Zhyvotovska L. V., Boiko D. I., Sokil A. A., Pogorilko O. V., Voloshyn V. A.

LITERATURE REVIEWS

Scentific article

Post-traumatic stress disorder (PTSD), the development of which is provoked by various emergencies – the most studied and, probably, the most common psychiatric disorder that occurs immediately after traumatic events and catastrophes of different origins. However, there is some uncertainty about the diagnosis and treatment of post-traumatic disorders. The research examined the current trends in the development of psychopharmacology of post-traumatic stress disorder using MDMA, D-cycloserine, cannabidiol, ketamine and neuropeptide Y. In the treatment of PTSD, psychotherapy is preferred, while pharmacotherapy is considered secondary. At the moment, the possibility of using the above-mentioned substances as part of complex and combined therapy is being considered from the point of view of their neurobiological effects, which affect various parts of the biochemical processes of memory reconsolidation. Researches in healthy people have shown that MDMA mediates the processing of emotional memory. DCS affects specific subtypes of NMDA receptors, one of the functions of which is the modulation of the responses to the extinction of fear. Thus, more extensive surveys using exposition therapy and fractional dosage will allow the role of DCS to be added as an additional therapy in the treatment of PTSD. Some investigators describe the relationship between the use of cannabis, as a form of self-treatment, and the force of traumatic events in adolescents as well as in adults. According to modern research, CBD increases the consolidation of averted extinction of memory in healthy people. Noteworthy is the preservation of the potential of neuroplasticity and the stimulation of the glutamatergic system with ketamine as a new direction in the pharmacotherapy of PTSD. Drugs are now at the preclinical stage, using NPY receptors as therapeutic targets. The intranasal administration of NPY is an interesting option, since it has the potential to increase the concentration of peptides directly into the central nervous system without significantly affecting peripheral structures. Such an approach worked successfully in rodent models in PTSD models. However, the systemic introduction of NPY modulators may have unwanted side effects as it has a stimulating effect on vasoconstriction, inflammation, angiogenesis and adipogenesis. Despite a number of positive results, many issues in this area remain unresolved and require further and in-depth study. Priority is the study of new experimental methods of therapy for PTSD that will improve existing rehab programs, improve quality of life and return patients to full social functioning.

PTSD, treatment, MDMA, cannabidiol, D-cycloserine, ketamin, neuropeptide Y.

1. Scherbak MG. Vyznachennya postravmatychnykh stresovykh rozladiv, shcho vynykly vnaslidok nadzvychaynykh sytuatsiy. Problemy ekstremalnoi ta kryzovoi psykholohii. 2009;6:238-48. [in Ukrainian].
2. Bohomolets OV, Pinchuk IYa, Ladyk-Bryzghalova АК. Poshyrenist ta struktura posttravmatychnykh porushen v uchasnykiv boiovykh dii. Arkhiv psykhiatrii. 2016;22:2(85):11-5. [in Ukrainian].
3. Koval IA. Diahnostyka i dyferentsiina diahnostyka hostroho stresovoho rozladu ta posttravmatychnoho stresovoho rozladu v zahalnomedychnii praktytsi. Problemy suchasnoi psykholohii. 2015;27:210-9. [in Ukrainian].
4.  Ihrunova KN. Psykhofyzyolohycheskyi mekhanyzm stressa. Tavrycheskyi medyko-byolohycheskyi vestnyk. 2004;8-16. [in Russian].
5. Unifikovanyi klinichnyi protokol pervynnoi, vtorynnoi (spetsializovanoi) ta tretynnoi (vysokospetsializovanoi) medychnoi dopomohy reaktsiia na vazhkyi stres ta rozlady adaptatsii. Posttravmatychnyi stresovyi rozlad: Nakaz Ministerstva okhorony zdorov’ia Ukrainy. 2016;121:57. [in Ukrainian].
6. Pishel VYa, Polyv’iana MYu. Problemni pytannia psykhofarmakoterapii posttravmatychnoho stresovoho rozladu. Arkhiv psykhiatrii. 2016;22:1(84):7-11. [in Ukrainian].
7. Korostii VI, Polishchuk VT, Zavorotnyi VI. Psykhofarmakoterapiia v kompleksnomu likuvanni ta reabilitatsii posttravmatychnoho stresovoho rozladu. Mizhnarodnyi nevrolohichnyi zhurnal. 2015;6(76):59-71. [in Ukrainian].
8. Hryn KV, Skrypnikov AM, Herasymenko LO, Shynder VV, vynakhidnyky; Ukrainska medychna stomatolohichna akademiia, patentovlasnyk. Sposib likuvannia posttravmatychnykh stresovykh rozladiv. Patent Ukrainy №125456. 2018 trav. 10. [in Ukrainian].
9. Guina J, Rossetter SR, DeRhodes BJ, Nahhas RW, Welton RS. Benzodiazepines for PTSD: A systematic review and Meta-Analysis. Journal of Psychiatric Practice. 2015;21:4:281-303.
10. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018;84:221-8.
11. Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009;324(5929):951-5.
12. Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis inthe amygdala for reconsolidation after retrieval. Nature. 2000;406(6797):722-6.
13. Bedi G, Phan KL, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology. 2009;207(1):73-83.
14. Carhart-Harris RL, Wall MB, Erritzoe D, Kaelen M, Ferguson B, De Meer I, et al. The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. Int. J. Neuropsychopharmacol. 2014;17(4):527-40.
15. Doss MK, Weafer J, Gallo DA, de Wit H. MDMA impairs both the encoding and retrieval of emotional recollections. Neuropsychopharmacology. 2018;43:791-800.
16. Lane RD, Ryan L, Nadel L, Greenberg L. Memory reconsolidation, emotional arousal, and the process of change in psychotherapy: new insights from brain science. Behav. Brain Sci. 2015;38:1.
17. Jafari M, Seese RR, Babayan AH, Gall CM, Lauterborn JC. Glucocorticoid receptors are localized to dendritic spines and influence local actin signaling. Mol. Neurobiol. 2012;46(2):304-15.
18. Meir Drexler S, Wolf OT. The role of glucocorticoids in emotional memory reconsolidation. Neurobiol. Learn. Mem. 2017;142:126-34.
19. de Quervain DJ, Bentz D, Michael T, Bolt OC, Wiederhold BK, Margraf J, et al. Glucocorticoids enhance extinction-based psychotherapy. Proc. Natl. Acad. Sci. U.S.A. 2011;108(16):6621-5.
20. Hamacher-Dang TC, Engler H, Schedlowski M, Wolf OT. Stress enhances the consolidation of extinction memory in a predictive learning task. Front. Behav. Neurosci. 2013;7:108.
21. de Quervain DJ, Margraf J. Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach. Eur. J. Pharmacol. 2008;583(2-3):365-71.
22. Mas M, Farre M, de la Torre R, Roset PN, Ortuno J, Segura J, et al. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-me thylenedioxymethamphetamine in humans. J. Pharmacol. Exp. Ther. 1999;290(1):136-45.
23. Lester SJ, Baggott M, Welm S, Schiller NB, Jones RT, Foster E, et al. Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A doubleblind, placebo-controlled trial. Ann. Intern. Med. 2000;133(12):969-73.
24. Jaycox LH, Foa EB, Morral AR. Influence of emotional engagement and habituation on exposure therapy for PTSD. J. Consult. Clin. Psychol. 1998;66(1):185-92.
25. 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(7):515-20.
26. 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.
27. Sheinin A, Shavit S, Benveniste M. Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine. Neuropharmacology. 2001;41(2):151-8.
28. Zhou Q, Sheng M. NMDA receptors in nervous system diseases. Neuropharmacology. 2013;74:69-75.
29. Davis M. NMDA receptors and fear extinction: implications for cognitive behavioral therapy. Dialogues Clin Neurosci. 2011;13(4):463-74.
30. Attari A, Rajabi F, Maracy MR. D-cycloserine for treatment of numbing and avoidance in chronic post traumatic stress disorder: a randomized, double blind, clinical trial. J. Res. Med. Sci. 2014;19(7):592-8.
31. Richardson R. Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications. Learn Mem. 2004;11(5):510-6.
32. Walker DL, Ressler KJ, Lu KT, 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(6):2343-51.
33. Goff DC. D-cycloserine: an evolving role in learning and neuroplasticity in schizophrenia. Schizophr. Bull. 2012;38(5):936-41.
34. Difede J, Cukor J, Wyka K, Olden M, Hoffman H, Lee FS, et al. D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial. Neuropsychopharmacology. 2014;39(5):1052-8.
35. de Kleine RA, Hendriks GJ, Kusters WJC, Broekman TG, van Minnen A. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol Psychiatry. 2012;71(11):962-8.
36. Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, et al. 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. 2014;171(6):640-8.
37. Bergamaschi MM, Queiroz RHC, Zuardi AW, Crippa JAS. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf. 2011;6:237-49.
38. Das RK, Kamboj SK, Ramadas M, Curran HV, Morgan CJA. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology. 2013;2:781-92.
39. Shannon S, Opila-Lehman J. Effectiveness of cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm. J. 2016;20:108-11.
40. Greer GR, Grob CS, Halberstadt AL. PTSD symptom reports of patients evaluated for the new mexico medical cannabis program. J. Psychoactive Drugs. 2014;46:73-7.
41. Hill MN, Campolongo P, Yehuda R, Patel S. Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology. 2018;43:80-102.
42. Bonn-Miller MO, Vujanovic AA, Feldner MT, Bernstein A, Zvolensky MJ. Posttraumatic stress symptom severity predicts marijuana use coping motives among traumatic event-exposed marijuana users. J. Trauma. Stress. 2007;20:577-86.
43. Bujarski SJ, Feldner MT, Lewis SF, Babson KA, Trainor CD, Leen-Feldner E, et al. Marijuana use among traumatic eventexposed adolescents: posttraumatic stress symptom frequency predicts coping motivations for use. Addict. Behav. 2012;37:53-9.
44. Cougle JR, Bonn-Miller MO, Vujanovic AA, Zvolensky MJ, Hawkins KA. Posttraumatic stress disorder and cannabis use in a nationally representative sample. Psychol. Addict. Behav. 2011;25:554-8.
45. Kevorkian S, Bonn-Miller MO, Belendiuk K, Carney DM, Roberson-Nay R, Berenz EC. Associations among trauma, posttraumatic stress disorder, cannabis use, and cannabis use disorder in a nationally representative epidemiologic sample. Psychol. Addict. Behav. 2015;29:633-8.
46. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-49.
47. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64.
48. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.
49. 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 trial. JAMA Psychiatry. 2014;71(6):681-8.
50. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry. 2011;69(8):754-61.
51. Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42(6):1210-9.
52. Murrough JW, Abdallah CG, Anticevic A, Collins KA, Geha P, Averill LA, et al. Reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder. Hum. Brain Mapp. 2016;37(9):3214-23.
53.  Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91-5.
54. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-6.
55. Loix S, De Kock M, Henin P. The anti-inflammatory effects of ketamine: state of the art. Acta Anaesthesiol Belg. 2011;62(1):47-58.
56. Liebenberg N, Joca S, Wegener G. Nitric oxide involvement in the antidepressant-like effect of ketamine in the flinders sensitive line rat model of depression. Acta Neuropsychiatr. 2015;27(2):90-6.
57. Rosa PB, Neis VB, Ribeiro CM, Moretti M, Rodrigues AL. Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors. Pharmacol. Rep. 2016;68(5):996-1001.
58. Kask A, Harro J, von Hörsten S, Redrobe JP, Dumont Y, Quirion R. The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y. Neurosci. Biobehav. Rev. 2002;26(3):259-83.
59. Caberlotto L, Fuxe K, Hurd YL. Characterization of NPY mRNA-expressing cells in the human brain: co-localization with Y2 but not Y1 mRNA in the cerebral cortex, hippocampus, amygdala, and striatum. J. Chem. Neuroanat. 2000;20(3-4):327-37.
60. Sabban EL, Alaluf LG, Serova LI. Potential of neuropeptide Y for preventing or treating post-traumatic stress disorder. Neuropeptides. 2016;56:19-24.
61. Kastin AJ, Akerstrom V. Nonsaturable entry of neuropeptide Y into brain. Am. J. Phys. 1999;276(3,Pt1):479-82.
62. Brothers SP, Wahlestedt C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol. Med. 2010;2(11):429-39.
63. Shoblock JR, Welty N, Nepomuceno D, Lord B, Aluisio L, Fraser I, et al. In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2- (diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y(2) receptor. Psychopharmacology. 2010;208(2):265-77.
64. Kutsenko NL, Mikityuk MV, Bobrova IP, Kaidashev IP. Vplyv fulereniv na rozvytok alerhichnoho zapalennya v eksperymenti. Problemy ekolohiyi ta medytsyny. 2009;13(5-6):6-12. [in Ukrainian].
65. Mittapalli GK, Vellucci D, Yang J, Toussaint M, Brothers SP, Wahlestedt C, et al. Synthesis and SAR of selective small molecule neuropeptide Y Y2 receptor antagonists. Bioorg. Med. Chem. Lett. 2012;22(12):3916-20.
66. Cippitelli A, Rezvani AH, Robinson JE, Eisenberg L, Levin ED, Bonaventure P, et al. The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety. Alcohol. 2011;45(6):567-76.
67. Morales-Medina JC, Dumont Y, Bonaventure P, Quirion R. Chronic administration of the Y2 receptor antagonist, JNJ-31020028, induced antidepressant like-behaviors in olfactory bulbectomized rat. Neuropeptides. 2012;46(6):329-34.
68. Verma D, Wood J, Lach G, Mietzsch M, Weger S, Heilbronn R, et al. NPY Y2 receptors in the central amygdala reduce cued but not contextual fear. Neuropharmacology. 2015;99:665-74.
69. Hirsch D, Zukowska Z. NPY and stress 30 years later: the peripheral view. Cell. Mol. Neurobiol. 2012;32(5):645-59.
70. Cohen S, Vainer E, Matar MA, Kozlovsky N, Kaplan Z, Zohar J, et al. Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different Zeitgeber times. Neuropsychopharmacology. 2015;40(3):774-90.
71. Serova LI, Tillinger A, Alaluf LG, Laukova M, Keegan K, Sabban EL. Single intranasal neuropeptide Y infusion attenuates development of PTSDlike symptoms to traumatic stress in rats. J. Neurosci. 2013;236:298-312.

«Bulletin of problems biology and medicine» Issue 2 Part 2 (151), 2019 year, 38-44 pages, index UDK 616.89-008-039.12-06:616.45-001.1/3:615.2/3

10.29254/2077-4214-2019-2-2-151-38-44