Strength of Evidence

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 IStrength of Evidence

Publication Details

Key Question 1

Table I-1

Cognitive processing therapy compared with inactive controls (waitlist or usual care).

Table I-2

Cognitive therapy compared with inactive controls (waitlist or usual care).

Table I-3

Metacognitive therapy compared with inactive controls (waitlist or usual care).

Table I-4

Stress inoculation training compared with waitlist.

Table I-5

Relaxation compared with treatment as usual.

Table I-6

Relaxation compared with cognitive restructuring.

Table I-7

Mindfulness Based Stress Reduction compared with treatment as usual.

Table I-8

Neurofeedback training compared with waitlist.

Table I-9

Exposure-based therapies compared with inactive controls (waitlist or usual care).

Table I-10

Exposure-based therapy compared with cognitive restructuring.

Table I-11

Exposure-based therapy compared with cognitive therapy.

Table I-12

Exposure-based therapy compared with cognitive processing therapy.

Table I-13

Exposure-based therapy compared with metacognitive therapy.

Table I-14

Exposure-based therapy compared with stress inoculation training.

Table I-15

Exposure-based therapy compared with relaxation.

Table I-16

Exposure-based therapy compared with EMDR.

Table I-17

Exposure-based therapy compared with IPT.

Table I-18

Exposure-based therapy compared with exposure therapy + cognitive restructuring.

Table I-19

CBT-mixed interventions compared with inactive controls (waitlist, usual care).

Table I-20

CBT-mixed interventions compared with relaxation: Head-to-head trials.

Table I-21

EMDR compared with inactive controls (waitlist, usual care).

Table I-22. EMDR compared with relaxation.

Table I-23

Seeking safety compared with inactive comparators.

Table I-24

Imagery rehearsal therapy (IRT) compared with waitlist (1 trial).

Table I-25

Narrative exposure therapy (NET) compared with an inactive control (waitlist or MA).

Table I-26

Brief eclectic psychotherapy (BEP) compared with waitlist.

Table I-27

Brief eclectic psychotherapy (BEP) compared with EMDR.

Table I-28

Trauma affect regulation compared with waitlist.

Table I-29

Interpersonal Therapy compared with Relaxation Therapy.

Table I-30

Memory Specificity Training compared with control (no treatment).

Table I-31

Structured Writing Therapy compared with usual care (substance abuse treatment).

Key Question 2

Table I-32

Placebo-controlled trials of alpha-blockers (prazosin).

Table I-33

Strength of evidence for divalproex compared with placebo.

Table I-34

Strength of evidence for tiagabine compared with placebo.

Table I-35

Strength of evidence for topiramate compared with placebo.

Table I-36. Olanzapine compared with placebo.

Table I-44

Placebo-controlled trials of mirtazapine.

Table I-45

Paroxetine + placebo compared with desipramine + placebo: Head-to-head trials.

Table I-46

Venlafaxine ER compared with sertraline: Head-to-head trials.

Table I-47

Sertraline compared with citalopram: Head-to-head trials.

Key Question 3

Table I-48

Head-to-head trials of psychological and pharmacological treatments: Fluoxetine compared with EMDR.

Key Question 4

Table I-49

Strength of evidence for adverse events for fluoxetine compared with placebo.

Table I-50

Strength of evidence for adverse events for paroxetine compared with placebo.

Table I-51

Strength of evidence for adverse events for venlafaxine compared with placebo.

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 I, Strength of Evidence.

Table I-1Cognitive processing therapy compared with inactive controls (waitlist or usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline to end of treatment in CAPS
5; 399	Medium; RCTs	Consistent	Direct	Imprecise	SMD -1.35 (95% CI, -1.77 to -0.94)	Moderate
Loss of Diagnosis
4; 299	Medium; RCTs	Consistent	Direct	Imprecise	RD 0.44 (95% CI, 0.26 to 0.62)	Moderate
Prevention/reduction of comorbid depression: mean change from baseline to end of treatment in BDI
5; 399	Medium; RCTs	Consistent	Direct	Precise	SMD -1.09 (95% CI, -1.52 to -0.65)	Moderate
Prevention/reduction of comorbid anxiety: mean change from baseline to end of treatment in STAI
2; 119	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial significantly favored CPT, the other found no differences	Insufficient
Quality of Life
2; 159	Medium; RCT	Inconsistent	Direct	Imprecise	One trial significantly favored CPT, the other found no differences in physical quality of life measures	Insufficient

: CAPS = Clinician Assessment PTSD Scale; CI = confidence interval; CPT = cognitive processing therapy; CR = cognitive restructuring; NA = not applicable; NNT = number needed to treat; RA = repeated assessments (a type of waitlist control group); RCT = randomized controlled trial; RD = risk difference; STAI = State-Trait Anxiety Inventory; UC = usual care; WL = waitlist

Table I-2Cognitive therapy compared with inactive controls (waitlist or usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline to end of treatment
4; 236	Medium; RCTs	Consistent	Direct	Imprecise	SMD range −2.0 to −0.3, p<0.05 for 4 of 4 trials.	Moderate
Loss of Diagnosis
4; 283	Medium; RCTs	Consistent	Direct	Imprecise	RD 0.55 (95% CI, 0.28 to 0.82).	Moderate
Prevention/reduction of comorbid depression: mean change from baseline to end of treatment on BDI
4; 283	Medium; RCTs	Consistent	Direct	Imprecise	WMD range −11.1 to −8.3 N=283, p<0.05 for 4 of 4 trials.	Moderate
Prevention/reduction of comorbid anxiety: mean change from baseline to end of treatment in BAI
4; 284	Medium; RCTs	Consistent	Direct	Imprecise	WMD range −5.6 to −18.7, p<0.05 for 3 of 4 trials	Moderate
Quality of Life
2; 199	Medium; RCT	Inconsistent	Direct	Imprecise	One trial significantly favored CT, the other found no differences in mental quality of life measures	Insufficient
Disability/functional impairment; mean change in SDS from baseline to posttreatment
3; 176	Medium; RCTs	Consistent	Direct	Precise	WMD range −11.3 to −2.2, p<0.05 for 3 of 3 trials	Moderate

a: Included trials compared CT with waitlist (Ehlers 2003 and Ehlers 2005), a self-help booklet (Ehlers 2003), and usual care (Muesser 2008).

b: Data were based on meta-analysis of CAPS total for Muesser 2008 and CAPS-intensity for the Ehlers 2003 and 2005 studies.

c: Direction of effects were consistent; magnitude of effects ranged from very large to small

: BAI = Beck Anxiety Inventory; CI = confidence interval; NA = not applicable; NNT = number needed to treat; RCT = randomized controlled trial; RD = risk difference; WL = waitlist.

Table I-3Metacognitive therapy compared with inactive controls (waitlist or usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline to end of treatment
1; 21	Medium; RCTs	NA, single study	Direct	Imprecise	WMD −27.7	Insufficient
Prevention/reduction of comorbid depression: mean change from baseline to end of treatment in BDI
1; 21	Medium; RCTs	NA, single study	Direct	Imprecise	Findings favor MCT, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety: mean change from baseline to end of treatment in BAI
1; 21	Medium; RCTs	NA, single study	Direct	Imprecise	Findings favor MCT, p<0.05	Insufficient

: BAI = Beck Anxiety Inventory; CI = confidence interval; NA = not applicable; NNT = number needed to treat; RCT = randomized controlled trial; RD = risk difference; WL = waitlist.

Table I-4Stress inoculation training compared with waitlist

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: PSS-I
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	WMD −10.5, p<0.05	Insufficient
Loss of Diagnosis
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.42, p<0.05	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	WMD −8.5, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety: STAI
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −11.4, p=ns	Insufficient

: BDI =; CI = confidence interval; NA = not applicable; PSS-I = Posttraumatic Stress Disorder Symptom Scale-Interview; RCT = randomized controlled trial

Table I-5Relaxation compared with treatment as usual

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction
1; 25	Medium; RCT	NA, single study	Direct	Imprecise	p=ns for 3 different measures	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 25	Medium; RCT	NA, single study	Direct	Imprecise	Favor relaxation but significance not reported	Insufficient
Prevention/reduction of comorbid anxiety: STAI
1; 25	Medium; RCT	NA, single study	Direct	Imprecise	Favor relaxation but p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-6Relaxation compared with cognitive restructuring

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: percentage of patients with at least 50% decrease in PSS symptoms at posttreatment
1; 34^a	Medium; RCT	NA, single study	Direct	Imprecise	RD, 0.17 favoring CR, p=ns	Insufficient
Loss of Diagnosis
1; 34^a	Medium; RCT	NA, single study	Direct	Imprecise	RD, 0.10 favoring CR, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI, mean change scores (im provement)
1; 34^a	Medium; RCT	NA, single study	Direct	Imprecise	WMD −5.0 favoring CR, p=ns	Insufficient
Prevention/reduction of comorbid anxiety

a: Total trial N was 81. Subjects were randomized to PE (23), CR (13), CBT- Mb (CR+PE) (24), or relaxation (21).¹²²

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-7Mindfulness Based Stress Reduction compared with treatment as usual

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: PCL
1; 50	Medium; RCT	NA, single study	Direct	Imprecise	WMD −3.0, p<0.05	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 50	Medium; RCT	NA, single study	Direct	Imprecise	WMD −2.8, p<0.05	Insufficient

: CI = confidence interval; NA = not applicable; PSS-I = Posttraumatic Stress Disorder Symptom Scale-Interview; RCT = randomized controlled trial

Table I-8Neurofeedback training compared with waitlist

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 52	Medium; RCT	NA, single study	Direct	Imprecise	WMD −20.3, p<0.05; also significant decreases in DTS scores	Insufficient
Loss of Diagnosis
1; 52	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.40, p<0.05	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	WMD −8.5, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety: STAI
1; 41	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −11.4, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; PSS-I = Posttraumatic Stress Disorder Symptom Scale-Interview; RCT = randomized controlled trial

Table I-9Exposure-based therapies compared with inactive controls (waitlist or usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS and all PTSD symptom measures
13; 885 (all); 8; 689 (CAPS)	Medium; RCTs	Consistent	Direct	Precise	SMD -1.23 (95% CI, -1.50 to -0.97) SMD(CAPS) -1.12 (95% CI, -1.42 to -0.82))	High
Loss of Diagnosis
6; 409	Medium; RCTs	Consistent	Direct	Precise	RD 0.56 (95% CI, 0.35 to 0.78)	High
Prevention/reduction of comorbid depression: BDI
10; 715	Medium; RCTs	Consistent	Direct	Precise	SMD -0.76 (95% CI, -0.91 to 0.60)	High
Prevention/reduction of comorbid anxiety
3; 286	N/A	Consistent	Direct	Imprecise	All favored CBT-exposure, p<0.05 for 2 of 3	Low
Disability/functional impairment
2; 221^a	Medium; RCTs	Inconsistent	Direct	Imprecise	Small trial (N=31) favored CBT-exposure, p<0.05 but other larger trial found no differences, p=ns	Insufficient

a: One trial did not provide sample sizes of each group, so this total includes the PE+CR group which was not included in this analysis.

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-10Exposure-based therapy compared with cognitive restructuring

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 38	Medium; RCT	NA, single study	Direct	Imprecise	p<0.05	Insufficient
Loss of Diagnosis
1; 38	Medium; RCT	NA, single study	Direct	Imprecise	p<0.05	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 38	Medium; RCT	NA, single study	Direct	Imprecise	p<0.05	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-11Exposure-based therapy compared with cognitive therapy

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1;62	Medium; RCT	NA, single study	Direct	Imprecise	WMD −4.0, p<0.05	Insufficient
Loss of Diagnosis
1; 62	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.16, p<0.05	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 62	Medium; RCT	NA, single study	Direct	Imprecise	WMD −1.9, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety
1; 62	Medium; RCT	NA, single study	Direct	Imprecise	P<0.05	Insufficient
Return to work or return to active duty: % of subjects actively working at 6 month follow up
1; 62	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.07, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-12Exposure-based therapy compared with cognitive processing therapy

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 124	Medium; RCT	NA, single study	Direct	Imprecise	WMD −4.0, p=ns	Insufficient
Loss of Diagnosis
1; 124	Medium; RCT	NA, single study	Direct	Imprecise	WMD 0, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 124	Medium; RCT	NA, single study	Direct	Imprecise	WMD −2.9, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-13Exposure-based therapy compared with metacognitive therapy

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: PDS
1; 22	Medium; RCT	NA, single study	Direct	Imprecise	WMD −10.5, p<0.05	Insufficient
Loss of Diagnosis
1;22	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.30, unknown statistical significance	Insufficient
Prevention/reduction of comorbid depression: BDI
1;22	Medium; RCT	NA, single study	Direct	Imprecise	WMD −7.6, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety: BAI
1;22	Medium; RCT	NA, single study	Direct	Imprecise	WMD −4.7, p<0.05	Insufficient

: BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; CI = confidence interval; NA = not applicable; RCT = randomized controlled trial.

Table I-14Exposure-based therapy compared with stress inoculation training

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 51	Medium; RCT	NA, single study	Direct	Imprecise	WMD −1.8, p=ns	Insufficient
Loss of Diagnosis
1; 51	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.18, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 51	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.2, p=ns	Insufficient

: NA = not applicable

Table I-15Exposure-based therapy compared with relaxation

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
3; 155	Medium; RCTs	Consistent	Direct	Imprecise	SMD -0.45 (-0.78 to -0.13), 3 trials, N=155	Moderate
Loss of Diagnosis
2; 85	Medium; RCTs	Consistent	Direct	Imprecise	RD range 0,20 to 0.47, both trials favored CBT-exposure, p<0.05 in 2 of 2 trials	Moderate
Prevention/reduction of comorbid depression: BDI or HAM-D
3; 155	Medium; RCTs	Consistent	Direct	Imprecise	SMD -0.39 (-0.71 to -0.07), 3 trials, N=155;	Moderate

: NA = not applicable

Table I-16Exposure-based therapy compared with EMDR

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
3; 199	2 Medium, 1 Low; RCTs	Consistent	Direct	Imprecise	P=ns in 3 of 3 trials	Low for no difference
Symptom Remission
0; 0	NA	NA	NA	NA	NA	Insufficient
Loss of Diagnosis
3; 199	2 Medium, 1 Low; RCTs	Inconsistent	Direct	Imprecise	No significant difference between groups, 2 of 3 favored PE and 1 of 3 favored EMDR	Insufficient
Prevention/reduction of comorbid depression: BDI
2; 91	Medium; RCTs	Consistent	Direct	Imprecise	P=ns	Insufficient

: CI = confidence interval; NA = not applicable; PE = prolonged exposure; RCT = randomized controlled trial

Table I-17Exposure-based therapy compared with IPT

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 78	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient
Symptom Remission
1;78	NA	NA, single study	NA	NA	RD 0.03, p=ns	Insufficient
Prevention/reduction of comorbid depression: HAM-D
1;78	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient
Quality of Life
1; 78	Medium, RCT	NA, single study	Direct	Imprecise	No significant difference between PE and IPT (−17.9 vs. −11.3, p=0.061)	Insufficient

: CI = confidence interval; NA = not applicable; PE = prolonged exposure; RCT = randomized controlled trial

Table I-18Exposure-based therapy compared with exposure therapy + cognitive restructuring

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS or PSS-I
4; 299	Medium; RCTs	Inconsistent	Direct	Imprecise	Two studies favored exposure + CR, one study favored CR; p=ns for 4 of 4 trials	Insufficient
Loss of Diagnosis
3; 146	Medium; RCTs	Imprecise	Direct	Imprecise	P=ns for 3 of 3 studies, one favored PE and two favored PE+CR	Insufficient
Prevention/reduction of comorbid depression: BDI
4; 299	Medium; RCTs	Consistent	Direct	Imprecise	P=ns in 4 of 4 studies	Low for no benefit

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-19CBT-mixed interventions compared with inactive controls (waitlist, usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency^a	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline to end of treatment for CAPS, all PTSD symptom measures
11; 709 (CAPS) 21; 1349 (all PTSD symptom measures)	Medium; RCTs	Consistent	Direct	Precise	SMD -1.01 (95% CI, -1.28 to -0.74) SMD (CAPS) -1.24 (95% CI, -1.67 to -0.81)	High
Remission (PCL)
1; 44	Medium; RCTs	NA, single study	Direct	Imprecise	0.40	Insufficient
Loss of Diagnosis
9; 474	Medium; RCTs	Consistent	Direct	Precise	RD 0.29 (0.17, 0.40)	High
Prevention/reduction of comorbid depression: mean change from baseline in BDI
15; 929	Medium; RCTs	Consistent	Direct	Precise	SMD -0.87 (95% CI, -1.14 to -0.61)	High
Prevention/reduction of comorbid anxiety: mean change from baseline in STAI
5; 257	Medium; RCTs	Consistent	Direct	Imprecise	WMD, −10.4 (−18.0 to −2.8); 5 trials, N=257; I squared=82.9	Moderate
Quality of Life
5; 416	Medium; RCTs	Inconsistent	Direct	Imprecise	Mixed results (3 of 5 no difference p=ns; 2 of 5 favored CBT-M p<0.05)	Insufficient^a
Disability/functional impairment
6; 350	Medium; RCTs	Consistent	Direct	Imprecise	All trials favored CBT-M, 4 of 6 met statistical significance.	Low^b

a: The use of four difference quality of life measures¹⁴⁹ across the five trials, (one of which included only subscale data, precluded the use of meta-analysis to pool findings). We downgraded the SOE grade for these inconsistencies further due to heterogeneity in measures.

b: We did not use meta-analysis to pool findings because of the diversity of measures used to different aspects of disability and functional impairment. We downgraded the SOE grades for these inconsistencies further due to heterogeneity in measures.

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-20CBT-mixed interventions compared with relaxation: Head-to-head trials

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction by CAPS
2; 85	Medium; RCTs	Consistent	Direct	Imprecise	WMD range −24.0 to −21.2, p<0.05 in 2 of 2 trials	Low
Disability/functional impairment by GHQ Global Improvement
1; 45	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.15, p=NS	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-21EMDR compared with inactive controls (waitlist, usual care)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction
8; 449	Medium; RCTs	Consistent	Direct	Imprecise	SMD -1.08 (95% CI, -1.82 to -0.35)	Moderate
Loss of Diagnosis
7; 427	Medium; RCTs	Consistent	Direct	Imprecise	RD 0.43 (0.25 to 0.61)	Moderate
Prevention/reduction of comorbid depression
7; 347	Medium; RCTs	Consistent	Direct	Imprecise	SMD -0.91 (95% CI, -1.58 to 0.24)	Moderate
Prevention/reduction of comorbid anxiety: mean change from baseline in STAI
4; 167	Medium; RCTs	Inconsistent	Direct	Imprecise	No significant difference in 3 of 4 trials.	Insufficient

: CI = confidence interval; EMDR = eye movement desensitization and reprocessing; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; RD = risk difference; SMD = Standardized mean difference; STAI = State Trait Anxiety Inventory; WMD = weighted mean difference

Table I-22EMDR compared with relaxation

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction
2; 64	Medium; RCTs	Inconsistent	Direct	Imprecise	Inconsistent findings across studies	Insufficient
Loss of Diagnosis at 3 month post-treatment followup
2; 64	Medium; RCTs	Inconsistent	Direct	Imprecise	Inconsistent findings across studies	Insufficient
Prevention/reduction of comorbid depression: BDI
2; 64	Medium; RCTs	Inconsistent	Direct	Imprecise	Inconsistent findings across studies	Insufficient
Prevention/reduction of comorbid anxiety: STAI
1; 23	Medium; RCT	NA, single study	Direct	Imprecise	Cohen’s d=1.15 (favoring EMDR), p<0.01	Insufficient

a: Two SMDs reported here because two meta-analyses were run because one of the two trials reported two measures of PTSD symptoms.⁴⁶ The first SMD is from our meta-analysis using the Mississippi Scale for Combat Related PTSD from the study reporting two measures; the second is using the IES from that trial. The other trial reported the CAPS.¹³³

: BDI = Beck Depression Inventory; CAPS = Clinician-Administered Post Traumatic Stress Disorder Scale; CI = confidence interval; EMDR = eye movement desensitization and reprocessing; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-23Seeking safety compared with inactive comparators

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS frequency and intensity, reduction from baseline to post-treatment
3; 232	Medium; RCT	Consistent	Direct	Imprecise	SMD of individual trials ranged from -0.22 to 0.04 Two of three trials favored treatment (no study p<0.05)	Low for no difference
Prevention/reduction of comorbid substance use
2; 163	Medium; RCT	Inconsistent	Direct	Imprecise	Mixed findings, p<0.05 for drug use but not alcohol use in 1 of 2 trials	Insufficient

: CAPS = Clinician-Administered Post Traumatic Stress Disorder Scale; BDI = Beck Depression Inventory; CI = confidence interval; IES = Impact of Events Scale; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-24Imagery rehearsal therapy (IRT) compared with waitlist (1 trial)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS mean change from baseline
1; 168	Medium; RCT	NA, Single study	Direct	Imprecise	WMD −21.0, p<0.05	Low
Prevention/reduction of comorbid depression: HAMD
1; 168	Medium; RCT	NA, Single study	Direct	Imprecise	p=ns	Insufficient
Prevention/reduction of comorbid anxiety: HAMA
1; 168	Medium; RCT	NA, Single study	Direct	Imprecise	p=0.04 because symptoms increased in inactive comparator group at followup	Insufficient

: CAPS = Clinician-Administered Post Traumatic Stress Disorder Scale; CI = confidence interval; HAM-D = Hamilton Depression Scale; HAM-A = Hamilton Anxiety Scale; IRT = imagery rehearsal therapy; NA = not applicable; NR = Not Reported; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; SF-36 = 36-Item Short-Form Health Survey; WL = waitlist

Table I-25Narrative exposure therapy (NET) compared with an inactive control (waitlist or MA)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline to post-treatment in PDS and CAPS
3; 232	Medium; RCTs	Consistent	Direct	Imprecise	SMD ranged from -1.95 to -0.79 across 3 individual studies (3 of 3 studies p<0.05)	Moderate
Loss of Diagnosis
2; 198	Medium; RCTs	Consistent	Direct	Imprecise	RD range 0.06 to 0.14, p<0.05 in 1 of 2 trials	Low
Prevention/reduction of comorbid depression
2; 68	Medium; RCTs	Inconsistent	Direct	Imprecise	Mixed evidence	Insufficient
Prevention/reduction of comorbid pain
1; 34	Medium; RCT	NA, single study	Direct	Imprecise	P<0.05	Insufficient

: CI = confidence interval; HSCL-25 = Hopkins Symptom Check List-25; NA = not applicable; NR = not reported; PDS = Posttraumatic Stress Diagnostic Scale; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; SOMS= Screening for Somatoform Symptoms Scale; SRQ-20 = Self-Reporting Questionnaire

Table I-26Brief eclectic psychotherapy (BEP) compared with waitlist

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: various outcome measures
1; 30^a	Medium; RCTs	NA, single study	Direct	Imprecise	WMD −10.8, p=ns	Insufficient
Symptom Remission
1; 30	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.13, p=ns	Insufficient
Loss of Diagnosis
3; 96	Medium; RCTs	Inconsistent	Direct	Imprecise	RD range 0.13 to 0.58^b	Low
Prevention/reduction of comorbid depression
3; 96	Medium; RCTs	Inconsistent	Direct	Imprecise	P<0.05 in 3 of 3 studies	Low
Prevention/reduction of comorbid anxiety
3; 96	Medium; RCTs	Inconsistent	Direct	Imprecise	P<0.05 in 3 of 3 studies	Low
Return to work
2; 66	Medium; RCTs	Inconsistent	Direct	Imprecise	P<0.05 for 1 of 2 trials^c	Insufficient

a: The three trials used different outcome measures—two found small or medium effect sizes using the CAPS and SI-PTSD, respectively. The other did not report enough data to determine effect sizes.

b: The three trials were consistent in the sense that they all found more subjects in the BEP group with loss of PTSD diagnosis compared with the WL group. However, the magnitude of the differences between groups was inconsistent

c: One trials reported percentage of subjects on sick leave and the other reported percentage who had returned to work.

: CI = confidence interval; mths = months; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-27Brief eclectic psychotherapy (BEP) compared with EMDR

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: IES-R and SI-PTSD
1; 140	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient
Loss of Diagnosis
1; 140	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.08 favoring EMDR, p=ns	Insufficient
Prevention/reduction of comorbid depression: HADS depression
1; 140	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient
Prevention/reduction of comorbid anxiety: HADS anxiety
1; 140	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient

: CI = confidence interval; mths, months; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-28Trauma affect regulation compared with waitlist

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
2; 173	Medium; RCT	Consistent	Direct	Imprecise	Between-group mean difference of -17.4 and -2.7 in individual studies Both favored treatment (1 of 2 studies p<0.05)	low
Symptom Remission
2; 173	Medium; RCT	Inconsistent	Direct	Imprecise	RD range −0.11 to 0.21, effect sizes in opposite directions	Insufficient
Loss of Diagnosis
2; 173	Medium; RCT	Inconsistent	Direct	Imprecise	RD range 0.01 to 0.26	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 93	Medium; RCT	NA, single study	Direct	Imprecise	WMD −4.1, p<0.05	Insufficient
Prevention/reduction of comorbid anxiety
1; 93	Medium; RCT	NA, single study	Direct	Imprecise	p=ns	Insufficient

: BDI= Beck Depression Inventory; CI = confidence interval; mths, months; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-29Interpersonal Therapy compared with Relaxation Therapy

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 72	Medium; RCT	NA, single study	Direct	Imprecise	WMD −6.3 favoring IPT, p<0.05	Insufficient
Remission (CAPS<20)
1; 72	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.04 favoring IPT	Insufficient
Prevention/reduction of comorbid depression: HAM-D
1; 72	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.3, p=ns	Insufficient
Quality of Life: Quality of Life Enjoyment and Satisfaction Questionnaire
1; 72	Medium; RCT	NA, single study	Direct	Imprecise	WMD −10.1 favoring IPT, p<0.05	Insufficient
Function: Inventory of Interpersonal Problems Questionnaire
1; 72	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.46 favoring IPT, p<0.05	Insufficient

: CI = confidence interval; HAM-D= Hamilton Depression Rating Scale; NA = not applicable; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-30Memory Specificity Training compared with control (no treatment)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: IES-R
1; 24	Medium; RCT	NA, single study	Direct	Imprecise	Greater reduction in scores among MEST group vs. controls (p<0.001)^a	Insufficient
Prevention/Reduction of Comorbid Depression: BDI-II
1; 24	Medium; RCT	NA, single study	Direct	Imprecise	No difference between groups in score change from baseline (scores NR)	Insufficient

a: Baseline and followup scores are shown in figure only.

: BDI-II = Beck depression inventory II questionnaire; CI = confidence interval; IES-R =Impact of Event Scale- Revised; NA = not applicable; NS= not significant; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-31Structured Writing Therapy compared with usual care (substance abuse treatment)^a

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: PDS
1; 34	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.3	Insufficient
Symptom Remission
1; 34	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.12, p=ns	Insufficient
Prevention/reduction of comorbid depression: reduction/remission of primary substance use diagnosis
1; 34	Medium; RCT	NA, single study	Direct	Imprecise	Days abstinent WMD 2.1 Substance use disorder Remission: (34.1; p=NS	Insufficient

a: Both groups received intensive treatment program for substance use disorders based on CBT and other components (e.g., individual therapy, social skills training, relapse prevention). No interventions related to PTSD symptoms were carried out during the usual substance abuse treatment program.

: CI = confidence interval; NA = not applicable; NS= not significant; PDS = Posttraumatic Stress Diagnostic Scale; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial

Table I-32Placebo-controlled trials of alpha-blockers (prazosin)

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
3; 117	Medium; RCTs	Consistent	Direct	Imprecise	SMD -0.52 (95% CI, -0.90 to -0.14)	Low
Prevention/reduction of comorbid depression
1; 40	Medium; RCT	NA, single study	Direct	Imprecise	WMD −5.0, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-33Strength of evidence for divalproex compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 85	Low; RCT	NA, single study	Direct	Imprecise	WMD −1.40, p=ns	Insufficient
Prevention/reduction of comorbid depression: MADRS
1; 85	Low; RCT	NA, single study	Direct	Imprecise	WMD −0.6, p=ns	Insufficient
Prevention/reduction of comorbid anxiety: HAM-A
1; 85	Low; RCT	NA, single study	Direct	Imprecise	WMD 1.4, p=ns	Insufficient

Table I-34Strength of evidence for tiagabine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 232	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.50, p-ns	Insufficient
Remission (CAPS less than 20)
1; 232	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.02, p=ns	Insufficient
Disability/functional impairment: Sheehan Disability Scale
1; 232	Medium; RCT	NA, single study	Direct	Imprecise	WMD 0.4, p=ns	Insufficient

Table I-35Strength of evidence for topiramate compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
3; 142	Medium; RCT	Consistent	Direct	Imprecise	SMD ranged from -1.85 to -0.38 across individual studies	Low
Symptom Remission
1; 40	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.21, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI or HAM-D
2; 75	Medium; RCT	NA, single study	Direct	Imprecise	Both favored topiramate, p=ns in 2 of 2 trials	Insufficient
Prevention/reduction of comorbid anxiety: HAM-A
1; 40	Medium; RCT	NA, single study	Direct	Imprecise	WMD −13.9, p=ns	Insufficient
Disability/functional impairment: Sheehan Disability Scale
1; 40	Medium; RCT	NA, single study	Direct	Imprecise	WMD −4.8, p=ns	Insufficient

Table I-36Olanzapine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS and SIPS
CAPS 2; 47 All PTSD symptom scales 3; 62	Medium; RCT	Consistent	Direct	Imprecise	SMD (CAPS) of -1.15 and -0.96 across individual studies. Both significantly favored treatment SMD ranged from -1.15 to 0.89 across individual studies. All studies favored treatment (2 of 3 studies p<0.05)	Low
Prevention/reduction of comorbid depression: CES-D
1; 19	Medium	NA, single study	Direct	Imprecise	WMD −0.37, p<0.05	Insufficient
Disability/functional impairment: Sheehan
2; 43	Medium, RCT	Inconsistent	Direct	Imprecise	WMD range −4.2 to 0.3, 1 of 2 trials favored olanzapine, 1 of 2 trials favored placebo, p<0.05 for 1 of 2 trials	Insufficient
Return to work or return to active duty
0; 0	NA	NA	NA	NA	NA	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial; SIPS = Single Item PTSD Screeners.

Table I-37Risperidone compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
4; 422	Medium; RCTs	Inconsistent	Direct	Imprecise	SMD -0.26 (95% CI, -0.52 to -0.01) in 1 of 4 trials	Low
Prevention/reduction of comorbid depression: HAM-D
1; 65	Medium; RCT	NA, single study	Direct	Imprecise	WMD −2.3, p=ns	Insufficient
Prevention/reduction of comorbid anxiety: HAM-A or PANSS
2; 105	Medium; RCT	Consistent	Direct	Imprecise	p<0.05 for 2 of 2 trials, favoring risperidone	Low

: CAPS = Clinician-Administered PTSD Scale; CI = confidence interval; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; NA = not applicable; PANSS = Positive and Negative Syndrome Scale; PTSD = posttraumatic stress disorder; RCT = randomized controlled trial; WMD = weighted mean difference.

Table I-38Citalopram compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)^a	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline in CAPS
1; 35	Medium; RCT	NA, single study	Direct	Imprecise	WMD 8.0, favoring placebo, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI, mean change from baseline
1; 35	Medium; RCT	NA, single study	Direct	Imprecise	WMD −0.47, p=ns	Insufficient

a: Data are from a single trial comparing citalopram, sertraline, and placebo.¹⁷⁵

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial.

Table I-39Fluoxetine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline in CAPS
4 (5 comparisons); 835	Medium; RCTs	Consistent	Direct	Precise	SMD -0.28 (95% CI -0.42 to -0.14)	Moderate
Symptom Remission: Percent of subjects with CAPS less than 20
1; 52	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.03, p=ns	Insufficient
Loss of Diagnosis: percent of subjects no longer meeting criteria for PTSD diagnosis
1; 59	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.14, p=ns	Insufficient
Prevention/reduction of comorbid depression: mean change from baseline in MADRS
3 (4 comparisons); 771	Medium; RCTs	Consistent	Direct	Precise	SMD -0.20 (95% CI -0.40 to 0.00)	Low for no difference
Prevention/reduction of comorbid anxiety: mean change from baseline in HAM-A
2 (3 comparisons); 712	Medium; RCTs	Inconsistent	Direct	Imprecise	WMD range −3.0 to −1.5, both favored fluoxetine, p<0.05 in 1 of 2 trials	Low
Disability/functional impairment: mean change from baseline in SDS
1; 54	Medium; RCT	NA, single study	Direct	Imprecise	WMD −5.8, p=ns	Insufficient

a: Data from subgroup analysis of subjects with combat-related PTSD in one trial (N=144 of the 301 from the main trial).¹⁷³

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-40Paroxetine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline in CAPS
2 (3 comparisons); 348	Medium; RCTs	Consistent	Direct	Imprecise	SMD of -0.56 to -0.44 in individual studies Both studies favored treatment (2 of 2 studies p<0.05)	Moderate
Symptom Remission
2; 348	Medium; RCTs	Consistent	Direct	Imprecise	RD of 0.13 and 0.19 across 2 individual studies (1 of 2 studies p<0.05)	Moderate
Prevention/reduction of comorbid depression: mean change from baseline in MADRS
2 (3 comparisons); 348	Medium; RCTs	Consistent	Direct	Imprecise	SMD ranged from -0.60 to 0.34 across individual studies Both studies favored treatment (2 of 2 studies p<0.05)	Moderate
Disability/functional impairment: mean change from baseline in SDS
2 (3 comparisons); 348	Medium; RCTs	Consistent	Direct	Imprecise	WMD range −2.6 to −1.9, both favored paroxetine, p<0.05 in 2 of 2 trials (3 of 3 comparisons)	Moderate

a: Data are the best available evidence from a trial of paroxetine (N=323) that defined remission as a CAPS-2 total score less than 20 and found a significantly greater proportion of paroxetine-treated subjects achieved remission compared with placebo at week 12 (29.4% vs. 16.5%, p=0.008). The difference (12.9% difference between paroxetine and placebo) would translate to a number needed to treat of 7.8 to achieve one remission.⁶⁵ The other trial contributing data for this outcome found similar percentages of subjects achieving remission (33% vs. 14%), but it was underpowered to detect anything but a very large difference for this outcome.¹⁷⁴

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-41Sertraline compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: mean change from baseline in CAPS
7; 1,085	Medium; RCTs	Consistent	Direct	Precise	SMD -0.20 (95% CI: -0.36 to -0.04)	Low
Symptom Remission: Percent of subjects achieving CAPS-SX₁₇ score less than 20
1; 352	Medium; RCT	NA, single study	Direct	Imprecise	RD 4.4, p=NS	Insufficient
Prevention/reduction of comorbid depression: mean change from baseline in HAM-D
7; 1,085	Medium; RCTs	Inconsistent	Direct	Imprecise	SMD -0.14 (95% CI: -0.33 to 0.06)	Low for no difference
Prevention/reduction of comorbid anxiety: mean change from baseline in HAM-A
2; 377	Medium; RCTs	Inconsistent	Direct	Imprecise	Effects in opposite direction, p=ns for 2 of 2 trials	Insufficient
Quality of Life: mean change in Q-LES-Q
2; 539	Medium; RCTs	Consistent	Direct	Imprecise	WMD range −8.4 to −2.4, p<0.05 in 1 of 2 trials	Low
Disability/functional impairment: mean change from baseline in SDS
1; 352	Medium; RCT	NA, single study	Direct	Imprecise	WMD −1.7, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-42Venlafaxine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: Change in CAPS
2; 687	Medium/RCT	Consistent	Direct	Precise	SMD of -0.35 and -0.26 for two individual studies	Moderate
Symptom Remission: defined by CAPS-Sx total score of 20 or less
2; 687	Medium/RCT	Consistent	Direct	Precise	RD of 0.12 and 0.15 across individual studies	Moderate
Prevention/reduction of comorbid depression: change in BDI
2; 687	Medium/RCT	Consistent	Direct	Precise	Between-group mean difference of -2.6 and 1.6 across individual studies. Both studies favored treatment.	Moderate
Prevention/reduction of comorbid anxiety
0; 0	NA	NA	NA	NA	NA	Insufficient
Quality of Life (change in Q-LES-Q-SF)
2; 687	Medium/RCT	Consistent (I² 0%)	Direct	Precise	WMD range 2.8 to 4.1, p<0.05 in 2 of 2 trials.	Moderate
Disability/functional impairment (change in SDS, and change in GAF)
2; 687	Medium/RCT	Consistent (I² 0%)	Direct	Precise	For SDS, WMD range −2.1 to −2.0, p<0.05 in 2 of 2 trials For GAF, WMD range 2.7 to 4.0, both trials favored venlafaxine, p<0.05 in 1 of 2 trials	Moderate

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-43Placebo-controlled trials of bupropion

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS
1; 30	Medium; RCT	NA, Single Study	Direct	Imprecise	WMD 4.7, p=ns	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 30	Medium; RCT	NA, single study	Direct	Imprecise	0.4, p=ns	Insufficient

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-44Placebo-controlled trials of mirtazapine

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design/Quality	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: DTS
1; 29	Medium; RCT	NA, single study	Direct	Imprecise	WMD −9.5, p=ns	Insufficient
PTSD Symptom Reduction: SPRINT
1; 29	Medium; RCT	NA, single study	Direct	Imprecise	WMD −3.76, p=ns	Insufficient
PTSD Symptom Reduction: SIPS
1; 29	Medium; RCT	NA, single study	Direct	Imprecise	WMD −10.8, p<0.05	Insufficient
Prevention/reduction of comorbid depression: HADS-D
1; 29	Medium; RCT	NA, single study	Direct	Imprecise	WMD −1.7, p=ns	Insufficient
Prevention/reduction of comorbid anxiety: HADS-A
1; 29	Medium; RCT	NA, single study	Direct	Imprecise	WMD −1.6, p<0.05	Insufficient

Table I-45Paroxetine + placebo compared with desipramine + placebo: Head-to-head trials^a

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS, mean change from baseline
1; 88	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −3.2 favoring desipramine+placebo, p<0.05	Low
Prevention/reduction of comorbid depression: HAM-D, mean change from baseline
1; 88	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −1.3 favoring paroxetine+placebo, p=ns,	Low
Prevention/reduction of comorbid alcohol dependence: heavy drinking days and drinks per drinking day
1; 88	Medium; RCT	NA, single study	Direct	Imprecise	Greater reduction with desipramine, p<0.05	Low

a: Data are from 1 trial of veterans with PTSD and comorbid alcohol dependence that compared Paroxetine + Naltrexone, Paroxetine + Placebo, Desiprimine + Naltrexone, and Desipramine + Placebo.

b: Data NR for drinking outcomes; p=0.009 for percentage of heavy drinking days and p=0.027 for drinks per drinking day; shown in Figure only; magnitude of difference NR and difficult to read clearly from the Figure, all groups ended up less than 20 standard drinks per week (from baselines above 70 drinks per week), but it appears that the Desipramine groups ended up in the 0 to 10 drinks per week range and the paroxetine groups ended up in the 10-20 range at the 12 week endpoint.

: CI = confidence interval; NA = not applicable; NR = not reported; RCT = randomized controlled trial

Table I-46Venlafaxine ER compared with sertraline: Head-to-head trials

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)^a	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS-SX₁₇, mean change from baseline
1; 538	Medium; RCT	NA, single study^b	Direct	Precise	WMD range, −2.1 favoring sertraline, p=ns	Low for no difference
Symptom Remission: SX17 score of ≤20 at week 12
1; 538	Medium; RCT	NA, single study^b	Direct	Precise	WMD, −5.9; p=ns,	Insufficient
Prevention/reduction of comorbid depression: HAM-D, mean change from baseline
2; 745	Medium; RCT	Consistent	Direct	Imprecise	WMD range −0.7 to −0.1, p=ns in 2 of 2 trials	Moderate for no difference
Quality of Life: Q-LES-Q or WHO-5, mean change
2; 745	Medium; RCT	Inconsistent	Direct	Imprecise	1 trial favored venlafaxine, the other favored sertraline, p=ns in both trials	Low for no difference
Disability/functional impairment: SDS
2; 745	Medium; RCT	Inconsistent	Direct	Imprecise	1 trial favored venlafaxine, the other favored sertraline, p=ns in both trials	Low for no difference

a: Data are from 1 multicenter trial comparing venlafaxine ER, sertraline, and placebo.⁶⁹

b: Although this is a single trial, it was a multicenter trial including 59 outpatient centers in the US. We considered this in our SOE grade.

: CI = confidence interval; NA = not applicable; NR = not reported; p=placebo; RCT = randomized controlled trial; S = sertraline; V = venlafaxine ER

Table I-47Sertraline compared with citalopram: Head-to-head trials

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)^a	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS, mean change from baseline
1; 58	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −11.1 favoring sertraline, p=ns	Insufficient
PTSD Symptom Reduction: IES, mean change from baseline
1; 58	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −5.9; p=ns,	Insufficient
Prevention/reduction of comorbid depression: BDI
1; 58	Medium; RCT	NA, single study	Direct	Imprecise	WMD, −2.9; p=ns	Insufficient

a: Data are from 1 RCT comparing sertraline, citalopram, and placebo.¹⁷⁵

: C = citalopram; CI = confidence interval; NA = not applicable; NR = not reported; p=placebo; RCT = randomized controlled trial; S = sertraline

Table I-48Head-to-head trials of psychological and pharmacological treatments: Fluoxetine compared with EMDR

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Mean, %, or Effect Size (ES)	High, Moderate, Low, Insufficient
PTSD Symptom Reduction: CAPS and PSS						Insufficient
Fluoxetine vs. EMDR 1; 59	Medium; RCT	Unknown (single study)	Direct	Imprecise	WMD −10.1 favoring fluoxetine, p=ns	Insufficient
Symptom Remission:
Fluoxetine vs. EMDR 1; 59	Medium; RCT	Unknown (single study)	Direct	Imprecise	RD 0.15, p=ns	Insufficient
Loss of Diagnosis
Fluoxetine vs. EMDR 1; 59 (post) 1; 50 (f/up)	Medium; RCT	Unknown (single study)	Direct	Imprecise	RD 0.03 favoring EMDR, p=ns	Insufficient
Prevention/reduction of comorbid depression
Fluoxetine vs. EMDR 1; 59 (post) 1; 50 (f/up)	Medium; RCT	Unknown (single study)	Direct	Imprecise	WMD −1.9, p=ns favoring EMDR	Insufficient

: BDI = Beck Depression Inventory; CAPS = Clinician-Administered PTSD Scale – total; f/up, 6 month followup; NR = not reported; NS = non-significant; post = post-treatment; wk = week.

Table I-49Strength of evidence for adverse events for fluoxetine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
Withdrawals due to Adverse Events
3; 712	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial showed no difference, one trial favored fluoxetine, and one had two arms providing conflicting results; p=ns in 3 of 3 trials	Insufficient
Headaches
3; 776	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial favored fluoxetine, two favored placebo; p=ns in 3 of 3 trials	Insufficient
Nausea
2; 712	Medium; RCTs	Consistent	Direct	Imprecise	Range 0.03 to 0.07 across two trials; p=ns in both trials	Low
Insomnia
1; 301	Medium; RCT	NA, single study	Direct	Imprecise	One study favored placebo, p=ns	Insufficient
Diarrhea
1; 44	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.24, p<0.05	Low
Somnolence
1; 411	Medium; RCT	NA, single study	Direct	Imprecise	RD range 0.04 to 0.06 (variation by dose), p-ns	Low

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-50Strength of evidence for adverse events for paroxetine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
Withdrawals due to Adverse Events
3; 911	Medium; RCTs	Consistent	Direct	Imprecise	All three studies favored placebo, p=ns in 3 of 3 studies	Insufficient
Nausea
1; 323	Medium; RCTs	NA, single study	Direct	Imprecise	RD 0.11, p<0.05^a	Low
Dry mouth
1; 323	Medium; RCT	NA, single study	Direct	Imprecise	RD 0.10, p<0.05	Low
Diarrhea
1; 563	Medium; RCT	NA, single study	Direct	Imprecise	Incidence of at least 10% and twice that of placebo⁶⁴	Insufficient
Somnolence
1; 323	Medium; RCTs	Consistent	Direct	Imprecise	RD 0.13, p<0.05^a	Low
Drowsiness
1; 25	Medium; RCT	NA, single study	Direct	Imprecise	One study favored paroxetine, p=ns	Insufficient
Sexual adverse effects
1; 563	Medium; RCT	NA, single study	Direct	Imprecise	Incidence of at least 10% and twice that of placebo⁶⁴	Insufficient

a: Data are based on the only trial (N=323) reporting sufficient data to determine the risk difference.⁶⁵ One additional trial (N=563) that provided narrative description reported that the most commonly reported adverse events associated with paroxetine use (with an incidence of at least 10% and twice that of placebo) were asthenia, diarrhea, abnormal ejaculation, impotence, nausea, and somnolence.⁶⁴

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Table I-51Strength of evidence for adverse events for venlafaxine compared with placebo

	Domains Pertaining to Strength of Evidence				Magnitude of Effect	Strength of Evidence
Number of Studies; Number of Subjects	Risk of Bias; Design	Consistency	Directness	Precision	Summary Effect Size (95% CI)	High, Moderate, Low, Insufficient
Withdrawals due to Adverse Events
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial favored venlafaxine, one trial favored placebo; none were statistically significant	Insufficient
Headaches
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial favored venlafaxine, one trial favored placebo; none were statistically significant	Insufficient
Nausea
2; 686	Medium; RCTs	Consistent	Direct	Precise	Both trials favored placebo to a statistically significant degree	Moderate
Insomnia
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial favored venlafaxine, one trial favored placebo; none were statistically significant	Insufficient
Dry mouth
2; 687	Medium; RCTs	Consistent	Direct	Imprecise	RD range 0.04 to 0.08, p<0.05 in 1 of 2 trials	Low
Diarrhea
1; 358	Medium; RCTs	NA, single study	Direct	Imprecise	P=ns	Insufficient
Dizziness
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	P=ns	Insufficient
Fatigue
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	Both trials favored placebo, none to a statistically significant degree	Insufficient
Somnolence
2; 687	Medium; RCTs	Inconsistent	Direct	Imprecise	One trial favored venlafaxine, one trial favored placebo; none were statistically significant	Insufficient
Decreased appetite
1; 358	Medium; RCTs	NA, single study	Direct	Imprecise	One trial favored venlafaxine, but not to a statistically significant degree	Insufficient
Constipation
2; 686	Medium; RCTs	Consistent	Direct	Imprecise	RD range 0.02 to 0.09 across 2 trials, p<0.05 in 1 of 2 trials	Low

: CI = confidence interval; NA = not applicable; RCT = randomized controlled trial

Appendix IStrength of Evidence

Key Question 1

Key Question 2

Key Question 3

Key Question 4

Publication Details

Copyright

Publisher

NLM Citation

Table I-1Cognitive processing therapy compared with inactive controls (waitlist or usual care)

Table I-2Cognitive therapy compared with inactive controls (waitlist or usual care)

Table I-3Metacognitive therapy compared with inactive controls (waitlist or usual care)

Table I-4Stress inoculation training compared with waitlist

Table I-5Relaxation compared with treatment as usual

Table I-6Relaxation compared with cognitive restructuring

Table I-7Mindfulness Based Stress Reduction compared with treatment as usual

Table I-8Neurofeedback training compared with waitlist

Table I-9Exposure-based therapies compared with inactive controls (waitlist or usual care)

Table I-10Exposure-based therapy compared with cognitive restructuring

Table I-11Exposure-based therapy compared with cognitive therapy

Table I-12Exposure-based therapy compared with cognitive processing therapy

Table I-13Exposure-based therapy compared with metacognitive therapy

Table I-14Exposure-based therapy compared with stress inoculation training

Table I-15Exposure-based therapy compared with relaxation

Table I-16Exposure-based therapy compared with EMDR

Table I-17Exposure-based therapy compared with IPT

Table I-18Exposure-based therapy compared with exposure therapy + cognitive restructuring

Table I-19CBT-mixed interventions compared with inactive controls (waitlist, usual care)

Table I-20CBT-mixed interventions compared with relaxation: Head-to-head trials

Table I-21EMDR compared with inactive controls (waitlist, usual care)

Table I-22EMDR compared with relaxation

Table I-23Seeking safety compared with inactive comparators

Table I-24Imagery rehearsal therapy (IRT) compared with waitlist (1 trial)

Table I-25Narrative exposure therapy (NET) compared with an inactive control (waitlist or MA)

Table I-26Brief eclectic psychotherapy (BEP) compared with waitlist

Table I-27Brief eclectic psychotherapy (BEP) compared with EMDR

Table I-28Trauma affect regulation compared with waitlist

Table I-29Interpersonal Therapy compared with Relaxation Therapy

Table I-30Memory Specificity Training compared with control (no treatment)

Table I-31Structured Writing Therapy compared with usual care (substance abuse treatment)a

Table I-32Placebo-controlled trials of alpha-blockers (prazosin)

Table I-33Strength of evidence for divalproex compared with placebo

Table I-34Strength of evidence for tiagabine compared with placebo

Table I-35Strength of evidence for topiramate compared with placebo

Table I-36Olanzapine compared with placebo

Table I-37Risperidone compared with placebo

Table I-38Citalopram compared with placebo

Table I-39Fluoxetine compared with placebo

Table I-40Paroxetine compared with placebo

Table I-41Sertraline compared with placebo

Table I-42Venlafaxine compared with placebo

Table I-43Placebo-controlled trials of bupropion

Table I-44Placebo-controlled trials of mirtazapine

Table I-45Paroxetine + placebo compared with desipramine + placebo: Head-to-head trialsa

Table I-46Venlafaxine ER compared with sertraline: Head-to-head trials

Table I-47Sertraline compared with citalopram: Head-to-head trials

Table I-48Head-to-head trials of psychological and pharmacological treatments: Fluoxetine compared with EMDR

Table I-49Strength of evidence for adverse events for fluoxetine compared with placebo

Table I-50Strength of evidence for adverse events for paroxetine compared with placebo

Table I-51Strength of evidence for adverse events for venlafaxine compared with placebo

Table I-31Structured Writing Therapy compared with usual care (substance abuse treatment)^a

Table I-45Paroxetine + placebo compared with desipramine + placebo: Head-to-head trials^a