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Appendix H Minority Opinion of Dr. Thomas Mellman I do not concur with the committee’s consensus on two conclusions and the comments that accompany those conclusions. My disagreement with the two conclusions is informed by three issues. I disagree with the committee’s decision to meet the study charge by making a general conclu- sion about each intervention, followed by a separate notation about “the restriction of the conclusion regarding the population, provider, setting of intervention, etc.” I believe that for the selective serotonin reuptake inhibi- tor (SSRI) class in particular, the effect of the medication in civilian and specific veteran subpopulations must be noted as separate conclusions. I also disagree with the degree of emphasis the committee placed on the effect of the “last observation carried forward” (LOCF) method for treating miss- ing data on study outcomes (i.e., the fact that use of LOCF is considered a major limitation). Finally, I believe that the distinction the committee makes between its evidence-based conclusions intended to inform policy- making and clinical practice guidelines (such as those developed by the In- ternational Society for Traumatic Stress Studies or the American Psychiatric Association) is ultimately not meaningful to practicing clinicians. The following text reflects my restatement of the conclusions and com- ments pertaining to SSRIs and novel antipsychotic medications. Refer to Chapter 5 and Appendix D for the committee’s discussion of dropouts and m ­ ethods for handling missing data, including LOCF. 209

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210 TREATMENT OF POSTTRAUMATIC STRESS DISORDER SSRI Conclusion The evidence is suggestive but not sufficient to conclude efficacy of SSRIs in general populations with PTSD. The available evidence is further suggestive that SSRIs are not effective in populations consisting of predominantly male veterans with chronic PTSD. Comment: If one divides the SSRI studies into categories that include com- bat veterans with chronic PTSD (Friedman et al., 2007; Hertzberg et al., 2000; and van der Kolk et al., 1994) and veterans with more recent expo- sure to war (Martenyi et al., 2002; Zohar et al., 2002) (all of these male or predominately male) then the 3 studies with male veterans with chronic PTSD have negative results and the preponderance of the studies with civil- ian populations (9 of 11) are positive (Brady et al., 2000; Connor et al., 1999; Davidson et al., 2001; Marshall et al., 2001, 2007; Martenyi et al., 2002; Tucker et al., 2000, 2001; van der Kolk et al., 1994), and the 2 non- positive studies (Davidson et al., 2006; van der Kolk et al., 2007 ) show nonsignificant trends favoring the SSRI (sertraline in one study, ­fluoxetine in the other). (This analysis counts van der Kolk’s 1994 study with veteran and civilian groups as 2 studies.) Limitations (e.g., high dropout rates) warrant “suggestive but not suf- ficient to conclude the efficacy” rather than “sufficient to conclude the ef- ficacy” of SSRIs. The positive studies tend to be large and well conducted by all criteria other than dropout rates and use of LOCF to address miss- ing data. Three of the larger, well-conducted positive studies have dropout rates that do not exceed 31 percent per group and the rates are similar in the treatment groups. The assumption that LOCF provides a conservative estimate in medication studies is supported by the extant short-term and long-term medication treatment trajectory data that shows continuing im- provement over time. Additional evidence that predominantly male veteran populations with chronic PTSD are less responsive to treatments in general comes from Schnurr et al. (2003), which is one of the few studies to not find an advantage of exposure-based cognitive-behavioral therapy over an active control. The Cochrane systematic review (Stein et al., 2006) that utilized meta-analysis (and is referred to in the report in Chapter 3, sec- tion on SSRIs) also supports the efficacy of SSRIs for PTSD in the general population. Novel Antipsychotic Medications Conclusion There is evidence that is suggestive but not sufficient to conclude the efficacy of new generation antipsychotic medications as add-on or ad- junctive for the treatment of PTSD.

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APPENDIX H 211 Comment: This evidence comes from studies where most of the participants had risperidone or olanzapine added to other medication regimens to which they had not adequately responded. Veterans with chronic PTSD are well represented in these studies. The fact that this literature highlights severely affected, treatment r ­ efractory veterans would seem of particular interest to VA. Although it would not be advisable to make clinical recommendations for the use of novel antipsychotic medications as a first-line therapy because of the nature of the evidence and concerns regarding their tolerability, it should be noted that three of the studies with few major limitations had positive results, and the remaining with a negative result had a very small total N (15) and should be considered separately as it evaluated olanzapine as a monotherapy. Thomas A. Mellman, MD REFERENCES Brady, K., T. Pearlstein, G. M. Asnis, D. Baker, B. Rothbaum, C. R. Sikes, and G. M. Farfel. 2000. Efficacy and safety of sertraline treatment of posttraumatic stress dis- order: A randomized controlled trial. Journal of the American Medical Association 283(14):1837-1844. Connor, K. M., S. M. Sutherland, L. A. Tupler, M. L. Malik, and J. R. Davidson. 1999. F ­ luoxetine in post-traumatic stress disorder. Randomised, double-blind study. British Journal of Psychiatry 175:17-22. Davidson, J. R., B. O. Rothbaum, B. A. van der Kolk, C. R. Sikes, and G. M. Farfel. 2001. Multicenter, double-blind comparison of sertraline and placebo in the treatment of post- traumatic stress disorder. Archives of General Psychiatry 58(5):485-492. Davidson, J., B. O. Rothbaum, P. Tucker, G. Asnis, I. Benattia, and J. J. Musgnung. 2006. Venlafaxine extended release in posttraumatic stress disorder: A sertraline- and placebo- controlled study. Journal of Clinical Psychopharmacology 26(3):259-267. Friedman, M. J., C. R. Marmar, D. G. Baker, C. R. Sikes, and G. M. Farfel. 2007. Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a department of veterans affairs setting. Journal of Clinical Psychiatry 68(5):711-720. Hertzberg, M. A., M. E. Feldman, J. C. Beckham, H. S. Kudler, and J. R. Davidson. 2000. Lack of efficacy for fluoxetine in PTSD: A placebo controlled trial in combat veterans. Annals of Clinical Psychiatry 12(2):101-105. Marshall, R. D., K. L. Beebe, M. Oldham, and R. Zaninelli. 2001. Efficacy and safety of p ­ aroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study. American Journal of Psychiatry 158(12):1982-1988. Marshall, R. D., R. Lewis-Fernandez, C. Blanco, H. Simpson, S.-H. Lin, D. Vermes, W. Garcia, F. Schneier, Y. Neria, A. Sanchez-Lacay, and M. R. Liebowitz. 2007. A controlled trial of paroxetine for chronic PTSD, dissociation and interpersonal problems in mostly minority adults. Depression and Anxiety 24(2):77-84. Martenyi, F., E. B. Brown, H. Zhang, A. Prakash, and S. C. Koke. 2002. Fluoxetine versus placebo in posttraumatic stress disorder. Journal of Clinical Psychiatry 63(3):199-206.

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212 TREATMENT OF POSTTRAUMATIC STRESS DISORDER Schnurr, P., M. Friedman, D. Foy, M. Shea, F. Hsieh, P. Lavori, S. Glynn, M. Wattenberg, and N. Bernardy. 2003. Randomized trial of trauma-focused group therapy for posttraumatic stress disorder: Results from a department of Veterans affairs cooperative study. Archives of General Psychiatry 60(5):481-489. Stein, D. J., J. C. Ipser, and S. Seedat. 2006. Pharmacotherapy for post traumatic stress dis­ order (PTSD). Cochrane Database Systematic Reviews (4):CD002795. Tucker, P., K. L. Smith, B. Marx, D. Jones, R. Miranda, Jr., and J. Lensgraf. 2000. ­Fluvoxamine reduces physiologic reactivity to trauma scripts in posttraumatic stress disorder. Journal of Clinical Psychopharmacology 20(3):367-372. Tucker, P., R. Zaninelli, R. Yehuda, L. Ruggiero, K. Dillingham, and C. D. Pitts. 2001. P ­ aroxetine in the treatment of chronic posttraumatic stress disorder: Results of a placebo- controlled, flexible-dosage trial. Journal of Clinical Psychiatry 62(11):860-868. van der Kolk, B. A., D. Dreyfuss, M. Michaels, D. Shera, R. Berkowitz, R. Fisler, and G. Saxe. 1994. Fluoxetine in posttraumatic stress disorder. Journal of Clinical Psychiatry 55(12):517-522. van der Kolk, B. A., J. Spinazzola, M. E. Blaustein, J. W. Hopper, E. K. Hopper, D. L. Korn, and W. B. Simpson. 2007. A randomized clinical trial of eye movement desensitiza- tion and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of post­ traumatic stress disorder: Treatment effects and long-term maintenance. Journal of Clinical ­Psychiatry 68(1):37-46. Zohar, J., D. Amital, C. Miodownik, M. Kotler, A. Bleich, R. M. Lane, and C. Austin. 2002. Double-blind placebo-controlled pilot study of sertraline in military veterans with post- traumatic stress disorder. Journal of Clinical Psychopharmacology 22(2):190-195.