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Forman-Hoffman V, Middleton JC, Feltner C, et al. Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder: A Systematic Review Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 May. (Comparative Effectiveness Review, No. 207.)
Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder: A Systematic Review Update [Internet].
Show detailsOverview of This Appendix
As explained in the Methods and Results chapters of the main report on posttraumatic stress disorder (PTSD), we did not include in our main analyses any trials that originally met our eligibility criteria but were rated high risk of bias. Our focus was solely on trials of either low or medium risk of bias. In some cases, however, these high risk-of- bias trials offered some additional information about our conclusions for efficacy or comparative effectiveness.
Reasons for rating trials as high risk of bias included problems that could relate to randomization and allocation concealment, similarity of compared groups at baseline, masking of patients and study personnel, use of intent-to-treat analysis, or overall and differential loss to followup. In general terms, these trials had flaws or were underpowered to show statistically significant differences. In some cases, significant (or nonsignificant) differences had very small effect sizes. Appendix E provides additional information and rationale for our risk-of-bias assessments. We had no trials rated high risk of bias for adverse events or harms.
Psychotherapy Trials
This appendix provides information on trial findings about psychotherapies (Key Question [KQ] 1) in the same basic order as the psychological interventions covered in the Results chapter – namely, cognitive behavioral interventions of all types, eye movement desensitization and reprocessing (EMDR), and other psychotherapies. Several of these various trials did have findings consistent with those reported in the main systematic review.
Tables in this appendix describe the trials. Entries are in alphabetical order by last name of the first author of the article(s) in question. For duration of treatment (or trial), in some cases the investigators reported only the number of sessions, rather than the length of the treatment or the trial (in, e.g., weeks or months). Some trials measured certain outcomes at some point, such as 3 months, after treatment ended (usually referred to as posttreatment). Disease severity was measured frequently by the Clinician-Administered PTSD Scale (CAPS); these are the data reported in the tables unless another instrument, such as the Davidson Trauma Scale or the PTSD Checklist, is specified. Severity measures can be reported as mean scores or a range of mean scores across groups for the CAPS or another PTSD measure listed. As in the main report, inactive arms for these trials included waitlist or usual care (which included treatment as usual as well).
Pharmacologic Trials
We also present information on the high risk-of-bias trials of pharmacological interventions (KQ 2). These include a wide array of antidepressants, anticonvulsants (or mood stabilizers), and antipsychotics, among other pharmacologic agents. As with psychological interventions, we report on both efficacy trials (placebo controls) and on comparative effectiveness (from head-to-head trials – i.e., active comparators). Several of these various trials did have findings consistent with those reported in the main systematic review.
Tables in this appendix describe the trials using the organization previously described.
Efficacy or Comparative Effectiveness of Psychological Interventions (Key Question 1)
Cognitive Behavioral Therapy
Several trials addressed a wide array of cognitive behavioral therapies (CBT). These included cognitive interventions, coping skills interventions, exposure treatments of various types, and interventions with “mixed” CBT components, including various combinations of psychoeducation, self-monitoring, stress management, relaxation training, skills training, exposure (imaginal, or in vivo, or both), cognitive restructuring, guided imagery, mindfulness training, breathing retraining, crisis/safety planning, and relapse prevention.
Three separate trials tested three cognitive interventions: two tested cognitive processing therapy (CPT) and one tested web-based cognitive therapy (CT) (see Table G-1). For the CPT trial with person-centered therapy (PCT) as the comparator, we considered PCT to be an active comparator but not one for which we were interested in examining the comparative effectiveness with interventions of interest. For the other CPT trail and the CT trial, both provided findings consistent with those from the trials described in the main report on all outcomes.
Table G-1Characteristics of cognitive intervention trials omitted from main analyses because of high risk of bias
Trial | Arm Dose (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female; % Nonwhite |
---|---|---|---|---|---|---|
Butollo et al., 2015204 | DET (74) CPT (74) (only 67 analyzed) | 24 sessions (6 months) | Type I Trauma Mixed | IES-R 66 to 67 | 36 | 66 NR |
Knaevelsrud et al., 2015224 | Web-based CT (79) Waitlist (80) | 5 weeks (3 months) | War-related Mixed | PDS 30.35 to 30.65 | 28 | 72 NR |
Suris et al., 2013253 | Randomized: CPT (72) PCT (57) Analyzed: CPT (52) PCT (34) | 12 weeks (1 week, 2 months, 4 months, 6 months) | Military sexual trauma | 82 to 85 | 46 | 85 66 |
CAPS = Clinician-Administered PTSD Scale; CPT = cognitive processing therapy; CT, cognitive therapy; PCT = patient-centered therapy; PDS = Posttraumatic Diagnostic Scale; F = female; N = total number randomized/assigned to intervention and control groups; PTSD = posttraumatic stress disorder; y = year.
We rated three trials of CBT- coping skills as high risk of bias (Table G-2). One trial compared stress inoculation training (SIT) with narrative exposure therapy (NET); another compared SIT with a waitlist group. The third trial tested an affect management intervention versus waitlist. Treatment-related improvements in reducing PTSD symptoms at posttreatment were reported for SIT versus waitlist only. These findings are consistent with the single trials of these interventions included in our qualitative synthesis.
Table G-2Characteristics of coping skills trials omitted from main analyses because of high risk of bias
Trial | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Foa et al., 1991210 | SIT (17) PE (14) SC (14) Waitlist (10) | 9 weeks (none) | Female Assault | Interviewer severity rating 24.4 to 25.8 | 32 | 100 27 |
Hensel-Dittman et al., 2011216 | NET (15) SIT (13) | 4 weeks (6 and 12 months) | Male and female Experienced organized violence | 85.2 to 96.5 | NR | NR NR |
Zlotnick et al., 1997259 | Affect management (17) Waitlist (16) | 15 weeks (none) | Female Childhood sexual abuse | DTS 66.9 to 74.7 | 39 | 100 3 |
CBT = cognitive behavioral therapy; CBT Cope = cognitive behavioral therapy-coping skills; CBT-M = cognitive behavioral therapy mixed; DTS = Davidson Trauma Scale; F = female; IES-R = Impact of Events Scale – Revised; N = total number randomized/assigned to intervention and control groups; NET = narrative exposure therapy; NR = not reported; PCL = PTSD Checklist; PE = prolonged exposure; PTSD = posttraumatic stress disorder; relax = relaxation; SC = supportive counseling; SIT = stress inoculation training; y = year.
We rated 17 trials of CBT - exposure interventions (see Table G-3). The types of “exposure” therapies differed appreciably across these trials. Like the included studies, a majority of the high risk-of-bias trials of exposure found that the CBT-exposure group did significantly better than the inactive comparator group, especially with respect to reducing PTSD symptoms (using any of the available symptom measures), achieving remission, and losing the PTSD diagnosis. Persons in the exposure interventions also tended to do better as well in reducing depression symptoms. Although these findings were similar to those from the low or medium risk-of-bias trials, precision was lower, with wider confidence intervals. Similar to the set of included trials, few high risk-of-bias trials examined anxiety symptoms, functional status, quality of life, and functional impairment outcomes; when they did, however, findings were similar to those of included studies.
Table G-3Characteristics of exposure trials omitted from main analyses because of high risk of bias
Study | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Ahmadizadeh et al., 2013198 | Exposure (25) Problem solving (25) Combined (25) Control (25) | 15 sessions (3 months) | Combat related | NR | 42 | NR NR |
Arntz et al., 2007199 | CBT-exposure (42) CBT-exposure (29) Cross-over (17) | 10 weeks (1 month) | Mixed | PSS-SR 25.0 to 29.4 | 35 | 66 28 |
Beidel et al., 2011201 | CBT-M (18) Exposure (17) | 17 weeks (none) | Male Combat | 84.9 to 90.6 | 59 | 0 0 |
Brom et al., 1989203 | Desen (31) Hypno (29) Psychoeducation (29) | 15 sessions (3 months) | Netherlands Mixed | IES 46.3 to 50.8 | 42 | 79 NR |
Butollo et al., 2015204 | DET (74) CPT (74) (only 67 analyzed) | 24 sessions (6 months) | Type I Trauma Mixed | IES-R 66 to 67 | 36 | 66 NR |
Feske et al., 2008209 | PE (11) Usual care (13) | 6 months | NR | PDS-I 34.9 to 35.2 | 43 | 100 95 |
Foa et al., 1991210 | SIT (17) PE (14) SC (14) Waitlist (10) | 9 weeks | Female Sexual abuse, assault | Interviewer severity rating 24.4 to 25.78 | 32 | 100 27 |
Franklin et al., 2017211 | PE via iPhone (10) PE via computer (7) TAU (8) | 10 sessions (1 month) | Veterans | 61.1 to 74.3 | 46 | 7 30 |
Ghafoori et al., 2017214 | PE (47) PCT (24) | 12 weeks | Male and Female Complex Trauma | 53.5 to 61.2 | 35 | 83 72 |
Ironson et al., 2002219 | EMDR (10) PE (12) | 6 weeks (3 months) | Domestic violence/child sexual abuse | PSS-SR 26.6 to 34.6 | NR | 77 NR |
Johnson et al., 2006221 | Randomized (Total: 51)a PE (Unclear) CM (Unclear) EMDR (Unclear) Waitlist (14) | Mean number of weekly sessionsc PE: 9.66 EMDR: 6.33 WL: 5.89 (3 months) | Female Mixed | 61.8 to 82.0 | 39 | 100 17 |
Keane et al., 1989223 | Flooding (11) Waitlist (13) | 14 to 16 sessionsb (6 months) | Male Combat | PTSD Symptom Checklist 36.4 to 36.5 | 35 | 0 21 |
McLay et al., 2011232 | VR-exposure (10) Usual care (10) | 10 weeks | Active duty service members | 82.8 to 83.5 | 24 | 5 NR |
Paunovic et al., 2001239 | Exposure (10) CBT-M (10) | 16 to 20 weeks (6 months) | Male and female Refugees | 95.1 to 98.4 | 38 | 15 NR |
Rauch et al., 2015245 | PE (18) PCT (18) | 10-12 sessions | Military veterans | 77 to 79 | 32 | 8 17 |
Ready et al., 2010246 | VR (6) PCT (5) | 10 sessions (6 months) | Male Combat | 93.8 | 58 | 0 46 |
Vera et al., 2011255 | PE (7) UC (7) | 15 sessions | Spanish Speaking Puerto Ricans Mixed | 53 to 73 | 46 | 0 100 |
- a
The number of participants randomized to each active treatment group was not reported. A total of 27 participants from the active treatment groups were analyzed, 9 in each treatment group.
CBT-M = cognitive behavioral therapy mixed; CAPS = Clinician-Administered PTSD Scale for DSM-IV; CPT = cognitive processing therapy; CM = Counting Method; CR = cognitive restructuring; desen = desensitization; DET = dialogical exposure therapy; EMDR = eye movement desensitization and reprocessing; F = female; f/u = followup; hypno = hypnotherapy; IES = Impact of Event Scale; IES-R = Impact of Event Scale – revised; NR = not reported; PCT = present-centered therapy (a type of supportive therapy); PE = prolonged exposure; PSS = PTSD symptom scale;; relax = relaxation; SC = supportive control; SIT = stress inoculation training; y = year.
Fifteen trials tested a considerable array of “mixed” CBT interventions (Table G-4). Generally, their findings were consistent with those from low or medium risk-of-bias trials on all the outcomes examined. Specifically, a majority of the high risk-of-bias studies found that the CBT- mixed group had significantly better results than did those in the various comparison groups; these included reducing PTSD symptoms, achieving remission, and losing the PTSD diagnosis, as well as reducing depression symptoms. Similar to the set of included study evidence, few of these omitted trials examined anxiety symptoms, substance use, functional status, quality of life or functional impairment outcomes; when they reported such findings, however, they were similar to those from included studies.
Table G-4Characteristics of mixed intervention trials omitted from main analyses because of high risk of bias
Trial | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Beck et al., 2009200 | CBT-M (17) MCC (16) | 14 weeks (3 months) | Male and female MVA | 57.3 to 57.8 | 43 | 82 11 |
Beidel et al., 2011201 | CBT-M (18) Exposure (17) | 17 weeks | Male Combat | 84.9 to 90.6 | 59 | 0 0 |
Difede et al., 2007206 | CBT-M (15) Usual care (16) | 12 weeks (12 to 13 weeks) | Disaster workers World Trade Center attack | 50.5 to 51.7 | 46 | 3 23 |
Dorrepaal et al., 2012207 | CBT-M (“Stabilitizing group treatment”) (38) Usual care (33) | 20 weeks (post) | Complex PTSD and severe comorbidity | DTS 80 to 90 | 39 | NR NR |
Dunne et al., 2012208 | TF-CBT (13) Waitlist (13) | 10 weeks (post) | MVC-related PTSD (specifically WAD) | PDS 21 to 23 | 32 | 50 NR |
Echeburua et al., 1996263 | CBT-M (10) CBT Cope (10) | 5 weeks (1, 3, 6, and 12 months) | Female Sexual assault | NR | 22 | 100 NR |
Lee et al., 2002227 | EMDR (12) CBT-Mb (SIT+PE) (12) | 7 weeks (3 months) | Male and female Mixed | IES 55.3 | 35 | 46 NR |
Littleton et al., 2016229 | Interactive online therapist-facilitated CBT (46) Psychoeducation self-help website (41) | 14 weeks (post, 3 months) | Rape related PTSD | PSS-I 23 to 23.7 | 22 | 100 47 |
Mueser et al., 2015234 | CBT for PTSD (104) Brief treatment (97) | 12 to 16 weeks (post, 6 months, 12 months) | PTSD and severe mental illness | 85.76 to 86.06 | 44 | 69 66 |
Margolies et al., 2013231 | CBTI plus IRT (20) Waitlist (20) | 4 sessions over 6 weeks (post collected 2 weeks after 6 week treatment period) | Combat Veterans | PSS-SR 39.8 to 41.8 | 38 | 10 60 |
Paunovic et al., 2001239 | Exposure (10) CBT-M (10) | 16 to 20 weeks (6 months) | Male and female Refugees | 95.1 to 98.4 | 38 | 15 NR |
Polak et al., 2015247 | TF-CBT plus breathing biofeedback (4) TF-CBT (4) | 5 to 18 sessions (post) | Chronic PTSD Mixed | IES-R 41.5 to 45 | 45 | 75 NR |
Power et al., 2002243 | EMDR (39) CBT-Ma (Exp+CR) (37) Waitlist (29) | 10 weeks | Male and female Mixed | IES 32.6 to 35.1 | 39 | 42 NR |
Stecker et al., 2014251 | Brief CBT (123) Usual care (151) | 1 session (1 month, 3 months, 6 months) | Veterans of Iraq war with PTSD | PTSD Checklist 59.2 to 59.7 | 29 | 13 31 |
Ulmer et al., 2011254 | CBT-M (12) Usual care (9) | 6 biweekly sessions, over 12 weeks | Male and female Recently deployed veterans | PCL-M 63.1 to 63.4 | 46 | 31.8 66.6 |
- a
The information provided after CBT-M indicates the content of the mixed intervention (see abbreviations below).
CBT Cope = cognitive behavioral therapy-coping skills; CBT-M = cognitive behavioral therapy-mixed; CR = cognitive restructuring; EMDR = eye movement desensitization and reprocessing; exp = exposure therapy; IES = Impact of Event Scale; MCC = minimum contact comparison group; NR = not reported; PCL-M = PTSD Checklist-Military Version; PE = prolonged exposure; relax = relaxation; SIT = stress inoculation training; y = year.
Eye Movement Desensitization and Reprocessing
Seven trials of eye movement desensitization and reprocessing (EMDR) were rated high risk of bias (see Table G-5). These seven trials had findings consistent with those from included trials on various outcomes. Like the trials rated either low or medium risk of bias, a majority of the high risk-of-bias studies found that the EMDR group had significantly better outcomes than patients in an inactive comparator group in terms of reducing PTSD symptoms, losing the PTSD diagnosis, and reducing depression. Few of these seven trials examined any other coexisting condition, functional status, quality of life, or disability or functional impairments.
Table G-5Characteristics of studies of eye movement desensitization and reprocessing omitted from main analyses because of high risk of bias
Trial | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Ironson et al., 2002219 | EMDR (10) PE (12) | 6 weeks (3 months) | Domestic violence Childhood sexual abuse | PSS-SR 26.6 to 34.6 | NR | 77 NR |
Johnson et al., 2006221 | Randomized (Total: 51)a PE (Unclear) CM (Unclear) EMDR (Unclear) Waitlist (14) | Mean number of weekly sessions PE: 9.66 EMDR: 6.33 Waitlist: 5.89 (3 months) | Female Mixed | 61.8 to 82.0 | 39 | 100 17 |
Karatzias et al., 2011222 | EMDR (23) EFT (23) | 8 weeks (3 months) | Male and female Mixed | 70.7 to 66.1 | 40 | 57 NR |
Lee et al., 2002227 | EMDR (12) SITPE (12) | 7 weeks (3 months) | Australian male and female Mixed | IES 55.3 | 35 | 46 NR |
Marcus et al., 1997230 | EMDR (NR) Usual care (NR) | NR - Variable number of sessions (none) | Male and female Mixed | IES 46.1 to 49.7 | 42 | 79 34 |
Power et al., 2002243 | EMDR (39) EXP+CR (37) Waitlist (29) | 10 weeks (15 months) | Male and female Mixed | IES 32.6 to 35.1 | 40 | 42 NR |
Zimmerman et al., 2007264 | EMDR (40) Usual care (49) | Twice a week for 68 days (12 to 60 months) | Male and female Mixed (91% male, German soldiers) | IES 36.1 NR | 28 | 9 NR |
- a
The number of participants randomized to each active treatment group was not reported. A total of 27 participants from the active treatment groups were analyzed, 9 in each treatment group.
CAPS = Clinician-Administered Post Traumatic Stress Disorder Scale; CBT-M = cognitive behavioral therapy-mixed; CI = confidence interval; CR = cognitive restructuring; EFT = Emotional Freedom Techniques; EMDR = eye movement desensitization and reprocessing; F = female; IES = Impact of Event Scale; MISS = Mississippi Scale for Combat-Related Post Traumatic Stress Disorder; N = number; NR = not reported; PE = prolonged exposure; PTSD = posttraumatic stress disorder; PSS-SR = Post Traumatic Stress Disorder Symptom Scale-Self-Report; SITPE = stress inoculation training with prolonged exposure; y = year.
Analyses of Other Psychological Interventions
Ten trials that we rated high risk of bias dealt with a variety of other psychological interventions (Table G-6). Three of these assessed narrative exposure therapy (NET); of these three, the one comparing NET with usual care found results consistent with those from medium risk-of-bias trials. The other two NET trials had active comparators -- stress inoculation therapy and psychoeducation. Whereas the IPT study rated high risk of bias tested the efficacy of IPT versus treatment as usual, the IPT study included in the main study findings compared the effectiveness of IPT versus two other treatments, precluding comparisons of the findings. Other studies rated high risk of bias assessed interventions (or comparators) not included for the main analyses, namely slow breathing (SB) feedback, and trauma-focused CBT (TF-CBT) plus breathing biofeedback; thus, we could not assess, for example, the consistency of the results.
Table G-6Characteristics of other psychological intervention trials omitted from main analyses because of high risk of bias
Trial | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Bichescu et al., 2007202 | NET (9) PED (9) | 10 weeks— 5 NET sessions, 1 PED session (6 months) | Male and female Political detainees | CIDI - PTSD 11.4 to 11.9 | 69 | 6 NR |
Brom et al.,1989203 | TD (31) Hypno (29) PDT (29) Waitlist (23) | ~4 months (given only as mean number of sessions) (3 months) | Male and female Mixed | NR | 42 | 79 NR |
Hensel-Dittman et al., 2011216 | NET (15) SIT (13) | 4 weeks (6 and 12 months) | Male and female Experienced organized violence | 85.2 to 96.5 | NR | NR NR |
Jiang et al., 2014220 | IPT plus TAU (27) TAU (22) | 12 weeks (none), 57% had clinical PTSD | Earth quake survivors w/MDD | 39.41 to 45.05 | 30 | 71 100 |
Krupnick et al., 2008226 | IPT (32) Waitlist (16) | 16 weeks (4 months) | Female Mixed | 62.6 to 65.2 | 32 | 100 94 |
Niles et al., 2012236 | MBSR (17) Psychoeducation (16) | 8 weeks (6 weeks) | Combat-related | 61 to 72 | 52 | 0 24 |
Noohi et al., 2017237 | Neuro-feedback (15) Control (15) | 25 sessions (45 days after treatment) | Males War related | IES-R 47.20 to 51.07 | 30 to 50 | 0 NR |
Polak et al., 2015247 | TF-CBT plus breathing biofeedback (4) TF-CBT (4) | 5 to 18 sessions (none) | Chronic PTSD Mixed | IES-R 41.5 to 45 | 45 | 75 NR |
Stenmark et al., 2013252 | NET (51) Usual care (30) | 10 sessions (1 and 6 months) | Refugees and asylum seekers from other countries living in Norway | 84 | 35 | 30 100 |
Wagner et al., 2007257 | BA (4) Usual care (4) | 4 to 6 sessions (none) | Male and female Recently Injured | PCL 54.2 to 55.5 | 34 | 38 50 |
Wahbeh et al., 2016258 | SB+biofeedback (25) Sitting quietly (25) | 6 weeks (1 month) | War veterans Mixed | PCL 54 to 55 | 53 | 6 14 |
BA = behavioral activation; CIDI = Composite International Diagnostic Interview – PTSD section; hypno = hypnotherapy; IPT = interpersonal therapy; MBSR = mindfulness-based stress reduction; N = numbers; NET = narrative exposure therapy; NR = not reported; PCL = PTSD Checklist; PDT = psychodynamic therapy; PED = psychoeducation; PTSD = posttraumatic stress disorder; SB = slow breathing; SIT = stress inoculation training; TD = trauma desensitization; TF-CBT = trauma-focused CBT; y = year.
Analyses of Efficacy or Comparative Effectiveness of Psychological Interventions by Patient Characteristics or Type of Trauma (Key Question 1a)
Two trials that we rated high risk of bias reported on the efficacy or comparative effectiveness of psychological interventions for individuals with versus those without certain patient characteristics (see Table G-7). These trials examined data for subgroup characteristics (age, high dissociation and PTSD symptom severity) different from the trials we had rated medium risk of bias; this difference precluded assessment of the consistency of the results.
Table G-7Characteristics of studies that evaluated efficacy or comparative effectiveness of interventions by patient characteristics or type of trauma omitted from main analyses because of high risk of bias
Trial | Arm (N) | Treatment Duration (Followup Post Treatment) | Population Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Butollo et al., 2015204 | G1: DET (74) G2: CPT (74) (only 67 analyzed) | 24 sessions (6 months) | Type I Trauma Mixed Subgroup analysis: age in years at median split | IES-R 66 to 67 | 36 | 66 NR |
Dorrepaal et al., 2012207 | CBT-M (“Stabilizing group treatment”) (38) Usual care (33) | 20 weeks (none) | Complex PTSD and severe comorbidity Subgroup analysis: dissociation and PTSD | DTS 80 to 90 | 39 | NR NR |
CPT = cognitive processing therapy; CBT-M = cognitive behavioral therapy – mixed; DET =dialogical exposure therapy; DTS =Davidson Trauma Scale; IES-R = Impact of Event Scale - Revised; N =number; NR = not reported; PTSD = posttraumatic stress disorder; y = year
Efficacy or Comparative Effectiveness of Pharmacologic Interventions (Key Question 2)
We present descriptions of a considerable number of trials of various classes or individual drugs that we had rated high risk of bias even though they otherwise met eligibility criteria for the pharmacologic interventions (KQ 2). Tables G-8 through G-13 and G-15 are placebo-controlled trials; Table G-14 is a trial testing a head-to-head comparison of different pharmacologic agents. The specific categories of medications with high risk of bias include alpha blockers, anticonvulsants, atypical antipsychotics, benzodiazepines, SSRIs, other second generation antipsychotics, and tricyclic antidepressants (no SNRI trial was rated as high risk of bias).
Generally, the tables for these KQ 2 trials follow the formats for those above describing the psychological interventions. Data reported about PTSD severity are mean CAPS scores or a range of mean CAPS scores for the intervention and control groups unless a different source of these data is specified.
Briefly, these trials mainly had analyzed only subjects who completed treatment (i.e., the investigators did not use an intention-to-treat analysis) or had very high attrition or differential attrition rates. The trials also tended to have small sample sizes Appendix provides additional rationale for risk of bias assessments.
We comment insofar as possible on the consistency of these data with the main study findings.
Alpha Blockers
We rated two trials as high risk of bias (Table G-8). Both compared prazosin with placebo.
Table G-8Characteristics of placebo-controlled trials of alpha blockers omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Petrakis et al., 2016241 | G1: Prazosin (16) (50) G2: Placebo (46) | 13 | Veterans with alcohol dependence, Combat | 71.86 to 75.86 | 44 | 6 19 |
Simpson et al., 2015250 | G1: Prazosin (16 or highest tolerated dose) (15) G2: Placebo (15) | 6 | Adults with alcohol dependence, Mixed/multiple | PSS-I 31.5 to 31.6 | 43 | 37 60 |
G = group; mg = milligrams; N = number; PSS-I = Posttraumatic Stress Disorder Symptom Scale-Interview
Anticonvulsants
We rated three placebo-controlled trials as high risk of bias (Table G-9). the interventions included one trial each of divalproex, lamotrigine, and topiramate.
Table G-9Characteristics of placebo-controlled trials of anticonvulsants omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Hamner et al., 2009215 | Divalproexa (16) Placebo (13) | 10 | Male and female Mixed | 77.1 | 52 | 4 7 |
Hertzberg et al., 1999217 | Lamotrigine (25 to 500) (11) Placebo (4) | 12 | Male and female Mixed | SI-PTSD 44.3 | 43 | 36 71 |
Lindley et al., 2007228 | Topiramate (50 to 200) (20) Placebo (20) | 7 | Male Combat veterans | 61.6 | 53 | 0 37.5 |
- a
Dose not reported; serum trough between 50-125 mcg/ml.
mg = milligram; N = number; PTSD = posttraumatic stress disorder; SI-PTSD = Structured Interview for PTSD; y = year.
Atypical Antipsychotics
We found no trials of atypical antipsychotics versus placebo that met our eligibility criteria but could be rated as either low or medium risk of bias. Four trials, however, were eligible but rated high risk of bias (Table G-10). Two trials tested risperidone, and one each tested aripiprazole or quetiapine,
Table G-10Characteristics of placebo-controlled trials of atypical antipsychotics omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Naylor et al., 2015235 | G1: Aripiprazole (5 to 20) (7) G2: Placebo (7) | 10 | Veterans, Combat Trauma | 82.29 to 90.60 | 34 | 36 50 |
Padala et al., 2006238 | Risperidone (0.5 to 8) (11) Placebo (9) | 12 | Female Mixed | 79.3 to 80.6 | 41 | 100 30 |
Rothbaum et al., 2008248 | Risperidone (0.5 to 3) (9) Placebo (11)a | 16 | Male and female Mixed | 56 to 60 | 34 | 80 30 |
Villarreal et al., 2016256 | G1: Quetiapine (25 to 800) (42) G2: Placebo (38) | 12 | Veterans w/chronic PTSD, Combat | 70.60 to 75.40 | 52 | 6 47 |
- a
This trial did not report the number of patients randomized in each group. Overall, 25 patients were randomized; the n reported is the number of participants analyzed in each group.
mg = milligram; N = number; NR = not reported; PTSD = posttraumatic stress disorder; y = year.
Benzodiazepines
A single trial in this drug class tested alprazolam against placebo (Table G-11). As noted in the main report, no benzodiazepine trial was rated as either low or medium risk of bias. Evidence is insufficient to determine the efficacy of benzodiazepines for improving outcomes for adults with PTSD.
Table G-11Characteristics of placebo-controlled trials of benzodiazepines omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Braun et al., 1990169 | Alprazolam (1.5 to 6) (7) Placebo (9) | 12 | Male and female Mixed | PTSD-Scale 30.0 to 30.9 | 38 | NR NR |
- a
When mean data for baseline PTSD severity were not reported for the total sample but were presented for each study arm, we provide the range across arms.
mg = milligram; N = number; NR = not reported; PTSD = posttraumatic stress disorder; PTSD-Scale = Posttraumatic Stress Disorder Scale; y = year.
Selective Serotonin Reuptake Inhibitors
Among the trials for SSRIs, one studied fluoxetine and one examined paroxetine (both against placebo) (Table G-12). A third was more complicated: sertraline combined with mirtazapine (a newer type of antidepressant in the class known as tetracyclic piperazinoazepine) against sertraline combined with placebo. Findings reported for these trials were generally consistent with what investigators found in low or medium risk-of bias trials.
Table G-12Characteristics of placebo-controlled trials of selective serotonin reuptake inhibitors omitted from main analyses because of high risk of bias
Study | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Hertzberg et al., 2000178 | Fluoxetine (10 to 60) (6) Placebo (6) | 12 | Male Combat veterans | DTS 106 to 111 | 46 | 0 58 |
Marshall et al., 2007177 | Paroxetine (10 to 60) (25) Placebo (27) | 10 | Male and female Mixed | 82.8 to 84.2 | 40 | 67 75 |
Schneier et al., 2015249 | G1: Mirtazapine (15 to 45 mg) plus sertraline (25 to 200mg) (18) G2: Sertraline (25 to 200mg) plus placebo (18) | 24 | Adults with chronic PTSD, Mixed/multiple | PCL 58.9 to 60.0 | 40 | 64 75 |
- a
When mean data for baseline PTSD severity were not reported for the total sample but were presented for each study arm, we provide the range across arms.
DTS = Davidson Trauma Scale; mg = milligram; N = number; PCL = PTSD = posttraumatic stress disorder; y = year.
Other Second-Generation Antidepressants
We rated one trial comparing nefazodone (a phenylpiperazine antidepressant) with placebo as high risk of bias (Table G-13).
Table G-13Characteristics of placebo-controlled trials of other second-generation antidepressants omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
Davis et al., 2004205 | Nefazodone (100 to 600) (27) Placebo (15) | 12 | Male and female Mixed | 81.0 to 83.2 | 54 | 2.4 46 |
Abbreviations: mg = milligram; N =number; PTSD = posttraumatic stress disorder; y = year.
One trial of nefazodone and an active comparator – sertraline (an SSRI) – was rated high risk of bias (Table G-14).
Table G-14Characteristics of one head-to-head pharmacotherapy trial omitted from main analyses because of high risk of bias
Study | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severitya | Mean Age (Y) | % Female % Nonwhite |
---|---|---|---|---|---|---|
McRae et al., 2004233 | Nefazodone (100 mg to 600 mg) (18) Sertraline (50 mg to 200 mg) (19) | 12 | Male and female Outpatient special mental health | 68.9 to 73.8 | 40 | 77 NR |
- a
When mean data for baseline PTSD severity were not reported for the total sample but were presented for each study arm, we provide the range across arms.
mg = milligram; N = number; NR = not reported; PTSD = posttraumatic stress disorder; Y= year.
Tricyclic Antidepressants
We rated three trials of otherwise meeting criteria for this section as high risk of bias (Table G-15). All were placebo-controlled trials conducted more than 20 years ago: one of amitriptyline, one of imipramine, and one of desipramine.
Table G-15Characteristics of placebo-controlled trials of tricyclic antidepressants omitted from main analyses because of high risk of bias
Trial | Arm Dose mg/Day (N) | Duration (Weeks) | Population Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female %Nonwhite |
---|---|---|---|---|---|---|
Davidson et al., 1990179 Davidson et al., 1993180 | Amitriptyline (50 to 300) (33) Placebo (29) | 8 | NR Combat veterans | IES 33.1 | 49 | NR NR |
Kosten et al., 1991182 | Imipramine (50 to 300) (23) Placebo (19) | 8 | Male Combat veterans | IES 35.6 | 39 | 0 NR |
Reist et al., 1989181 | Total (27) Desipramine (50 to 200) (NR) Placebo (NR) | 4 | Male Combat veterans | IES 55.2 to 56.2 | 38 | 0 NR |
Note: When mean data for baseline PTSD severity were not reported for the total sample but were presented for each study arm, we provide the range across arms.
F = female; IES = Impact of Event Scale; mg = milligram; N = total number randomized/assigned to intervention and control groups; NR = not reported; PTSD = posttraumatic stress disorder; y = year.
Psychotherapy Versus Pharmacotherapy for Adults With Posttraumatic Stress Disorder (Key Question 3)
Of the two trials bias that attempted to address KQ 3 and that we rated as high risk of bias (Table G-16) one trial compared paroxetine with CBT and the other trial compared paroxetine with PE therapy. As with the information for KQ 1 and KQ 2, disease severity is measured by CAPS unless another source is specified. Prolonged exposure plus paroxetine was not a combined intervention of interest for KQ 3 because it tested a combined psychotherapy and pharmacology intervention.
Table G-16Characteristics of studies directly comparing pharmacotherapies and psychotherapies omitted from main analyses because of high risk of bias
Study | Arm (N) | Treatment Duration (Followup) | Population, Trauma Type | Baseline PTSD Severity | Mean Age (Y) | % Female %Nonwhite |
---|---|---|---|---|---|---|
Frommberger et al., 2004212 | Paroxetine (11)a CBT (10) | 12 weeks (3 and 6 months) | Male and female, Mixed | 70.5 | 43 | 57 NR |
Popiel et al., 2015242 | Paroxetine (57)b PE (114) Paroxetine + PE (57) (group not of interest to this KQ) | 12 weeks (1 yr) | Male and female, Motor vehicle accident | SCID-I symptoms: 11.7 to 11.8 | 39 | 22 NR |
- a
Titrated from 10 mg/day to max 50 mg/day (mean = 28 mg/day).
- b
A dose of 20 mg/day was achieved in 3 to 7 days.
CBT = cognitive behavioral therapy; mg = milligram; N = number; NR = not reported; PE = prolonged exposure; PTSD = posttraumatic stress disorder; SCID-I = Structured Clinical Interview for Axis I Disorders; yr = year.
Both trials found that participants in the psychological intervention groups (CBT and PE) experienced greater reductions in PTSD symptoms than those in the paroxetine groups. These findings are consistent with those from a medium risk-of-bias trial in our analyses, which compared EMDR with fluoxetine.
- Overview of This Appendix
- Efficacy or Comparative Effectiveness of Psychological Interventions (Key Question 1)
- Analyses of Efficacy or Comparative Effectiveness of Psychological Interventions by Patient Characteristics or Type of Trauma (Key Question 1a)
- Efficacy or Comparative Effectiveness of Pharmacologic Interventions (Key Question 2)
- Psychotherapy Versus Pharmacotherapy for Adults With Posttraumatic Stress Disorder (Key Question 3)
- Documentation of Trials Rated High Risk of Bias - Psychological and Pharmacologi...Documentation of Trials Rated High Risk of Bias - Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder: A Systematic Review Update
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