Skip to main content
SpringerLink
Log in

Augmentation of Evidence-Based Psychotherapy for PTSD With Cognitive Enhancers

  • Disaster Psychiatry: Trauma, PTSD, and Related Disorders (E Foa and A Asnaani, Section Editors)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Exposure-based therapy has proven to be useful to treat various anxiety disorders as well as post-traumatic stress disorder (PTSD). Despite its efficacy, a fair proportion of patients remain symptomatic after treatment. Different lines of research have put considerable efforts to investigate ways to enhance the efficacy of exposure-based therapy, which could ultimately lead to better clinical outcomes for patients. Given that this type of therapy relies on extinction learning principles, neuroscience research has tested different adjuncts that could be used as cognitive enhancers through their impact on extinction learning and its consolidation. The current review will summarize some of the latest compounds that have received attention and show some promise to be used in clinical settings to improve the efficacy of exposure-based therapy.

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. Foa EB. Prolonged exposure therapy: past, present, and future. Depress Anxiety. 2011;28:1043–7.

    Article  PubMed  Google Scholar 

  2. Vervliet B, Craske MG, Hermans D. Fear extinction and relapse: state of the art. Annu Rev Clin Psychol. 2013;9:215–48.

    Article  PubMed  Google Scholar 

  3. McNally RJ. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin Psychol Rev. 2007;27:750–9.

    Article  PubMed  Google Scholar 

  4. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol. 2012;63:129–51.

    Article  PubMed  Google Scholar 

  5. Bouton ME, Moody EW. Memory processes in classical conditioning. Neurosci Biobehav Rev. 2004;28:663–74.

    Article  PubMed  Google Scholar 

  6. Garfinkel SN, Abelson JL, King AP, Sripada RK, Wang X, Gaines LM, et al. Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. J Neurosci. 2014;34:13435–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res. 2008;42:515–20.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009;66:1075–82.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Bouton ME. Context and behavioral processes in extinction. Learn Mem. 2004;11:485–94.

    Article  PubMed  Google Scholar 

  10. Rescorla RA. Behavioral studies of Pavlovian conditioning. Annu Rev Neurosci. 1988;11:329–52.

    Article  CAS  PubMed  Google Scholar 

  11. Bouton ME, Westbrook RF, Corcoran KA, Maren S. Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biol Psychiatry. 2006;60:352–60.

    Article  PubMed  Google Scholar 

  12. Nader K, Schafe GE, LeDoux JE. The labile nature of consolidation theory. Nat Rev Neurosci. 2000;1:216–9.

    Article  CAS  PubMed  Google Scholar 

  13. Ledgerwood L, Richardson R, Cranney J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci. 2003;117:341–9.

    Article  CAS  PubMed  Google Scholar 

  14. Ledgerwood L, Richardson R, Cranney J. D-cycloserine facilitates extinction of learned fear: effects on reacquisition and generalized extinction. Biol Psychiatry. 2005;57:841–7.

    Article  CAS  PubMed  Google Scholar 

  15. Parnas AS, Weber M, Richardson R. Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem. 2005;83:224–31.

    Article  CAS  PubMed  Google Scholar 

  16. Walker DL, Ressler KJ, Lu K-T, Davis M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:2343–51.

    CAS  PubMed  Google Scholar 

  17. 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;61:1136–44.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Hofmann SG, Fang A, Gutner CA. Cognitive enhancers for the treatment of anxiety disorders. Restor Neurol Neurosci. 2014;32:183–95.

    PubMed  Google Scholar 

  20. Rodrigues H, Figueira I, Lopes A, Gonçalves R, Mendlowicz MV, Coutinho ESF, et al. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis. PloS One. 2014;9, e93519.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Smits JAJ, Rosenfield D, Otto MW, Powers MB, Hofmann SG, Telch MJ, et al. D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia. Biol Psychiatry. 2013;73:1054–8. This study points to the importance of only administering DCS following successful therapy sessions. Subjects who had successful therapy sessions and did receive DCS showed better outcomes than the placebo-treated group. However, for subjects who had high levels of fear following therapy and who received DCS, the outcome was worse than the placebo-treated group.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Hofmann SG, Otto MW, Pollack MH, Smits JA. D-cycloserine augmentation of cognitive behavioral therapy for anxiety disorders: an update. Curr Psychiatry Rep. 2015;17:532. Very recent and good review that summarizes the use of DCS as an adjunct to therapy.

    Article  PubMed  Google Scholar 

  23. Hofmann SG, Wu JQ, Boettcher H. D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders. Biol Mood Anxiety Disord. 2013;3:11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. McGaugh JL, Roozendaal B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr Opin Neurobiol. 2002;12:205–10.

    Article  CAS  PubMed  Google Scholar 

  25. Roozendaal B, Barsegyan A, Lee S. Adrenal stress hormones, amygdala activation, and memory for emotionally arousing experiences. Prog Brain Res. 2008;167:79–97.

    Article  CAS  PubMed  Google Scholar 

  26. Dębiec J, Bush DEA, LeDoux JE. Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats–a possible mechanism for the persistence of traumatic memories in PTSD. Depress Anxiety. 2011;28:186–93.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Soeter M, Kindt M. Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation. Neuropsychopharmacoly. 2012;37:1204–15.

    Article  CAS  Google Scholar 

  28. Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature. 1994;371:702–4.

    Article  CAS  PubMed  Google Scholar 

  29. Maheu FS, Joober R, Beaulieu S, Lupien SJ. Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term declarative memory for emotionally arousing material. Behav Neurosci. 2004;118:420–8.

    Article  CAS  PubMed  Google Scholar 

  30. Van Stegeren AH, Everaerd W, Cahill L, McGaugh JL, Gooren LJ. Memory for emotional events: differential effects of centrally versus peripherally acting beta-blocking agents. Psychopharmacology. 1998;138:305–10.

    Article  PubMed  Google Scholar 

  31. Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry. 2002;51:189–92.

    Article  CAS  PubMed  Google Scholar 

  32. Debiec J, Ledoux JE. Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience. 2004;129:267–72.

    Article  CAS  PubMed  Google Scholar 

  33. Soeter M, Kindt M. Dissociating response systems: erasing fear from memory. Neurobiol Learn Mem. 2010;94:30–41.

    Article  PubMed  Google Scholar 

  34. Soeter M, Kindt M. Disrupting reconsolidation: pharmacological and behavioral manipulations. Learn Mem. 2011;18:357–66.

    Article  CAS  PubMed  Google Scholar 

  35. Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci. 2009;12:256–8.

    Article  CAS  PubMed  Google Scholar 

  36. Spring JD, Wood NE, Mueller-Pfeiffer C, Milad MR, Pitman RK, Orr SP. Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli. Psychophysiology. 2014.

  37. Lonergan MH, Olivera-Figueroa LA, Pitman RK, Brunet A. Propranolol’s effects on the consolidation and reconsolidation of long-term emotional memory in healthy participants: a meta-analysis. J Psychiatry Neurosci. 2013;38:222–31.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res. 2008;42:503–6.

    Article  PubMed  Google Scholar 

  39. Brunet A, Thomas É, Saumier D, Ashbaugh AR, Azzoug A, Pitman RK, et al. Trauma reactivation plus propranolol is associated with durably low physiological responding during subsequent script-driven traumatic imagery. Can J Psychiatry Rev Can Psychiatr. 2014;59:228–32.

    Google Scholar 

  40. Wood NE, Rosasco ML, Suris AM, Spring JD, Marin M-F, Lasko NB, et al. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015;225:31–9.

    Article  PubMed  Google Scholar 

  41. Graham BM, Milad MR. Inhibition of estradiol synthesis impairs fear extinction in male rats. Learn Mem. 2014;21:347–50. This study demonstrated that blockade of estradiol in males impaired extinction recall. This suggests that estradiol is an important regulator of fear not only in females, but also in males.

    Article  PubMed  Google Scholar 

  42. Graham BM, Milad MR. Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women. Biol Psychiatry. 2013;73:371–8. This study demonstrates how hormonal contraceptive use induces a deficit in extinction recall. It also demonstrates how estradiol administration to naturally cycling women can increase extinction recall.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Milad MR, Igoe SA, Lebron-Milad K, Novales JE. Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience. 2009;164:887–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry. 2011;70:920–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Herbison AE, Simonian SX, Thanky NR, Bicknell RJ. Oestrogen modulation of noradrenaline neurotransmission. Novartis Found Symp. 2000;230:74–85.

    Article  CAS  PubMed  Google Scholar 

  46. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend. 1998;51:173–87.

    Article  CAS  PubMed  Google Scholar 

  47. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77:299–318.

    Article  CAS  PubMed  Google Scholar 

  48. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530–4.

    Article  CAS  PubMed  Google Scholar 

  49. Pamplona FA, Prediger RDS, Pandolfo P, Takahashi RN. The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats. Psychopharmacology. 2006;188:641–9.

    Article  CAS  PubMed  Google Scholar 

  50. Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. J Eur Coll Neuropsychopharmacol. 2008;18:849–59.

    Article  CAS  Google Scholar 

  51. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacoly. 2005;30:516–24.

    Article  CAS  Google Scholar 

  52. Papini S, Sullivan GM, Hien DA, Shvil E, Neria Y. Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: a critical review of preclinical research. Biol Psychol. 2014;104C:8–18.

    Google Scholar 

  53. Heitland I, Klumpers F, Oosting RS, Evers DJJ, Leon Kenemans J, Baas JMP. Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Transl Psychiatry. 2012;2, e162.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Klumpers F, Denys D, Kenemans JL, Grillon C, van der Aart J, Baas JMP. Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans. J Psychopharmacol Oxf Engl. 2012;26:471–8.

    Article  CAS  Google Scholar 

  55. Rabinak CA, Angstadt M, Sripada CS, Abelson JL, Liberzon I, Milad MR, et al. Cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology. 2013;64:396–402.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Rabinak CA, Angstadt M, Lyons M, Mori S, Milad MR, Liberzon I, et al. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiol Learn Mem. 2014;113:125–34. Important study demonstrating how THC can promote activation of the vmPFC and hippocampus during extinction recall.

    Article  CAS  PubMed  Google Scholar 

  57. Neumeister A, Seidel J, Ragen BJ, Pietrzak RH. Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder. Psychoneuroendocrinology. 2015;51:577–84.

    Article  CAS  PubMed  Google Scholar 

  58. Lebron-Milad K, Milad MR. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol Mood Anxiety Disord. 2012;2:3.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Glover EM, Jovanovic T, Mercer KB, Kerley K, Bradley B, Ressler KJ, et al. Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder. Biol Psychiatry. 2012;72:19–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012;96:32–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Lin A-L, Poteet E, Du F, Gourav RC, Liu R, Wen Y, et al. Methylene blue as a cerebral metabolic and hemodynamic enhancer. PLoS One. 2012;7:e46585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Wrubel KM, Barrett D, Shumake J, Johnson SE, Gonzalez-Lima F. Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness. Neurobiol Learn Mem. 2007;87:209–17.

    Article  CAS  PubMed  Google Scholar 

  63. Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004;11:633–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Telch MJ, Bruchey AK, Rosenfield D, Cobb AR, Smits J, Pahl S, et al. Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Am J Psychiatry. 2014;171:1091–8. First clinical report suggesting that methylene blue could be a good adjunct to exposure therapy. The paper also points to the importance of administering MB only following successful sessions.

    Article  PubMed  Google Scholar 

  65. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001;294:1030–8.

    Article  CAS  PubMed  Google Scholar 

  66. Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem. 2004;279:40545–59.

    Article  CAS  PubMed  Google Scholar 

  67. Gräff J, Tsai L-H. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol. 2013;53:311–30. Very good review on HDAC inhibitors, their actions, their potential use as cognitive enhancers as well as some limitations that need to be taken into account.

    Article  PubMed  Google Scholar 

  68. Lattal KM, Barrett RM, Wood MA. Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci. 2007;121:1125–31.

    Article  CAS  PubMed  Google Scholar 

  69. Fujita Y, Morinobu S, Takei S, Fuchikami M, Matsumoto T, Yamamoto S, et al. Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene. J Psychiatr Res. 2012;46:635–43.

    Article  PubMed  Google Scholar 

  70. Itzhak Y, Anderson KL, Kelley JB, Petkov M. Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice. Neurobiol Learn Mem. 2012;97:409–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Bredy TW, Barad M. The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn Mem. 2008;15:39–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM. Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry. 2012;72:25–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Whittle N, Singewald N. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem Soc Trans. 2014;42:569–81. Very good review on HDAC inhibitors and how they could apply to the treatment of anxiety by using them as adjunct for therapy. Limitations and challenges are also discussed.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Marie-France Marin, Sylwia Fowler Lonak, and Mohammed R. Milad declare that they have 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.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, 02129, USA

    Marie-France Marin, Sylwia Fowler Lonak & Mohammed R. Milad

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, 02129, USA

    Marie-France Marin & Mohammed R. Milad

Authors
  1. Marie-France Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylwia Fowler Lonak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed R. Milad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed R. Milad.

Additional information

This article is part of the Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marin, MF., Lonak, S.F. & Milad, M.R. Augmentation of Evidence-Based Psychotherapy for PTSD With Cognitive Enhancers. Curr Psychiatry Rep 17, 39 (2015). https://doi.org/10.1007/s11920-015-0582-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11920-015-0582-0

Keywords

Search

Navigation