2018.18020138.This study calls into question the purported mechanism of action of ketamine treatment in major depression.

  88. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019:appi.ajp.2019.19040423. doi:https://doi.org/10.1176/appi.ajp.2019.19040423.

  89. Albott CS, Lim KO, Forbes MK, Erbes C, Tye SJ, Grabowski JG, et al. Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry. 2018;79(3):17m11634. https://doi.org/10.4088/JCP.17m11634.

    Article  PubMed  Google Scholar 

  90. • Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical TrialIV ketamine for treatment of chronic PTSDIV ketamine for treatment of chronic PTSD. JAMA Psychiatry. 2014;71(6):681–8. https://doi.org/10.1001/jamapsychiatry.2014.62.The first large placebo-controlled, randomized clinical trial demonstrating a rapid-acting therapeutic effect of ketamine on PTSD symptoms.

    Article  CAS  PubMed  Google Scholar 

  91. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101(5):774–8. https://doi.org/10.1016/j.neuron.2019.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bedi G. 3,4-methylenedioxymethamphetamine as a psychiatric treatment. JAMA Psychiatry. 2018;75(5):419–20. https://doi.org/10.1001/jamapsychiatry.2018.0063.

    Article  PubMed  Google Scholar 

  93. Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front Psychiatry. 2019;10:650. https://doi.org/10.3389/fpsyt.2019.00650.

    Article  PubMed  PubMed Central  Google Scholar 

  94. • Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of {+/−}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011;25(4):439–52. https://doi.org/10.1177/0269881110378371.The first randomized controlled trial demonstrating a therapeutic effect for MDMA-assisted psychotherapy on PTSD symptoms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. • Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5(6):486–97. https://doi.org/10.1016/s2215-0366(18)30135-4.A large phase 2 trial replicating the therapeutic effects of MDMA-assisted psychotherapy on PTSD with additional dose-response characterization.

    Article  PubMed  Google Scholar 

  96. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (+/− 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-traumatic stress disorder (PTSD). J Psychopharmacol. 2013;27(1):40–52. https://doi.org/10.1177/0269881112464827.

    Article  CAS  PubMed  Google Scholar 

  97. Ot'alora GM, Grigsby J, Poulter B, Van Derveer JW 3rd, Giron SG, Jerome L, et al. 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295–307. https://doi.org/10.1177/0269881118806297.

    Article  CAS  Google Scholar 

  98. Dunlop BW, Kaye JL, Youngner C, Rothbaum B. Assessing treatment-resistant posttraumatic stress disorder: the emory treatment resistance interview for PTSD (E-TRIP). Behav Sci (Basel, Switzerland). 2014;4(4):511–27. https://doi.org/10.3390/bs4040511.

    Article  Google Scholar 

  99. Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60(11):1439–45. https://doi.org/10.1176/ps.2009.60.11.1439.

    Article  PubMed  Google Scholar 

  100. Simon NM, Connor KM, Lang AJ, Rauch S, Krulewicz S, LeBeau RT, et al. Paroxetine CR augmentation for posttraumatic stress disorder refractory to prolonged exposure therapy. J Clin Psychiatry. 2008;69(3):400–5. https://doi.org/10.4088/jcp.v69n0309.

    Article  PubMed  Google Scholar 

  101. Rothbaum BO, Cahill SP, Foa EB, Davidson JRT, Compton J, Connor KM, et al. Augmentation of sertraline with prolonged exposure in the treatment of posttraumatic stress disorder. J Trauma Stress. 2006;19(5):625–38. https://doi.org/10.1002/jts.20170.

    Article  PubMed  Google Scholar 

  102. Buhmann CB, Nordentoft M, Ekstroem M, Carlsson J, Mortensen EL. The effect of flexible cognitive–behavioural therapy and medical treatment, including antidepressants on post-traumatic stress disorder and depression in traumatised refugees: pragmatic randomised controlled clinical trial. Br J Psychiatry. 2018;208(3):252–9. https://doi.org/10.1192/bjp.bp.114.150961.

    Article  Google Scholar 

  103. Otto MW, Hinton D, Korbly NB, Chea A, Ba P, Gershuny BS, et al. Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: a pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone. Behav Res Ther. 2003;41(11):1271–6. https://doi.org/10.1016/S0005-7967(03)00032-9.

    Article  PubMed  Google Scholar 

  104. Popiel A, Zawadzki B, Pragłowska E, Teichman Y. Prolonged exposure, paroxetine and the combination in the treatment of PTSD following a motor vehicle accident. A randomized clinical trial – the “TRAKT” study. J Behav Ther Exp Psychiatry. 2015;48:17–26. https://doi.org/10.1016/j.jbtep.2015.01.002.

    Article  PubMed  Google Scholar 

  105. van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper EK, Korn DL, et al. A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: treatment effects and long-term maintenance. The Journal of clinical psychiatry. 2007;68(1):37–46. https://doi.org/10.4088/jcp.v68n0105.

    Article  PubMed  Google Scholar 

  106. Rauch SM, Kim H, Powell C, et al. Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2018. https://doi.org/10.1001/jamapsychiatry.2018.3412.

Download references

Author information

Author notes

  1. Vecheslav Federchenco and Alba Lara contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Dell Medical School, The University of Texas at Austin, Austin, USA

    Gregory A. Fonzo Ph.D.

  2. General Psychiatry Residency, Dell Medical School, The University of Texas at Austin, Austin, USA

    Vecheslav Federchenco M.D. & Alba Lara M.D.

Authors
  1. Gregory A. Fonzo Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vecheslav Federchenco M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alba Lara M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregory A. Fonzo Ph.D..

Ethics declarations

Conflict of interest

Gregory A. Fonzo declares that he has no conflict of interest.

Vecheslav Federchenco declares that he has no conflict of interest

Alba Lara declares that she has no conflict of interest

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Topical Collection on PTSD

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fonzo, G.A., Federchenco, V. & Lara, A. Predicting and Managing Treatment Non-response in Posttraumatic Stress Disorder. Curr Treat Options Psych 7, 70–87 (2020). https://doi.org/10.1007/s40501-020-00203-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40501-020-00203-1

Keywords

Search

Navigation