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Letters to the Editor

Toward Rational Use of Benzodiazepines in Posttraumatic Stress Disorder

See replies by Lund et al and Capehart and related article by Lund et al.

Toward Rational Use of Benzodiazepines in Posttraumatic Stress Disorder

To the Editor: A recent study in the Journal by Lund et al1 has provided important data: benzodiazepines are still prescribed to 30.6% of an American veteran posttraumatic stress disorder (PTSD) population, although from 1999 to 2009 there was a 17% decline. In a comment,2 Capehart encourages this trend, assuming that this decline may reflect greater use of evidence-based therapies. Indeed, expert consensus guidelines3,4 recommend against the use of benzodiazepines in PTSD, even though there is only 1 randomized controlled trial (RCT) that did not find a significant advantage of benzodiazepines over placebo.5 Furthermore, PTSD is highly comorbid with substance disorders and therefore prone to detrimental addiction effects,6-8 and benzodiazepine-induced anterograde amnesia has been proposed to interfere negatively with exposure-based psychotherapies.9 Substantial ambivalence exists regarding the proper use of benzodiazepines in PTSD, as illustrated by a prescription frequency variation of 14.7%-56.8% among 137 facilities in the United States.10 Moreover, the preponderance of clinical research on selective serotonin reuptake inhibitors (SSRIs) in PTSD has made some wonder why benzodiazepines are prescribed at all.2

Still, preclinical evidence has offered promising potential. In particular, data from studies on the reconsolidation phase of memory, which is activated by reexposure to conditioned stimuli, show that specific traumatic memory is fragile and prone to disruption,11 as demonstrated with propranolol in humans.12,13 The animal research finding that midazolam is capable of obliterating long-term fear is promising for the use of benzodiazepines in PTSD.14 Rodent studies have repeatedly shown that the immediately reduced contextual fear responding produced by systemic midazolam does not recover over time following reexposure.14-17 This effect seems to depend on the age of the memory; a longer interval between the initial acquisition of fear memories and their reactivation may require longer reactivation periods and higher doses to weaken them.17 The effects of benzodiazepines on blockade of traumatic memory reconsolidation therefore deserve further attention.

In fact, new pharmacologic strategies are requisite as current PTSD therapies remain unsatisfactory. One needs to bear in mind that the magnitude of the effects of SSRIs is limited and remission is rarely achieved.4,18 Furthermore, the latest Cochrane Review19 concludes that there is no clear evidence to show that any particular class of medication is more effective in PTSD or better tolerated than any other. The bulk of trials showing efficacy to date have been with SSRIs, but there is a paucity of literature on benzodiazepines. The 1990 RCT by Braun et al5 is extensively cited in psychiatric literature to demonstrate the notion that benzodiazepines are ineffective in PTSD, but has very low power (N = 10), confounding withdrawal effects, and it included only treatment-refractory, chronic PTSD patients who were unresponsive to several antidepressants. To date, there is no evidence on the effects of benzodiazepines on reconsolidation of traumatic memory in PTSD.

Lund and colleagues1 accurately mention that simply advocating against current benzodiazepine use in PTSD, without providing alternative strategies, is not an option. Future research is warranted; finding the optimal memory reactivation length may become a great clinical challenge of trial-and-error, as benzodiazepine administration may time-dependently both inhibit and promote forgetting in PTSD.

References

1. Lund BC, Bernardy NC, Alexander B, et al. Declining benzodiazepine use in veterans with posttraumatic stress disorder. J Clin Psychiatry. 2012;73(3):292-296. PubMed doi:10.4088/JCP.10m06775

2. Capehart BP. Benzodiazepines, posttraumatic stress disorder, and veterans: good news and why we’ re not done yet. J Clin Psychiatry. 2012;73(3):307-309. PubMed doi:10.4088/JCP.11com07079

3. Veterans Health Administration, Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Post-Traumatic Stress. Version 2.0. Washington, DC: Veterans Health Administration, Department of Defense; 2010.

4. Bandelow B, Zohar J, Hollander E, et al; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders—first revision. World J Biol Psychiatry. 2008;9(4):248-312. PubMed doi:10.1080/15622970802465807

5. Braun P, Greenberg D, Dasberg H, et al. Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry. 1990;51(6):236-238. PubMed

6. Risse SC, Whitters A, Burke J, et al. Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder. J Clin Psychiatry. 1990;51(5):206-209. PubMed

7. Jacobsen LK, Southwick SM, Kosten TR. Substance use disorders in patients with posttraumatic stress disorder: a review of the literature. Am J Psychiatry. 2001;158(8):1184-1190. PubMed doi:10.1176/appi.ajp.158.8.1184

8. O’ Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry. 2005;66(suppl 2):28-33. PubMed

9. 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):439-457. PubMed doi:10.1016/S0005-7967(01)00024-9

10. Lund BC, Abrams TE, Bernardy NC, et al. Benzodiazepine prescribing variation and clinical uncertainty in treating posttraumatic stress disorder. Psychiatr Serv. 2012; 64(1):21-27. PubMed

11. Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature. 2000;406(6797):722-726. PubMed doi:10.1038/35021052

12. Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci. 2009;12(3):256-258. PubMed doi:10.1038/nn.2271

13. Brunet A, Orr SP, Tremblay J, et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res. 2008;42(6):503-506. PubMed doi:10.1016/j.jpsychires.2007.05.006

14. Makkar SR, Zhang SQ, Cranney J. Behavioral and neural analysis of GABA in the acquisition, consolidation, reconsolidation, and extinction of fear memory. Neuropsychopharmacology. 2010;35(8):1625-1652. PubMed

15. Bustos SG, Maldonado H, Molina VA. Midazolam disrupts fear memory reconsolidation. Neuroscience. 2006;139(3):831-842. PubMed doi:10.1016/j.neuroscience.2005.12.064

16. Zhang S, Cranney J. The role of GABA and anxiety in the reconsolidation of conditioned fear. Behav Neurosci. 2008;122(6):1295-1305. PubMed doi:10.1037/a0013273

17. Bustos SG, Maldonado H, Molina VA. Disruptive effect of midazolam on fear memory reconsolidation: decisive influence of reactivation time span and memory age. Neuropsychopharmacology. 2009;34(2):446-457. PubMed doi:10.1038/npp.2008.75

18. Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry. 2010;71(7):839-854. PubMed doi:10.4088/JCP.10r06218blu

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

Serge A. Steenen, MSc

Roos van Westrhenen, MD, PhD

Miranda Olff, PhD

m.olff@amc.uva.nl

Author affiliations: Department of Psychiatry, Academic Medical Center, University of Amsterdam (Mr Steenen and Dr Olff); and Department of Psychiatry, VU University Medical Center, VU University Amsterdam (Dr van Westrhenen), Amsterdam, the Netherlands.

Potential conflicts of interest: None reported.

Funding/support: None reported.

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