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Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence (2008)

Chapter: 3 Evidence and Conclusions: Pharmacotherapy

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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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Suggested Citation:"3 Evidence and Conclusions: Pharmacotherapy." Institute of Medicine. 2008. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press. doi: 10.17226/11955.
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3 Evidence and Conclusions: Pharmacotherapy T he committee included 37 studies of pharmacotherapy in their review (reasons for exclusion are listed in the individual sections below). Of the included studies, 14 had no major limitations and were judged most informative to the committee’s conclusions regarding the efficacy of a treatment modality. Brief descriptions of the studies and evidence tables of key data provided are provided on the pages that follow. The commit- tee identified 22 individual drugs that are organized below in seven classes and a miscellaneous “other drugs” category. Trauma types in these studies included combat (both former American and international troops), sexual abuse, physical assault, accidental injury, witnessing (e.g., acts of genocide) and motor vehicle accidents. When analyzing the studies by sex, population, or trauma type, the committee categorized each study as being “predominantly” one type of sex, population, or trauma if 80 percent of the study population or more were of one type of sex, population, or trauma. The committee labeled the study as “mixed” if 79 percent or less of the study population were of one type of sex, population, or trauma. Twelve studies had a predominantly male population (7 for female population, 14 for mixed), 13 studies were predominantly in veteran populations whose primary trauma was combat, 10 studies in civilian populations predominantly included victims of sexual abuse, and 14 studies had a mixed trauma type. The committee found that, in most cases, if the study was predominantly in a veteran population, the participants were mostly male, and if the study was predominantly in Some studies did not include sex and/or trauma type. 55

56 TREATMENT OF POSTTRAUMATIC STRESS DISORDER a sexually abused population, participants were mostly female although there are instances where this is not the case. For studies in populations with mixed trauma type, the sex was also generally mixed. ALPHA-ADRENERGIC BLOCKERS The committee identified a small number of studies examining the effects of prazosin, an alpha-adrenergic blocker, on posttraumatic stress disorder (PTSD). Only two studies met inclusion criteria, and in neither was PTSD the primary outcome. Trauma for participants in both studies was combat-related (primarily from the Vietnam War). The mean age of participants was approximately 55 years. Neither study directly reported the duration of illness but clearly time of exposure was during the war the participant was involved in. In the study that reported race/ethnicity, 73 percent of participants were white (Raskind et al., 2007). The length of treatment in the two studies was 9 and 8 weeks, respectively. The single randomized trial meeting inclusion criteria was small and focused on nightmares and sleep disturbance as the primary outcomes ( ­ Raskind et al., 2007), demonstrating improvement in those completing treatment. Total Clinician Administered PTSD Scale (CAPS) scores were not significantly different between treatment and control patients at the end of the trial. There also was a small (n = 10) crossover study (Raskind et al., 2003) that focused on sleep disturbance with similar results. Synthesis: The committee found the studies on alpha-adrenergic blockers to be limited in number, and not focused on overall PTSD outcomes. Thus the committee judged the overall body of evidence to be scant and low quality. The committee is uncertain about the presence of an effect, and believes that future well-designed studies will have an important impact on confidence in the effect and the size of the effect. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of prazosin in the treatment of PTSD. Comment Although the committee judged the evidence inadequate to determine the efficacy of prazosin as a treatment of PTSD in general populations for overall PTSD outcomes, there are two small studies suggesting efficacy for combat-related nightmares and sleep disturbance in veterans.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 57 Exclusion Notes All open-label trials were excluded, as was a retrospective chart review (Raskind et al., 2002) and a study that did not use an overall PTSD out- come measure (Taylor et al., 2006). See Table 3-1 for a summary of the two included clinical trials. ANTICONVULSANTS The committee identified a small number of studies examining the effects of anticonvulsants such as topiramate, tiagabine, and lamotrigine on PTSD. Most studies were excluded because they were open label or uncontrolled. Participants in the anticonvulsant studies suffered a variety of traumas including combat-related, sexual and physical abuse and/or assault, witnessing, and serious accident or injury. The mean age of study participants was 43 years old with a range from late-20s to mid-50s. One study reported the duration of illness to be an average of 13 years, and duration of illness and time since trauma was not reported in the other studies (Davidson et al., 2007). In one study ethnicity was not reported, and the others had predominantly black (71 percent) and white (90 percent) populations, respectively. All studies were double-blinded and included a placebo control. Treat- ment length was 12 weeks for all studies. Only one study conducted follow- up after completion of treatment (1-year follow-up) (Hertzberg, 1999). All studies measured adverse events associated with the treatment condition. The main PTSD outcome measures used in the selective serotonin reuptake inhibitors (SSRIs) studies were CAPS-Total and SI-PTSD. Of the three randomized controlled trials (RCTs), two had major limi- tations including high differential and total dropout rates (Davidson et al., 2007; Tucker et al., 2007) and neither showed a positive effect on a primary PTSD outcome. The third qualifying RCT showed a positive effect of treat- ment with lamotrigine, but the trial was too small (a total of 15 patients) to reach statistical significance or estimate an effect size (Hertzberg et al., 1999). Synthesis: The committee found the overall body of evidence regarding anticonvulsants to be scant and low quality. The committee is uncertain about the presence of an effect, and believes that future well-designed stud- ies will have an important impact on confidence in the effect and the size of the effect. This study looked at daytime psychological stress, and used an E-Stroop test (word lists) to evaluate outcomes.

58 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-1  Alpha-Adrenergic Blockers PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Raskind Male, combat Total (34)d LOCFe CAPS- et al., Prazosin (17) 90.0% Total 2007c PL (17) 92.5% Raskind Male, combat Total (10)f LOCF CAPS- et al., Prazosin (5) 100%g Total 2003 PL (5) 100% Crossover Study aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cStudy focus was sleep and nightmares. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of anticonvulsants in the treatment of PTSD. Exclusion Notes Several open-label trials with anticonvulsants have been completed (Berlant, 2004; Berlant and van Kammen, 2002; Clark et al., 1999; Lipper et al., 1986), none of which were included. The committee identified one maintenance study (Connor et al., 2006) on tiagabine that was not included in its assessment of efficacy. This study was an open-label discontinuation study with 29 patients in the open-label portion following 18 responders who were randomized to either treatment or placebo. Patients in the main- tenance phase who were randomized to tiagabine generally maintained the benefits obtained during the open-label portion although there was a 40 percent dropout rate compared to a 12.5 percent dropout rate in the placebo group. See Table 3-2 for a summary of the three included clinical trials.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 59 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~77 N/A No major limitations –13 No –7 — Yes ~82 N/A No major limitations 21.8 Yes 2.9 — dStudy began with 40 patients, 6 failed to complete any scheduled outcome assessment (after randomization) because of protocol discontinuation. eIt is not clear if this was for all measures or just CAPS nightmare item scores. fSeven were receiving one or more of the following medications for PTSD: selective serotonin reuptake inhibitors (N = 5), trazodone (N = 2), benzodiazepines (N = 4), anticonvulsants (N = 2), hydroxyzine (N = 2), and risperidone (N = 1). Medications and psychotherapy were maintained unchanged during the study. gResults for first half of study before crossover. NOVEL ANTIPSYCHOTIC MEDICATIONS The committee identified seven trials of novel antipsychotics olanzapine or risperidone in the treatment of individuals with PTSD (Bartzokis et al., 2005; Butterfield et al., 2001; Hamner et al., 2003; Monnelly et al., 2003; Padala et al., 2006; Reich et al., 2004; Stein et al., 2002). The participants in these studies had suffered from several traumas including combat (mostly U.S. participants) and sexual and physical abuse and/or assault. The mean age in these studies was approximately 45 years, with a range of 19–68 years. None of the studies reported duration of illness or time since trauma. Most studies provided information about ethnicity of the participants. In most studies the majority of the patients were white with a smaller number of studies reporting non-white participants at approximately 10 percent to 29 percent. More than half (54 percent) of one study’s population was comprised of black participants. All studies were double-blinded and included a placebo control. The treatment period ranged from 5–16 weeks, and only one study conducted follow-up after completion of treatment (3-month follow-up) (Bartzokis et

60 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-2  Anticonvulsants PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Davidson Female Total (232) NR (ITT) CAPS- et al., (66%) and Tiagabine (116) 66% Total 2007 Male; S&NS PL (116) 55% assault (53%), witnessing, accident Tucker et Female, mixed Total (40)c LOCF CAPS- al., 2007 abuse Topiramate (20) 70% Total PL (20) 80% Hertzberg Male and Total (15) LOCF SI-PTSDd et al., Female, Lamotrigine (11) 83% 1999 combat (71%) PL (4) 80% aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline al., 2004). All studies measured adverse events associated with the treat- ment condition. The main PTSD outcome measures used in these studies were CAPS-Total, Patient Checklist for PTSD-Military Version (PCL-M), and Structured Interview for PTSD (SI-PTSD). One of these studies, a trial of risperidone, included only PTSD patients with “comorbid psychotic features” (Hamner et al., 2003). Three of the studies described participants as being treatment resistant in the following terms: “probably treatment resistant” (Bartzokis et al., 2005), “somewhat treatment refractory” (Hamner et al., 2003), and “SSRI-resistant” (Stein et al., 2002). One of the olanzapine studies was small with high dropouts and failed to show a benefit (Butterfield et al., 2001). The second olanzapine study was also small with a high rate of dropout and used last observation carried forward (LOCF) to adjust for missing values, but showed a statisti- cally significant improvement in CAPS scores (Stein et al., 2002). Of the five studies of risperidone, it was the primary treatment rather than an add- on to other therapy in only one trial (Padala et al., 2006), and that study

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 61 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~82.5 CAPS-Total <20 Dropout between 45% –30.7 No (remission) and 34%; handling of –30.2 — 16% missing data unclear 14% Yes ~88 CAPS scores <20 Dropout between 30% –52.7 No (remission) and 40% using LOCF –42 — 42% 21% Yes Duke Dropout 17% and 20% —e Global Rating using LOCF; trial too — 50% small to estimate effect 25% size scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cITT population is reported at 38, with 19 in each treatment condition. dOnly individual scores were given (no means or analysis were calculated) for SI-PTSD. eTrial too small to reach statistical significance or estimate an effect size. was judged weakly informative with respect to efficacy because handling of missing values was not reported. In the three risperidone trials judged by the committee to be most informative with respect to efficacy, the drug had small positive effects, but dropout rates were close to 30 percent, with LOCF used to manage missing values in all but one of the studies (Bartzokis et al., 2005; Reich et al., 2004; Stein et al., 2002), raising concern about the precision of the point estimate of benefit. In all three studies, ­risperidone was an adjunctive or augmenting therapy (although only half of the patients in Reich were on other psychotropics), and of the three, two had popula- tions that included treatment-resistant patients (Bartzokis et al., 2005; Stein et al., 2002). Synthesis: The committee found the studies on novel antipsychotics to be limited. The number of studies was small, and several had major limita- tions in study design. All but one were small (fewer than 30 subjects per treatment condition), and the size of the effect was small (e.g., decrease in

62 TREATMENT OF POSTTRAUMATIC STRESS DISORDER CAPS ~ 10) in those that were statistically significant. Most of the studies focused on a population of patients with PTSD that had some special fea- ture, such as treatment refractory or psychotic symptoms. Thus the commit- tee judged the overall body of evidence to be low quality. The committee is not confident that the effect is present; and further high-quality research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of the novel antipsychotics olanzapine and risperidone in the treatment of PTSD. Comment Although the committee judged the evidence inadequate to determine the efficacy of risperidone as a treatment of PTSD in general popula- tions, there are three studies suggesting efficacy for the adjunctive use of r ­ isperidone in individuals inadequately responsive to other therapy. Exclusion Notes No open-label studies were included (Ahearn et al., 2006; Aukst-­Margeti et al., 2004). There was one head-to-head trial comparing ­olanzapine and fluphenazine, but because the efficacy for both of these drugs has not yet been proven, it was not considered in this review (Pivac et al., 2004). See Table 3-3 for a summary of the seven included clinical trials. BENZODIAZEPINES The committee identified only one placebo-controlled RCT of ­alprazolam with a primary PTSD outcome, which showed that the drug was ineffec- tive. The participants in the study suffered from three different trauma types: combat-related (40 percent), motor vehicle accident, or accidental serious injury. The mean age was 37 years, with a range of 19–56 years. Duration of illness and time since exposure were not reported, nor was race/­ethnicity. This study was double-blinded and included a placebo con- trol. The treatment lasted 5 weeks and had no post-treatment follow-up. The outcome measure used was the PTSD Scale which consists of each of the 12 items that make up Diagnostic and Statistical Manual of Mental Disorders (DSM)-III criteria. However, the trial was very small (fewer than Please refer to Dr. Thomas Mellman’s minority opinion on this conclusion in Appendix H.   his T study also used sleep as its primary outcome.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 63 10 subjects per treatment condition), had a high dropout rate, and did not address missing values (Braun et al., 1990). Synthesis: The committee found the overall body of evidence regarding benzodiazepines to be scant and low quality. The committee is uncertain about the presence of an effect, and believes that future well-designed s ­ tudies will have an important impact on confidence in the effect and the size of the effect. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of benzodiazepines in the treatment of PTSD. Comment The available evidence is uninformative for the primary use of b ­ enzo­diazepines in patients with PTSD. The absence of a robust body of evi­ dence regarding benzodiazepines is remarkable in that they are ­commonly prescribed for patients with PTSD, perhaps as a treatment for anxiety symp- toms, while many clinical guidelines recommend against using them at all in this setting (APA, 2004; VA/DOD, 2004). The committee did not examine the evidence regarding the benefits or harms of using benzodiazepines in treating specific symptoms in patients with PTSD. Exclusion Notes There are several open-label studies on benzodiazepines, none of which were included, as well as one case-series and one nonrandomized small trial where the patients were treated within approximately 6.7 days after the trauma (range of 2–18 days) so could not have had diagnosed PTSD (Gelpin et al., 1996). There were two trials that focused only on sleep and did not include an overall PTSD outcome that were excluded (Cates et al., 2004; Randall et al., 1995). See Table 3-4 for a summary of the one included clinical trial. MONOAMINE OXIDASE INHIBITORS The committee identified four RCTs examining the effects of the mono- amine oxidase inhibitors (MAOIs) phenelzine or brofaromine (a selective MAOI not available in the United States) compared with a placebo control (Baker et al., 1995; Katz et al., 1994; Kosten et al., 1991; Shestatzky et al., 1988). Participants in studies had suffered a variety of traumas includ- ing combat-related (mostly American former troops), sexual and physical abuse or assault, serious injury, and motor vehicle accidents. The ages in

64 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-3  Novel Antipsychotic Medications PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Padala et Female, S&NS Total (20) LOCF CAPS- al., 2006 abuse Risperidone (11) 82% Total PL (9) 67% Bartzokis Male, combat Total (65) Mixed model and ITT CAPS- et al., Risperidoned 67% Total 2004 (33) PL (32) 81% Reich et Female, mixed Total (21) Random effects time modeling CAPS-2 al., 2004 abuse and LOCF in some cases Risperidone (12) 75% PL (19) 78% Hamner Male, combat Total (40) LOCF CAPS- et al., Risperidone 58% Total 2003 (20e) PL (20f) 66% Monnelly Male, combat Total (16) Not clear PCL-Mh et al., Risperidone (8)   87.5% 2003g PL (8) 100.0% Stein et Male, combat Total (19) LOCF CAPS- al., 2002i Olanzapine (10) 70% Total PL (9) 78% Butterfield Female, sexual Total (15) LOCF SI-PTSD et al., assault, combat Olanzapine (10) 70% 2001 (20%) PL (5) 80% aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 65 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~87c N/A Dropout 18% and 33% –30 Yes using LOCF with a –7 — 15% differential Yes ~100 N/A Dropout 33% and 19% –14.3 Yes –4.6 — Yes ~64 N/A No major limitations –29.6 Yes –18.6 — Yes ~90 N/A Dropout 42% and 33% –9 No using LOCF –10.1 — Yes ~71 N/A Dropout 12.5% in –10 Yes one arm; handling of –0.5 — missing data unclear Yes ~85 N/A Dropout 30% and 22% –14.8 Yes using LOCF –2.67 — Yes ~52 N/A Dropout 30% and 20% –20.5 No using LOCF — cActual numbers not given—read off of a line graph. dAdjunctiveto stable psychotropic Rx regimen. e19 evaluable. f18 evaluable. gThe main focus of this study was anger but measured overall PTSD as well. Adjunctive to stable psychotropic Rx regimen. hPatient Checklist for PTSD-Military Version-self report. iAdjunctive to stable psychotropic Rx regimen.

66 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-4  Benzodiazepines PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Braun et Sex NR, Total (16) Not clear PTSD al., 1990 combat (40%), Alprazolam (7) 57% Scale accidental injury PL (9) 67% Crossover Study aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when these trials ranged from 26 to 73 years. One study reported duration of illness, which ranged from 2 to 12 years (Shestatzky et al., 1988). Duration of illness and time since exposure was not reported in the other studies. Race/­ethnicity was only reported in one study, and participants were pre- dominantly white (88 percent) (Kosten et al., 1991). The treatment period for these studies ranged from 5 weeks to 14 weeks. None of the studies conducted follow-up after completion of treat- ment. Two studies measured adverse events associated with the treatment condition (Baker et al., 1995; Katz et al., 1994). The main PTSD outcome measures used in the MAOI studies were CAPS-Total, Impact of Events Scale (IES), and the PTSD Scale. One of the phenelzine trials failed to show a significant benefit, but it was extremely small, and dropouts were high with weak treatment of missing values (Shestatzky et al., 1988). The second study of phenelzine was larger and showed significant benefit, but dropouts approached 50 percent with weak treatment of missing values (Kosten et al., 1991). The two studies of brofaromine (Baker et al., 1995; Katz et al., 1994) had a primary PTSD outcome, and both failed to show a beneficial effect. How- ever, because study designs were weak in the treatment of missing values to address the substantial dropout rates, the committee could not conclude that brofaromine was ineffective. Synthesis: The committee found the overall body evidence regarding MAOIs to be scant and low quality. The committee is uncertain about the presence of an effect, and believes that future well-designed studies will have an im- portant impact on confidence in the effect and the size of the effect.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 67 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~30 N/A Dropout 43% and –4.3 No 33%; handling of –1.2 — missing data unclear provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of the MAOIs phenelzine and brofaromine in the treatment of PTSD. Exclusion Notes There are several open-label trials or trials in MAOIs with no compari- son group, none of which were included (Davidson et al., 1987; Lerer et al., 1987; Neal et al., 1997). There was one head-to-head study comparing moclobemide and tianeptine. The efficacy of either of these drugs has not been proven, so this trial was excluded from the committee’s review. See Table 3-5 for a summary of the four included clinical trials. SELECTIVE SEROTONIN REUPTAKE INHIBITORS The committee found that the literature on SSRIs was the most extensive for any of the pharmacotherapies, identifying 14 studies meeting inclusion criteria (Brady et al., 2000; Connor et al., 1999; Davidson et al., 2001a, 2006b; Friedman et al., 2007; Hertzberg et al., 2000; Marshall et al., 2001, 2007; Martenyi et al., 2002a; Tucker et al., 2001, 2003; van der Kolk et al., 1994, 2007; Zohar et al., 2002). The studies examined different drugs (sertraline, fluoxetine, paroxetine, and citalopram) and dosage regimens for varying periods of time and differed in dropout rates (which were generally in the range of 30 percent), and many studies handled missing values with LOCF or conducted the analysis only on those completing treatment. Participants in the SSRI studies had suffered a variety of traumas in- cluding combat-related (U.S. and international participants), sexual and

68 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-5  MAOIs PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Baker et Male (78%), Total (118) LOCF CAPS- al., 1995 combat, sexual Brofaromine 70.3% overall Total assault (56) NR PL (58) NR Katz et Male (76%), Total (64) LOCF CAPS- al., 1995 physical assault, Brofaromine 70% Total injury (33) PL (31) 71% Kosten et Male, combat Total (60) LOCF IESd al., 1991 Phenelzine (19) 51.6% overall Impraminec (23) PL (18) Shestatzky Sex NR, Total (13) Not clear PTSD et al., combat, car 77% overall Scale 1988 accident Phenelzine (7) NR PL (6) NR Crossover Study aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline p ­ hysical abuse and/or assault, witnessing, and serious accident or injury. The age range of study participants was from 18 to late 60s, with most s ­ tudies reporting a mean age between the mid-30s and mid-40s. Three s ­ tudies reported durations of illness that were approximately 6, 12, and 18 years (Brady et al., 2000; Connor et al., 1999; Friedman et al., 2007). Six studies reported time since trauma that ranged from about 13 to 24 years (Brady et al., 2000; Davidson et al., 2001a; Friedman et al., 2007; Marshall et al., 2001; Tucker et al., 2001; van der Kolk et al., 2007). One study re- ported the percent of participants who had their first trauma as a child vs. first trauma as an adult (van der Kolk et al., 1994) and one study reported the trauma type as the Vietnam war for the entire study ­populations so it could be inferred that was the time of trauma (Hertzberg et al., 2000). Five studies did not report any information on either ­duration of illness or time

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 69 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~80 N/A Dropout data –27.18 Yes aggregated with 30% –24.68 — overall dropout using LOCF Yes ~81 N/A Dropout ~30% using –41.6 No LOCF –30.2 — Yes ~33.5 N/A Dropout data –13.6 Yes aggregated with 48% –9.1 Yes overall dropout using –1.7 — LOCF Yes ~20e N/A Dropout data –7 No aggregated with 33% –6.8 — overall dropout with unclear handling of missing data scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cTrycyclic antidepressant. dImpact of Events Scale. eOnly results from first randomization are included here. since trauma (Davidson et al., 2006b; Marshall et al., 2007; Martenyi et al., 2002a; Tucker et al., 2003; Zohar et al., 2002). All but three ­studies provided information about the race/ethnicity of participants. In most studies the majority of participants were white, with a smaller number of studies reporting percentages of non-white participants to be approximately 10–33 percent. In two studies participants were mostly minorities, with 25 percent white in one (Marshall et al., 2007) and 42 percent white in another (Hertzberg et al., 2000). Most of the studies had a 2-week washout period before treatment and did not allow other prescription medications to be used during the study period. All studies were double-blinded and included a placebo control. The treatment period for most studies was 12 weeks but some were 5, 8, or 10 weeks. Only one study conducted follow-up after completion of treatment

70 TREATMENT OF POSTTRAUMATIC STRESS DISORDER (van der Kolk et al., 2007). All but two studies measured adverse events associated with the treatment condition (Connor et al., 1999; Zohar et al., 2002). The main PTSD outcome measures used in the SSRI studies were CAPS, CAPS-2, CAPS-SX, and Duke Global Rating. Of the 14 trials, 7 were judged weakly informative with respect to efficacy because of study limitations such as high differential and/or total dropout rates and weak or absent treatment of missing values (Connor et al., 1999; Davidson et al., 2006b; Hertzberg et al., 2000; Marshall et al., 2001, 2007; Tucker et al., 2001; van der Kolk et al., 1994). Further, the 14 studies were not all statistically significant in showing a positive effect: 7 demonstrated a benefit and 7 demonstrated no benefit (although some of these may have been too underpowered to detect a benefit). Among the 7 studies with the fewest design limitations, 4 demonstrated a benefit (Brady et al., 2000; Davidson et al., 2001a; Martenyi et al., 2002a; Tucker et al., 2003) and 3 demonstrated no benefit (Friedman et al., 2007; van der Kolk et al., 2007; Zohar et al., 2002). The most recent, largest, and best- designed trial in predominantly male combat veterans showed no benefit in primary PTSD outcomes (Friedman et al., 2007), but had a high differential dropout rate between treatment and control conditions and used LOCF to account for missing values. Given the extensive literature for this class, the committee also orga- nized the 7 studies with the fewest limitations by population/trauma type into three groups: 2 of 2 studies in veterans are negative (­Friedman et al., 2007; Zohar et al., 2002); 3 of 4 studies in civilians are positive (Brady et al., 2000; Davidson et al., 2001a; Tucker et al., 2003), 1 negative (van der Kolk et al., 2007); and 1 study in a mixed (close to evenly divided) popula- tion is positive (Martenyi et al., 2002a). The ­committee did not formally consider whether a quantitative meta-analysis would be possible with the 7 most informative studies, and could not determine whether there was an association between population type and outcome. The committee also noted that virtually all of the trials were industry sponsored. Publication of the largest multicenter, industry-sponsored trial of sertraline demonstrating no effect on PTSD outcomes (Friedman et al., 2007) was delayed more than 10 years, leading to concern about publica- tion bias. Synthesis: The committee found that the body of evidence regarding ­SSRIs presented unusual challenges. Many studies were excluded because of weaknesses in design. Although the overall body of evidence might be characterized as moderate quality, the best studies did not consistently point in the same clinical direction demonstrating benefit. The committee believes that it is uncertain whether future high-quality studies will show an effect. Thus the committee is not confident in the presence of an effect

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 71 and believes that any estimate of effect is uncertain, including in relevant subpopulations (such as veterans). Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of SSRIs in the treatment of PTSD. Comment The committee concluded that the evidence is inadequate to determine the efficacy of SSRIs in the treatment of PTSD based on weaknesses in study designs and inconsistency of results. The committee also observed that SSRIs are widely prescribed, have a good safety profile, and might often find indications for use in veterans with PTSD because of comorbid major depression and anxiety disorders. The committee’s conclusion about the SSRI literature was difficult to reach. Several consensus clinical practice guidelines recommend SSRIs as a first line of pharmacologic treatment for PTSD. The committee distin- guished between the principles used in developing guidelines and its own task of evaluating the evidence for efficacy. The former task, i.e., making clinical practice guidelines (and treatment decisions based on them), can be accomplished even when the scientific evidence is not definitive. The committee believes that the weight of the scientific evidence is insuf- ficient to determine the efficacy of SSRIs. The most recent studies continue to be divided in their findings regarding the efficacy of SSRIs. Therefore the committee’s conclusion echoes those of other recent evidence-based assess- ments such as that of the Cochrane systematic review (Stein et al., 2006) and the 2007 Australian Guidelines for the Treatment of Adults with Acute Stress Disorder and Posttraumatic Stress Disorder. While recognizing that Please refer to Dr. Thomas Mellman’s minority opinion on this conclusion in Appendix H. From the Cochrane systematic review (Stein et al., 2006): “The current evidence base of RCTs is unable to demonstrate superior efficacy or acceptability for any particular medica- tion class. Although some have suggested that the SSRIs are more effective than older anti­ depressants (Dow, 1997; Penava, 1996), class membership did not contribute significantly to the variation observed in symptom severity outcomes between trials, while the confidence intervals for the summary statistic of responder status on the seven SSRI trials overlapped with that of the MAOI and TCA [tricyclic antidepressant] trials. . . . Nevertheless, the SSRI trials constitute the bulk of the evidence for the efficacy of medication in treating PTSD, both in terms of the number of studies and their size. The finding of the effectiveness of the SSRIs were also more robust to differences in the particular summary statistic employed than was the case for either the amitryptiline or mirtazapine trials. It is therefore reasonable to support the expert consensus (Ballenger, 2000, 2004; Foa, 1999) that SSRIs constitute the first-line medication choice in PTSD.”

72 TREATMENT OF POSTTRAUMATIC STRESS DISORDER some studies are suggestive of benefit in general civilian (i.e., nonveteran) populations, the committee noted that there are important limitations in study designs and inconsistent results even in the civilian studies. Finally, the committee noted that sertraline and paroxetine are approved by the Food and Drug Administration (FDA) to treat PTSD. The four ­ tudies submitted to FDA to gain approval were included in the literature s reviewed by the committee (Brady et al., 2000, and Davidson et al., 2001a, for ­sertraline; Marshall et al., 2001, and Tucker et al., 2001, for ­paroxetine). The committee’s review had a different purpose than the regulatory one at the core of FDA’s approval process. The committee was also able to review a larger number of studies and used different criteria to judge study quality and the overall body of evidence than did FDA in its review. Exclusion Notes The committee did not include any open-label trials in its review. The committee also did not include any studies for which PTSD was not the primary outcome of the trial. Of these studies, one focused on co-­occurring a ­ lcohol dependence (Brady et al., 2005), one utilized quality-of-life mea- sures (Rapaport et al., 2002), and one was a psychometric study on the D ­ avidson Trauma Scale (Davidson, 2004). There were also eight head-to- head trials comparing one SSRI to another, SSRIs to cognitive behavioral therapy (CBT), and SSRIs to drugs in other drug classes (Chung et al., 2004; Frommberger et al., 2004; McRae et al., 2004; Onder et al., 2006; Otto et al., 2003; Saygin et al., 2002; Smajkic et al., 2001; Spivak et al., 2006). See Table 3-6 for a summary of the 14 included clinical trials. The committee also identified four maintenance studies using SSRIs (Davidson et al., 2001b, 2005; Londborg et al., 2001; Martenyi et al., 2002b). Martenyi et al. (2002b) used data from another Martenyi et al., (2002a) trial—a 12-week randomized controlled trial included in the com- mittee’s review—and was a relapse prevention trial. Responders from the initial trial were randomized to either continued treatment (N = 69) or to placebo (N = 62) for 6 months. The sample size in the initial trial was 226. An analysis of time to relapse showed that the treatment (fluoxetine) was statistically significantly superior to placebo in relapse prevention. Of the treatment group, 82.6 percent completed the relapse prevention phase compared to 66.1 percent of the placebo group. FDA granted approval to sertraline in 1999 and paroxetine in 2001 to treat PTSD. Defined as participants who responded to treatment by a 50 percent decrease in the eight- item Treatment Outcome PTSD Scale (TOP-8) score from baseline, a Clinical Global Impres- sion Severity Scale (CGI-S) score of 42, and not meeting the DSM-IV diagnostic criteria for PTSD.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 73 The Davidson et al., 2005, trial was an open-label discontinuation study. The first 6 months were open-label only (N = 123), then ­responders were randomized to either treatment (fluoxetine) (N = 30) or placebo (N = 32)10 and treated over the next 6 months. Three patients in the treatment group and two in the placebo group dropped out of the study early, and LOCF was employed for missing data. Rates of relapse were 22 percent for treatment versus 50 percent for placebo (P = .02), and time to relapse on treatment was longer than for placebo (P = .02, log-rank statistic) on Clinical Global Impressions (CGI). No other measures showed statistical significance. The Davidson et al., 2001b, trial was designed differently than the 2005 study. The study began with a 12-week randomized treatment period (acute phase) (N = 380 with 275 completers) followed by a 24-week open-label for all acute-phase completers regardless of responder status (N = 252 with 155 completers). The final phase was a 28-week double-blind, placebo- controlled treatment for responders11 to continuation treatment (139 were eligible with 96 randomized—46 to sertraline and 50 to placebo). Of the treatment group, 82.6 percent completed the final phase of the study, while 92 percent of the placebo group completed the final study phase. Sertraline demonstrated a significant advantage over placebo in prevention of PTSD relapse (sertraline: 5.3 percent; placebo: 26.1 percent) and in sustaining improvement in PTSD symptoms. Longborg et al. (2001) is a continuation study of which the first phase of the study consisted of 12 weeks with a placebo control. The subjects were pooled from two identical RCTs conducted in 24 centers in the United States. Patients who completed those studies were eligible to take part in a 24-week open-label continuation study within 3 days of their last visit. Two hundred and fifty patients were entered into the continuation phase, of which approximately 50 percent had been in each the treatment and placebo conditions in the initial study. Only the 128 patients who had been in the treatment condition (sertraline) were analyzed in the study. All 925 responders in the initial phase maintained their response during the 6 months of continuation treatment. Fifty-four percent of acute-phase non- responders12 became responders during continuation therapy. High baseline PTSD scores (CAPS-2 score greater than 75) significantly predicted a longer time to respond to treatment.  Defined as “minimal improvement.” 10Approximately 31 percent of the sample in the second phase were veterans. 11Defined as participants who responded to treatment by a Clinical Global Impression Im- provement Scale (CGI-I) score of less than or equal to 2 (much or very much improved) and a 30 percent or greater improvement in the total severity score in part 2 of the CAPS-PTSD Scale. 12Defined as participants who responded to treatment by at least a 30 percent decrease in the CAPS-2 total severity score and a CGI score of 1 or 2.

74 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-6  SSRIs PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Friedman Male, combat Total (169) LOCF CAPS-2 et al., (71%), S&NS Sertraline (86) 70% 2007 assault PL (83) 83% Marshall Male and Total (52) Mixed efffects models and CAPS- et al., Female, mixed LOCF/ITT Total 2007c assault Paroxetine (25) 68% PL (27) 48% van der Female, S&NS Total (88) LOCF CAPS- Kolk et abuse, injury Fluoxetine (30) 87% Total al., 2007 EMDR (29) 83% PL (29) 90% Davidson Male and Total (538)d LOCF and observed cases CAPS-SX et al., Female, S&NS analysis are endpoint 2006b abuse, 9% 65% overall combat Venlafaxinee NR (179) NR Sertraline (173) NR PL (179) Tucker et Female (74%), Total (58) LOCF CAPS- al., 2003 S&NS abuse Citalopram (25) 80% Total Sertraline (23) 74% PL (10) 70% Martenyi Male, Total (301) LOCF CAPS- et al., witnessing, Fluoxetine (226) Mean exposure to treatmentf Total 2002a combat (48%) PL (75) 80 days of 84 (international) 79 days of 84 Zohar et Male, combat Total (42) LOCF CAPS-2 al., 2002 (Israeli) Sertraline (23) 73.9% PL (19) 73.7% Davidson Female (77%), Total (208) LOCF CAPS-2 et al., S&NS abuse Setraline (100) 70% 2001a PL (108) 73%

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 75 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~72 >30% CAPS-2 Dropout 30% and 17% –13.1 No reduction using LOCF –15.4 — 34.5% 42.7% Yes ~83 N/A Dropout 32% and 52% –25.7 Yes with a 20% differential –6.3 — Yes NR Loss of PTSD No major limitations –33.23 No diagnosis –39.15 No 73% –30.95 — 76% 59% Yes ~82 CAPS-SX ≤ 20 Dropout data –41.51 Yes (remission) aggregated with 35% –39.44 No 30.2% overall dropout using –34.17 — 24.3% mainly LOCF 19.6% Yes ~90 N/A Dropout of 20%, 36%, –30.72 Yes and 30% using LOCF –41.82 Yes –13.6 — Yes ~80.5 >50% reduction in Actual dropout rates –34.6 Yes TOP-8 and CGI-S not provided; used –26.8 — of 1 or 2 LOCF 59.9% 43.8% Yes ~92 >30% CAPS-2 Dropout ~26% using –18.7 No reduction and LOCF –13.5 — CGI-I of 1 or 2 41% 20% Yes ~80 >30% CAPS-2 Dropout 30% and 33% –33 Yes reduction and CGI using LOCF –26.2 — score of 1 or 2 60% 38% continued

76 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-6  Continued PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Marshall 2:1 Female, Total (563) LOCF and general linear CAPS-2 et al., mixed trauma Paroxetine 20 models in some cases 2001 (no combat) mg (188) 67% Paroxetine 40 62% mg (187) 65% PL (188) Tucker et Female (66%), Total (307) LOCF CAPS-2 al., 2001 S&N assault, Paroxetine (151) 61.6% witness, injury PL (156) 60.3% Brady et Male (73%), Total (187) LOCF CAPS-2 al., 2000 S&NS abuse, Setraline (94) 69.1% misc (including PL (93) 72.0% combat) Hertzberg Male, combat Total (12) Completer analysis DTS et al., Fluoxetine (6)   83.3% 2000 PL (6) 100.0% Connor et Female, S&NS Total (53) LOCF Duke al., 1999 abuse Fluoxetine (27) 77.7 % Global PL (26) 57.7% Rating van der Male (65%), Total (64) No treatment of missing CAPS- Kolk et combat (48%), Fluoxetine (33) valuesi Total al., 1994 S&NS abuse PL (31) 63.6% Fluoxetine TCg 86.7% Fluoxetine VAh PL TC PL VA aInthe population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cThe results presented in this table are for the randomized acute phase of this study only,

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 77 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~75 Global Dropout 33%, 38%, –39.6 Yes improvement score and 35% using LOCF –37.9 Yes 1 = very much –25.3 — improved, 2 = much improved 62% 54% 37% Yes 74.3, 73.2 <20 CAPS score = Dropout ~38% and –35.5 Yes remission 40% using LOCF –24.7 — 30% 20% Yes ~75 >30% decrease in Dropout 31% and 28% 33 Yes CAPS-2 score and using LOCF 23.2 — CGI-I of 1 or 2 53% 32% Yes ~108 Duke Global Rating Dropout ~17% in –3 No 17% one arm with a ~17% –9 — 33% differential dropout; completer analysis only Yes Baseline NR Responder (Duke Dropout ~22% and Score of 1: cutoff of 1–2) ~42% with a 20% 59% Yes 85% differential using LOCF 19% 62% Yes ~82 N/A Dropout ~36% and –35 Yes ~13% with a 23% –12 No differential and no –17 — handling of missing –3 — data and not the maintenance phase, which only included patients who were “much improved” or “very much improved.” dSeven dropped out before receiving study drug. eAntidepressant. fMartenyi (2002a) does not report actual dropout rates, only average length of treatment, which may be considered rough to completer rates, but it may conceal important information. g23 patients total from a trauma clinic (TC). h24 patients total from a VA site. iData were reported by intake site: trauma clinic (nonveterans) and VA site.

78 TREATMENT OF POSTTRAUMATIC STRESS DISORDER OTHER ANTIDEPRESSANTS The committee identified three RCTs of the tricyclic antidepressants imipramine, desipramine, and amitriptyline that included placebo controls (Davidson et al., 1990; Kosten et al., 1991; Reist, 1989). Participants in the tricyclic antidepressant studies all suffered from combat-related trauma (all U.S.). Age was reported in two of the three studies and ranged from 28 to 64 years with a mean age of about 38 years. None of the studies reported duration of illness or time since exposure. Race/ethnicity was only reported in one study and participants were predominantly white (88 percent) (Kosten et al., 1991). The treatment period for these studies ranged from 4 to 6 weeks. None of the studies conducted follow-up after completion of treatment. One study measured adverse events associated with the treatment condition ( ­ Davidson et al., 1990). The main PTSD outcome measures used in the tricyclic antidepressant studies was IES. All three trials used a weak study design. The studies analyzed only those who completed treatment and suf- fered from high dropout rates; thus the committee found it impossible to judge whether the modest improvements were valid. The committee identified one RCT of mirtazapine, showing a ­modest benefit of treatment; but the study was small and did not use a ­ robust method for handling the dropout rates and managing missing values ( ­ Davidson et al., 2003). The committee identified one RCT of nefazodone, showing a modest benefit of treatment; but the study was small, of short duration, and did not use a robust method for handling dropouts and man- aging missing values (Davis et al., 2004). Finally, the committee identified two large RCTs of venlafaxine. However, both had dropout rates exceed- ing 30 percent with weak treatment of missing values (LOCF) and showed very small changes in CAPS, although they were statistically significant ( ­ Davidson et al., 2006a, 2006b). Synthesis: The committee found that the overall body of evidence regarding other antidepressants to be low quality because of study limitations and a small number of studies for each drug. The committee is not confident in the presence of an effect and believes that any estimate of effect is uncertain. Further research is very likely to have an important impact on confidence in the estimate of effect of any of these agents and is likely to change the estimate. Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of other antidepressants in the treatment of PTSD.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 79 Exclusion Notes No open-label trials were included on tricyclic antidepressants. There were two prior RCTs comparing phenelzine and impramine to placebo (Frank et al., 1988; Kosten et al., 1992), but those were superseded by the updated and more complete1991 study by Kosten and colleagues so only that study was included. See Table 3-7 for a summary of the three included clinical trials. Open trials of mirtazepine were not included (Kim et al., 2005). One study was excluded because it was not randomized (Connor and Sutherland et al., 1999). One study was excluded because it was a comparative trial (Chung et al., 2004) (compared mirtazapine and sertraline). See Table 3-8 for a summary of the one included clinical trial. Open trials of nefazodone were not included (Garfield et al., 2001). There were two head-to-head trials comparing nefazodone to sertraline that were not included (McRae et al., 2004; Saygin et al., 2002). See Table 3-9 for a summary of the one included clinical trial. Open trials of venlafaxine were not included nor was the one head- to-head trial comparing venlafaxine to sertraline and paroxetine (Smajkic et al., 2001). See Table 3-10 for a summary of the two included clinical trials. OTHER DRUGS The committee identified studies of naltrexone, cycloserine, and i ­nositol, but not all met inclusion criteria. An RCT of naltrexone, an opioid ­ antagonist, was conducted in patients with alcohol dependence, approximately one-third of whom also had PTSD, finding reductions in alcohol intake and improvements in CAPS scores (Petrakis et al., 2006). The committee found the single study difficult to interpret with respect to the overall treatment of PTSD, while recognizing that the study suggests a benefit to using naltrexone in an important subpopulation. The participants in the single study of D-cycloserine had suffered from work or traffic accidents, terrorist attacks, and physical abuse. The age range was 22 to 61 years. Duration of illness ranged from 1 to 20 years. Race/ethnicity was not reported. This was a double-blind study with a placebo control and a crossover study design. Treatment lasted 12 weeks, and the study did not have post-treatment follow-up. The PTSD outcome measure used in this study was CAPS-Total (Heresco-Levy et al., 2002). The participants in the inositol study suffered trauma from combat, serious accidents, and physical assault. The mean age was 40 years, with a range from 25 to 56 years. Time since trauma ranged from 6 months to 28 years. Race/ethnicity was not reported. This was a double-blind study

80 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-7  Tricyclic Antidepressants PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Kosten et Male, combat Total (60) LOCF IES al., 1991 Phenelzinec (19) 51.6% overall Impramine (23) Not clear PL (18) Davidson Male, combat Total (46) No treatment of missing IES et al., Amitriptyline values, completer analysis 1990 (25) 71% completed 8 weeks PL (21) overall NR NR Reist et Male, combat Total (27)d Completer analysis only IOE, al., 1989 Desipramine 77.7–66.6%e intrusion (NR) NR (I) and Crossover PL (NR) NR avoidance Study (A) aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline TABLE 3-8  Mirtazapine PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Davidson Sex NR, mixed Total (29) LOCF SPRINT et al., Mirtazapine (17) 69% overall 2003 PL (9) NR NR aInthe population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 81 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~33.5 N/A Dropout data –13.6 Yes aggregated with ~48% –9.1 Yes overall dropout using –1.7 — LOCF Yes ~34 N/A Dropout data 4 wks: –5.7 No aggregated with 39% 8 wks: –6.8 overall dropout; no 4 wks: –2.7 — handling of missing 8 wks: –2.9 data; completer analysis Yes A: ~ 27 No N/A Dropout data I: ~ 28 aggregated; no handling A: –0.4 No of missing data; I: –0.9 completer analysis; A: –0.1 — total IOE score I: –0.4 — not provided, only subscales scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cMAOI. d21 continued to crossover period. eNot clear if patients dropped out before or after crossover. Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~22 Yes Response rate Dropout data –7 — 67% aggregated with 31% –7 22% overall dropout using LOCF provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm.

82 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-9  Nefazodone PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Davis et Male, combat Total (42) LOCF CAPS- al., 2004 Nefazodone (27) 52% Total PL (15) 60% aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when TABLE 3-10  Venlaflaxine PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Davidson Male and Total (329) LOCF CAPS- et al., Female, mixed Venlaflaxine 70% SX 2006a trauma (12% (161) combat) PL (168) 67% Davidson Male and Total (538)c LOCF and observed cases CAPS- et al., Female, S&NS Venlafaxine analysis are endpoint SX 2006b abuse, 9% (179) 65% overall combat Sertalined (173) NR PL (179) NR NR aInthe population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from with a placebo control and a crossover study design. Treatment lasted 4 weeks, and the study did not have post-treatment follow-up. The PTSD outcome measure used in this study was IES (Kaplan et al., 1996). The studies of inositol and cycloserine were small, used a weak cross- over design, and failed to show improvement in overall PTSD measures (Heresco-Levy et al., 2002; Kaplan et al., 1996).

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 83 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~82 >30% improvement Dropout of 48% and (2:1 –19.1 Yes in CAPS-Total 40% using LOCF design) –13.5 — 47% 42% provided, or by subtracting data reported at treatment completion (not follow-up data) from baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~82 CAPS ≤20 Dropout of 30% and –51.8 Yes 50.9% 33% using LOCF –44.8 — 37.5% Yes ~82 CAPS-SX ≤20 Dropout data –41.51 Yes (remission) aggregated with 35% –39.44 No 30.2% overall dropout using –34.17 — 24.3% mainly LOCF 19.6% baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cSeven dropped out before receiving study drug. dSSRI. Synthesis: The committee found that the overall body of evidence regard- ing other drugs to be low quality because of study limitations and a small number of studies for each drug. The committee is not confident in the presence of an effect and believes that any estimate of effect is uncertain. Further research is very likely to have an important impact on confidence in the estimate of effect of any of these agents and is likely to change the estimate.

84 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-11  Other Rx Treatments PTSD Handling of Dropouts and Outcome Study Populationa Arm (N) % Completed Tx by Arm Measure Heresco- Male, accident, Total (11) 64% overall CAPS- Levy et physical abuse D-cycloserine (6) NR Total al., 2002 PL (5) NR Crossover Study Kaplan et Male and Total (17) Completer IES al., 1996 Female, Inositol (NR) No treatment of missing mixed trauma PL (NR) values Crossover Study aIn the population column, male alone or female alone denotes that at least 80% of the study population was male or female. If only one trauma type is listed, at least 80% of the study population reported that type of trauma. bPTSD outcome measure change data were obtained either directly from the study, when provided, or by subtracting data reported at treatment completion (not follow-up data) from Conclusion: The committee concludes that the evidence is inadequate to determine the efficacy of naltrexone, cycloserine, or inositol in the treatment of PTSD. Exclusion Notes Several case studies or series, open-label trials, uncontrolled trials, and RCTs have been conducted on various pharmacotherapies not included in the classes outlined above. Several other studies were excluded, and the rea- sons are briefly described here. In one RCT only 36 percent of the sample was diagnosed with PTSD so was excluded (Petrakis et al., 2006). One study compared tianeptine with fluoxetine and moclobemide, but had no placebo group so was excluded (Onder et al., 2006). Dow and Kline (1997) was excluded because it used several different drugs, had no comparison group or blinding, adverse events were not distinguished from efficacy fail- ures, and it had many uncontrolled variables. A study examining sildenafil was excluded, because it only focused on erectile dysfunction (Orr et al., 2006). A study on naloxone was excluded, because it only looked at pain and not overall PTSD (Pitman et al., 1990). Another study by Pitman and colleagues that was excluded examined PTSD outcomes but the treatment

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 85 Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations Yes ~59 N/A Dropout data –4.4 No aggregated with 36% –6.8 — overall dropout; no handling of missing data Yes ~35 N/A Dropout data NR; –3.8c No completer analysis only 0.4 — baseline data (before treatment began). Average baseline score when reported or when baseline scores for all arms are nearly the same; otherwise, baseline scores listed individually in order of arm. cResults at 4 weeks. (propranolol) began within 6 hours after the traumatic event so the subjects could not have been diagnosed with PTSD (Pitman et al., 2002). See Table 3-11 for a summary of the two included RCTs. SUMMATION Based on its assessment of the medications for which randomized controlled trials were available—alpha-adrenergic blockers, anticonvul- sants, novel antipsychotic medications, benzodiazepines, MAOIs, SSRIs, and other antidepressants—the committee found the evidence for all classes of drugs reviewed inadequate to determine efficacy for patients with PTSD. Important comments are appended to the conclusions for alpha-adrenergic blockers, novel antipsychotics, benzodiazepines, and SSRIs. REFERENCES Ahearn, E. P., M. Mussey, C. Johnson, A. Krohn, and D. Krahn. 2006. Quetiapine as an adjunctive treatment for post-traumatic stress disorder: An 8-week open-label study. International Clinical Psychopharmacology 21(1):29-33. APA (American Psychiatric Association). 2004. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: APA.

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EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 89 McRae, A. L., K. T. Brady, T. A. Mellman, S. C. Sonne, T. K. Killeen, M. A. Timmerman, and W. Bayles-Dazet. 2004. Comparison of nefazodone and sertraline for the treatment of posttraumatic stress disorder. Depression and Anxiety 19(3):190-196. Monnelly, E. P., D. A. Ciraulo, C. Knapp, and T. Keane. 2003. Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder. Journal of Clinical Psychopharmacology 23(2):193-196. Neal, L. A., W. Shapland, and C. Fox. 1997. An open trial of moclobemide in the treat- ment of post-traumatic stress disorder. International Clinical Psychopharmacology 12(4):231-237. Onder, E., U. Tural, and T. Aker. 2006. A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earth- quake. European Psychiatry: The Journal of the Association of European Psychiatrists 21(3):174-179. Orr, G., M. Weiser, M. Polliack, G. Raviv, D. Tadmor, and L. Grunhaus. 2006. Effectiveness of sildenafil in treating erectile dysfunction in PTSD patients: A double-blind, placebo- controlled crossover study. Journal of Clinical Psychopharmacology 26(4):426-430. Otto, M. W., D. Hinton, N. B. Korbly, A. Chea, P. Ba, B. S. Gershuny, and M. H. Pollack. 2003. Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: A pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone. Behaviour Research and Therapy 41(11):1271-1276. Padala, P. R., J. Madison, M. Monnahan, W. Marcil, P. Price, S. Ramaswamy, A. U. Din, D. R. Wilson, and F. Petty. 2006. Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women. International Clinical Psychopharmacology 21(5):275-280. Petrakis, I. L., J. Poling, C. Levinson, C. Nich, K. Carroll, E. Ralevski, and B. Rounsaville. 2006. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biological Psychiatry 60(7):777-783. Pitman, R. K., B. A. van der Kolk, S. P. Orr, and M. S. Greenberg. 1990. Naloxone-reversible analgesic response to combat-related stimuli in posttraumatic stress disorder. A pilot study. Archives of General Psychiatry 47(6):541-544. Pitman, R. K., K. M. Sanders, R. M. Zusman, A. R. Healy, F. Cheema, N. B. Lasko, L. Cahill, and S. P. Orr. 2002. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biological Psychiatry 51(2):189-192. Pivac, N., D. Kozaric-Kovacic, and D. Muck-Seler. 2004. Olanzapine versus fluphenazine in an open trial in patients with psychotic combat-related post-traumatic stress disorder. Psychopharmacology 175(4):451-456. Randall, P. K., J. D. Bremner, J. H. Krystal, L. M. Nagy, G. R. Heninger, A. L. Nicolaou, and D. S. Charney. 1995. Effects of the benzodiazepine antagonist flumazenil in PTSD. Biological Psychiatry 38(5):319-324. Rapaport, M. H., J. Endicott, and C. M. Clary. 2002. Posttraumatic stress disorder and ­quality of life: Results across 64 weeks of sertraline treatment. Journal of Clinical Psychiatry 63(1):59-65. Raskind, M. A., C. Thompson, E. C. Petrie, D. J. Dobie, R. J. Rein, D. J. Hoff, M. E. McFall, and E. R. Peskind. 2002. Prazosin reduces nightmares in combat veterans with post­ traumatic stress disorder. Journal of Clinical Psychiatry 63(7):565-568. Raskind, M. A., E. R. Peskind, E. D. Kanter, E. C. Petrie, A. Radant, C. E. Thompson, D. J. Dobie, D. Hoff, R. J. Rein, K. Straits-Troster, R. G. Thomas, and M. M. McFall. 2003. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: A placebo-controlled study. American Journal of Psychiatry 160(2):371-373.

90 TREATMENT OF POSTTRAUMATIC STRESS DISORDER Raskind, M. A., E. R. Peskind, D. J. Hoff, K. L. Hart, H. A. Holmes, D. Warren, J. Shofer, J. O’Connell, F. Taylor, C. Gross, K. Rohde, and M. E. McFall. 2007. A parallel group ­ placebo controlled study of prazosin for trauma nightmares and sleep distur- bance in ­ combat veterans with post-traumatic stress disorder. Biological Psychiatry 61(8):928-934. Reich, D. B., S. Winternitz, J. Hennen, T. Watts, and C. Stanculescu. 2004. A preliminary study of risperidone in the treatment of posttraumatic stress disorder related to childhood abuse in women. Journal of Clinical Psychiatry 65(12):1601-1606. Reist, C., C. D. Kauffmann, R. J. Haier, C. Sangdahl, E. M. DeMet, A. Chicz-DeMet, and J. N. Nelson. 1989. A controlled trial of desipramine in 18 men with posttraumatic stress disorder. American Journal of Psychiatry 146(4):513-516. Saygin, M. Z., M. Z. Sungur, E. U. Sabol, and P. Cetinkaya. 2002. Nefazodone versus s ­ ertraline in the treatment of posttraumatic stress disorder. Bulletin of Clinical Psycho- pharmacology 12(1):1-5. Shestatzky, M., D. Greenberg, and B. Lerer. 1988. A controlled trial of phenelzine in post- traumatic stress disorder. Psychiatry Research 24(2):149-155. Smajkic, A., S. Weine, Z. Djuric-Bijedic, E. Boskailo, J. Lewis, and I. Pavkovic. 2001. ­Sertraline, paroxetine, and venlafaxine in refugee posttraumatic stress disorder with depression symptoms. Journal of Traumatic Stress 14(3):445-452. Spivak, B., R. D. Strous, G. Shaked, E. Shabash, M. Kotler, and A. Weizman. 2006. ­Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: A double-blind, fixed-dosage, controlled trial. Journal of Clinical Psycho­ pharmacology 26(2):152-156. Stein, D. J., J. C. Ipser, and S. Seedat. 2006. Pharmacotherapy for post traumatic stress d ­ isorder (PTSD). Cochrane Database Systematic Reviews (4):CD002795. Stein, M. B., N. A. Kline, and J. L. Matloff. 2002. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: A double-blind, placebo-controlled study. American Journal of Psychiatry 159(10):1777-1779. Taylor, F. B., K. Lowe, C. Thompson, M. M. McFall, E. R. Peskind, E. D. Kanter, N. Allison, J. Williams, P. Martin, and M. A. Raskind. 2006. Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biological Psychiatry 59(7):577-581. 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. Tucker, P., R. Potter-Kimball, D. B. Wyatt, D. E. Parker, C. Burgin, D. E. Jones, and B. K. Masters. 2003. Can physiologic assessment and side effects tease out differences in PTSD trials? A double-blind comparison of citalopram, sertraline, and placebo. Psycho­ pharmacology Bulletin 37(3):135-149. Tucker, P., R. P. Trautman, D. B. Wyatt, J. Thompson, S. C. Wu, J. A. Capece, and N. R. Rosenthal. 2007. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: A randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 68(2):201-206. VA (Veterans Affairs), DoD (Department of Defense), Management of Post-Traumatic Stress Working Group. 2004. VA/DoD clinical practice guideline for the management of post- traumatic stress, version 1.0. Washington, DC: Department of Veterans Affairs and Department of Defense. 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.

EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 91 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 desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: Treatment effects and long-term maintenance. Journal of Clinical Psy- chiatry 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.

KEY for Tables 4-1 through 4-9: BEP = brief eclectic psychotherapy N/A = not available CBT = cognitive behavior therapy NR = not reported CS = coping skills; examples: ns = not significant CS-B = biofeedback OT = other therapy DO = dropout rate PCT = present-centered therapy (active E = exposure control) E+CR = exposure plus cognitive PE = prolonged exposure restructuring PTSD outcome measures—refer to list of E+CS = exposure plus coping skills acronyms in Appendix E for full name EMDR = eye movement desensitization of measure and reprocessing S&NS assault = sexual and nonsexual assault F = female Ss = subjects ITT = intent-to-treat analysis SSRI = selective serotonin reuptake inhibitor LOCF = last observation carried forward Tx = treatment MC = minimum care UC = usual care MVA = motor vehicle accident WL = wait list 92

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Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Get This Book
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Mental disorders, including posttraumatic stress disorder (PTSD), constitute an important health care need of veterans, especially those recently separated from service. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence takes a systematic look the efficacy of pharmacologic and psychological treatment modalities for PTSD on behalf of the Department of Veterans Affairs. By reviewing existing studies in order to draw conclusions about the strength of evidence on several types of treatment, the Committee on the Treatment of Posttraumatic Stress Disorder found that many of these studies were faulty in design and performance, and that relatively few of these studies have been conducted in populations of veterans, despite suggestions that civilian and veteran populations respond differently to various types of treatment. The committee also notes that the evidence is scarce on the acceptability, efficacy, or generalizability of treatment in ethnic and cultural minorities, as few studies stratified results by ethnic background.

Despite challenges in the consistency, quality, and depth of research, the committee found the evidence sufficient to conclude the efficacy of exposure therapies in treating PTSD. The committee found the evidence inadequate to determine efficacy of different types of pharmacotherapies, of three different psychotherapy modalities, and of psychotherapy delivered in group formats. The committee also made eight critical recommendations, some in response to the VA's questions related to recovery and the length and timing of PTSD treatment, and others addressing research methodology, gaps in evidence and funding issues.

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