Documentation of Trials Rated High Risk of Bias

Valerie Forman-Hoffman; Jennifer Cook Middleton; Cynthia Feltner; Bradley N. Gaynes; Rachel Palmieri Weber; Carla Bann; Meera Viswanathan; Kathleen N. Lohr; Claire Baker; Joshua Green

Appendix GDocumentation of Trials Rated High Risk of Bias

Overview 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-1

Characteristics of cognitive intervention trials omitted from main analyses because of high risk of bias.

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-2

Characteristics of coping skills trials omitted from main analyses because of high risk of bias.

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-3

Characteristics of exposure trials omitted from main analyses because of high risk of bias.

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-4

Characteristics of mixed intervention trials omitted from main analyses because of high risk of bias.

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-5

Characteristics of studies of eye movement desensitization and reprocessing omitted from main analyses because of high risk of bias.

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-6

Characteristics of other psychological intervention trials omitted from main analyses because of high risk of bias.

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-7

Characteristics 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.

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-8

Characteristics of placebo-controlled trials of alpha blockers omitted from main analyses because of high risk of bias.

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-9

Characteristics of placebo-controlled trials of anticonvulsants omitted from main analyses because of high risk of bias.

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-10

Characteristics of placebo-controlled trials of atypical antipsychotics omitted from main analyses because of high risk of bias.

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-11

Characteristics of placebo-controlled trials of benzodiazepines omitted from main analyses because of high risk of bias.

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-12

Characteristics of placebo-controlled trials of selective serotonin reuptake inhibitors omitted from main analyses because of high risk of bias.

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-13

Characteristics of placebo-controlled trials of other second-generation antidepressants omitted from main analyses because of high risk of bias.

One trial of nefazodone and an active comparator – sertraline (an SSRI) – was rated high risk of bias (Table G-14).

Table G-14

Characteristics of one head-to-head pharmacotherapy trial omitted from main analyses because of high risk of bias.

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-15

Characteristics of placebo-controlled trials of tricyclic antidepressants omitted from main analyses because of high risk of bias.

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-16

Characteristics of studies directly comparing pharmacotherapies and psychotherapies omitted from main analyses because of high risk of bias.

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.

Publication Details

Copyright

Publisher

Agency for Healthcare Research and Quality (US), Rockville (MD)

NLM Citation

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.) Appendix G, Documentation of Trials Rated High Risk of Bias.

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.

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 Severity^a	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.

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 Severity^a	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 sessions^c 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 sessions^b (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.

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-M^b (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-M^a (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.

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 Severity^a	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.

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.

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

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 Severity^a	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

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 Severity^a	Mean Age (Y)	% Female % Nonwhite
Hamner et al., 2009²¹⁵	Divalproex^a (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.

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 Severity^a	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.

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 Severity^a	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.

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 Severity^a	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.

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 Severity^a	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.

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 Severity^a	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.

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.

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.