On the road to translation for PTSD treatment: Theoretical and practical considerations of the use of human models of conditioned fear for drug development

Current Topics in Behavioral Neurosciences

Volumn 28, Issue , 2016, Pages 173-196

  Risbrough, Victoria B ^a,b   Glenn, Daniel E ^a   Baker, Dewleen G ^a,b  

^a Center of Excellence for Stress and Mental Health   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anxiety; Consolidation; D cycloserine; Exposure; Extinction; Fear; Norpepinephrine; Panic disorder; Posttraumatic stress disorder

Indexed keywords

CYCLOSERINE;

ANXIETY; COGNITIVE BEHAVIORAL THERAPY; DEPRESSION; ENDOPHENOTYPE; FEAR; GENOTYPE PHENOTYPE CORRELATION; HUMAN; MENTAL HEALTH; NERVE CELL PLASTICITY; PANIC; PERFORMANCE; POSTTRAUMATIC STRESS DISORDER; PREFRONTAL CORTEX; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; SIGNAL TRANSDUCTION; CONDITIONING; DRUG DEVELOPMENT; DRUG EFFECTS; EMOTION; REINFORCEMENT; STRESS DISORDERS, POST-TRAUMATIC; TRANSLATIONAL RESEARCH;

CONDITIONING (PSYCHOLOGY); DRUG DISCOVERY; EMOTIONS; EXTINCTION, PSYCHOLOGICAL; FEAR; HUMANS; STRESS DISORDERS, POST-TRAUMATIC; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84988624753     PISSN: 18663370     EISSN: 18663389     Source Type: Book Series    
DOI: 10.1007/7854_2015_5010     Document Type: Chapter

References (136)

1. Acheson DT, Risbrough VB (2015) Oxytocin enhancement of fear extinction: a new target for facilitating exposure-based treatments? Biol Psychiatry 78: 154-155
2. Acheson DT, Gresack JE, Risbrough VB (2012a) Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology 62: 674-685
3. Acheson DT, Stein MB, Paulus MP, Ravindran L, Simmons AN, Lohr JB, Risbrough VB (2012b) Effects of anxiolytic treatment on potentiated startle during aversive image anticipation. Hum Psychopharmacol 27: 419-427
4. Acheson D, Feifel D, de Wilde S, McKinney R, Lohr J, Risbrough V (2013) The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology 229: 199-208
5. Acheson DT, Feifel D, Kamenski M, McKinney R, Risbrough VB (2015a) Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. Depress Anxiety 32: 400-407
6. Acheson DT, Geyer MA, Risbrough VB (2015b) Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty marines. Psychoneuroendocrinology 51: 495-505
7. Acheson D, Ehler L, Resovsky J, Tsan E, Risbrough V (2015c) Fear extinction memory performance in a sample of stable, euthymic patients with bipolar disorder. J Affect Disord 185: 230-238
8. Aikins DE, Jackson ED, Christensen A, Walderhaug E, Afroz S, Neumeister A (2011) Differential conditioned fear response predicts duloxetine treatment outcome in male veterans with PTSD: a pilot study. Psychiatry Res 188: 453-455
9. Alvarez RP, Chen G, Bodurka J, Kaplan R, Grillon C (2011) Phasic and sustained fear in humans elicits distinct patterns of brain activity. Neuroimage 55: 389-400
10. Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, Bannister TD, Almli L, Stevens JS, Bradley B, Binder EB, Wahlestedt C and Ressler KJ (2013) Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med 5: 188ra173
11. Armony JL, Dolan RJ (2001) Modulation of auditory neural responses by a visual context in human fear conditioning. NeuroReport 12: 3407-3411
12. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th Ed). Washington DC
13. Avery SN, Clauss JA, Blackford JU (2015) The human BNST: functional role in anxiety and addiction. Neuropsychopharmacology 41;126-141
14. Baker DG, Nievergelt CM, Risbrough VB (2009) Post-traumatic stress disorder: emerging concepts of pharmacotherapy. Expert Opin Emerg Drugs 14: 251-272
15. Berger W, Mendlowicz MV, Marques-Portella C, Kinrys G, Fontenelle LF, Marmar CR, Figueira I (2009) Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry 33: 169-180
16. Besnard A, Sahay A (2015) Adult hippocampal neurogenesis, fear generalization, and stress. Neuropsychopharmacology 41: 1-21
17. Bontempo A, Panza KE, Bloch MH (2012) D-cycloserine augmentation of behavioral therapy for the treatment of anxiety disorders: a meta-analysis. J Clin Psychiatry 73: 533-537
18. Bouton ME (1993) Context, time and memory retrieval in the interference paradigms of Pavlovian learning. Psychol Bull 114: 90-99
19. Bouton ME (2014) Why behavior change is difficult to sustain. Prev Med 68: 29-36
20. Bouton ME, Todd TP (2014) A fundamental role for context in instrumental learning and extinction. Behav Process 104: 13-19
21. Bouton ME, Westbrook RF, Corcoran KA, Maren S (2006) Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biol Psychiatry 60: 352-360
22. Bowers ME, Ressler KJ (2015) An overview of translationally informed treatments for posttraumatic stress disorder: animal models of pavlovian fear conditioning to human clinical trials. Biol Psychiatry 78(5): E15-E27
23. Braff DL (2015) The importance of endophenotypes in schizophrenia research. Schizophr Res 163: 1-8
24. Briscione MA, Jovanovic T, Norrholm SD (2014) Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors. Front Psychiatry 5: 88
25. Bui E, Orr SP, Jacoby RJ, Keshaviah A, LeBlanc NJ, Milad MR, Pollack MH, Simon NM (2013) Two weeks of pretreatment with escitalopram facilitates extinction learning in healthy individuals. Hum Psychopharmacol 28: 447-456
26. Burghardt NS, Bauer EP (2013) Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits. Neuroscience 247: 253-272
27. Cameron C, Watson D, Robinson J (2014) Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J Clin Psychopharmacol 34: 559-564
28. Castren E, Hen R (2013) Neuronal plasticity and antidepressant actions. Trends Neurosci 36: 259-267
29. Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B (2014) Maximizing exposure therapy: an inhibitory learning approach. Behav Res Ther 58: 10-23
30. Cuthbert B, Insel T (2013) Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med 11: 126
31. Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Curran HV, Morgan CJ (2013) Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology 226: 781-792
32. Daskalakis NP, Yehuda R, Diamond DM (2013) Animal models in translational studies of PTSD. Psychoneuroendocrinology 38: 1895-1911
33. de Kleine RA, Hendriks GJ, Kusters WJ, Broekman TG, van Minnen A (2012) A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol Psychiatry 71: 962-968
34. de Kleine RA, Hendriks GJ, Smits JA, Broekman TG, van Minnen A (2014) Prescriptive variables for d-cycloserine augmentation of exposure therapy for posttraumatic stress disorder. J Psychiatr Res 48: 40-46
35. Deschaux O, Spennato G, Moreau JL, Garcia R (2011) Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear. Psychopharmacology 215: 231-237
36. Difede J, Cukor J, Wyka K, Olden M, Hoffman H, Lee FS, Altemus M (2014) D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial. Neuropsychopharmacology 39: 1052-1058
37. Dirikx T, Hermans D, Vansteenwegen D, Baeyens F, Eelen P (2007) Reinstatement of conditioned responses in human differential fear conditioning. J Behav Ther Exp Psychiatry 38: 237-251
38. Do Monte FH, Souza RR, Wong TT, Carobrez Ade P (2013) Systemic or intra-prelimbic cortex infusion of prazosin impairs fear memory reconsolidation. Behav Brain Res 244: 137-141
39. Donaldson ZR, Hen R (2015) From psychiatric disorders to animal models: a bidirectional and dimensional approach. Biol Psychiatry 77: 15-21
40. Dunsmoor DE, Paz R (2015) Fear generalization and anxiety: behavioral and neural mechanisms. Biol Psychiatry 78: 336-343
41. Dymond S, Dunsmoor JE, Vervliet B, Roche B, Hermans D (2014) Fear generalization in humans: systematic review and implications for anxiety disorder research. Behav Ther. doi: 10.1016/j. beth.2014.10.001
42. Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE, Grinevich V, Kendrick KM, Maier W, Hurlemann R (2014) Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 78: 194-202
43. Effting M, Kindt M (2007) Contextual control of human fear associations in a renewal paradigm. Behav Res Ther 45: 2002-2018
44. Fani N, Tone EB, Phifer J, Norrholm SD, Bradley B, Ressler KJ, Kamkwalala A, Jovanovic T (2012) Attention bias toward threat is associated with exaggerated fear expression and impaired extinction in PTSD. Psychol Med 42: 533-543
45. Fitzgerald PJ, Seemann JR, Maren S (2014) Can fear extinction be enhanced? A review of pharmacological and behavioral findings. Brain Res Bull 105: 46-60
46. Foa EB, Hembree EA, Cahill SP, Rauch SA, Riggs DS, Feeny NC, Yadin E (2005) Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics. J Consult Clin Psychol 73: 953-964
47. Garcia-Leal C, Del-Ben CM, Leal FM, Graeff FG, Guimaraes FS (2010) Escitalopram prolonged fear induced by simulated public speaking and released hypothalamic-pituitary-adrenal axis activation. J Psychopharmacol 24: 683-694
48. Galatzer-Levy IR, Bryant RA (2013) 636,120 ways to have posttraumatic stress disorder. Perspect Psychol Sci 8(6): 651-662
49. Garfinkel SN, Abelson JL, King AP, Sripada RK, Wang X, Gaines LM, Liberzon I (2014) Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. J Neurosci 34: 13435-13443
50. Gilbertson MW, Williston SK, Paulus LA, Lasko NB, Gurvits TV, Shenton ME, Pitman RK, Orr SP (2007) Configural cue performance in identical twins discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal function. Biol Psychiatry 62: 513-520
51. Glenn DE, Minor TR, Vervliet B, Craske MG (2014) The effect of glucose on hippocampal-dependent contextual fear conditioning. Biol Psychiatry 75: 847-854
52. Glover EM, Phifer JE, Crain DF, Norrholm SD, Davis M, Bradley B, Ressler KJ, Jovanovic T (2011) Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures. Depress Anxiety 28: 1058-1066
53. Glover EM, Jovanovic T, Norrholm SD (2015) Estrogen and extinction of fear memories: implications for posttraumatic stress disorder treatment. Biol Psychiatry 78: 178-185
54. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160: 636-645
55. Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ (2007) Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 64: 1242-1250
56. Grillon C (2002) Associative learning deficits increase symptoms of anxiety in humans. Biol Psychiatry 51: 851-858
57. Grillon C (2009) D-Cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms. Biol Psychiatry 66: 636-641
58. Grillon C, Baas JMP, Pine DS, Lissek S, Lawley M, Ellis V, Levine J (2006) The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry 60: 760
59. Grillon C, Levenson J, Pine DS (2007) A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study. Neuropsychopharmacology 32: 225-231
60. Grillon C, Lissek S, Rabin S, McDowell D, Dvir S, Pine DS (2008) Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am J Psychiatry: appi.ajp.2007.07101581
61. Grillon C, Chavis C, Covington MF, Pine DS (2009a) Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study. Neuropsychopharmacology 34: 964-971
62. Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M (2009b) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66: 47-53
63. Guastella AJ, Lovibond PF, Dadds MR, Mitchell P, Richardson R (2007) A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans. Behav Res Ther 45: 663-672
64. Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS (2009) A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 34: 917-923
65. Haaker J, Golkar A, Hermans D, Lonsdorf TB (2014) A review on human reinstatement studies: an overview and methodological challenges. Learn Mem 21: 424-440
66. Hermans D, Dirikx T, Vansteenwegenin D, Baeyens F, Van den Bergh O, Eelen P (2005) Reinstatement of fear responses in human aversive conditioning. Behav Res Ther 43: 533-551
67. Hetrick SE, Purcell R, Garner B, Parslow R (2010) Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev: CD007316
68. Hofmann SG, Otto MW, Pollack MH, Smits JA (2015) D-cycloserine augmentation of cognitive behavioral therapy for anxiety disorders: an update. Curr Psychiatry Rep 17: 532
69. Institute of Medicine (2014) Treatment for posttraumatic stress disorder in military and veteran populations: final assessment. Committee on the assessment of ongoing efforts in the treatment of posttraumatic stress disorder, board on the health of select populations, Institute of Medicine, Washington (DC), National Academies Press (US), Jun 17 2014
70. Jovanovic T, Norrholm SD, Keyes M, Fiallos A, Jovanovic S, Myers KM, Davis M, Duncan EJ (2006) Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm. Behav Neurosci 120: 995-1004
71. Jovanovic T, Kazama A, Bachevalier J, Davis M (2012) Impaired safety signal learning may be a biomarker of PTSD. Neuropharmacology 62: 695-704
72. Kheirbek MA, Tannenholz L, Hen R (2012) NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J Neurosci 32: 8696-8702
73. Klumpers F, Denys D, Kenemans JL, Grillon C, van der Aart J, Baas JM (2012) Testing the effects of Delta9-THC and D-cycloserine on extinction of conditioned fear in humans. J Psychopharmacol 26: 471-478
74. Kuriyama K, Honma M, Soshi T, Fujii T, Kim Y (2011) Effect of D-cycloserine and valproic acid on the extinction of reinstated fear-conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial. Psychopharmacology 218: 589-597
75. Lebron-Milad K, Tsareva A, Ahmed N, Milad MR (2013) Sex differences and estrous cycle in female rats interact with the effects of fluoxetine treatment on fear extinction. Behav Brain Res 253: 217-222
76. Lee JLC, Milton AL, Everitt BJ (2006) Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26: 10051-10056
77. Lenzenweger MF (2013) Endophenotype, intermediate phenotype, biomarker: definitions, concept comparisons, clarifications. Depress Anxiety 30: 185-189
78. Lissek S, van Meurs B (2014) Learning models of PTSD: theoretical accounts and psychobiological evidence. Int J Psychophysiol S0167-8760(14)01647-X. doi: 10.1016/j.ijpsycho.2014.11.006. [Epub ahead of print]
79. Lissek S, Rabin SJ, Heller RE, Luckenbaugh D, Geraci M, Pine DS, Grillon C (2010) Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatr 167: 47-55
80. Lissek S, Bradford DE, Alvarez RP, Burton P, Espensen-Sturges T, Reynolds RC, Grillon C (2014a) Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. Soc Cogn Affect Neurosci 9: 1134-1142
81. Lissek S, Kaczkurkin AN, Rabin S, Geraci M, Pine DS, Grillon C (2014b) Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear. Biol Psychiatry 75: 909-915
82. Litvin Y, Pentkowski NS, Blanchard DC, Blanchard RJ (2007) CRF type 1 receptors in the dorsal periaqueductal gray modulate anxiety-induced defensive behaviors. Horm Behav 52: 244-251
83. Lommen MJ, Engelhard IM, Sijbrandij M, van den Hout MA, Hermans D (2013) Pre-trauma individual differences in extinction learning predict posttraumatic stress. Behav Res Ther 51: 63-67
84. Lonergan MH, Olivera-Figueroa LA, Pitman RK, Brunet A (2013) Propranolol’s effects on the consolidation and reconsolidation of long-term emotional memory in healthy participants: a meta-analysis. J Psychiatry Neurosci 38: 222-231
85. Maren S, Holmes A (2015) Stress and fear extinction. Neuropsychopharmacology 41: 58-79
86. Maren S, Aharonov G, Fanselow MS (1997) Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav Brain Res 88: 261-274
87. Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63: 129-151
88. Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK, Rauch SL (2006) Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans. Behav Neurosci 120: 1196-1203
89. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK (2008) Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res 42: 515-520
90. Milad MR, Furtak SC, Greenberg JL, Keshaviah A, Im JJ, Falkenstein MJ, Jenike M, Rauch SL, Wilhelm S (2013) Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry 70: 608-618; quiz 554
91. Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36: 567-584
92. Nader K (2015) Reconsolidation and the dynamic nature of memory. Cold Spring Harb Perspect Biol 7: a021782
93. Neumann DL (2008) The effects of context changes on the reinstatement of extinguished conditioned behavior in a conditioned suppression task with humans. Learn Motiv 39: 114-135
94. Neumann DL, Lipp OV, Cory SE (2007) Conducting extinction in multiple contexts does not necessarily attenuate the renewal of shock expectancy in a fear-conditioning procedure with humans. Behav Res Ther 45: 385-394
95. Norberg MM, Krystal JH, Tolin DF (2008) A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 63: 1118
96. Norrholm SD, Jovanovic T, Olin IW, Sands LA, Karapanou I, Bradley B, Ressler KJ (2011) Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity. Biol Psychiatry 69: 556-563
97. O’Donnell ML, Varker T, Holmes AC, Ellen S, Wade D, Creamer M, Silove D, McFarlane A, Bryant RA, Forbes D (2013) Disability after injury: the cumulative burden of physical and mental health. J Clin Psychiatry 74: e137-e143
98. Otis JM, Werner CT, Mueller D (2015) Noradrenergic regulation of fear and drug-associated memory reconsolidation. Neuropsychopharmacology 40: 793-803
99. Rabinak CA, Angstadt M, Sripada CS, Abelson JL, Liberzon I, Milad MR, Phan KL (2013) Cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology 64: 396-402
100. Rasetti R, Weinberger DR (2011) Intermediate phenotypes in psychiatric disorders. Curr Opin Genet Dev 21: 340-348
101. Raskind MA, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, Homas D, Hill J, Daniels C, Calohan J, Millard SP, Rohde K, O’Connell J, Pritzl D, Feiszli K, Petrie EC, Gross C, Mayer CL, Freed MC, Engel C, Peskind ER (2013) A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry 170: 1003-1010
102. Rescorla RA, Heth CD (1975) Reinstatement of fear to an extinguished stimulus. J Exp Psychol Anim Behav Process 1: 88-96
103. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61: 1136-1144
104. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470: 492-497
105. Risbrough V (2010) Behavioral correlates of anxiety. Curr Top Behav Neurosci 2: 205-228
106. Robison-Andrew EJ, Duval ER, Nelson CB, Echiverri-Cohen A, Giardino N, Defever A, Norrholm SD, Jovanovic T, Rothbaum BO, Liberzon I, Rauch SA (2014) Changes in trauma-potentiated startle with treatment of posttraumatic stress disorder in combat Veterans. J Anxiety Disord 28: 358-362
107. Rodebaugh TL, Lenze EJ (2013) Lessons learned from D-cycloserine: the promise and limits of drug facilitation of exposure therapy. J Clin Psychiatry 74: 415-416
108. Rodebaugh TL, Levinson CA, Lenze EJ (2013) A high-throughput clinical assay for testing drug facilitation of exposure therapy. Depress Anxiety 30: 631-637
109. Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A (2014) Preliminary, open-label, pilot study of add-on oral Delta9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig 34: 587-591
110. Rothbaum BO, Davis M (2003) Applying learning principles to the treatment of post-trauma reactions. Ann NY Acad Sci 1008: 112-121
111. Rothbaum B, Foa EB, Riggs DS, Murdock T, Walsh W (1992) A prospective examination of post-traumatic stress disorder in rape victims. J Trauma Stress 5: 455-475
112. Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, Davis M, Bradley B, Duncan EJ, Rizzo A, Ressler KJ (2014) A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am J Psychiatry 171: 640-648
113. Rougemont-Bücking A, Linnman C, Zeffiro TA, Zeidan MA, Lebron-Milad K, Rodriguez-Romaguera J, Rauch SL, Pitman RK, Milad MR (2011) Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci Ther 17: 227-236
114. Rudy JW, Huff NC, Matus-Amat P (2004) Understanding contextual fear conditioning: insights from a two-process model. Neurosci Biohehav Rev 28: 675-685
115. Scheeringa MS, Weems CF (2014) Randomized placebo-controlled D-cycloserine with cognitive behavior therapy for pediatric posttraumatic stress. J Child Adolesc Psychopharmacol 24: 69-77
116. Schmidt U (2015) A plea for symptom-based research in psychiatry. Eur J Psychotraumatol 6: 27660
117. Schneier FR, Neria Y, Pavlicova M, Hembree E, Suh EJ, Amsel L, Marshall RD (2012) Combined prolonged exposure therapy and paroxetine for PTSD related to the World Trade Center attack: a randomized controlled trial. Am J Psychiatry 169: 80-88
118. Sevenster D, Beckers T, Kindt M (2012) Retrieval per se is not sufficient to trigger reconsolidation of human fear memory. Neurobiol Learn Mem 97: 338-345
119. Shvil E, Rusch HL, Sullivan GM, Neria Y (2013) Neural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literature. Curr Psychiatry Rep 15: 358
120. Silva M, Hetem LA, Guimaraes FS, Graeff FG (2001) Opposite effects of nefazodone in two human models of anxiety. Psychopharmacology 156: 454-460
121. Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149: 150-190
122. Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B (2012) PTSD and gene variants: new pathways and new thinking. Neuropharmacology 62: 628-637
123. Soeter M, Kindt M (2015) Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience. Front Behav Neurosci 9: 122
124. Sokol N, Lovibond PF (2012) Cross-US reinstatement of human conditioned fear: return of old fears or emergence of new ones? Behav Res Ther 50: 313-322
125. Steckler T, Risbrough V (2012) Pharmacological treatment of PTSD-established and new approaches. Neuropharmacology 62: 617-627
126. Steiger F, Nees F, Wicking M, Lang S, Flor H (2015) Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder. Int J 2015 Jul 3. pii: S0167-8760(15)30002-7. doi: 10.1016/j.ijpsycho.2015.06.009. [Epub ahead of print]
127. Tabbert K, Stark R, Kirsch P, Vaitl D (2006) Dissociation of neural responses and skin conductance reactions during fear conditioning with and without awareness of stimulus contingencies. Neuroimage 32: 761-770
128. Thomas JL, Wilk JE, Riviere LA, McGurk D, Castro CA, Hoge CW (2010) Prevalence of mental health problems and functional impairment among active component and national guard soldiers 3 and 12 months following combat in Iraq. Arch Gen Psychiatry 67: 614-623
129. Vervliet B (2008) Learning and memory in conditioned fear extinction: effects of d-cycloserine. Acta Psychol 127: 601-613
130. Vervliet B, Craske MG, Hermans D (2013) Fear extinction and relapse: state of the art. Annu Rev Clin Psychol 9: 215-248
131. Walker DL, Ressler KJ, Lu KT, Davis M (2002) 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 JID 8102140(22): 2343-2351
132. Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463: 199-216
133. Wilker S, Elbert T, Kolassa IT (2014) The downside of strong emotional memories: how human memory-related genes influence the risk for posttraumatic stress disorder-a selective review. Neurobiol Learn Mem 112: 75-86
134. Wood NE, Rosasco ML, Suris AM, Spring JD, Marin M-F, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK (2015) Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res 225: 31-39
135. Woods AM, Bouton ME (2006) D-cycloserine facilitates extinction but does not eliminate renewal of the conditioned emotional response. Behav Neurosci 120: 1159-1162
136. Zhang L, Hu XZ, Li H, Li X, Smerin S, Benedek DM, Ursano R (2011) Startle response related genes. Med Hypotheses 77: 685-691