3
Evidence and Conclusions: Pharmacotherapy

The 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 committee 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.1 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

1

Some studies did not include sex and/or trauma type.



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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.1 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 1Some studies did not include sex and/or trauma type. 

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 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.

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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).2 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. 2This study looked at daytime psychological stress, and used an E-Stroop test (word lists) to evaluate outcomes.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-1 Alpha-Adrenergic Blockers PTSD Handling of Dropouts and Outcome Populationa Study Arm (N) % Completed Tx by Arm Measure Total (34)d LOCFe Raskind Male, combat CAPS- et al., Prazosin (17) 90.0% Total 2007c PL (17) 92.5% Total (10)f Raskind Male, combat LOCF CAPS- 100%g et al., Prazosin (5) 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.

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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

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0 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-2 Anticonvulsants PTSD Handling of Dropouts and Outcome Populationa Study 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 Total (40)c Tucker et Female, mixed LOCF CAPS- al., 2007 abuse Topiramate (20) 70% Total PL (20) 80% SI-PTSDd Hertzberg Male and Total (15) LOCF 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

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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

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 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.3 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 risperidone in individuals inadequately responsive to other therapy. Exclusion Notes No open-label studies were included (Ahearn et al., 2006; Aukst-Margeti et al., 2004)4. 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 3Please refer to Dr. Thomas Mellman’s minority opinion on this conclusion in Appendix H. 4 This study also used sleep as its primary outcome.

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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 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 benzodiazepines in the treatment of PTSD. Comment The available evidence is uninformative for the primary use of benzodiazepines 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

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-3 Novel Antipsychotic Medications PTSD Handling of Dropouts and Outcome Populationa Study 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- Risperidoned et al., 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 (20e) 2003 PL (20f) 66% PCL-Mh Monnelly Male, combat Total (16) Not clear 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.

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY Baselineb and Statistically Loss of Diagnosis Double- Change in Significant? or Clinical Blind? PTSD Measure (versus control) Improvement (%) Principal Limitations ~87c Yes 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. dAdjunctive to 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.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-9 Nefazodone PTSD Handling of Dropouts and Outcome Populationa Study 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 Populationa Study 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% Total (538)c Davidson Male and LOCF and observed cases CAPS- et al., Female, S&NS Venlafaxine analysis are endpoint SX 2006b abuse, 9% (179) 65% overall Sertalined (173) combat NR PL (179) NR NR 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 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).

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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 CAPS ≤20 Yes ~82 Dropout of 30% and –51.8 Yes 33% using LOCF 50.9% –44.8 — 37.5% CAPS-SX ≤20 Yes ~82 Dropout data –41.51 Yes aggregated with 35% (remission) –39.44 No overall dropout using 30.2% –34.17 — mainly LOCF 24.3% 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.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER TABLE 3-11 Other Rx Treatments PTSD Handling of Dropouts and Outcome Populationa Study 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

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 EVIDENCE AND CONCLUSIONS: PHARMACOTHERAPY 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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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