Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that develops in approximately 10% of all people exposed to trauma, with exact prevalence depending on trauma type (eg, higher odds on interpersonal violence compared to natural disasters).1 Exposure to at least one traumatic event (defined as exposure to actual or threatened death, serious injury, or sexual violence) occurs in 70% of the general population.1 Consequently, PTSD is a common mental health problem. PTSD may be diagnosed if symptoms of reexperiencing, avoidance, negative alterations in affect and cognition, and hyperarousal and hyperreactivity symptoms are present for at least 1 month.2 Because traumatic events are the point of reference for PTSD symptom onset, the first hours to weeks posttrauma provide a window of opportunity for preventive interventions. Prevention is highly relevant, as many patients do not seek treatment, resulting in high risk of chronicity.3
People exposed to trauma often require medical evaluation due to (suspected) injuries or life-threatening medical conditions. Acute care settings (eg, emergency department [ED], intensive care unit [ICU]) may be places to identify and preventively treat people recently exposed to trauma. Pharmacological preventive interventions are usually less time-consuming and more readily and easily applicable in clinical practice compared to nonpharmacological interventions. In addition, pharmacotherapy may specifically target biological risk factors etiologically involved in PTSD development. For in-depth background information on hypothesized neurobiological mechanisms of PTSD development we recommend an article by Ross et al.4
In this article, we discuss current evidence on pharmacological preventive interventions for PTSD in adults that is relevant for health care professionals working with people recently exposed to trauma (eg, mental health professionals, ED and ICU staff, rescue workers, general practitioners). We discuss the state of the field of pharmacological prevention for PTSD initiated within 1 month posttrauma and recommendations for clinical practice and future directions. Of relevance, initiating prevention within the first hours posttrauma is usually considered immediate intervention, whereas administering treatment within days to weeks is considered early intervention. Indicated or targeted preventive interventions are directed toward people recently exposed to trauma at increased risk for PTSD based on risk factors or early symptoms and are generally considered to be more effective than interventions delivered to all people recently exposed to trauma.3
Current Evidence for Clinical Practice
In this article, we review multiple randomized controlled trials (RCTs) and prospective and retrospective observational studies that investigated relationships between pharmacological interventions given within hours to weeks posttrauma and subsequent development of PTSD. We follow and extend the latest guidelines of the International Society of Traumatic Stress Studies (ISTSS) on prevention and treatment of PTSD in adults,5 which group pharmacological interventions into different recommendation categories based on study quality and effectiveness. For pharmacological prevention of PTSD, the highest level of recommendation achieved is “intervention with emerging evidence,” indicating that available studies show better outcomes for the investigated agent compared to the control condition but requirements for higher recommendation levels supporting clinical implementation were not met. We additionally discuss agents not included in the ISTSS guidelines if the effects were investigated in multiple observational studies. Although the ISTSS guidelines allow interventions initiated within 3 months posttrauma, all interventions reviewed in this article were initiated within 1 month after trauma. Where possible, we report effect sizes (either as published or calculated by the authors) (Table 1) to facilitate interpretation of findings and comparison of effects between individual studies.
Pharmacological Agents Investigated in Relation to PTSD Prevention
Interventions with Emerging Evidence
Glucocorticoids. Glucocorticoids are the end-product of the hypothalamic-pituitary-adrenal axis, which is activated by (traumatic) stress. As glucocorticoids are important agents in terminating the stress response and modulate fear memory processes in neural limbic-frontal circuitries, glucocorticoid administration early posttrauma is hypothesized to attenuate PTSD development by influencing stress reactivity and recovery as well as fear memory processes associated with the etiology of PTSD.6
Two recent meta-analyses demonstrated a probable beneficial effect of hydrocortisone administration initiated within 12 hours posttrauma on PTSD symptoms from 3 to possibly 31 months posttrauma.7,8 These included two RCTs in ED patients with risk factors for PTSD, one RCT in cardiac surgery patients, and one RCT in patients with septic shock.7 Sijbrandij et al.8 additionally included one RCT in cardiac surgery patients. The risk for PTSD was significantly lower in hydrocortisone-treated patients compared to placebo.7,8 A significant medium-large effect size was observed for PTSD symptom reduction.8 Administration and dosing strategies were different between studies, but effect heterogeneity was low. In ED patients who experienced an acute stress reaction to the trauma, Zohar et al.6 assessed the effects of a single high dose of hydrocortisone (intravenous [IV] bolus of 100–140 mg), whereas another study used oral hydrocortisone at dose of 20 mg twice a day for 10 days, followed by a 6-day tapering period in ED patients with high levels of peritraumatic dissociation.7 The cardiac surgery and septic shock studies initiated 100 mg of hydrocortisone IV perioperatively and during septic shock, respectively.7,8 The dose was tapered during days 4 to 12 after surgery. The most recent study on glucocorticoids (which was not included in the meta-analyses described above) assessed the effects of a single perioperative administration of dexamethasone (a synthetic glucocorticoid) on subsequent PTSD development in more than 1,100 cardiac surgery patients, but observed a beneficial preventive effect only in female patients.9 Recently, an RCT in ED patients was completed in which a single IV bolus of 90 to 140 mg of hydrocortisone was administered within 6 hours posttrauma;10 the results have not yet been published. In all of the published studies, side effects seemed to be limited but were not consistently reported. Observational studies in acutely ill ICU patients demonstrated inconsistent results, with both a protective effect11,12 and no effect13 of hydrocortisone administration on subsequent PTSD symptoms. Of all currently investigated pharmacological agents, we consider glucocorticoids to be the most promising, but widescale use in clinical practice is not yet recommended.
Insufficient Evidence to Recommend
The category “insufficient evidence to recommend” is used in the ISTSS guidelines for interventions that do not show at least emerging evidence for clinical efficacy.5 Within this category, we distinguish between interventions that we believe need further investigation to determine efficacy and interventions that are likely ineffective in preventing PTSD.
Propanolol. Early posttrauma administration of the beta-blocking agent propranolol was hypothesized to attenuate PTSD development by dampening autonomic stress reactivity and inhibiting trauma memory formation by blocking beta-adrenoreceptors in the limbic system. The above-mentioned meta-analyses included three RCTs on the effects of propranolol given early posttrauma.7,8 Sijbrandij et al.8 additionally included two observational studies (of which one included beta-blocking agents metoprolol, carvedilol, and atenolol) and two studies in children. In both meta-analyses, there was no beneficial effect of propranolol initiated between 6 hours to 48 hours posttrauma in patients with traumatic injury.7,8 Heterogeneity was low,7,8 although the administered dose differed between studies, with maximum dosage varying from 80 to 200 mg daily. The treatment was tapered within 2 to 4 weeks. All RCTs were small (n = 29–48). However, based on multiple RCTs and low overall effect sizes from meta-analyses, we do not consider propranolol a promising intervention.
Escitalopram. Two RCTs assessed the preventive effect of the selective serotonin reuptake inhibitor (SSRI) escitalopram (20 mg) initiated within 1 month posttrauma14,15 in patients with traumatic injury, of which one was a large RCT (n = 353) in patients with traumatic injury meeting at least two Diagnostic and Statistical Manual of Mental Disorders, fourth edition16 criteria for acute stress disorder (re-experiencing and hyperarousal).15 Although SSRIs are effective in treating fully established PTSD, these studies demonstrated early initiation of SSRI treatment is unlikely to influence disease onset and establishment. In subgroup analyses in patients who experienced intentional trauma, PTSD symptom severity 1 year posttrauma was reduced in patients treated with escitalopram compared to participants treated with placebo, with a medium-to-large but statistically nonsignificant effect.15 Nevertheless, considering the consistently low effect size in people recently exposed to trauma at increased risk for PTSD based on high early symptoms, we do not recommend escitalopram for clinical practice.
Docosahexaenoic acid. Fatty acid administration is hypothesized to affect PTSD risk by facilitating adult hippocampal neurogenesis, which may beneficially affect neural fear memory processes associated with PTSD development. Two RCTs assessed effects of high-dose fatty acids (1,470 mg of docosahexaenoic acid [DHA] plus 147 mg of eicosapentaenoic acid [EPA], and 1,568 mg of DHA plus 156.8 mg of EPA, respectively) initiated within 10 days posttrauma for a length of 12 weeks but failed to demonstrate differences in PTSD symptoms between treatment and placebo groups.17,18 In subgroup analyses, Matsuoka et al.17 did not find a beneficial effect in participants who experienced a life threat. Nishi et al.18 reported a significant reduction in PTSD symptoms in women only; no sex-differential effects were found by Matsuoka et al.17 We do not recommended fatty acids for clinical practice, considering the low effect sizes, reasonably sized studies, and absence of indications for efficacy in indicated or targeted population.
Gabapentin. In a small RCT, trauma-exposed ED patients treated with the anticonvulsant gabapentin at a dose of 1,200 mg per day initiated within 2 days posttrauma did not have fewer PTSD symptoms at 1 month posttrauma than those treated with placebo.7 At 4 months posttrauma, there was no significant difference in PTSD rates between gabapentin- and placebo-treated patients. We do not recommend gabapentin for clinical practice, as there is no indication for clinical efficacy and no clear neurobiological rationale for preventive effects.
Oxytocin. The neuropeptide oxytocin, which is involved in emotion and (social) salience processing, motivation, memory, and stress recovery, was hypothesized to attenuate PTSD development by targeting both neurobiological and psychosocial PTSD risk factors such as low perceived social support.19 A recent RCT in ED patients exposed to trauma demonstrated repeated oxytocin administration (40 IU twice a day for 8 days) initiated within 12 days posttrauma resulted in fewer PTSD symptoms up to 6 months posttrauma, but only in people with high levels of acute PTSD symptoms at treatment initiation.19 This finding is promising, but currently oxytocin cannot be recommended for clinical practice; the results need to be replicated first, as results were derived from secondary analyses.
The agents discussed in the following text were not included in the ISTSS PTSD prevention and treatment guidelines.5 As there are multiple observational studies associating these agents with PTSD development, they are relevant to discuss. Considering the ISTSS recommendation categories, these agents would all fall into the “insufficient evidence to recommend” category.
Benzodiazepines. Although benzodiazepines, which are gamma aminobutyric acid-receptor agonists, are widely used anxiolytics and sedatives, multiple observational studies, one small RCT, and one controlled clinical (nonrandomized, nonblinded) trial suggest that benzodiazepine administration early posttrauma does not reduce risk for PTSD development and may potentially enhance subsequent PTSD symptoms. The RCT included 22 patients with traumatic injury randomized to temazepam at a dose of 15 to 30 mg at bedtime or placebo for 7 days, initiated on average at 14 days posttrauma.7 At 6 weeks posttrauma, PTSD symptom severity scores were higher in patients treated with temazepam compared to those treated with placebo, but were statistically nonsignificant with a medium effect size. Fifty-five percent of temazepam-treated versus 27% of placebo-treated participants were diagnosed with PTSD approximately 2 months posttrauma, which also was a nonsignificant difference. In a nonrandomized, nonblinded clinical study, clonazepam or alprazolam initiated within 2 to 18 days posttrauma was associated with a PTSD diagnosis at 6 months posttrauma compared to pair-matched controls; symptom severity scores did not significantly differ between groups.20 A recent review and meta-analysis pooled results from these controlled trials and observational prospective studies in patients with traumatic injury and patients in the ICU and demonstrated an association between early posttrauma benzodiazepine administration and subsequent higher PTSD symptoms, although heterogeneity was high.21 Of note, this meta-analysis also included observational studies in which pre- or peritrauma benzodiazepine use in relation to PTSD development was assessed. Four other observational studies in ICU patients were not included, of which one did,22 and three did not,11,23,24 demonstrate a significant association between early posttrauma benzodiazepine use and worse PTSD outcome. Although high-quality RCTs are lacking and observational studies have a high risk for bias, all observational studies demonstrated either no or adverse associations between early posttrauma benzodiazepine administration and PTSD development. Additionally, benzodiazepines have been found to interfere with adaptive fear memory processes in rodents, healthy people, and in patients with PTSD.21 Therefore, we do not recommend benzodiazepines for clinical practice as a preventive intervention for PTSD.
Opiates. Opiate administration early posttrauma is hypothesized to reduce PTSD symptom development by inhibiting overconsolidation of traumatic memories. Considering severe pain is a risk factor for PTSD development,3 it is additionally hypothesized that opiates may reduce PTSD risk by adequate pain reduction. Several prospective and retrospective observational studies demonstrated associations between opiate administration after traumatic injury and during ICU treatment and reduced PTSD risk. In a prospective observational study in patients with traumatic injury, opiate administration within 48 hours posttrauma was associated with lower PTSD symptoms and prevalence at 6 weeks and 1 year posttrauma.25 In a retrospective observational study in traumatic injury patients, Bryant et al.26 demonstrated that a PTSD diagnosis at 3 months posttrauma was associated with lower morphine doses in the first 48 hours after hospital admission. In military personnel a negative relationship was found between morphine administration during traumatic injury treatment and subsequent PTSD diagnosis as registered in medical records up to 2 years later.27 Observational studies in ICU patients show inconsistent relationships between opiate use and PTSD development. Two studies in ICU patients demonstrated no significant association between opiate dose and PTSD symptoms 3 and 12 months later.22,23 In ICU patients with acute lung injury, high-dose opiates were associated with increased PTSD risk, whereas longer duration of opiate treatment was associated with lower PTSD risk.11 This suggests the need to investigate dose and treatment duration as potential moderators of effects on PTSD development. Although these findings from observational studies are promising, we do recommend waiting for further evidence before implementing opiates in clinical practice.
Ketamine. The N-methyl-D-aspartate receptor antagonist ketamine is commonly used as an anesthetic and analgesic, but it also has anxiolytic properties. Three retrospective observational studies of ketamine reported mixed results, with the largest study showing no beneficial effects.28–30 Interpretation of these studies is compromised by multiple potential confounding factors, such as coadministration of benzodiazepines and/or opiates, and differences in patient characteristics. Therefore, we recommend waiting for higher-level evidence on the efficacy of ketamine in preventing PTSD before implementation into clinical practice.
Clinical Recommendations and Future Directions
Currently, no pharmacological preventive intervention for PTSD has sufficient evidence justifying implementation in clinical practice. Glucocorticoid administration within 12 hours posttrauma to indicated populations is the most promising option. High-quality RCTs are needed to replicate previous findings and to assess optimal administration route, dosage, and duration of treatment. Studies on sex-differential effects and the most efficacious synthetic glucocorticoid are also recommended. Finally, as not all people exposed to trauma come to the attention of health care professionals within 12 hours posttrauma, future studies should investigate the efficacy of glucocorticoid treatment initiated beyond the first 12 hours posttrauma.
There is insufficient evidence to recommend beta-blocking agents, escitalopram, fatty acids, gabapentin, oxytocin, benzodiazepines, opiates, and ketamine for clinical practice. There are no indications that early posttrauma initiation of propranolol, benzodiazepines, or escitalopram reduces PTSD development in people exposed to trauma with early PTSD symptoms. Future studies on these agents are not of high priority, as expected efficacy is low. We urge clinicians to use caution in prescribing benzodiazepines early posttrauma to alleviate acute anxiety or sleep disturbances, due to potential long-term increase in PTSD symptom development. Although there was only one RCT on gabapentin, we do not recommend further studies, for there is no clear neurobiological rationale for the preventive effects of gabapentin.
Multiple observational studies in patients with traumatic injury and patients in ICUs show potential protective effects of opiate administration on PTSD development. Because observational studies are prone to bias, RCTs are highly needed. The beneficial effects of intranasal oxytocin as a preventive intervention should be replicated considering the large effect-size in people exposed to trauma with high levels of acute PTSD symptoms. Because there are only observational studies with mixed results on ketamine as a preventive intervention, an RCT is advised to increase the level of evidence on its efficacy.
Besides pharmacological efficacy, other issues need to be investigated before routine implementation of pharmacological preventive interventions for PTSD may be recommended and feasible. First, tools for accurate identification of high-risk people early posttrauma are highly needed. Reliable identification of high-risk people will enable more efficacious, feasible, and cost-effective indicated prevention of PTSD because it would allow for targeting of pharmacological interventions to people at highest risk. Prevention targeted at all people exposed to trauma may result in unnecessary treatment and could interfere with adaptive recovery in people at low risk. Of relevance, three of six RCTs demonstrating beneficial effects of the studied agent found beneficial effects in people exposed to trauma with previously identified risk factors for PTSD (peritraumatic dissociation,7 acute stress reaction,7 high early symptoms19). It should be noted that beneficial effects in specific subgroups (ie, those at highest risk but also those with vulnerabilities in neurobiological pathways targeted by the specific interventions) remained undetected in previous studies investigating effects of interventions in a nonindicated population. Computational models combining early posttrauma ready-to-use characteristics (such as heart rate, blood pressure, pain score, demographics, and psychiatric history) are promising for early PTSD risk assessment31 and should be further investigated.
Second, there is little knowledge on the acceptability of pharmacological preventive intervention for PTSD. All studies discussed here report high decline rates. The reasons for this remain largely unknown but could be related to reluctance to take medication. In a study by Shalev et al.,14 participants were allowed to decline up to 2 of 4 possible treatment allocations (ie, prolonged exposure, cognitive therapy, escitalopram/placebo, and waitlist/late-prolonged exposure). More than 40% (42.6%) declined medication; decline rates were much lower for the psychotherapy conditions (1.8%–5%). Qualitative research should provide insights into the needs and wishes of people exposed to trauma regarding information about pharmacological preventive interventions and potential PTSD risk.
Third, most EDs, ICUs, and other health care facilities treating people exposed to trauma currently lack personnel and logistics to routinely identify, follow-up and (if necessary), adequately refer people exposed to trauma to preventive PTSD treatment. Implementation studies translating research settings to the reality of clinical practice are needed to facilitate implementation of pharmacological preventive interventions for PTSD.
In line with the latest ISTSS PTSD treatment and prevention guidelines,5 we conclude that routine implementation of pharmacological preventive interventions for PTSD should not currently be recommended, although emerging evidence from multiple moderate and low-quality RCTs and observational studies suggests hydrocortisone administration initiated within 12 hours posttrauma may reduce subsequent PTSD development, especially when delivered to populations with risk factors. In addition, observational studies and single RCTs demonstrated potential beneficial effects of opiates and oxytocin. High-quality RCTs, as well as studies addressing the issues outlined above regarding risk identification, acceptability, and implementation, are pivotal to further advance the field and to ultimately realize effective and clinically applicable pharmacological preventive interventions for PTSD.
- Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. Trauma and PTSD in the WHO world mental health surveys. Eur J Psychotraumatol. 2017;8(suppl 5):1353383. doi:. doi:10.1080/20008198.2017.1353383 [CrossRef]
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
- Shalev AY, Barbano A. Prevention of PTSD: events severity and initial response. Psychiatr Ann.2019;49(7):294–301. doi:10.3928/00485713-20190605-01 [CrossRef].
- Ross DA, Arbuckle MR, Travis MJ, Dwyer JB, van Schalkwyk GI, Ressler KJ. An integrated neuroscience perspective on formulation and treatment planning for posttraumatic stress disorder. JAMA Psychiatry.2017;74(4):407–415. doi:. doi:10.1001/jamapsychiatry.2016.3325 [CrossRef]
- Bisson J, Forbes D, Berliner L, et al. ISTSS Posttraumatic Stress Disorder Prevention and Treatment Guidelines. Oakbrook Terrace, IL: International Society for Traumatic Stress Studies; 2018.
- Zohar J, Yahalom H, Kozlovsky N, et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur Neuropsychopharmacol.2011;21(11):796–809. doi:. doi:10.1016/j.euroneuro.2011.06.001 [CrossRef]
- Amos T, Stein DJ, Ipser JC. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2014;7(7):CD006239. doi:10.1002/14651858.CD006239.pub2 [CrossRef].
- Sijbrandij M, Kleiboer A, Bisson JI, Barbui C, Cuijpers P. Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis. Lancet Psychiatry.2015;2(5):413–421. doi:. doi:10.1016/S2215-0366(14)00121-7 [CrossRef]
- Kok L, Hillegers MH, Veldhuijzen DS, et al. The effect of dexamethasone on symptoms of posttraumatic stress disorder and depression after cardiac surgery and intensive care admission: longitudinal follow-up of a randomized controlled trial. Crit Care Med. 2016;44(3):512–520. doi:. doi:10.1097/CCM.0000000000001419 [CrossRef]
- ClinicalTrials.gov. Efficacy of single dose IV hydrocortisone in post traumatic stress disorder (PTSD) prevention. https://clinicaltrials.gov/ct2/show/NCT00855270?cond=ptsd+hydrocortisone&rank=1. https://clinicaltrials.gov/ct2/show/NCT00855270?cond=ptsd+hydrocortisone&rank=1. Accessed June 4, 2019.
- Bienvenu OJ, Gellar J, Althouse BM, et al. Post-traumatic stress disorder symptoms after acute lung injury: a 2-year prospective longitudinal study. Psychol Med.2013;43(12):2657–2671. doi:. doi:10.1017/S0033291713000214 [CrossRef]
- Schelling G, Stoll C, Kapfhammer HP, et al. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder and health-related quality of life in survivors. Crit Care Med. 1999;27(12):2678–2683. doi:10.1097/00003246-199912000-00012 [CrossRef]
- Boer KR, van Ruler O, van Emmerik AAP, et al. Factors associated with posttraumatic stress symptoms in a prospective cohort of patients after abdominal sepsis: a nomogram. Intensive Care Med. 2008;34(4):664–674. doi:. doi:10.1007/s00134-007-0941-3 [CrossRef]
- Shalev AY, Ankri Y, Israeli-Shalev Y, Peleg T, Adessky R, Freedman S. Prevention of posttraumatic stress disorder by early treatment: results from the Jerusalem Trauma Outreach and Prevention study. Arch Gen Psychiatry.2012;69(2):166–176. doi:. doi:10.1001/archgenpsychiatry.2011.127 [CrossRef]
- Zohar J, Fostick L, Juven-Wetzler A, et al. Secondary prevention of chronic PTSD by early and short-term administration of escitalopram: a prospective randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2018;79(2). pii: 16m10730. doi:. doi:10.4088/JCP.16m10730 [CrossRef]
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing; 1994.
- Matsuoka Y, Nishi D, Hamazaki K, et al. Docosahexaenoic acid for selective prevention of posttraumatic stress disorder among severely injured patients: a randomized, placebo-controlled trial. J Clin Psychiatry. 2015;76(8):e1015–e1022. doi:. doi:10.4088/JCP.14m09260 [CrossRef]
- Nishi D, Koido Y, Nakaya N, et al. Fish oil for attenuating posttraumatic stress symptoms among rescue workers after the great east Japan earthquake: a randomized controlled trial. Psychother Psychosom. 2012;81(5):315–317. doi:. doi:10.1159/000336811 [CrossRef]
- van Zuiden M, Frijling JL, Nawijn L, et al. Intranasal oxytocin to prevent posttraumatic stress disorder symptoms: a randomized controlled trial in emergency department patients. Biol Psychiatry. 2017;81(12):1030–1040. doi:. doi:10.1016/j.biopsych.2016.11.012 [CrossRef]
- Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996;57(9):390–394.
- Guina J, Rossetter SR, DeRhodes BJ, Nahhas RW, Welton RS. Benzodiazepines for PTSD: a systematic review and meta-analysis. J Psychiatr Pract. 2015;21(4):281–303. doi:. doi:10.1097/PRA.0000000000000091 [CrossRef]
- Girard TD, Shintani AK, Jackson JC, et al. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study. Crit Care. 2007;11(1):R28. doi:. doi:10.1186/cc5708 [CrossRef]
- Patel MB, Jackson JC, Morandi A, et al. Incidence and risk factors for intensive care unit-related post-traumatic stress disorder in veterans and civilians. Am J Respir Crit Care Med. 2016;193(12):1373–1381. doi:. doi:10.1164/rccm.201506-1158OC [CrossRef]
- Battle CE, James K, Bromfield T, Temblett P. Predictors of post-traumatic stress disorder following critical illness: a mixed methods study. J Intensive Care Soc. 2017;18(4):289–293. doi:. doi:10.1177/1751143717713853 [CrossRef]
- Mouthaan J, Sijbrandij M, Reitsma JB, et al. The role of early pharmacotherapy in the development of posttraumatic stress disorder symptoms after traumatic injury: an observational cohort study in consecutive patients. Gen Hosp Psychiatry. 37(3):230–235. doi:10.1016/j.genhosppsych.2015.02.010 [CrossRef].
- Bryant RA, Creamer M, O'Donnell M, Silove D, McFarlane AC. A study of the protective function of acute morphine administration on subsequent posttraumatic stress disorder. Biol Psychiatry.2009;65(5):438–440. doi:. doi:10.1016/j.biopsych.2008.10.032 [CrossRef]
- Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med.2010;362(2):110–117. doi:. doi:10.1056/NEJMoa0903326 [CrossRef]
- McGhee LL, Maani CV, Garza TH, Slater TM, Petz LN, Fowler M. The intraoperative administration of ketamine to burned U.S. service members does not increase the incidence of post-traumatic stress disorder. Mil Med. 2014;179(suppl 8):41–46. doi:. doi:10.7205/MILMED-D-13-00481 [CrossRef]
- McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008;64(suppl 2):S195–S198. doi:. doi:10.1097/TA.0b013e318160ba1d [CrossRef]
- Schönenberg M, Reichwald U, Domes G, Badke A, Hautzinger M. Effects of peritraumatic ketamine medication on early and sustained posttraumatic stress symptoms in moderately injured accident victims. Psychopharmacology (Berl). 2005;182(3):420–425. doi:. doi:10.1007/s00213-005-0094-4 [CrossRef]
- Rosellini AJ, Dussaillant F, Zubizarreta JR, Kessler RC, Rose S. Predicting posttraumatic stress disorder following a natural disaster. J Psychiatr Res. 2018;96:15–22. doi:. doi:10.1016/j.jpsychires.2017.09.010 [CrossRef]
Pharmacological Agents Investigated in Relation to PTSD Prevention
||Number and Study Design
||Effect Size Posttraumatic Stress Disorder Diagnosisb
||Effect Size Posttraumatic Stress Disorder Symptomsb
||Recommendation Category ISTSS Guidelines
||6 RCTs (5 HC, 1 DEX)
||Meta-analyses—medium to large beneficial effect:Amos et al.7: Relative risk = 0.17, NNTB = 7–14
Sijbrandij et al.8c: IRR = 0.38, NNT = 7.04
||Meta-analysis—medium beneficial effect: Sijbrandij et al.8c: Hedges' g = −0.73, NNT = 2.5
||Meta-analyses—small to medium beneficial effect: Amos et al.7: Relative risk = 0.62, NNTB = 14–27
Sijbrandij et al.8c: IRR = 0.95, NNT = 59
||Meta-analysis—small beneficial effect: Sijbrandij et al.8c: Hedges' g = −0.1, NNT = 20
||Small beneficial effect: Cohen's d = −0.09–0.20, Hedges' g = −0.05–0.09.
Medium beneficial effect for intentional trauma: Cohen's d = −0.50 to 0.58
||Small beneficial effect: OR = 0.75
||Small beneficial effect: Cohen's d = −0.04
||Small adverse-no effect: Cohen's d = 0.11-0
||Large beneficial effect: Cohen's d = 0.86
||Meta-analysis—small adverse effect: Guina et al.20d: standardized effect size = −0.4
Controlled studies—large adverse effect: OR = 3.20–7.5
Observational studies—inconsistent effect: OR = 0.68–5.07
||Small adverse effect: rho = 0.3
||Not included in ISTSS guideline
||Inconsistent, mainly medium beneficial effects: OR = 0.27–2.13
||Small adverse effect: rho = 0.07
||Not included in ISTSS guideline
||Inconsistent effect: OR = 0.42–1.17
||Small adverse-no effect: Cohen's d = 0.10 to 0Women only, inconsistent effect size: Cohen's d = −032 to 0.16
||Not included in ISTSS guideline