Received: 19 July 2019 | Revised: 6 October 2019 | Accepted: 7 November 2019 DOI: 10.1111/cpsp.12310 L I T E R AT U R E R E V I E W Treatment augmentation for posttraumatic stress disorder: A systematic review Olivia Metcalf1 | Caleb Stone1 | Mark Hinton1 | Meaghan O’Donnell1 | Malcolm Hopwood2 | Alexander McFarlane3 | David Forbes1 | Dzenana Kartal1 Loretta Watson1 | Isabella Freijah1 | Tracey Varker1 | 1 Phoenix Australia - Centre for Posttraumatic Mental Health, Department of Psychiatry, University of Melbourne, Carlton, VIC, Australia 2 Department of Psychiatry, University of Melbourne, Carlton, VIC, Australia 3 Centre for Traumatic Stress Studies, University of Adelaide, Adelaide, SA, Australia Correspondence Olivia Metcalf, Level 3, Alan Gilbert Building, 161 Barry Street Carlton, Victoria, Australia, 3053. Email: olivia.metcalf@unimelb.edu.au Funding information This work was supported by Centenary of Anzac Centre, a Department of Veterans’ Affairs funded initiative of Phoenix Australia. 1 | Abstract This systematic review examined the efficacy of all augmentation approaches for first-line posttraumatic stress disorder (PTSD) interventions. From 9,890 records, 34 trials were eligible for inclusion, covering 28 different augmentation approaches. Overall, augmentation approaches were ineffective if they targeted a mechanism similar to the first-line treatment. Augmentation approaches combining two guideline-recommended treatments were largely ineffective, reflecting ceiling effects. Pharmacological augmentation approaches targeting fear extinction mechanisms were largely ineffective, or worsened outcomes relative to prolonged exposure alone, as these approaches may inadvertently strengthen fear memories. Augmentation approaches targeting general cognitive enhancement showed promise and provided support for augmentation interventions that require little cognitive or emotional work and target mechanisms different than the first-line treatment. KEYWORDS adjunctive, augmentation, fear extinction, first-line treatment, PTSD IN T RO D U C T ION After decades of intensive research efforts, several international posttraumatic stress disorder (PTSD) treatment guidelines now identify trauma-focused psychological interventions, such as cognitive processing therapy (CPT), prolonged exposure (PE), and eye movement desensitization and reprocessing (EMDR) to be first-line treatments for PTSD (American Psychological Association, 2017; Australian Centre for Posttraumatic Mental Health, 2013; Bisson et al., 2019; NICE, 2018). In addition, while traumafocused psychological interventions come with the strongest recommendations within these guidelines, pharmacological interventions such as SSRIs are also recommended in instances where psychotherapy is unavailable or unacceptable, or when an individual does not respond to psychotherapy alone. While outcomes from first-line PTSD treatments are often promising, a significant minority of individuals do not improve with treatment. For example, in the largest study of PE to date, 50% of participants retained their diagnosis (Foa et al., 2018). Moreover, a recent meta-analysis showed the average number needed to treat for trauma-focused therapies is as high as four (i.e., four patients treated for one patient to lose diagnosis; Cusack et This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Clinical Psychology: Science and Practice published by Wiley Periodicals, Inc. on behalf of American Psychological Association. Clin Psychol Sci Pract. 2020;27:e12310. https://doi.org/10.1111/cpsp.12310 wileyonlinelibrary.com/journal/cpsp | 1 of 21 2 of 21 | al., 2016). Treatment success has also been shown to vary by population, with around two-thirds of military/veteran populations retaining their PTSD diagnosis after treatment with CPT or PE (Steenkamp, Litz, Hoge, & Marmar, 2015). These outcomes have highlighted the prevalence of treatment resistance in PTSD and what strategies might be utilized to increase treatment success with first-line interventions (McFarlane, 2019). There is substantial scope for the improvement of PTSD treatment outcomes (Forbes et al., 2019). The past decade has seen a range of new so-called augmentation approaches termed “adjunct,” “add-on,” “adjuvant,” “combination,” “synergistic,” “supplemental,” and “enhanced,” which describe additional interventions designed to enhance outcomes from first-line PTSD treatments. The range of PTSD treatment augmentation approaches are diverse, varying significantly in their purported therapeutic mechanisms, theoretical orientations, and their ultimate treatment goals. Moreover, from a temporal perspective, augmentation approaches can be used in a preparatory manner, concurrently, or after receiving a first-line treatment. Advances in our understanding of the mechanisms that underpin PTSD, as well as new developments in neuroscience, cognitive psychology, and pharmacology have produced several novel approaches to augmentation (Forbes et al., 2019). Several augmentation strategies have taken a largely cognitive or neuroscientific approach (Weisman & Rodebaugh, 2018), with the aim of improving ability to cognitively engage with trauma-focused treatments or improve processing of the traumatic memory, such as speeding up the fear extinction process. Examples include enhancing working memory or attention control (McDermott et al., 2016), repetitive transcranial magnetic stimulation (rTMS; Fryml et al., 2019; Kozel et al., 2018), exercise interventions that in turn increase brain-derived neurotrophic factor which facilitates fear extinction (BDNF; Powers et al., 2015), and some pharmacological approaches such as D-cycloserine (de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012; Litz et al., 2012). D-cycloserine is a partial agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor and is purported to facilitate fear extinction via its action in the basolateral amygdala (Norberg, Krystal, & Tolin, 2008). D-cycloserine has shown some success as an augmentation strategy for exposure therapy in other anxiety disorders, including panic disorder (e.g., Otto et al., 2003) and social anxiety disorder (e.g., Hofmann et al., 2006). Other augmentation strategies work by addressing hyperarousal and include acupuncture (Zhang, Feng, Xie, Xu, & Chen, 2011), breathing biofeedback (Rosaura Polak, Witteveen, Denys, & Olff, 2015), and pharmacological approaches (Tuerk et al., 2018) which may work twofold, by both directly reducing hyperarousal (a symptom of PTSD) METCALF ET AL. Public health statements • While outcomes from first-line posttraumatic stress disorder (PTSD) treatments show promise, there remains a need to improve the effectiveness of available interventions. As such, there is a growing interest in “augmentation,” which is the addition of therapeutic elements to PTSD treatments in order to improve outcomes. • Currently, we have limited knowledge about what types of interventions are being used for augmentation, and whether or not they are effective. • We reviewed all of the available evidence on augmentation interventions for first-line PTSD treatments and found that interventions which target a similar therapeutic mechanism to first-line treatments are ineffective. However, interventions that target global cognitive enhancement hold potential. • Our manuscript highlights the importance of a personalized approach to treatment augmentation and sets out a clear path forward for future PTSD treatments. and increasing ability to tolerate the distress that may result during trauma-focused treatments. Alternatively, augmentation can involve adding elements of other psychological therapies, such as cognitive restructuring (Foa et al., 2005), imagery rescripting (Arntz, Tiesema, & Kindt, 2007), emotion regulation (Bryant et al., 2013), and social skills training (Cloitre et al., 2010) to trauma-focused treatments in order to broaden an individual's coping skills. Importantly, a number of augmentation strategies likely work by targeting several components, such as exercise, which might both facilitate the extinction process (in the manner described), in addition to decreasing hyperarousal. To date, there is no systematic review examining the efficacy of all current augmentation approaches to evidence-based PTSD treatments. A 2010 Cochrane review, limited to any pharmacological and any psychological therapy combination for PTSD, was unable to draw conclusions due to the limited number of studies (Hetrick, Purcell, Garner, & Parslow, 2010). More studies are now available indicating that this review is timely. Importantly, we aimed to examine the putative theoretical mechanisms via which promising augmentation approaches work to better outcomes from first-line PTSD interventions. For example, it remains unknown whether augmentation approaches are most effective if they better prepare the individual for a first-line PTSD treatment, such as by increasing an individual's ability to engage with or recall the traumatic memory | METCALF ET AL. or alternatively by increasing an individual's ability to cope with the potential distress of trauma-focused therapeutic work. Conversely, the best augmentation approaches may work by reducing PTSD symptomology directly with a more low intensity form of therapy, which works twofold by first helping the individual engage with trauma-focused interventions and providing an additive effect by increasing overall symptom reduction. Understanding of the mechanisms of augmentation has significant potential to guide future research and increase treatment success for patients with PTSD. 2 | M ET H OD The findings of this review are reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA) statement. The research question was formulated using the population, intervention, comparison, and outcome (PICO) framework in order to structure, contain, and set the scope for the question (Moher, Liberati, Tetzlaff, & Altman, 2010). Full articles were retrieved for inclusion if they meet the following inclusion criteria: 1. The population was adults (mean age > 18) with diagnosed PTSD 2. The trial used a controlled trial methodology 3. At least two arms received the same first-line PTSD treatment, and at least one of those arms also received an augmentation intervention 4. An outcome measure was change in PTSD symptoms For the purpose of this review, augmentation was defined as any psychological, nonpsychological, or pharmacological intervention, delivered prior to, concurrently, or after a first-line PTSD treatment, where the focus of the augmentation was to improve PTSD symptoms and/or improve readiness for treatment, engagement, or retention in the first-line treatment. 2.1 | Search strategy This systematic review was conducted using the following databases for peer-reviewed literature published from inception to December 21, 2018: PsycINFO, EMBASE, PubMed, CINAHL, and Cochrane Central Register of Controlled Trials (CENTRAL). An example search strategy is provided in Supplementary Online Material. Given the diverse terminology currently used to describe studies in the augmentation literature, the above search strategy was constructed to be as broad as possible, ensuring all RCTs involving first-line PTSD treatments were captured. | 2.2 3 of 21 Data extraction Following full-text assessment, one reviewer extracted the data and another checked the data. Any disagreements about trial inclusion or exclusion were resolved by discussion with a third reviewer. Extracted data included population, trauma type, first-line treatment, augmentation approach, schedule, dosage, and outcomes. | 2.3 Quality assessment Trial quality and risk of bias was assessed using an NHMRC checklist (National Health & Medical Research Council, 1999). Trials were assessed according to method of treatment assignment, control of selection bias after treatment assignment, blinding procedures, and additional trial limitations. Two reviewers assessed individual trials for quality and risk of bias, and disagreements were resolved by discussion with a third reviewer. The overall certainty of the evidence base was assessed with GRADE (Grading of Recommendation, Assessment, Development and Evaluation; Guyatt et al., 2008). Using GRADE, randomized controlled trials are associated with high certainty evidence and adjusted using the following aspects: methodological limitations of the trials, indirectness of the evidence to the PICO question, imprecision of estimates, inconsistency of the evidence, and the likelihood of publication bias. A body of evidence is downgraded or upgraded to a final rating of high (i.e., further research is very unlikely to alter confidence in the estimate of effect), moderate, low, or very low (i.e., there are high levels of uncertainty about the estimate). 3 | RESULTS From a yield of 9,890 records (see Figure 1), 4,105 records were screened on title and abstract and 189 records were screened on full-text. Of these, 34 trials were eligible for inclusion, and all were RCTs. There was significant diversity in augmentation approach, with 28 different types of augmentation interventions included in the trials. The characteristics of each trial are included in Table 1. Overall, there were concerns with the quality of the trials. The RCTs generally had some methodological issues, with concerns around randomization and blinding methods. Details of the quality assessment can be found in Table 2. Due to the diversity of the outcome measures, the low number of trials for each directly comparable augmentation approach, and the sheer diversity of the 34 trials included, it was deemed unsuitable for data pooling and meta-analyses. Instead, a narrative synthesis of the quality of the evidence using | Identification METCALF ET AL. Records identified through database searching PsycINFO (n = 1639), EMBASE (n = 2308), CINAHL (n = 1054), PubMed (n = 2201), Central (n = 2688). n = 9890 Screening 4 of 21 Records screened on title and abstract (n = 4105) F I G U R E 1 PRISMA flowchart of search for studies. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses (www.prisma-statement.org) Duplicates removed (n = 5785) Included Eligibility Records excluded (n = 3916) Full-text articles assessed for eligibility (n = 189) Number of full-text articles included (n = 34) Full text articles excluded (n = 155) Wrong intervention (n = 58) Secondary analysis (not of interest; n = 53) Wrong patient population (n = 15) Wrong study design (n = 11) Not a peer reviewed paper (n = 7) Not in English (n = 7) Wrong outcomes (n = 4) GRADE was conducted (Murad, Mustafa, Schunemann, Sultan, & Santesso, 2017). The 28 augmentation interventions were grouped on the basis of the purported mechanism of augmentation, resulting in the following eight groups (see Table 3): global cognitive enhancers (n = 5 studies; transcutaneous electrical acupoint stimulation, acupoint stimulation, rTMS, CogSMART); specific cognitive enhancers (n = 6; cognitive restructuring, imagery rescripting, attention training, art therapy); emotional distress reducers (n = 4; breathing biofeedback; emotion regulation training; STAIR; stress inoculation training); fear extinction (n = 7; D-cycloserine; exercise; hydrocortisone; methylene blue; oxytocin; yohimbine); first-line psychological and/or pharmacological treatment combinations (i.e., “first-line combinations”; n = 6; CBT; paroxetine; PE; sertraline); pharmacological polytherapy (n = 2; risperidone; mirtazapine); sleep improvement (n = 2; imagery rehearsal therapy; sleep-directed hypnosis); and social rehabilitation (n = 2; trauma management therapy; behavioral family therapy). Only four of the augmentation interventions had more than one trial (cognitive restructuring; D-cycloserine; paroxetine; and rTMS). The remaining 24 of the augmentation interventions had a single RCT. Due to space limits, the outcomes of the GRADE assessments are detailed for the four augmentation interventions evaluated in more than one trial only, with a complete description of all augmentation interventions available in the Supplementary Material. Results for each study by mechanism are reported below. 3.1 3.1.1 | Global cognitive enhancers | rTMS Two RCTs investigated the efficacy of rTMS to augment firstline PTSD treatments (i.e., CPT/PE; Fryml et al., 2019; Kozel et al., 2018). An RCT (N = 103) of veterans with combat-related PTSD were randomized to receive CPT with sham rTMS or CPT plus 30-min sessions of rTMS delivered immediately prior to each CPT session (Kozel et al., 2018). Participants received 12 rTMS sessions in total. Treatment augmentation with rTMS led to significantly greater reductions on measures of PTSD symptoms during treatment, posttreatment, and at six-month follow-up (p ≤ .023, d ≥ 0.79) relative to no rTMS augmentation. Treatment dropout was 40.7% in the augmentation condition and 38.8% in the CPT alone condition. Three participants requested termination of rTMS due to adverse effects (two active and one sham). A second, very small RCT (N = 8) of veterans with combat-related PTSD randomized participants to receive PE alone, or PE concurrently with 30min sessions of rTMS (8 sessions total; Fryml et al., 2019). There was a 15% greater reduction in CAPS scores at session five in the augmentation condition, the only outcomes reported in the trial. The quality of the evidence for rTMS as an augmentation approach to first-line PTSD treatment was graded as “low” (serious quality issues, serious imprecision; see Table 2). We have low confidence based on current evidence that rTMS is an effective augmentation to first-line traumafocused interventions, on PTSD symptoms at posttreatment. Study Characteristics of the treatment augmentation trials for PTSD Population (N), trauma type First-line treatment Augmentation approach Schedule Dosage Secondary outcomes Study outcomes and adverse events Global cognitive enhancers Feng et al. (2019) Civilians (180), mixed CBT Two conditions: 1: TEAS 2: TEAS + sertraline Concurrent 25–100 mg sertraline; 12 sessions of 50Hz frequency with pulse width of 50 μs TEAS Self-reported PTSD symptoms; depression; clinical response; remission CBT + TEAS produced significant reductions in PTSD (p<.001−0.008, d = 0.48– 1.33); further improvements were seen in CBT + TEAS + sertraline (p < .001−0.050, d = 0.36–2.19). Both augmentation conditions had greater response and remission rates (p < .001). Completion rates were 78.3%, 88.3%, and 91.7% of participants in CBT alone, CBT + TEAS, and CBT + TEAS + sertraline, respectively. No severe adverse events reported, and overall incidence of events was greater in CBT + TEAS + sertraline (p < .001) Fryml et al. (2019) Veterans (8), war related PE rTMS Concurrent 8 × 30 min weekly sessions at 120% motor threshold, 10Hz, 5-s train duration, 10-s intertrain interval (6,000 pulses) Depression; anxiety; self-reported PTSD symptoms PE + rTMS produced significant reductions in symptoms of depression in the fourth and fifth PE sessions (p ≤ .013) and a 15% greater reduction in CAPS scores at session five Jak et al. (2019) Veterans with comorbid traumatic brain injury (101), unspecified CPT CogSMART + CPT Concurrent 12 × 60–75 min weekly sessions. Augmented treatment sessions lasted on average 13 min longer to accommodate hybrid elements Postconcussive symptom severity; quality of life; client satisfaction; neuropsychological functioning CogSMART + CPT produced no additional benefit for PTSD, postconcussive symptom severity, or quality of life (p > .050), but greater improvement on measures of neuropsychological functioning (p = .006−0.022, r = 0.24−0.33). Dropout was 43% and 51% in CogSmart + CPT and CPT, respectively (p = .548) Kozel et al. (2018) Veterans (103), combat related CPT rTMS Concurrent (prior to each CPT session) 12 × 30 min weekly sessions at 110% motor threshold, 1Hz, continuously (1,800 pulses) Self-reported PTSD symptoms; depression; psychosocial functioning rTMS + CPT had greater reductions in PTSD symptoms during, post, and at six-month follow-up (p ≤ .023, d ≥ 0.79). There were no differences on other measures (p ≥ .180, d ≤ 0.37). Treatment dropout was 40.7% in CPT + rTMS; 38.8% in the CPT. Three participants terminated rTMS due to adverse effects METCALF ET AL. TABLE 1 | 5 of 21 (Continues) Zhang et al. (2011) (Continued) Population (N), trauma type First-line treatment Augmentation approach Schedule Dosage Secondary outcomes Civilians (91), natural disaster CBT Acupoint stimulation Concurrent 50 Hz × 30 min “every other day” for 1 week - Both conditions reduced in PTSD symptoms (p < .010), with greater reductions in the augmentation condition (p < .050) | Study 6 of 21 TABLE 1 Study outcomes and adverse events Specific cognitive enhancers Arntz et al. (2007) Civilians (71), mixed IE Imagery rescripting (IR) Concurrent 5 × 60 min weekly sessions (within 9 × 90 min weekly sessions of therapy) Hostility; anger; guilt; shame; anxiety There was no difference in PTSD symptom reduction between conditions in completer and ITT analyses (p > .050). Improvements in anger, hostility, and guilt were seen in PE + IR. Dropout was greater in IE alone (51% vs. 25%, p = .031) Bryant et al. (2003) Civilians (40), nonsexual assault of motor vehicle accident IE Cognitive restructuring (CR) Concurrent 6 × 25 min weekly sessions (within 8 × 90 min weekly sessions of IE) Anxiety; depression; catastrophic cognitions In completer analysis, participants in IE + CR scored lower on measures of PTSD intrusion symptoms (p < .010) and depression (p < .050) at posttreatment, and on PTSD overall (p < .050) and catastrophic cognitions (p < .050) at 6-month follow-up. In ITT analysis, IE + CR had lower PTSD symptoms (p < .050) at 6-m follow-up. In IE + CR, 40% recorded good end-state functioning (15% in IE alone; p < .070). Dropout was 25% for both conditions Campbell, Decker, Kruk, & Deaver, (2016) Male veterans (11), combat related CPT Art therapy Concurrent (component of residential treatment program) 8 × 75 min sessions Treatment satisfaction; interview content analysis; participant artwork There were significant reductions in PTSD and depression, but no differences between conditions (p > .050). Dropout was higher in the CPT alone condition (40%) than CPT + Art (0%) Foa et al. (2005) Civilian women (153), sexual or nonsexual assault. PE Cognitive restructuring (CR) Concurrent 15- to 25-min weekly sessions (within 9–12 × 90–120 min weekly sessions of PE) Depression; social adjustment; selfreported PTSD symptoms There were no significant differences between conditions in completer or ITT analyses. Twelve serious adverse events resulted in withdrawal from the study METCALF ET AL. (Continues) (Continued) Population (N), trauma type First-line treatment Augmentation approach Kuckertz et al. (2014) Active duty military members (37), unspecified PE or CPT + psychopharmacology for immediate symptom management Marks et al. (1998) Civilians (47), mixed Study Secondary outcomes Schedule Dosage Study outcomes and adverse events Attention training Concurrent (optional as part of inpatient care) 14 × 384 trial sessions completed on consecutive days (though variability was allowed) Attentional bias Significant reductions in PTSD and depression symptoms were observed for both groups, although the effects were larger in the augmentation condition (p < .001, d = 3.17 vs. p = .002, d = 1.81 and p = .003, d = 3.03 vs. p = .002, d = 2.03, respectively). There was a significant reduction in attention bias variability in the attention training group (p = .040, d = 0.68). All dropouts (21.6%) were in the attention training group PE Cognitive restructuring (CR) Concurrent 10 × 45 min weekly sessions (within 10 × 105 min weekly sessions of PE) Self-reported PTSD symptoms; depression; anxiety, general health; social and occupational adjustment There were no additional improvements with PE + CR compared with PE alone. Thirteen percent of participants in PE alone and 20.8% in PE + CR dropped out METCALF ET AL. TABLE 1 Emotional distress reducers Bryant et al. (2013) Civilians (70), motor vehicle accident and assault CBT Emotional regulation training (ERT) Prior 4 × 90 min weekly sessions Anxiety; depression; distress; posttraumatic cognitions; treatment credibility PTSD symptoms were reduced in CBT + ERT at six-month follow-up in the ITT analysis (p < .001, d = 0.43). Improvements in anxiety, posttraumatic cognitions, and intrusions (p ≤ .010, d = 0.19–0.77) were also reported in CBT + ERT. Three adverse effects leading to dropout were reported (two in CBT). About 73% of participants completed treatment Cloitre et al. (2010) Civilian women (66), childhood sexual or physical abuse Modified PE STAIR Prior 8 × weekly sessions Depression; anxiety; anger expression; social support PTSD remission was greater in PE + STAIR posttreatment (p = .040, OR = 5.67), and at three-month (p = .010, OR = 4.23) and 6-month (p < .001, OR > 10) follow-up. Self-reported interpersonal problems were also lower in PE + STAIR at three-month (p = .010, d = 0.63) and 6-month (p = .003, d = 0.77) follow-up. Dropout was less in PE + STAIR (15.2% vs. 39.4%, p = .030), and fewer adverse events (p = .006) | 7 of 21 (Continues) (Continued) First-line treatment Augmentation approach Foa et al. (1999) Civilian women (55), sexual or nonsexual assault PE Rosaura Polak et al. (2015) Civilians (8), mixed de Kleine et al. (2012) Secondary outcomes | Population (N), trauma type Study 8 of 21 TABLE 1 Schedule Dosage Study outcomes and adverse events Stress inoculation training (SIT) Concurrent 2 × 120 then 7 × 90 min twice weekly sessions Depression; anxiety PE alone recorded greater reductions in self-reported anxiety (p < .010) and depression (p < .025), but not PTSD (p = .110) in ITT analysis; with greater reduction in self-reported anxiety in completer analysis (p < .050). Dropouts were PE + SIT (27%); PE alone (8%) Trauma focussed CBT Breathing biofeedback Concurrent Administered during therapy “hotspots” from session 3 onwards - PTSD symptoms reduced for both conditions (p < .001), but did not differ between conditions (p = .061) Civilians (75), mixed PE D-Cycloserine Concurrent (administered 1 hr before each exposure session) 50 mg Anxiety; depression; general psychopathology No difference in PTSD symptoms between conditions; those in augmentation condition were more likely to show treatment response posttreatment (p = .040, OR = 2.83). Dropout did not differ significantly. One participant from each condition was excluded due to adverse effects Flanagan, Sippel, Wahlquist, MoranSanta Maria, & Back, (2018) Civilians (17), mixed PE Intranasal oxytocin Concurrent (45 min prior to each weekly PE session) 40 International Units (IU) of intranasal spray Self-reported PTSD symptoms; depression; treatment feasibility; and acceptability No significant differences between conditions (p > .050). Dropout was 25% in PE + oxytocin and 22.2% in PE alone. One adverse event was reported in PE alone Litz et al. (2012) Male veterans (26), combat-related PE D-Cycloserine Concurrent 50 mg 30 min prior to the start of imaginal exposure in sessions 2–5 Self-reported PTSD symptoms; depression The augmentation condition performed significantly worse on measures of PTSD and depression at posttreatment (p < .05, g = 0.40–0.73). There were no significant effects at three- or six-month follow-up (p > .100). Treatment dropout was 15.4% in PE alone and 30.8% for PE + DCS. Three participants from the augmentation condition reported clinically significant symptom worsening Fear extinction METCALF ET AL. (Continues) (Continued) Population (N), trauma type First-line treatment Augmentation approach Schedule Dosage Powers et al. (2015) Civilians (9), unspecified PE Exercise Concurrent 30 min of moderate intensity exercise immediately prior to PE sessions - PTSD symptom reduction and brain-derived neurotrophic factor (BDNF) increase were both greater in the augmentation condition (between-groups effect sizes: d = 2.65 and d = 1.08, respectively) Tuerk et al. (2018) Male veterans (26), combat related PE Yohimbine 1 hr prior to first imaginal exposure session (session 3 of PE) 26.1 mg one-time oral dose Self-reported/ clinical interview PTSD symptoms; depression; subjective distress; heart rate; and blood pressure No differences between conditions in PTSD symptom reduction, remission rate, or depression. Participants in the augmentation condition experienced increased heart rate (p < .040), systolic blood pressure (p = .020), and subjective distress (p = .001). Traumacued heart rate reactivity was lower in the augmentation condition (p < .001, d = 0.25). Treatment dropout was 33.3% in PE alone and 35.7% in the augmentation condition. One participant in the augmentation condition administered rescue medication before the session Yehuda et al. (2015) Veterans (24), mixed PE Hydrocortisone Concurrent (delivered 20 min prior to sessions 3–10 of PE) 30 mg ingested orally Self-reported PTSD symptoms; depression PTSD symptoms change was greater for the augmentation condition (p < .050, d = 0.43); no differences between conditions posttreatment. Dropout was less in the augmentation condition (8.3% vs. 58.3%, p = .027) Zoellner et al. (2017) Civilians (31), mixed IE Methylene blue Concurrent (after IE sessions 2–6) 260 mg dose Depression; trauma related negative beliefs; disability; quality of life The augmentation condition did not differ significantly from IE alone on measures of PTSD severity or diagnosis, depression, negative beliefs, disability, or quality of life (physical vitality) at three-month followup (d = 0.05–0.46). Quality of life (mental health) was greater in the augmentation condition (p = .020, d = 0.58). One participant in the augmentation condition was discontinued due to adverse events. Dropout rate was 33.3% in the augmentation condition and 6.3% in IE alone Study Secondary outcomes Study outcomes and adverse events METCALF ET AL. TABLE 1 First-line combination | 9 of 21 (Continues) 10 of 21 TABLE 1 (Continued) Augmentation approach Schedule Dosage Secondary outcomes Otto et al. (2003) Refugee women (10), Cambodian genocide. Sertraline CBT Concurrent 10 sessions (unspecified duration) Depression; anxiety; and somatisation The augmentation condition recorded improvements in symptoms of PTSD, anxiety, and somatisation relative to controls (d = 0.45–1.77) Popiel et al. (2015) Civilians (228), motor vehicle accident Two conditions: 1: PE 2: Paroxetine PE + Paroxetine Concurrent 10–12 × 90 min weekly sessions of PE; 20 mg/ day of drug Depression All conditions improved significantly in selfreported PTSD symptoms, and improvements were maintained at twelve-month follow-up. Refusal to begin therapy was higher in the augmentation condition (31.6%) than PE alone (4.3%) (p < .010), but not significantly less than paroxetine alone (47.4%) (p = .090). Dropout was 12.2%, 18.4%, and 22.8% in the paroxetine alone, PE alone, and augmentation conditions, respectively Rauch et al. (2019) Veterans (223), combat related Two conditions: 1: PE 2: Sertraline PE + Sertraline Concurrent 50−200 mg/day of sertraline; 13 × 90 min PE sessions Self-reported PTSD; clinically meaningful change; response; remission PTSD significantly improved for all conditions (p < .001); with no differences in PTSD symptom reduction (p ≥ .050), response rates (p = .360), or remission rates (p = .180). Treatment adherence was highest in the sertraline alone condition (73.2%), followed by the augmentation condition (53.6%) and PE alone (46.3%) (p = .005) Rothbaum et al. (2006) Civilians (65), mixed. Sertraline PE Post 10 × 90–120 min twice weekly sessions Depression; anxiety There was no difference between conditions in PTSD symptom reduction, depression, or anxiety at any time point (p > .050). Treatment dropout was numerically higher in the augmentation condition (18%) than in sertraline alone (3%) (p > .050) Schneier et al. (2012) Civilians (37), terrorist attack PE Paroxetine Concurrent Maximum dose of 50 mg/ day Treatment response; depression; quality of life and satisfaction Participants in the augmentation condition had greater improvement in PTSD symptoms (p = .010), rate of remission (42.1% vs. 16.7%, p = .030), response rate (63.2% vs. 38.9%, p = .040), and quality of life (p = .020). Treatment dropout was 31.6% in the augmentation condition and 27.8% in PE alone Study outcomes and adverse events (Continues) METCALF ET AL. First-line treatment | Population (N), trauma type Study Study Simon et al. (2008) METCALF ET AL. TABLE 1 (Continued) Population (N), trauma type First-line treatment Augmentation approach Schedule Dosage Secondary outcomes Civilians (25), mixed PE Paroxetine Concurrent 12.5–62.5 mg/day - There were no differences between conditions for PTSD symptoms or illness severity or improvement (p > .050, d = 0.20–0.35). Remission rates were 14% for PE alone and 33% for the augmentation condition (p = .343). Treatment dropout was 27.3% in the augmentation condition and 14.3% in PE alone. Three adverse events lead to study discontinuation (one from the augmentation condition) Study outcomes and adverse events Pharmacotherapy polytherapy Rothbaum et al. (2008) Civilians (25), mixed Sertraline Risperidone Concurrent Titrated to maximum 3 mg/day Depression; schizophrenia; symptom severity PTSD symptoms improved in both conditions with no difference between conditions (p = .800). Five participants (20%) withdrew from the study, all of which were in the augmentation condition and four of which were due to adverse events likely to be study related Schneier et al. (2012) Civilians (36), mixed. Sertraline Mirtazapine Concurrent 15−45 mg/day Remission and response rate; depression; selfreported PTSD symptoms; sleep quality; sexual function; quality of life; and overall functioning There was no difference between conditions in PTSD symptoms (p = .170, d = 0.51), although remission rate was higher in the augmentation condition (39% vs. 11%, p = .042). Depression symptoms improved more in the augmentation condition (p = .023, d = −0.63). Treatment dropout was 66% in the augmentation condition and 85% in sertraline alone. Treatment was discontinued due to adverse events in ten participants (four in augmentation condition) (Continues) | 11 of 21 (Continued) Population (N), trauma type First-line treatment Augmentation approach Schedule Dosage Secondary outcomes Study outcomes and adverse events | Study 12 of 21 TABLE 1 Sleep improvement Belleville et al. (2018) Civilians (42), sexual assault. CBT Imagery rehearsal therapy (IRT) Prior 5 × 60 min weekly sessions Functional impairment; quality of life The augmentation condition reported reduced sleep impairments over the course of IRT (d = 0.72–1.13), but no significant differences between conditions post-CBT treatment (p = .098−0.257, d = 0.45–0.63). There were no differences in PTSD symptom reduction, functional impairment, or quality of life between conditions following CBT (p > .050). Treatment dropout was 12.7% and 26.7% in the augmentation and CBT alone conditions, respectively Galovski et al. (2016) Civilian females (108), sexual, or physical assault. CPT Sleep-directed hypnosis Prior 3 × 60 min weekly sessions Sleep quality Participants in the augmentation condition recorded significant improvements in sleep and depression following the sleep intervention relative to CPT alone (p < .050). These differences were not present at three-month follow-up. There were no differences between conditions for PTSD symptoms or treatment dropout (40.9% augmentation vs. 47.9% CPT alone, p = .499) Social rehabilitation Beidel et al. (2011) Male veterans (35), combat related. PE Trauma management therapy Post 14 × 90 min weekly or biweekly sessions Secondary psychological symptoms; treatment credibility; patient satisfaction There were no differences in PTSD symptom reduction, but greater self-reported social engagement in the augmentation condition (p < .025). Treatment dropout was 14.3% across both conditions Glynn et al. (1999) Male veterans (29), combat related. Directed therapeutic exposure Behavioral family therapy Post 16 × 60 min sessions (offered on declining contact basis) Social problem-solving Augmentation had no effect on PTSD symptoms or social adjustment. Dropout was higher in the augmentation condition (p < .010), with 35% withdrawing before beginning. Nine hospital inpatient admissions occurred during the study (seven from the augmentation condition) METCALF ET AL. Abbreviations: CBT, Cognitive behavioral therapy; CogSMART, Cognitive Symptom Management and Rehabilitation Therapy; CPT, cognitive processing therapy; IE, imaginal exposure; PE, prolonged exposure; rTMS, repetitive transcranial magnetic stimulation; STAIR, Skills Training in Affect and Interpersonal Regulation; TEAS, transcutaneous electrical acupoint stimulation. Quality and bias outcomes Augmentation approach Study Design Treatment Assignment Control of Selection Bias Blinding Outcome Assessment Feng et al. (2019) RCT Y Y Y Y Cognitive enhancement - global TEAS; sertraline rTMS Fryml et al. (2019) RCT Y N Y Y CogSMART Jak et al. (2019) RCT Y Y Y Y rTMS Kozel et al. (2018) RCT Y Y Y Y Acupoint stimulation Zhang et al. (2011) RCT N N N Y Imagery rescripting Arntz et al. (2007) RCT N Y N Y Cognitive restructuring Bryant et al. (2003) RCT Y Y Y Y Art therapy Campbell et al. (2016) RCT Y N N Y Cognitive restructuring Foa et al. (2005) RCT Y Y Y Y Attention training Kuckertz et al. (2014) RCT N N Y Y Cognitive restructuring Marks et al. (1998) RCT Y Y Y Y Emotional regulation training Bryant et al. (2013) RCT Y Y Y Y STAIR Cloitre et al. (2010) RCT Y Y Y Y Stress inoculation training Foa et al. (1999) RCT Y Y Y Y Breathing biofeedback Rosaura Polak et al. (2015) RCT N N N Y Yohimbine Tuerk et al. (2018) RCT Y Y Y Y D-Cycloserine de Kleine et al. (2012) RCT Y Y Y Y Oxytocin Flanagan et al. (2018) RCT Y N Y Y D-Cycloserine Litz et al. (2012) RCT Y Y Y Y METCALF ET AL. TABLE 2 Cognitive enhancement – specific Emotional distress Fear extinction | 13 of 21 (Continues) 14 of 21 TABLE 2 (Continued) Design Treatment Assignment Control of Selection Bias Blinding Outcome Assessment Exercise Powers et al. (2015) RCT Y N Y Y Hydrocortisone Yehuda et al. (2015) RCT Y Y Y Y Methylene blue Zoellner et al. (2017) RCT Y Y Y Y | Study Augmentation approach First-line combination CBT Otto et al. (2003) RCT N N N Y Paroxetine Popiel et al. (2015) RCT Y Y Y Y Sertraline Rauch et al. (2019) RCT Y Y Y Y Prolonged exposure Rothbaum et al. (2006) RCT N N Y Y Paroxetine Schneier et al. (2012) RCT Y Y Y Y Paroxetine Simon et al. (2008) RCT N Y Y Y Risperidone Rothbaum et al. (2008) RCT N Y Y Y Mirtazapine Schneier et al. (2012) RCT Y Y Y Y Imagery rehearsal therapy Belleville et al. (2018) RCT Y Y N Y Sleep-directed hypnosis Galovski et al. (2016) RCT Y Y Y Y Trauma management therapy Beidel et al. (2011) RCT N N Y Y Behavioral family therapy Glynn et al. (1999) RCT Y N Y Y Pharmacotherapy Sleep impairment Social rehabilitation METCALF ET AL. Abbreviations: CBT, cognitive behavioral therapy; CogSMART, Cognitive Symptom Management and Rehabilitation Therapy; N, poor quality/high risk of bias; RCT, randomized controlled trial; rTMS, repetitive transcranial magnetic stimulation; STAIR, Skills Training in Affect and Interpersonal Regulation; TEAS, transcutaneous electrical acupoint stimulation; Y, high quality/low risk of bias. | METCALF ET AL. TABLE 3 Augmentation intervention mechanisms Mechanism Purported therapeutic outcome Global cognitive enhancers Improving overall cognitive/neurological functioning, such as increased executive control or neuroplasticity Specific cognitive enhancers Improving particular aspects of cognition related to trauma, such as attention bias or accessing the trauma memory Emotional distress reduction Reducing the distress that often accompanies trauma-focused treatment work Fear extinction Improving or speeding up the fear extinction process of PE First-line combinations Combining a first-line pharmacological or psychological treatment with another Pharmaco-polytherapy Combining a novel pharmacological treatment with a first-line pharmacological treatment Sleep improvement Improving sleep deficits common in PTSD Social rehabilitation Improving social functioning, commonly impaired in PTSD The remaining augmentation interventions in the global cognitive enhancement group had a single study and were rated as follows: transcutaneous electrical acupoint stimulation received a GRADE rating of low certainty, and acupoint stimulation and CogSMART both received a very low rating. 3.2 3.2.1 | Specific cognitive enhancers | 15 of 21 cognitive restructuring as an augmentation approach to PE was graded as “moderate” (serious imprecision). We have moderate confidence that there is no effect for cognitive restructuring as an augmentation to first-line PTSD treatment, on PTSD symptoms at posttreatment. The remaining augmentation interventions in the specific cognitive enhancement group had a single study and were rated as follows: attention training, art therapy, and imagery rescripting all received a GRADE rating of very low certainty. Cognitive restructuring Three RCTs investigated the efficacy of cognitive restructuring to augment first-line PTSD treatments (i.e., PE/IE) (Bryant, Moulds, Guthrie, Dang, & Nixon, 2003; Foa et al., 2005; Marks, Lovell, Noshirvani, Livanou, & Thrasher, 1998). A large RCT (N = 179) of females with trauma related to sexual or nonsexual assault were randomized to receive PE alone or PE with cognitive restructuring concurrently (Foa et al., 2005). There were no significant differences between conditions in completer or ITT analyses for PTSD or depression. Two smaller RCTs compared imaginal exposure (IE) alone to IE with cognitive restructuring (n = 40; Bryant et al., 2003) and PE alone to PE with cognitive restructuring (n = 47; Marks et al., 1998). The first RCT found mostly no effect, with significant reductions in measures of depression and PTSD intrusions only for completers in the augmentation condition. Treatment dropout was 25% for both conditions. The second RCT found no additional improvements in the augmentation condition compared with PE alone. In addition, 13% of participants in PE alone and 21% in the augmentation condition dropped out of treatment. The quality of the evidence for 3.3 | Emotional distress reduction The four augmentation interventions in the emotional distress reduction mechanism group each had a single study and were rated as follows: emotion regulation training and stress inoculation training received a GRADE rating of low, while breathing biofeedback and STAIR received a GRADE rating of very low. 3.4 3.4.1 | Fear extinction | D-cycloserine Two RCTs investigated the efficacy of D-cycloserine to augment first-line PTSD treatments (i.e., PE) (de Kleine et al., 2012; Litz et al., 2012). An RCT (N = 67) of males and females with various trauma types were randomized to receive PE alone or PE with 50mg D-cycloserine one hour prior to each PE session (de Kleine et al., 2012). There were no significant differences between conditions in completer | 16 of 21 METCALF ET AL. or ITT analyses for PTSD. A smaller RCT (N = 26) of male veterans with combat-related PTSD were randomized to receive PE alone or PE with 50 mg of D-cycloserine 30 min prior to sessions 2–5 of the PE protocol (Litz et al., 2012). The augmentation condition performed significantly worse on measures of PTSD and depression at posttreatment (p < .05, g = 0.40–0.73). There were no significant effects at three- or six-month follow-up (p > .100). Treatment dropout was 15.4% for the PE alone condition and 30.8% for the augmentation condition. The quality of the evidence for D-cycloserine as an augmentation approach to PE was graded as “moderate” (serious imprecision). Thus, we have moderate confidence that there is no effect for D-cycloserine as an augmentation to first-line PTSD treatment, on PTSD symptoms at posttreatment. The remaining five augmentation interventions in the fear extinction group had a single study each and were rated as follows: hydrocortisone, methylene blue, yohimbine, exercise, and oxytocin all received a GRADE rating of very low. 3.5 3.5.1 | First-line combination | Paroxetine Three RCTs investigated the efficacy of paroxetine to augment first-line PTSD treatments (i.e., PE; Popiel, Zawadzki, Praglowska, & Teichman, 2015; Schneier et al., 2012; Simon et al., 2008). Paroxetine is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class and is itself recognized as a first-line treatment for PTSD in international guidelines (e.g., NICE, 2018). A large, three-arm RCT (N = 228) of male and female motor vehicle accident survivors were randomized to receive PE alone, 20 mg/day of paroxetine alone, or PE concurrently with 20 mg/day of paroxetine (Popiel et al., 2015). PTSD remission rate in the augmentation condition (51.2%) did not differ from paroxetine alone (43.3%, p = .510) or PE alone (65.4%, p = .110) in ITT analyses. Similar results were observed for self-rated PTSD symptoms in both completer and ITT analyses. Of those who did begin treatment, 12.2%, 18.4%, and 22.8% dropped out of the paroxetine alone, PE alone, and augmentation conditions, respectively. Two smaller RCTs of 37 survivors of the World Trade Center's attack (Schneier et al., 2012) and 25 treatment-refractory individuals with mixed trauma types (Simon et al., 2008) randomized participants to receive PE alone or PE concurrently with paroxetine. In the first RCT, participants in the augmentation condition had a significantly greater improvement in PTSD symptoms (p = .010) and a significantly greater rate of remission (42.1% vs. 16.7%, p = .030). In the second RCT, participants who remained symptomatic after eight sessions of PE were randomly assigned to an augmentation phase of the study, in which an additional five PE sessions were delivered with or without paroxetine. There were no significant differences between conditions for PTSD symptoms or illness severity or improvement (p > .050, d = 0.20–0.35). Remission rates were 14% for the PE alone condition and 33% for the augmentation condition (p = .343). The quality of the evidence for paroxetine as an augmentation approach to PE was graded as “very low” (serious quality issues, serious imprecision, serious inconsistency, and serious publication bias). We have low confidence that paroxetine is an effective augmentation to first-line PTSD treatment. The remaining three first-line combination augmentation interventions had a single study and were rated as follows: sertraline received a GRADE rating of low, and CBT and PE received a GRADE rating of very low. | 3.6 Pharmaco-polytherapy The two augmentation interventions in the pharmaco-polytherapy group had a single study and were rated as follows: mirtazapine and risperidone both received a GRADE rating of very low. | 3.7 Sleep improvement The two augmentation interventions in the sleep improvement group had a single study and were rated as follows: sleep-directed hypnosis received a GRADE rating of low while imagery rehearsal therapy received a GRADE rating of very low. | 3.8 Social rehabilitation The two augmentation interventions in the social rehabilitation group had a single study and were rated as follows: trauma management therapy and behavioral family therapy both received a GRADE rating of very low. 4 | DISCUSSION Although several recommended first-line treatments for PTSD exist, a significant minority of participants do not respond or remit following treatment, leading to significant interest in approaches to improve outcomes via augmentation. The aim of this systematic review was to assess the evidence for interventions that augment first-line PTSD treatments. A METCALF ET AL. total of 34 studies were eligible for inclusion with significant diversity among them. Many studies used varying terms to describe augmentation, indicating a need for uniformity in terminology in the field. Future studies should use the word augmentation to ensure consistency. Of the reviewed studies, 28 different types of augmentation interventions were identified, which fit broadly into eight categories based on the hypothesized mechanism of action to improve treatment outcomes (see Table 3). Four types of augmentation interventions (cognitive restructuring; D-cycloserine; rTMS; and paroxetine) had more than a single study, and a GRADE ranking was undertaken. The GRADE ranking indicated that we have moderate certainty that D-cycloserine is ineffective as an augmentation of first-line interventions for PTSD, with a small RCT indicating that it may be potentially harmful. The GRADE ranking indicated that we have moderate certainty that there is no effect for cognitive restructuring as an augmentation to first-line PTSD treatment. rTMS and paroxetine had a low and very low certainty of evidence, respectively, meaning we have little confidence that the observed effects are “true effects” of the treatment. The remaining 24 types of augmentation interventions were rated as low or very low. The results were surprising and counterintuitive to clinical and research common sense in a number of ways. The number of null findings in the studies reviewed here was significant, with 86% of the studies reporting no significant additional effect of the augmentation intervention on PTSD symptoms at posttreatment relative to the first-line treatment alone. In part, some of these findings may be due to the nature of augmentation, in that first-line treatments are effective at reducing PTSD symptoms, reducing the overall variance required to detect significant improvement. In particular, the augmentation mechanism of combining a first-line psychological treatment with a recommended pharmacotherapy provided no further benefit. Six studies combined a first-line trauma-focused psychological intervention (CPT; n = 1; or PE; n = 5), with a first-line pharmacotherapy. Four of the five studies combining PE with pharmacotherapy reported null findings. The sixth study, CPT augmented with sertraline, was a very small RCT. The overall pattern of findings indicates a poor potential for improvement associated with a combination of first-line trauma-focused psychological interventions augmented with first-line pharmacotherapy, and vice versa, for PTSD. Secondly, this review indicated that regardless of the mechanism approach taken, the addition of elements from other psychological therapies such as cognitive restructuring, imagery rescripting, or stress inoculation training to first-line psychological interventions such as PE provided no additional benefit, and in some instances, worsened PTSD outcomes relative to the first-line intervention alone. A | 17 of 21 potential explanation is that such augmentation approaches are disadvantageous because they are excessively demanding on participant's cognitive and emotional resources, which are already taxed from most first-line psychological interventions (Bryant et al., 2003; Foa et al., 1999). Another potential consideration is that, in order to keep total treatment time matched in an RCT protocol, the augmentation condition may receive less active first-line psychological treatment components being delivered to account for the time taken to deliver the other psychological therapy elements, reducing the dose of the first-line treatment (Marks et al., 1998). Finally, all trauma-focused interventions may work by essentially targeting the same dysfunctional cognitions, which means that the elements from other cognitive behavioral based therapies may be too similar to result in any additional meaningful change from the original trauma-focused interventions (Foa et al., 2005). A further interesting finding in this review is that all six of the studies that targeted fear extinction with a pharmacological approach (i.e., D-cycloserine; hydrocortisone; intranasal oxytocin; methylene blue; and yohimbine) in combination with PE either worsened PTSD outcomes or showed no benefit relative to PE alone. The pattern of results across these diverse interventions casts doubt on the value of pharmacological approaches to augment fear extinction in conjunction with PE. One explanation may be the timing of the augmentation approach relative to the progression in PE. If given too early, a pharmacological fear extinction intervention may simply consolidate or enhance the fear memory itself, perhaps via a stress interaction (Giustino & Maren, 2018), whereas later on in the PE protocol it may target fear extinction and consolidation of new memories (Litz et al., 2012). Interestingly, the only fear extinction approach that showed positive findings was a nonpharmacological approach (exercise), which works via increasing BDNF in a more indirect manner (Powers et al., 2015). Positive results were shown primarily in the augmentation mechanism of general cognitive enhancers (i.e., the goal is to improve general cognitive function, such as executive functioning or neuroplasticity). Many of these approaches, such as acupoint stimulation and rTMS, require little cognitive effort on behalf of the participant, which may partially account for their efficacy when paired with a cognitively intense trauma-focused intervention. Although the GRADE certainty rating for rTMS was low, this was due primarily to the low overall sample size of the two RCTs, and another large-scale, well-conducted RCT showing positive results would likely be sufficient to result in a moderate GRADE rating to support this augmentation approach. Overall, the patterns of findings across the studies may also be explained by ceiling effects, in the cases where the augmentation approach is too similar to the first-line intervention, or acts on the same underlying mechanism. Ceiling | 18 of 21 METCALF ET AL. effects may explain the limited success with studies employing PE and fear extinction techniques, as PE itself targets fear extinction with a high degree of success. Comparably, ceiling effects may apply when the augmentation approach adds elements of established psychotherapies (e.g., cognitive restructuring) to other cognitive-based interventions or delivers two medications (e.g., Rothbaum et al., 2008). Ceiling effects are unlikely to apply to global cognitive enhancers, further supporting this augmentation approach, and other augmentation approaches that target differing mechanisms evident in PTSD beyond fear extinction. A final critical issue is that PTSD in some populations (such as military veterans and first responders where there is an accumulation of exposure) may have a series of stages ranging from subsyndromal, through recent onset, to a chronic state with multiple comorbidities. The treatment trials to date do not consider the probability of different responses or augmentation effects during the different stages of the disorder. Hence, this may account for the lack of apparent benefits of many of the treatments reviewed (McFarlane et al., 2017). 5 5.1 | CO NC LU S ION | Future directions Given that the majority of augmentation approaches reviewed were implemented in a single study only, more well-designed research trials are needed before clear recommendations can be made regarding their efficacy. In particular, for the few augmentation interventions that indicated potentially positive findings, such as rTMS, acupuncture-based approaches, and exercise, large-scale RCTs should be conducted to confirm their efficacy. Experimental and mechanistic work should continue to focus on key mechanisms of PTSD eligible for augmentation, such as cognitive biases and memory (Foa et al., 2005), as well as the timing of fear extinction approaches. Researchers should consider the potential for ceiling effects and dilution of efficacy of first-line treatments when developing future augmentation interventions. Furthermore, trials should focus on identifying residual symptoms which are common even in those who are substantially assisted by treatment. Not all symptoms of PTSD are equally responsive to particular interventions (Larsen, Fleming, & Resick, 2019; Schnurr & Lunney, 2019), and research is needed on variables that predict treatment resistance such as duration of illness and types of neurobiological dysregulation (McFarlane, 2019). Although some studies reviewed here used comprehensive outcome measures, all future augmentation studies should use measures of readiness for psychotherapy, treatment retention, and speed of response rates. In the absence of a significant additive effect on PTSD symptoms, an augmentation approach may nevertheless have meaningful impacts on engagement, response, and retention. Alternatively, while some augmentation approaches are no more effective at reducing global measures of PTSD symptoms, they may lead to improvements in the target of the augmentation specifically, which correspond to comorbid difficulties with PTSD (e.g., attentional bias, sleep impairments, cognitive functioning; see Beidel, Frueh, Uhde, Wong, & Mentrikoski, 2011; Belleville, Dubé-Frenette, & Rousseau, 2018; Galovski et al., 2016), and are a treatment priority for patients. Personalized medicine developments, such as machine learning techniques, will provide insights into subgroups of individuals who may benefit most from an augmentation strategy that targets associated difficulties in PTSD (Lebois, Seligowski, Wolff, Hill, & Ressler, 2019). Such approaches will also support the individualization of PTSD augmentation approaches. The emerging research reviewed here discourages a one-size-fits-all approach to certain augmentation approaches (Litz et al., 2012). For example, in some studies the augmentation was only effective in those with more severe symptoms (e.g., de Kleine et al., 2012; Rothbaum et al., 2006; Yehuda et al., 2015) and may be suitable for those with refractory symptoms. The future studies that uncover these nuances will yield critical information needed to improve clinical decision algorithms and treatment outcomes for PTSD sufferers (Forbes et al., 2019; Marshall & Cloitre, 2000). Finally, while outside the scope of the current review, a crucial element that warrants evaluation is the method by which treatment outcomes are assessed and treatment response is defined. This is a point of considerable variability in PTSD research, with the potential to significantly alter interpretation of findings and therefore treatment recommendations. 5.2 | Limitations This review was limited in several ways. Firstly, the diversity of augmentation approaches covered in the reviewed literature prevented conducting a meta-analysis. As augmentation approaches increase in popularity, a meta-analysis update in coming years will be more feasible. Secondly, the lack of independent replications for the majority of the augmentation approaches limits the ability to make judgements about their efficacy. Thirdly, although including only RCTs of first-line treatments ensures a higher quality of evidence, it meant that much of the PTSD treatment augmentation literature that pairs a second-line or emerging PTSD treatment with an augmentation approach is yet to be systematically reviewed. Doing so would undoubtedly provide additional useful information to guide future research and clinical practice in particular, where augmentation of | METCALF ET AL. treatments proliferates. Fourthly, although the distinction between augmentation and dismantling studies was made in consultation with clinical experts, it may nevertheless be subject to debate as no unifying definition of augmentation currently exists. 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