Article

The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members

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Abstract

Predisposing factors for posttraumatic stress disorder (PTSD) include experiencing a traumatic event, threat of injury or death, and untreated pain. Ketamine, an anesthetic, is used at low doses as part of a multimodal anesthetic regimen. However, since ketamine is associated with psychosomatic effects, there is a concern that ketamine may increase the risk of developing PTSD. This study investigated the prevalence of PTSD in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) service members who were treated for burns in a military treatment center. The PTSD Checklist-Military (PCL-M) is a 17-question screening tool for PTSD used by the military. A score of 44 or higher is a positive screen for PTSD. The charts of all OIF/OEF soldiers with burns who completed the PCL-M screening tool (2002-2007) were reviewed to determine the number of surgeries received, the anesthetic regime used, including amounts given, the total body surface area burned, and injury severity score. Morphine equivalent units were calculated using standard dosage conversion factors. The prevalence of PTSD in patients receiving ketamine during their operation(s) was compared with patients not receiving ketamine. Of the 25,000 soldiers injured in OIF/OEF, United States Army Institute of Surgical Research received 603 burned casualties, of which 241 completed the PCL-M. Of those, 147 soldiers underwent at least one operation. Among 119 patients who received ketamine during surgery and 28 who did not; the prevalence of PTSD was 27% (32 of 119) versus 46% (13 of 28), respectively (p = 0.044). Contrary to expectations, patients receiving perioperative ketamine had a lower prevalence of PTSD than soldiers receiving no ketamine during their surgeries despite having larger burns, higher injury severity score, undergoing more operations, and spending more time in the ICU.

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... 10 NMDA receptor activation has been shown to increase formation of spontaneous intrusive memories (depressive or anxious), and high activity of the NMDA receptor may be a risk factor for actually developing PTSD. 11 As ketamine functions as an antagonist to the NMDA receptor, it may be a promising drug target to lower PTSD symptoms as such. ...
... Ketamine's nature is that it can create a transient dissociative state and has been thought to either facilitate or worsen PTSD in the past. 11 It is a controlled and possibly addicting substance. ...
... Another study by McGhee and colleagues utilized the PCL-M to determine the diagnosis of PTSD in patients and aimed to determine the prevalence of PTSD in 603 burn patients during their procedure compared to those who did not. 11 Two hundred completed the PCL-M and 147 underwent at least one procedure. They found that patients receiving ketamine displayed a lower prevalence of PTSD. ...
Article
Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.
... Finally, 10 studies that met (five RCT studies, three case-control studies, and two cohort studies) our predetermined inclusion criteria were included in this study. The results of the risk of bias assessment are shown in Figure 2. A total of 10 studies reported the effects of ketamine on the occurrence of PTSD after battlefield rescue or in burned patients (31)(32)(33) as well as symptom changes in early PTSD patients with a dose of ketamine (0.5 mg/kg) (30,34,37) and the same dose for chronic PTSD patients (25,26,35). ...
... Three studies (31)(32)(33) including 503 patients (ketamine 349, control 154) in the battlefield reported no significant reduction in PTSD prevalence (Figure 3) with ketamine (no dose list) based on a risk ratio (95% CI) of 0.86 (0.61-1.20), p = 0.38, I 2 = 52% compared with the control. Three studies (30,34,37) including 67 patients (ketamine 29, control 38) reported scores that changed in early PTSD based on ASDS (four subscales, including dissociation, reexperiencing, avoidance and hyperarousal) (37), IES-R, PCL, and CAPS scales (Figure 4). ...
... Although the explanation for the difference in the results is unclear, our findings are also supported by Mion et al. (33) given that ketamine did not increase the risk of PTSD. The use of ketamine during a stressful event may reduce the preventive effect, but have no effect on the subsequent development of PTSD (31,33). ...
Article
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Background Post-traumatic stress disorder (PTSD) is a serious stress-related disorder caused by traumatic experiences. However, identifying a key therapy that can be used for PTSD treatment remains difficult. Ketamine, a well-known dissociative anesthetic, is considered safe to be used in anesthesia, pain management, and antidepressant actions since 1970. At present, it is still controversial whether PTSD can be treated with ketamine. The authors performed a meta-analysis to determine whether the use of perioperative ketamine lowers the incidence of PTSD. Methods Cochrane Central Register of Controlled Trials, Embase, PubMed, and Web of Science were searched to examine the use of ketamine for the treatment of PTSD among soldiers with combating experience. Studies were included if they were randomized placebo-controlled, case-control, and cohort studies. The primary outcome was the incidence of PTSD in the later stage of the wounded or burn soldiers. The secondary outcome was the influence of ketamine on PTSD-scale scores for early and chronic PTSD, respectively. Results Our search yielded a total of three studies ( n = 503 patients) comparing the use of ketamine ( n = 349) to control ( n = 154). The available evidence showed no significant difference in the incidence of PTSD between combatant soldiers on the battlefield with or without ketamine treatment (risk ratio = 0.81, 95% CI, 0.63–1.04; P = 0.10). In 65 patients from three trials, ketamine was not only ineffective in treating early PTSD but also lead to exacerbation of the disease (risk ratio = 2.45, 95% CI, 1.33–3.58; P < 0.001). However, in 91 patients from the other three trials, ketamine is effective in treating chronic PTSD (risk ratio = −3.66, 95% CI, −7.05 to −0.27; P = 0.03). Conclusion Ketamine was not effective on lower the PTSD incidence for soldiers on the battlefield, nor on the PTSD-scale scores in early PTSD patients. However, it may improve the PTSD-scale scores for chronic conditions. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255516 , PROSPERO, identifier: CRD42021255516.
... One RCT 93 and two open-label trials expressly focused on ketamine treatment for post-traumatic stress disorder symptoms, 94,95 whereas the other five retrospectively examined the effects of peri-Ketamine treatment for mental and health substance use disorders traumatic anaesthetic ketamine administration during treatment for physical injury. [96][97][98][99][100] The first retrospective study found that patients who were administered ketamine following trauma exposure demonstrated increased post-traumatic stress disorder symptoms at 1 year, 96 and a subsequent study by the same group identified increased symptoms of acute stress disorder, a precursor to post-traumatic stress disorder, 3 days subsequent to emergency treatment in people given ketamine compared with opioid and other analgesics. 97 Three studies examining post-traumatic stress disorder in USA military personnel who had been administered ketamine for service-related injuries reported conflicting results. ...
... In the first study, receiving perioperative ketamine was associated with lower post-traumatic stress disorder prevalence (27% compared with 46%) among those who had not received ketamine, despite increased burn size, longer hospital stay and increased number of operations in the ketamine group. 98 Ketamine use during surgical procedures also had a significant but weak negative correlation with post-traumatic stress disorder. 98 In contrast, two subsequent studies reported comparable rates of post-traumatic stress disorder and post-traumatic stress disorder symptoms among ketamine and non-ketamine groups, although one of these studies was reported to have low power (<%80). ...
... 98 Ketamine use during surgical procedures also had a significant but weak negative correlation with post-traumatic stress disorder. 98 In contrast, two subsequent studies reported comparable rates of post-traumatic stress disorder and post-traumatic stress disorder symptoms among ketamine and non-ketamine groups, although one of these studies was reported to have low power (<%80). 99,100 Three studies focused on ketamine for the treatment of posttraumatic stress disorder. ...
Article
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Background In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions. Aims In light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders. Method The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist. Results We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis. Conclusions Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.
... The peri-operative use of ketamine has been shown to reduce the prevalence of PTSD in burned soldiers [7]. However, subsequent data analysis by the same research team involving a larger cohort of patients found that intra-operative ketamine use had no effect on the incidence of PTSD [8]. ...
... Regarding the effects of ketamine in relation to psychological reactions to stress, scarce clinical evidence leads to conflicting results. Ketamine administered during stressful events may aggravate [3,11,12], prevent [7] or have no effect [8] on the subsequent development of PTSD. Since the first clinical experiments, the psychomimetic effect of ketamine has been The table includes ketamine and morphine administration on the battlefield and in the field hospital. ...
... Studies have demonstrated that besides its amnesic, anxiolytic [17] and antidepressant properties, ketamine is able to alleviate the symptoms of PTSD in both animals [17,18] and humans [9]. McGhee et al. found that ketamine may protect burned soldiers from PTSD [7] although this was not confirmed in a later study involving a larger cohort [8]. Subanaesthetic doses of ketamine have not been shown to worsen dissociative symptoms in subjects with PTSD [19] and a randomised, controlled trial demonstrated that ketamine was superior to midazolam for reducing PTSD symptoms [9]. ...
... 29 One study examined the prevalence of PTSD in service members who were treated for burns in a military treatment center. 33 The use of the NMDA receptor antagonist ketamine lowered the prevalence of PTSD among service members who were treated for burns. The suggested mechanism is preventing memory consolidation after trauma exposure. ...
... The suggested mechanism is preventing memory consolidation after trauma exposure. 33 ...
... Of the 147 service members who underwent at least one surgical operation at the burn center, the group that had received intraoperative ketamine showed significantly lower prevalence of PTSD (32 of 119) than the group that had not (13 of 28) despite higher burn severity and number of surgeries in the former group. 7 Although a more recent retrospective chart review study in a larger sample of burned service members who had received intraoperative ketamine (n = 189) or had not (n = 100) did not replicate these findings, PTSD prevalence did not differ statistically between the two groups, suggesting that intraoperative ketamine after trauma does not increase risk of PTSD development. 8 A recent retrospective matched cohort study of US service members injured in combat who received (n = 107) or did not receive (n = 1,051) ketamine for analgesia during hospitalization yielded similar findings, but dosing data were not available. ...
Article
Posttraumatic stress disorder (PTSD) is a highly prevalent, chronic, and disabling condition for which currently available pharmacotherapies are insufficiently effective. Ketamine, which is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising and rapid-acting novel treatment intervention for this disorder. Findings from a proof-ofconcept, randomized, controlled crossover study of single-dose intravenous ketamine administration (compared to single-dose midazolam) in patients with chronic PTSD suggest that ketamine is associated with rapid improvement in core PTSD symptoms and comorbid depressive symptoms, and is generally well tolerated. Additional research is needed to confirm its efficacy and safety for patients with PTSD. Results from ongoing trials of repeated intravenous administration for PTSD are expected to yield more definitive evidence. Potential mechanisms of action as well as future research directions are discussed.
... Moreover, we do not know when in their course of care the drug was administered relative to other interventions. Our study focused on mortality differences; therefore, it remains unclear whether the same findings would apply to other end-points, such as changes in ICP or more long-term outcomes such as neurologic function at discharge, functional outcomes, chronic headaches, or PTSD [27,28]. Our data do not include shock index or other such confounders. ...
Article
Background The Tactical Combat Casualty Care (TCCC) guidelines recommend ketamine as the primary battlefield analgesic in the setting of moderate-to-severe pain and hemodynamic compromise. However, despite recent studies failing to support the association between ketamine and worse outcomes in head trauma, TCCC guidelines state that ketamine may worsen severe traumatic brain injury. We compared mortality outcomes following head trauma sustained in a combat setting between ketamine recipients and non-recipients. Methods This is a secondary analysis of previously published data in the Department of Defense Trauma Registry from January 2007 to August 2016. We isolated patients with an abbreviated injury scale of 3 or greater for the head body region. We compared mortality between prehospital ketamine recipients and non-recipients. Results Our initial search yielded 28,222 patients, of which 4,183 met the inclusion criteria: 209 were ketamine-recipients and 3,974 were non-recipients. The ketamine group had a higher percentage injured by explosives (59.81% vs. 53.57%, p<0.001) and gunshot wounds (28.71% vs. 22.07%, p<0.001) and were more frequently located in Afghanistan (100% vs. 68.0%, p<0.001). The ketamine group had higher rates of tourniquet application (24.4% vs. 8.5%, p<0.001) and had lower survival proportion (75.1% alive vs. 83.0%, p=0.003). All differences were significant. On univariable analysis, the ketamine group had worse odds of survival with (OR: 0.62; 95%CI: 0.45-0.86). When controlling for the presence of an airway intervention and mechanism of injury, the finding was non-significant (OR: 1.09; 95% CI: 0.76-1.55). Conclusions In our prehospital combat study, after controlling for confounders, we found no association between administration of prehospital ketamine and worse survival outcomes for casualties with head injuries. However, despite the lack of difference in overall survival noted, those who received ketamine and died had a higher risk ratio for time to death.
... By contrast, a study by McGhee and colleagues of 147 US service members found a lower prevalence of PTSD in those who had received ketamine during surgery (McGhee et al., 2008). This retrospective chart review study was conducted in burn victims who had undergone at least one surgery. ...
Chapter
A serious lack of effective pharmacotherapeutic interventions for posttraumatic stress disorder (PTSD) raises the urgent need for the development of novel treatments. Ketamine—a noncompetitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist in use for decades as an anesthetic and analgesic agent—has more recently been demonstrated to have rapid-onset antidepressant effects in patients with treatment-resistant depression (TRD). In the present review of ketamine as an emerging novel pharmacotherapeutic intervention for chronic PTSD, we discuss findings from the first proof-of-concept, randomized clinical trial (RCT) of single-dose intravenous ketamine in patients with chronic PTSD, as well as open-label studies and current practice. We introduce ongoing RCTs investigating the efficacy of repeated ketamine infusions in rapidly reducing symptoms and maintaining improvement in samples of individuals with PTSD stemming from civilian and military traumas. Additionally, we discuss mixed findings from published reports on ketamine administration in the acute aftermath of trauma. Studies in animal models of chronic stress have investigated molecular mechanisms underlying ketamine's effects, generating a shift in the conceptualization of PTSD as a disorder of impaired neural connectivity. We review animal studies examining the potential of ketamine to modify the expression of fear by altering memory reconsolidation or enhancing fear extinction, as well as others investigating ketamine administration prophylactically prior to stress exposure. We introduce the need for additional study in humans to evaluate whether ketamine might enhance the efficacy of psychotherapeutic interventions in individuals with chronic PTSD, harnessing a window of ketamine-induced neuroplasticity. While research on ketamine for PTSD is still in its early stages, it brings about the promise of novel and more effective treatments for this disabling condition.
... Our lab and others have shown that a single injection of (R,S)ketamine before stress can protect against stress-induced depressive-like behavior and social avoidance as well as attenuate learned fear, suggesting the possibility of developing resilienceenhancing pharmacotherapy [32][33][34][35]. In addition, select studies in human subjects demonstrate that (R,S)-ketamine may prevent psychiatric disorders such as PTSD and post-partum depression (PPD), but the data in human populations remain unclear [36][37][38][39]. However, it is still unknown whether stereospecific (R,S)-ketamine metabolites, which lack the adverse side effects of their parent compound, can have the same prophylactic efficacy of their racemic precursor [28]. ...
Article
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Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.
... The administration of safe, effective analgesia in the pre-hospital environment is imperative 40,46 . Ketamine, with its favourable pharmacokinetic and pharmacodynamic properties, is an extremely attractive option in a wide variety of settings. ...
Article
Objective Analgesia in the prehospital setting is an extremely important, yet controversial topic. Ketamine, a N-methyl D-aspartate (NMDA) receptor antagonist, has been commonly used in the prehospital setting, including recommendations by the US Department of Defense and by the Royal Australian College of Pain Medicine, despite the paucity of high-level evidence. Methods Accordingly, a review of the literature was conducted using several electronic medical literature databases from the earliest available records to the time at which the search was conducted (October 2018). Results The search strategy yielded a total of 707 unique papers, of which 43 were short-listed for full review, and ultimately, ten papers were identified as meeting all the relevant inclusion criteria. The included studies varied significantly in the prehospital context and in the means of administering ketamine. There was only low-grade evidence that ketamine offered a safe and effective analgesia when used as the only analgesic, and only low-grade evidence that it was as effective as alternative opioid options. However, there was moderate evidence that co-administration of ketamine with morphine may improve analgesic efficacy and reduce morphine requirement. Conclusions Overall, ketamine as a prehospital analgesic may be best used in combination with opioids to reduce opioid requirement. It is suggested that future studies should use a standardized approach to measuring pain reduction. Future studies should also investigate short-term side effects and long-term complications or benefits of prehospital ketamine.
... In addition to propranolol and hydrocortisone, observational studies have associated early morphine use with reduced rates of PTSD 21 and other drugs, including SSRIs 22 , gabapentin 23 , α-omega fatty acids 24 and ketamine 25 have also been investigated for the prevention of PTSD. Previous systematic reviews in this area have highlighted both the sparsity and the poor quality of the trials 24,26 . ...
Article
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Post-traumatic stress disorder (PTSD) is a common mental disorder associated with significant distress and reduced functioning. Its occurrence after a severe traumatic event and association with characteristic neurobiological changes make PTSD a good candidate for pharmacological prevention and early treatment. The primary aim for this systematic review and meta-analysis was to assess whether pharmacological interventions when compared to placebo, or other pharmacological/psychosocial interventions resulted in a clinically significant reduction or prevention of symptoms, improved functioning or quality of life, presence of disorder, or adverse effects. A systematic search was undertaken to identify RCTs, which used early pharmacotherapy (within three months of a traumatic event) to prevent and treat PTSD and acute stress disorder (ASD) in children and adults. Using Cochrane Collaboration methodology, RCTs were identified and rated for risk of bias. Available data was pooled to calculate risk ratios (RR) for PTSD prevalence and standardised mean differences (SMD) for PTSD severity. 19 RCTs met the inclusion criteria; 16 studies with adult participants and three with children. The methodological quality of most trials was low. Only hydrocortisone in adults was found to be superior to placebo (3 studies, n = 88, RR: 0.21 (CI 0.05 to 0.89)) although this was in populations with severe physical illness, raising concerns about generalisability. No significant effects were found for the other pharmacotherapies investigated (propranolol, oxytocin, gabapentin, fish oil (1470 mg DHA/147 mg EPA), fish oil (224 mg DHA/22.4 mg EPA), dexamethasone, escitalopram, imipramine and chloral hydrate). Hydrocortisone shows the most promise, of pharmacotherapies subjected to RCTs, as an emerging intervention in the prevention of PTSD within three months after trauma and should be a target for further investigation. The limited evidence for hydrocortisone and its adverse effects mean it cannot be recommended for routine use, but, it could be considered as a preventative intervention for people with severe physical illness or injury, shortly after a traumatic event, as long as there are no contraindications. More research is needed using larger, high quality RCTs to establish the most efficacious use of hydrocortisone in different populations and optimal dosing, dosing window and route. There is currently a lack of evidence to suggest that other pharmacological agents are likely to be effective.
... In preclinical models, NMDAR antagonists blocked induction (36) and expression (41) of behavioral sensitization by stress, and blocked crosssensitization between stress and stimulants (36,43,44). In humans, intraoperative administration of NMDAR antagonist ketamine may reduce PTSD risk (54,55), and a single infusion of 0.5 mg/kg ketamine compared to midazolam in patients with PTSD resulted in rapid (within 24 h) and sustained (at least 7 days) improvement in PTSD symptoms (56,57). Finally, the lowaffinity NMDAR antagonist memantine improved hyperarousal and depressive symptoms in individuals with PTSD (58). ...
Article
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Background: Individuals with post-traumatic stress disorder (PTSD) have a heightened sensitivity to subsequent stressors, addictive drugs, and symptom recurrence, a form of behavioral sensitization. N-methyl-D-aspartate receptors (NMDARs) are involved in the establishment and activation of sensitized behavior. Objective: We describe a protocol of a randomized placebo-controlled Phase 1b proof-of-mechanism trial to examine target engagement, safety, tolerability, and possible efficacy of the NMDAR antagonist lanicemine in individuals with symptoms of PTSD (Clinician Administered PTSD Scale [CAPS-5] score ≥ 25) and evidence of behavioral sensitization measured as enhanced anxiety-potentiated startle (APS; T-score ≥ 2.8). Methods: Subjects (n = 24; age range 21–65) receive three 60-min intravenous infusions of placebo or 100 mg lanicemine over 5 non-consecutive days. Primary endpoint is change in APS from pre-treatment baseline to after the third infusion. NMDAR engagement is probed with resting state EEG gamma band power, 40 Hz auditory steady state response, the mismatch negativity amplitude, and P50 sensory gating. Change in CAPS-5 scores is an exploratory clinical endpoint. Bayesian statistical methods will evaluate endpoints to determine suitability of this agent for further study. Conclusion: In contrast to traditional early-phase trials that use symptom severity to track treatment efficacy, this study tracks engagement of the study drug on expression of behavioral sensitization, a functional mechanism likely to cut across disorders. This experimental therapeutics design is consistent with recent NIMH-industry collaborative studies, and could serve as a template for testing novel pharmacological agents in psychiatry. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03166501.
... Conversely, except for few human findings reporting prophylactic effects of perioperative ketamine use for trauma-related disorders and depression (Ma et al., 2019;McGhee, Maani, Garza, Gaylord, & Black, 2008), there seems to be a general agreement in clinical studies showing that treatment with ketamine soon after accidental trauma is associated with increased symptoms of PTSD, such as dissociation, reexperiencing, hyperarousal and avoidance in the aftermath of the event (Schönenberg et al., 2008), which contribute to the development of a long-lasting PTSD symptomatology (Schönenberg et al., 2005) and are highly predictive of the severity and duration of subsequent PTSD (Bryant, Moulds, & Guthrie, 2000). These reports corroborate our previous (Morena et al., 2017) and present findings that the use of ketamine anesthesia shortly after a traumatic event may represent a risk factor for the development of trauma-related disorders. ...
Article
Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.
... Case reports have indicated that ketamine or ketamine analogues may be an effective treatment for veterans with PTSD. 22 McGhee et al 23 reported the somewhat serendipitous finding that PTSD in Operation Iraqi Freedom/Operation Enduring Freedom veterans who received ketamine during surgeries was 27% compared with 46% in those who did not receive ketamine. In a recent study by Albott et al, 24 veterans with comorbid treatment-resistant depression (TRD) and PTSD were administered 6 ketamine infusions of 0.5 mg/kg over a 12-day period. ...
Article
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Introduction: Combat veterans are at high risk for the development of posttraumatic stress disorder (PTSD) and substance use disorders. Ketamine has been shown to be an effective treatment for numerous mental health disorders, although research on its efficacy in combat-related PTSD in veterans is very limited. Methods: The study population consisted of 30 US military veterans with combat-related PTSD. Participants underwent a standard induction series of six 1-hour ketamine infusions with the goal of obtaining a transpersonal dissociative experience. Participants were given a series of self-report questionnaires to assess for changes in symptoms of depression, PTSD, and substance use prior to the first and sixth infusions. Results: Symptoms of depression as measured by change in score on the Patient Health Questionnaire decreased significantly from an average of 18.9 to 9.5 (P < .001). Similarly, symptoms of PTSD as measured by change in score on the PSTD Checklist for DSM-5 dropped significantly from an average of 56.2 to 31.3 (P < .001). Self-reported levels of substance use did not significantly decrease during the study period, although the level of use trended down. Conclusions: This observational study suggests that high-dose ketamine infusion therapy, which induced a transpersonal dissociative experience, could be a valuable tool in the treatment of combat-related PTSD. Further study is needed to better elucidate ketamine's mechanism of action with regards to the treatment of PTSD.
... These results have also been replicated in 4 different mouse models of stress in a dose-specific manner, in both mice and rats [22,25], as well as in male [25] and female rodents [26,27]. In addition to protecting against depressive-like behavior, prophylactic (R,S)-ketamine has been found to be efficacious in post-traumatic stress disorder (PTSD) [28] and postpartum depression (PDD) in humans [29]. ...
Article
Individuals with peripheral inflammation are a particularly vulnerable population for developing depression and are also more resistant towards traditional antidepressants. This signals the need for novel drugs that can effectively treat this patient population. Recently, we have demonstrated that (R,S)-ketamine is a prophylactic against a variety of stressors, but have yet to test if it is protective against inflammatory-induced vulnerability to a stressor. Here, male 129S6/SvEv mice were administered saline or (R,S)-ketamine (30 mg/kg) 6 days before an injection of vehicle (VEH) or lipopolysaccharide (LPS) (0.83 or 1.0 mg/kg, serotypes O111:B4 or O127:B8). Twenty-four hours after LPS administration, mice were administered a contextual fear conditioning (CFC) paradigm, followed by a context re-exposure and the forced swim test (FST). In a separate cohort, we tested if (R,S)-ketamine was effective as a prophylactic against polyinosinic-polycytidylic acid (PIC), a viral mimetic. (R,S)-ketamine was effective as a prophylactic for attenuating learned fear in the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was also effective as a prophylactic for decreasing stress-induced depressive-like behavior in the O111:B4 and O127:B8 strains of LPS. Both of these effects were limited to administration of 1.0, but not 0.83 mg/kg of the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was not effective against either stress phenotype following PIC administration. These data suggest that prophylactic (R,S)-ketamine may protect against selective inflammation-induced stress phenotypes following an inflammatory challenge. Future studies will be necessary to determine if (R,S)-ketamine can be useful in patient populations with peripheral inflammation.
... Brachman et al. [11] showed that prophylactic ketamine attenuates stress-induced depressive behavior in three mouse models of stress. A previous study found that burned soldiers receiving perioperative ketamine have a lower prevalence of PTSD [12]. However, a follow-up study from the same research group did not support their initial findings [13]. ...
Article
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Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brain-derived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.
... The authors concluded that those receiving perioperative ketamine had lower rates of PTSD than those who did not receive ketamine, despite having larger burn areas, higher injury severity scores, more ICU time, and more surgeries. 57 There is one published case report of a veteran given a single dose of intravenous ketamine (35 mg) and propofol (34 mg) over 20 min for the management of severe, treatment-resistant depression with suicidal ideation. His depression improved immediately post-infusion, and his PTSD scores dropped significantly on PCL-M. ...
Article
Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.
... Three retrospective observational studies of ketamine reported mixed results, with the largest study showing no beneficial effects. Interpretation of these studies is compromised by multiple potential confounding factors, such as coadministration [28][29][30] https://www.healio.com/psychiatry/journals/psycann/2019-7-49-7/%7bb59…vention-of-ptsd-current-evidence-for-clinical-practice?fat=72XK3Y8TLE ...
... A few studies examined the effect of ketamine in anesthetic doses in mitigating PTSD symptoms in humans [62,63]. These studies found that patients receiving ketamine (as part of a medical procedure) in anesthetic levels reduced severity of PTSD symptoms relative to non-ketamine-infused patients. ...
Article
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Purpose Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a lifetime prevalence of 6.1% in the general adult population. Clinical guidelines for the treatment of PTSD suggest the use of trauma-focused psychotherapies such as prolonged exposure (PE) and cognitive-behavioral therapy (CBT). As a second-level intervention, these guidelines suggest the use of psychotropic medications, mainly selective serotonin reuptake inhibitors (SSRIs). To date, however, studies have shown that both psychotherapeutic and psychopharmacologic treatments have limited efficacy, with remission rates around 40–70% and dropout rates of up to 50%. This paper reviews a new and emerging treatment approach of medication-augmented psychotherapy for PTSD, with an emphasis on augmenting prolonged exposure therapy (PE) with sub-anesthetic ketamine infusion. Based on animal and human research on fear extinction and memory reconsolidation, neurobiological changes that emerge following a ketamine infusion can enhance learning and thus benefit exposure-based psychotherapies for PTSD. Summary Medication-augmented exposure-based psychotherapies represent a promising direction for the treatment of PTSD, with some positive results in small-scale studies. More studies (phase 2 and 3) should be performed to determine if this multimodal treatment approach may help mitigate PTSD symptoms in trauma-exposed individuals who do not respond to standard monotherapeutic approaches.
... Zohar et al. (2011) highlight the significance of "golden hours", i.e. focusing on a defined and limited "window of opportunity" namely the first 6 hours after the trauma exposure in order to effectively consolidate trauma memory. For example, McGhee et al. (2008) found that in a group of burned service men those treated with the NMDA receptor antagonist ketamine during hospitalization had lower incidence of PTSD. Such clinical findings support the utility of novel pharmacological tools targeting NMDA receptor subunits or function could be of benefit while avoiding some of the side effects inherent to NMDA receptor blockade (Steckler & Risbrough, 2012). ...
Conference Paper
This thesis aimed to advance the field of knowledge into declarative recall of trauma memory. Investigations into trauma narratives have consistently confirmed that PTSD is associated with deficits in verbal memory, as well as over general autobiographical memory, avoidance or suppression of memories, and negative interpretation of memory symptoms. Chapter one investigated through a systematic search of the literature whether specific linguistic markers, such as greater use of negative affect words, insight and causation words could be identified within trauma narratives in an adult population. The review concluded that analysing trauma narratives enables us to understand the memory disturbances linked to post traumatic stress disorder and thus to develop increasingly effective psychological interventions to promote trauma adaptation. The linguistic correlates of trauma identified in chapter one were used to inform which linguistic markers should be analysed in chapter two, “recall of ‘trauma- related’ events following nitrous oxide: linguistic and psychophysiological correlates of recall”. Together with linguistic correlates of trauma, chapter two investigated the relationship between nitrous oxide inhalation and physiological changes (heart rate variability) during encoding and recall. Early pharmacological interventions have been found to hold some promise in reducing the emergence of PTSD symptoms, possibly by preventing or reducing initial consolidation of traumatic memories. Clinical findings support the utility of novel pharmacological tools targeting NMDA receptor subunits and NMDA receptors have been shown to play an important role in memory reconsolidation. Using existing data, the current study sought to extend a recently published study on nitrous oxide and involuntary emotional memories using the ‘trauma video’ paradigm. The final chapter provided a critical appraisal of the work undertaken in the current thesis. This included critical reflection on the process of undertaking research into declarative recall of trauma memory.
... However, previous studies have shown associations with adequate analgesia and decreased post-traumatic stress disorder. (22,23) Finally, although the investigation of new drugs requires significant preclinical research, members did not reach a consensus on which pre-clinical models best mirror the experience of battlefield pain. Future work to develop and utilize models that both reflect pain consistent polytraumatic injuries and consider A C C E P T E D 13 factors such as hemodynamic compromise from blood loss may enhance combat casualty care research. ...
... On the one hand, two observational studies suggest that ketamine worsens the risk of developing PTSD symptoms [67,68]; however, questions have been raised about their methodology [62]. On the other hand, a retrospective review of medical records of burn victims suggested reduced prevalence of PTSD among those receiving intraoperative ketamine [69]. However, a subsequent study found no differences [70]. ...
Article
Full-text available
Over the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine’s effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine’s complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine’s rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine’s action.
... There was some specificity for lanicemine's impact on this cluster (Table 3), as its effects on other PTSD symptom clusters were either small (e.g., reexperiencing, negative alterations in cognition/ mood) or failed to distinguish from placebo (e.g., reexperiencing). In humans, intraoperative administration of NMDAR antagonist ketamine may reduce PTSD risk (McGhee et al., 2008;McGhee et al., 2014) and a single and repeated infusions of ketamine, compared to midazolam in patients with PTSD, resulted in rapid and sustained and improvement in PTSD (Albott et al., 2018;Feder et al., 2014; Our results are also consistent with evidence of improvement in hyperarousal symptoms in individuals with PTSD following treatment with low-affinity NMDAR antagonists such as memantine (Battista et al., 2007). ...
... In terms of the side effect profile, more agitation was reported in ketamine treated subjects relative to morphine treatment [9.5% difference (95% CI 4% to 16%) (Tran et al., 2014). Retrospective assessment of PTSD in burned service members determined that racemic ketamine administered intraoperatively following trauma may mitigate subsequent development of symptoms (McGhee et al., 2008). This is important given the intimate association between TBI and PTSD (Vasterling et al., 2018;Wisco et al., 2014;Zaninotto et al., 2016). ...
Article
Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic, analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7–16 post injury and again from day 35–43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.
... Previous studies showed a preventative effect for developing PTSD. 11 As compared to opioids, ketamine has been shown to reduce pain more than opioid analgesics within the first 30 minutes of administration 2 and have less adverse effects. 1 However, ketamine for pain is an off-label use of the drug and thus this presents challenges with developing delivery solutions such as autoinjectors. ...
Article
Introduction Previous studies demonstrate that a significant proportion of casualties do not receive pain medication prehospital after traumatic injuries. To address possible reasons, the U.S. Military has sought to develop novel delivery methods to aid in administration of pain medications prehospital. We sought to describe the dose and route of ketamine administered prehospital to help inform materiel solutions. Materials and Methods This is a secondary analysis of a previously described dataset focused on prehospital data within the Department of Defense Trauma Registry from 2007 to 2020. We isolated encounters in which ketamine was administered along with the amount dosed and the route of administration in nonintubated patients. Results Within our dataset, 862 casualties met inclusion for this analysis. The median age was 28 and nearly all (98%) were male. Most were battle injuries (88%) caused by explosives (54%). The median injury severity score was 10 with the extremities accounting to the most frequent seriously injured body region (38%). The mean dose via intravenous route was 50.4 mg (n = 743, 95% CI 46.5-54.3), intramuscular was 66.7 mg (n = 234, 95% CI 60.3-73.1), intranasal was 56.5 mg (n = 10, 39.1-73.8), and intraosseous was 83.3 mg (n = 34, 66.3-100.4). Most had a medic or CLS in their chain of care (87%) with air evacuation as the primary mechanism of evacuation (86%). Conclusions The average doses administered were generally larger than the doses recommended by Tactical Combat Casualty Care guidelines. Currently, guidelines may underdose analgesia. Our data will help inform materiel solutions based on end-user requirements.
... Clinical recommendation to pursue repeated KAP was prompted by three factors. First, the patient's psychiatric and medical history that detailed unsuccessful treatment attempts, including pharmacotherapies, behavioral treatments, and nutritional counseling-even at higher levels of eating disorder care; and significant trauma to which accumulating evidence has shown ketamine to yield positive effects for (49)(50)(51). Second, her severe functional impairment in three major life domains, including academic work, social and family engagement, and personal responsibilities. ...
Article
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Background: Bulimia nervosa is a disabling psychiatric disorder that considerably impairs physical health, disrupts psychosocial functioning, and reduces overall quality of life. Despite available treatment, less than half of sufferers achieve recovery and approximately a third become chronically ill. Extreme and enduring cases are particularly resistant to first-line treatment, namely antidepressants and cognitive behavioral therapy, and have the highest rate of premature mortality. Here, we demonstrate that in such cases, repeated sessions of ketamine assisted psychotherapy (KAP) is an effective treatment alternative for improving symptoms. Case Presentation: A 21-year-old woman presented with extreme and enduring bulimia nervosa. She reported recurrent binge-eating and purging by self-induced vomiting 40 episodes per day, which proved refractory to both pharmacological and behavioral treatment at the outpatient, residential, and inpatient level. Provided this, her physician recommended repeated KAP as an exploratory and off-label intervention for her eating disorder. The patient underwent three courses of KAP over 3 months, with each course consisting of six sessions scheduled twice weekly. She showed dramatic reductions in binge-eating and purging following the first course of treatment that continued with the second and third. Complete cessation of behavioral symptoms was achieved 3 months post-treatment. Her remission has sustained for over 1 year to date. Conclusions: To our knowledge, this is the first report of repeated KAP used to treat bulimia nervosa that led to complete and sustained remission, a rare outcome for severe and enduring cases, let alone extreme ones. Additionally, it highlights the degree to which KAP can be tailored at the individual level based on symptom severity and treatment response. While its mechanism of action is unclear, repeated KAP is a promising intervention for bulimia nervosa that warrants future research and clinical practice consideration.
... For example, recent Phase III trials of MDMA for PTSD are showing significant reductions in PTSD symptoms after treatment (Mitchell et al., 2021). Similarly, one study found that giving intraoperative ketamine to US army burn victims resulted in significant reductions in the prevalence of PTSD (McGhee et al., 2008). Besides, a preliminary trial compared intravenous ketamine to midazolam in patients with PTSD and found ketamine produced significantly rapid and pronounced reduction in PTSD symptom severity 24 h after infusion and comorbid depressive symptoms compared to midazolam (Feder et al., 2014). ...
Article
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Trauma exposure across the lifespan produces risks for posttraumatic stress disorder (PTSD), depression, anxiety, as well as global disability in functioning. This retrospective clinical chart review is the first of its kind to assess the utility of sublingual ketamine-assisted body-centered psychotherapy in trauma-exposed patients in a real world clinic setting. De-identified clinical records data on self-reported symptom measures were retrospectively analyzed for patients ( N = 18; M age = 45.22, SD = 12.90) entering ketamine-assisted psychotherapy treatment in an outpatient clinic between 2018 and 2020. Patients who completed six sessions of ketamine therapy reported meaningful (e.g., medium effect size) improvements in PTSD symptoms ( P = 0.058; d = −0.48) and global disability in functioning ( P = 0.050; d = −0.52) and statistically significant and meaningful improvements in depression ( P = 0.019; d = −0.53). There were no improvements in anxiety symptoms. Sublingual ketamine-assisted psychotherapy was associated with heterogenous clinical utility among patients with trauma-exposure in an outpatient setting. This study was underpowered and unrepresentative of the population of ketamine patients in the United States. Replication of these findings is needed with larger and more diverse patient samples.
... There was some specificity for lanicemine's impact on this cluster (Table 3), as its effects on other PTSD symptom clusters were either small (e.g., reexperiencing, negative alterations in cognition/ mood) or failed to distinguish from placebo (e.g., reexperiencing). In humans, intraoperative administration of NMDAR antagonist ketamine may reduce PTSD risk (McGhee et al., 2008;McGhee et al., 2014) and a single and repeated infusions of ketamine, compared to midazolam in patients with PTSD, resulted in rapid and sustained and improvement in PTSD (Albott et al., 2018;Feder et al., 2014; Our results are also consistent with evidence of improvement in hyperarousal symptoms in individuals with PTSD following treatment with low-affinity NMDAR antagonists such as memantine (Battista et al., 2007). ...
Article
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Background Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. Methods Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. Results Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. Conclusion We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.
... Future research in more controlled environments than the combat theater will need to evaluate which combination of multimodal analgesics delivered using RA may influence PTSD symptom trajectories and subsequently pain outcomes after serious injury. For example, researchers have observed that the administration of ketamine, a key component of multimodal pain management, soon after combat-related injury was associated with a lower prevalence of PTSD, however pain outcomes were not examined [43]. ...
Article
Objective This study evaluated the association between pain outcomes and post-traumatic stress disorder (PTSD) symptom trajectories after combat-related injury, while adjusting for receipt of regional anesthesia (RA) soon after injury. Methods The PTSD symptom trajectories of N = 288 combat-injured service members were examined from within a month of injury up to two-years after. Linear mixed-effects models evaluated the association between PTSD symptom trajectories and average pain and pain interference outcomes while adjusting for receipt of RA during combat casualty care. Results Four PTSD trajectories were characterized: resilient, recovering, worsening, and chronic. Differential pain presentations were associated with PTSD symptom trajectories, even after adjusting for receipt of RA. Compared to those with a resilient PTSD symptom trajectory, individuals presenting with chronic PTSD trajectories were estimated to experience average pain scores 2.61 points higher (95% CI: 1.71, 3.14). Participants presenting with worsening (β = 1.42; 95% CI: 0.77, 1.78) and recovering PTSD trajectories (β = 0.65; 95% CI: 0.09, 1.08) were estimated to experience higher average pain scores than participants with resilient PTSD trajectories. Significant differences in pain interference scores were observed across PTSD trajectories. Receiving RA was associated with improved pain up to two years after injury (β =-0.31; 95% CI: -0.90, -0.04), however no statistically significant association was detected between RA and PTSD trajectories. Conclusions PTSD trajectories were associated with greater pain intensity and interference following combat injury even when accounting for receipt of early RA for pain management. These findings underscore the need to jointly assess pain and PTSD symptoms across the trauma care continuum.
... A stereospecific version of (R,S)-ketamine, Spravato (esketamine) (Janssen Pharmaceuticals, Inc., Beerse, Belgium), recently became the first novel Food & Drug Administration-approved treatment for MDD in nearly 20 years (14,15). (R,S)-ketamine can also prevent the onset of learned fear and behavioral despair in mice (16)(17)(18)(19)(20)(21)(22)(23)(24) and may prevent postpartum depression and posttraumatic stress disorder in humans (25)(26)(27)(28). However, despite (R,S)-ketamine's remarkable actions, the compound's side effects include psychotropic effects and high abuse potential, representing a hurdle toward its development as a clinical treatment. ...
Article
BACKGROUND Major depressive disorder (MDD) is a common, recurrent illness. Recent studies have implicated the N-methyl-D-aspartate receptor (NMDAR) in the pathophysiology of MDD. (R,S)-ketamine, an NMDAR antagonist, is an effective antidepressant, but has numerous side effects. Here, we characterized a novel NMDAR antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior. METHODS Saline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning (CFC) in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus (HPC) was quantified with immunohistochemistry or western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu Ammonis 3 (vCA3) one week after injection. RESULTS Given after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPAR-mediated bursts in vCA3, indicating a common neurobiological mechanism for further study. CONCLUSIONS Our results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM’s mechanism of action with the goal of clinical development.
... Increasing evidence also suggests that ketamine, in sub-anesthetic doses, stimulates neurogenesis (Clarke et al., 2017;Duman et al., 2012), cell proliferation (Bai et al., 2013), and synaptogenesis (Duman et al., 2012;Li et al., 2010). An initial study indicated that ketamine decreased the incidence of PTSD in combat veterans who received ketamine during the operation for burns as compared with those who didn't receive ketamine (McGhee et al., 2008). However, another study by the same group did not endorse their initial results (McGhee et al., 2014). ...
Article
Posttraumatic stress disorder (PTSD) is a devastating medical illness, for which currently available pharmacotherapies have poor efficacy. Accumulating evidence from clinical and preclinical animal investigations supports that ketamine exhibits a rapid and persistent effect against PTSD, though the underlying molecular mechanism remains to be clarified. In this literature review, we recapitulate the achievements from early ketamine studies to the most up-to-date discoveries, with an effort to discuss an inclusive therapeutic role of ketamine for PTSD treatment and its possible therapeutic mechanism. Ketamine seems to have an inimitable mechanism of action entailing glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity.
... This makes it ideal in austere situations [53][54][55][56]. Ketamine has been demonstrated as an effective prevention and treatment for PTSD [37,[57][58][59][60][61]. It also appears to be neuroprotective (thought to be related to anti-inflammatory properties) [62][63][64][65], which may explain its role in decreased incidence of PTSD. ...
Article
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Purpose of Review Battlefield medicine is a dynamic and chaotic environment in which to provide care. However, it is critically important for the medical practitioner to provide adequate analgesia for the wounded. Throughout the last two decades of conflict, there have been several changes to how analgesia and sedation are provided in the prehospital setting. Recent Findings Despite the recommendations from the Committee on Tactical Combat Casualty Care (CoTCCC), adherence to the guidelines has been poor to moderate. Additionally, Prolonged Field Care (PFC) guidelines offer additional recommendations, which can differ from CoTCCC guidelines. There are several factors that impact adherence including conflicting references, leadership, and logistical issues. Expanding the current prehospital approach to analgesia and sedation may help increase adherence. Summary The two prominent guidelines for military prehospital care, TCCC and PFC, offer an evidence-based approach to providing analgesia and sedation on the battlefield that should help increased optimal battlefield analgesia.
... • The experimental use of 5HT 4 receptor agonists in reducing anxiety and depressive symptoms in healthcare workers exposed to chronic stress (Chen et al., 2020b). • The use of ketamine, already approved for the acute treatment of depression and suicidal behavior in humans, in subjects at high risk of pandemic-related stress (McGhee et al., 2008;Weinbroum, 2021); the efficacy of this drug appears to depend on intact monoamine pathways (Bowman et al., 2020). ...
Article
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Healthcare workers are at a high risk of psychological morbidity in the face of the COVID-19 pandemic. However, there is significant variability in the impact of this crisis on individual healthcare workers, which can be best explained through an appreciation of the construct of resilience. Broadly speaking, resilience refers to the ability to successfully adapt to stressful or traumatic events, and thus plays a key role in determining mental health outcomes following exposure to such events. A proper understanding of resilience is vital in enabling a shift from a reactive to a proactive approach for protecting and promoting the mental well-being of healthcare workers. Research in the past decade has identified six areas that provide promising leads in understanding the biological basis of individual variations in resilience. These are: (1) the key role played by the monoamines noradrenaline and serotonin, (2) the centrality of the hypothalamic-pituitary-adrenal axis in influencing stress vulnerability and resilience, (3) the intimate links between the immune system and stress sensitivity, (4) the role of epigenetic modulation of gene expression in influencing the stress response, (5) the role played by certain neuropeptides as a natural “brake” mechanism in the face of stress, and (6) the neurobiological mechanisms by which environmental factors, such as exercise, diet, and social support, influence resilience to subsequent life events. Though much of this research is still in its early stages, it has already provided valuable information on which strategies – including dietary changes, lifestyle modification, environmental modification, psychosocial interventions, and even pharmacological treatments – may prove to be useful in fostering resilience in individuals and groups. This paper examines the above evidence more closely, with a specific focus on the challenges faced by healthcare workers during the COVID-19 pandemic, and provides suggestions regarding how it may be translated into real-world interventions, as well as how the more tentative hypotheses advanced in this field may be tested during this critical period.
... W. Kalivas, 1995;Wolf, 1998;Wolf & Jeziorski, 1993;Wolf, White, & Hu, 1994). Effects of ketamine on sensitization are rapid (Gaytan, Swann, & Dafny, 2002) and ketamine has been shown clinically to reduce trauma-related symptoms and PTSD (Albott et al., 2018;Feder et al., 2014;McGhee, Maani, Garza, Gaylord, & Black, 2008) although not all studies have reported this Table 3. Each time point demonstrated significant separation among the three groups using an adjusted alpha value of at least .05, ...
Article
Background: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response. Methods: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations. Results: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01). Limitations: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available. Conclusions: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.
Chapter
Burn injury is a threat in both the civilian and military environments. Given the growing threat of terrorism and the fact that the vast majority of terrorist acts involve the use of explosive devices, clinicians must be familiar with the injury patterns, treatment issues, and terminology surrounding explosive incidents. Most explosive events involve some form of burn injury to those exposed. An understanding of burns is necessary for all personnel involved in the planning, response, and treatment of explosive events to reduce morbidity and mortality. Specialized resources, such as burn centers and treatment modalities, are important for the care, treatment, and recovery of burn victims.
Article
Opioid use disorder (OUD) is a mounting public health problem with substantial morbidity and mortality. Stress involvement in the course of OUD is generally accepted, but little is understood about the underlying neurobiological mechanisms in part due to a lack of laboratory-based models for chronic stress exposure. Post-traumatic stress disorder (PTSD) may be construed as a psychopathological prototype of chronic stress owing to the essential diagnostic criteria of experiencing and reliving a stressful event(s). Literature search on OUD and PTSD neurobiology was undertaken and the relevant data were integrated within four key areas: (1) OUD and PTSD comorbidity; (2) neurobiological overlap between OUD and PTSD; (3) chronic opioids- and stress-induced alterations of the reward-, stress- (i.e., "anti-reward") and related circuits and (4) mechanistically informed treatments of OUD and/or PTSD. Our findings suggest that even in the absence of prior opioid exposure PTSD patients may be susceptible for the development of OUD by the reason of similar (to those induced by opioids) reward alterations that may be targeted for therapeutic interventions.
Article
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Objective PTSD is increasingly recognized following medical traumas although is highly heterogeneous. It is difficult to judge which medical contexts have the most traumatic potential and where to concentrate further research and clinical attention for prevention, early detection and treatment. The objective of this study was to compare PTSD prevalence in different medical populations. Methods A systematic review of the literature on PTSD following medical traumas was conducted as well as a meta-analysis with final pooled result and 95% confidence intervals presented. A metaregression was used to investigate the impact of potential effect modifiers (PTSD severity, age, sex, timeline) on study effect size between prevalence studies. Results From 3278 abstracts, the authors extracted 292 studies reporting prevalence. Using clinician-administered reports, the highest 24 month or longer PTSD prevalence was found for intraoperative awareness (18.5% [95% CI=5.1%-36.6%]) and the lowest was found for epilepsy (4.5% [95% CI=0.2%-12.6%]). In the overall effect of the metaregression, only medical events or procedures emerged as significant (p = 0.006) Conclusion This review provides clinicians with greater awareness of medical contexts most associated with PTSD, which may assist them in the decision to engage in more frequent, earlier screening and referral to mental health services.
Article
Background : Post-traumatic stress disorder (PTSD) is a debilitating mental disease with high morbidity and major social and economic relevance. No efficient treatment for PTSD has thus far been identified. Clinical research has shown that ketamine can rapidly alleviate symptoms in patients with chronic PTSD; however, its pharmacological mechanism has yet to be determined. Methods : This study aimed to identify a model of single prolonged stress (SPS), which induced PTSD-like features in adult mice. Once the model was established, stress-related behavioral changes in the mouse model were evaluated after intraperitoneal injection of ketamine (10 mg/kg). Alterations in certain proteins (HCN1, BDNF, and PSD95) and synaptic ultrastructure in the prefrontal cortex (PFC) and hippocampus (HIP) were measured. Results : The mice under the SPS model exhibited anxiety- and depression-like behaviors and induced spatial cognitive deficits, accompanied by elevated HCN1 protein expression in the PFC and HIP, reduced brain-derived neurotrophic factor (BDNF) and PSD95 proteins, and alterations in synaptic morphology. After ketamine administration, the SPS-treated mice restored their protein levels and synaptic ultrastructure in the PFC, and their PTSD-like behaviors improved. However, learning and memory in the SPS-treated mice did not improve in the water maze test, and no significant changes in protein level and synaptic ultrastructure in the HIP were shown. Limitations : The electrophysiological mechanism of the HCN1 ion channel after ketamine administration was not explored. Conclusion : Ketamine could generally improve SPS-induced mood dysfunction in mice but exerted no effect on the spatial cognitive function, which could be related to the alterations in synaptic morphology and function mediated by HCN1-related BDNF signaling in the PFC and HIP.
Article
Current pharmacotherapy for post-traumatic stress disorder (PTSD), a debilitating psychiatric condition that develops in a subset of traumatized individuals, is inadequate. Over the past two decades, numerous studies have shown that ketamine, a non-competitive NMDA receptor antagonist, exerts rapid antidepressant effects in both humans and rodents, but the anxiolytic profile of ketamine, as well as its ability to treat PTSD-related symptoms, is still unclear. Thus, we examined the ability of a single administration of ketamine to prevent the onset of PTSD-like sequelae in a chronic psychosocial stress model of PTSD. Adult male and female Sprague-Dawley rats were exposed to a cat on two occasions, in combination with chronic social instability. Immediately following the cat exposure on Day 1, rats were given intraperitoneal injections of 10 mg/kg or 15 mg/kg ketamine or vehicle; control rats were injected with vehicle. Three weeks after the second cat exposure, we assessed symptoms of hyperarousal and anxiety-like behavior in the rats. In males, chronic stress led to greater anxiety on the elevated plus maze and in the open field; in females, chronic stress resulted in an exaggerated startle response and greater anxiety in the open field. These effects were most effectively prevented by the administration of 10 mg/kg ketamine. These findings demonstrate that ketamine can prophylactically prevent the onset of PTSD-like behaviors in males and females. Their sex-dependent nature is consistent with previous preclinical research and highlights the need for future research to examine their neurobiological basis.
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Burn injuries are among the most frequently encountered incidents for prehospital personnel. Prioritized response, patient assessment and management, and safe, timely transport of the burn patient to a designated burn center within an organized regional system is correlated with significantly improved patient outcomes. Educating EMS personnel to apply critical thinking to promote maintenance of oxygenation and adequate ventilation through selective airway management, maintain organ perfusion and limit secondary injury, manage pain, frequently reassess the patient, and promptly transport to the appropriate facility are all critical to appropriate management of the burn patient. Proactive medical oversight fosters optimal care through use of evidence-based treatment protocols and application of field triage criteria to appropriately direct patient destination.
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Objective: Acute pain management is fundamental in prehospital trauma care. Early pain control may decrease the risk of developing post-traumatic stress disorder (PTSD) and chronic pain. Fentanyl and ketamine are frequently used off-label, but there is a paucity of comparative data to guide decision-making about treatment of prehospital severe, acute pain. This trial will determine whether the addition of single dose of intranasal ketamine to fentanyl is more effective for the treatment of acute traumatic pain than administration of fentanyl alone. Methods: This two-part study consists of prehospital and 90-day follow-up components (NCT02866071). The prehospital trial is a blinded, randomized, controlled trial of adult men (age 18-65 years) rating pain ≥7/10 after an acute traumatic injury of any type. Women will be excluded due to inability to confirm pregnancy status and unknown fetal risk. Paramedics will screen patients receiving standard of care fentanyl and, after obtaining standard informed consent, administer 50 mg intranasal ketamine or matching volume saline as placebo. Upon emergency department (ED) arrival, research associates will serially assess pain, concomitant treatments, and adverse side effects. Enrolled subjects will be approached for consent to participate in the 90-day follow-up study to determine rates of PTSD and chronic pain development. The primary outcome of the prehospital study is reduction in pain on the Verbal Numerical Rating Scale between baseline and 30-minutes after study drug administration. The proportion achieving a reduction of ≥2-points will be compared between study arms using a Chi-square test. Secondary outcomes of the prehospital trial include reduction in reported pain at the time of ED arrival and at 30 minutes intervals for up to three hours of ED care, the incidence of adverse events, and additional opiate requirements prior to ED arrival and within the first three hours of ED care. The outcomes in the follow-up study are satisfaction with life and development of PTSD or chronic pain at 90 days after injury. An intention-to-treat approach will be used. Conclusion: These studies will test the hypotheses that ketamine plus fentanyl, when compared to fentanyl alone, effectively manages pain, decreases opiate requirements, and decreases PTSD at 90 days.
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Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.
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Post-traumatic stress disorder (PTSD) is a complex disorder that involves dysregulation of multiple neurobiological systems. The traumatic stressor plays a causal role in producing psychological dysfunction and the pattern of findings suggests that the hypothalamic–pituitary–adrenal (HPA) axis, which is instrumental for stress adaptation, is critically dysfunctional in PTSD. Given the lack of understanding of the basic mechanisms and underlying pathways that cause the disorder and its heterogeneity, PTSD poses challenges for treatment. Targeting the endocannabinoid (ECB) system to treat mental disorders, and PTSD in particular, has been the focus of research and interest in recent years. The ECB system modulates multiple functions, and drugs enhancing ECB signaling have shown promise as potential therapeutic agents in stress effects and other psychiatric and medical conditions. In this review, we focus on the interaction between the ECB-HPA systems in animal models for PTSD and in patients with PTSD. We summarize evidence supporting the use of cannabinoids in preventing and treating PTSD in preclinical and clinical studies. As the HPA system plays a key role in the mediation of the stress response and the pathophysiology of PTSD, we describe preclinical studies suggesting that enhancing ECB signaling is consistent with decreasing PTSD symptoms and dysfunction of the HPA axis. Overall, we suggest that a pharmacological treatment targeted at one system (e.g., HPA) may not be very effective because of the heterogeneity of the disorder. There are abnormalities across different neurotransmitter systems in the pathophysiology of PTSD and none of these systems function uniformly among all patients with PTSD. Hence, conceptually, enhancing ECB signaling may be a more effective avenue for pharmacological treatment.
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Introduction: Acute stress disorder (ASD) and post-traumatic stress disorder (PTSD) are chronic diseases which can affect patients following a severe trauma. As these patients typically first present to the emergency department, it is critical for emergency physicians to remain updated on the use of ketamine or other anesthetic agents which may impede development or reduce symptoms which may impair normal functioning. The purpose of this clinical review was is to review the literature regarding how the use of peritraumatic ketamine could decrease the incidence of ASD and PTSD. In 2019, the authors completed a MEDLINE search was performed yielding 25 articles which were initially evaluated by the first and second authors. Four articles which met inclusion criteria are discussed in this manuscript. Summary of evidence: Although two earlier research groups have found that peritraumatic ketamine administration contributed to increased symptoms of PTSD (e g., reexperiencing, dissociation, avoidance, and hyperarousal), two later studies have indicated that ketamine had no effect on PTSD development. Additionally, one 2012 study group has suggested propofol use may alleviate PTSD symptoms at six months post-trauma. Another 2017 study team found that the number of surgical procedures was directly correlated with increased PTSD development. Conclusions: Based on the literature to date, peritraumatic ketamine does not appear to influence the prevention nor development of ASD and subsequent PTSD. More research is needed to clarify the psychopharmacologic effects of ketamine when used in the management of reactions to acute trauma experiences. Based on the results of the two later works, future research is indicated considering whether propofol may contribute to PTSD development.
Chapter
Blast-injured patients may have occult injuries that should be fully evaluated prior to transport, as patient movement can worsen clinical status. There are multiple modes of transportation which all offer different benefits, but similarly present both logistical and clinical challenges. The best way to manage casualty evacuation to a higher level of care is to match the clinical scenario with available resources. Furthermore, having a framework for evaluation and movement will lead to more organized and safer care.
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RationaleSince the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus.Objectives To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD.Methods We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm).ResultsExposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats.Conclusion The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD.
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Cyclic 3',5' adenosine monophosphate (cAMP) is a second messenger of the beta adrenergic receptor (betaAR). Ketamine causes an increase in the intracellular accumulation of cAMP in several non-human tissue preparations. A "species effect" may explain the differing results of ketamine on betaAR mediated responses, thus reports of a ketamine-induced increase in cAMP in other species may not be applicable to humans. The effect of ketamine (10(-3), 10(-4), or 10(-5) M) pretreatment (60 and 120 min) on isoproterenol [ISO, a beta adrenergic receptor (AR) agonist] or forskolin [FSK, an activator of adenylylcyclase (AC)]-induced intracellular accumulation of cAMP in a human airway smooth muscle (tracheal) cell line (HASM) was evaluated. In an in vitro HASM culture, cells with or without pretreatment were labeled with [3H]adenine to produce [3H]ATP, and following stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP, the intracellular accumulation of [3H]cAMP was measured by sequential chromatography over Dowex and alumina columns. Pretreatment of the HASM cells with ketamine (10(-3) and 10(-4) M) caused a reduction (P < 0.05, when compared to untreated cells) in ISO-induced cAMP accumulation, but did not effect cAMP accumulation following FSK stimulation. This effect of ketamine was greater at 120 min of pretreatment than at 60 min (10(-3) M ketamine only)(P < 0.05). No effect was found at either time period following pretreatment of the HASM cells with ketamine 10(-5) M. These results demonstrate that pretreatment of the HASM cells with ketamine reduces ISO-induced cAMP accumulation. Since only ISO-induced cAMP was effected by ketamine, these data suggest that ketamine inhibits production of cAMP proximal to AC in the cAMP production pathway. These results also demonstrate that a mechanism other than that involving the betaAR and intracellular cAMP accumulation is responsible for the ketamine induced bronchodilation in humans.
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The current combat operations in Iraq and Afghanistan have involved US military personnel in major ground combat and hazardous security duty. Studies are needed to systematically assess the mental health of members of the armed services who have participated in these operations and to inform policy with regard to the optimal delivery of mental health care to returning veterans. We studied members of 4 US combat infantry units (3 Army units and a Marine Corps unit) using an anonymous survey that was administered to the subjects either before their deployment to Iraq (n=2530) or 3 to 4 months after their return from combat duty in Iraq or Afghanistan (n=3671). The outcomes included major depression, generalized anxiety, and posttraumatic stress disorder (PTSD), which were evaluated on the basis of standardized, self-administered screening instruments. Exposure to combat was significantly greater among those who were deployed to Iraq than among those deployed to Afghanistan. The percentage of study subjects whose responses met the screening criteria for major depression, generalized anxiety, or PTSD was significantly higher after duty in Iraq (15.6% to 17.1%) than after duty in Afghanistan (11.2%) or before deployment to Iraq (9.3%); the largest difference was in the rate of PTSD. Of those whose responses were positive for a mental disorder, only 23% to 40% sought mental health care. Those whose responses were positive for a mental disorder were twice as likely as those whose responses were negative to report concern about possible stigmatization and other barriers to seeking mental health care. This study provides an initial look at the mental health of members of the Army and the Marine Corps who were involved in combat operations in Iraq and Afghanistan. Our findings indicate that among the study groups there was a significant risk of mental health problems and that the subjects reported important barriers to receiving mental health services, particularly the perception of stigma among those most in need of such care. The recent military operations in Iraq and Afghanistan, which have involved the first sustained ground combat undertaken by the United States since the war in Vietnam, raise important questions about the effect of the experience on the mental health of members of the military services who have been deployed there. Research conducted after other military conflicts has shown that deployment stressors and exposure to combat result in considerable risks of mental health problems, including posttraumatic stress disorder, major depression, substance abuse, impairment in social functioning and in the ability to work, and the increased use of healthcare services. One study that was conducted just before the military operations in Iraq and Afghanistan began found that at least 6% of all US military service members on active duty receive treatment for a mental disorder each year. Given the ongoing military operations in Iraq and Afghanistan, mental disorders are likely to remain an important healthcare concern among those serving there. Many gaps exist in the understanding of the full psychosocial effect of combat. The all-volunteer force deployed to Iraq and Afghanistan and the type of warfare conducted in these regions are very different from those involved in past wars, differences that highlight the need for studies of members of the armed services who are involved in the current operations. Most studies that have examined the effects of combat on mental health were conducted among veterans years after their military service had ended. A problem in the methods of such studies is the long recall period after exposure to combat. Very few studies have examined a broad range of mental health outcomes near to the time of subjects' deployment. Little of the existing research is useful in guiding policy with regard to how best to promote access to and the delivery of mental health care to members of the armed services. Although screening for mental health problems is now routine both before and after deployment and is encouraged in primary care settings, we are not aware of any studies that have assessed the use of mental health care, the perceived need for such care, and the perceived barriers to treatment among members of the military services before or after combat deployment. We studied the prevalence of mental health problems among members of the US armed services who were recruited from comparable combat units before or after their deployment to Iraq or Afghanistan. We identified the proportion of service members with mental health concerns who were not receiving care and the barriers they perceived to accessing and receiving such care.
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The authors' goal was to examine the course and predictors of posttraumatic stress symptoms among persons hospitalized for burns. A total of 301 participants completed self-report measures assessing peritraumatic mental state, anxiety related to pain, and posttraumatic stress symptoms. Twenty-six percent of the participants were suffering from posttraumatic stress symptoms at 2-3 weeks postburn and 15% of them at 12 months postburns. In general, a decrease in symptoms was observed over time, although a substantial part of the participants with acute stress symptoms suffers from chronic posttraumatic stress symptoms 1-year postburn. Symptoms were predicted by anxiety measures and objective factors, such as female gender, locus, and severity of injury.
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Our previous studies have demonstrated that the JNK signaling pathway plays an important role in ischemic brain injury and is mediated via glutamate receptor 6. Others studies have shown that N-methyl-d-aspartate (NMDA) receptor is involved in the neuroprotection of ischemic preconditioning. Here we examined whether ischemic preconditioning down-regulates activation of the mixed lineage kinase-JNK signaling pathway via NMDA receptor-mediated Akt1 activation. In our present results, ischemic preconditioning could not only inhibit activations of mixed lineage kinase 3, JNK1/2, and c-Jun but also enhanced activation of Akt1. In addition, both NMDA (an agonist of NMDA receptor) and preconditioning showed neuroprotective effects. In contrast, ketamine, an antagonist of NMDA receptor, prevented the above effects of preconditioning. Further studies indicated that LY294002, an inhibitor of phosphoinositide 3-kinase that is an upstream signaling protein of Akt1, could block neuroprotection of preconditioning, and KN62, an inhibitor of calmodulin-dependent protein kinase, also achieved the same effects as LY294002. Therefore, both phosphoinositide 3-kinase and calmodulin-dependent protein kinase are involved in the activation of Akt1 in ischemic tolerance. Taken together, our results indicate that preconditioning can inhibit activation of JNK signaling pathway via NMDA receptor-mediated Akt1 activation and induce neuroprotection in hippocampal CA1 region.
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Background: There has been growing empirical examination of the co-occurrence of pain and post-traumatic stress disorder (PTSD) symptoms, and existing evidence suggests that the symptoms associated with each have a close association. To date, however, the association has only been examined within samples of mostly male participants. Aim: In the present study, pain and PTSD symptoms were examined in a sample of 221 female veterans who utilised the VA Healthcare System between 1998 and 1999. Method: Women who visited the clinic between 1998 and 1999 were mailed a self-report questionnaire package designed to elicit information regarding general health (including pain experiences), military and trauma history, childhood abuse and neglect, and PTSD symptoms. Analyses were conducted to identify differences in pain experience between those women classified as having PTSD, subsyndromal PTSD, and no PTSD. Analyses were also conducted to determine the degree to which pain-related (e.g., current pain, interference with activity) variables predicted PTSD symptom cluster scores. Results: The three groups differed significantly on a number of pain-related variables. Analyses suggested that pain-related variables were significant predictors of PTSD symptom cluster scores. Conclusions: These results indicate that the association between pain and PTSD symptoms, previously observed in primarily male samples, is generalisable to females. Clinical implications and possible mechanisms of association are discussed.
Article
Purpose: Cyclic 3',5' adenosine monophosphate (cAMP) is a second messenger of the beta adrenergic receptor (BAR). Ketamine causes an increase in the intracellular accumulation of cAMP in several non-human tissue preparations. A "species effect" may explain the differing results of ketamine on beta AR mediated responses, thus reports of a ketamine-induced increase in cAMP in other species may not be applicable to humans. Methods: The effect of ketamine (10(-3), 10(-4), or 10(-5) M) pretreatment (60 and 120 min) on isoproterenol [ISO, a beta adrenergic receptor (AR) agonist] or forskolin [FSK, an activator of adenylylcyclase(AC)]-induced intracellular accumulation of cAMP in a human airway smooth muscle (tracheal) cell line (HASM) was evaluated. in an in vitro HASM culture, cells with or without pretreatment were labeled with [H-3]adenine to produce [H-3]ATP and following stimulation with ISO or FSK to convert the [H-3]ATP to [H-3]cAMP the intracellular accumulation of [H-3]cAMP was measured by sequential chromatography over Dowex and alumina columns. Results: Pretreatment of the HASM cells with ketamine (10(-3) and 10(-4) M) caused a reduction (P < 0.05, when compared to untreated cells) in ISO-induced cAMP accumulation, but did not effect cAMP accumulation following FSK stimulation, This effect of ketamine was greater at 120 min of pretreatment than at 60 min (10(-3) M ketamine only)(P < 0.05). No effect was found at either time period following pretreatment of the HASM cells with ketamine 10(-5). Conclusions: These results demonstrate that pretreatment of the HASM cells with ketamine reduces ISO-induced cAMP accumulation. Since only ISO-induced cAMP was effected by ketamine, these data suggest that ketamine inhibits production of cAMP proximal to AC in the cAMP production pathway. These results also demonstrate that a mechanism other than that involving the beta AR and intracellular cAMP accumulation is responsible for the ketamine induced brondchodilation in humans.
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The authors' goal was to examine subjective and objective predictors of posttraumatic stress disorder (PTSD). Hospitalized burn patients were assessed 1 week after injury with both objective predictors (percent of burned area and facial disfigurement) and subjective predictors (emotional distress and perceived social support). The patients were then assessed 2, 6, and 12 months later for development of PTSD. Among 51 patients, 18 (35.3%) met PTSD criteria at 2 months. High rates of PTSD were also found at 6 months (N = 16, 40.0% of the 40 available patients) and 12 months (N = 14, 45.2% of the 31 available patients). PTSD was predicted by subjective variables assessed at baseline, but patients with more severe burns were not more likely to develop PTSD. The DSM-III-R diagnosis of PTSD relies on an objective evaluation of the stressor's severity. The prospective data in this study support those who argue that evaluations of the severity of the stressor might also take into account subjective factors.
Article
1. Stable N-methyl-D-aspartic acid (NMDA) receptor-mediated currents in cultured mouse hippocampal neurons were evoked by 20 ms pressure pulse applications of L-aspartate, repeatedly applied at 30 or 40 s intervals, to the cell body region of the neurone. We have characterized the voltage- and use-dependent blockade of the currents by three dissociative anaesthetics: ketamine, phencyclidine (PCP) and MK-801 in mouse hippocampal neurones grown in dissociated tissue culture. 2. We have used a simple model of the blockade, based on the 'guarded receptor hypothesis' to interpret our data. The model assumes that receptors are maximally activated at the peak of the response with an open probability (Po) approaching 1, that there is no desensitization and that the blocking drug only associates with, or dissociates from, receptor channels which have been activated by agonist (e.g. open channels). 3. The model allows us to estimate forward and reverse rate constants for binding of the blockers to open channels from measurements of the steady-state level of blockade and the rate of change of the current amplitude per pulse during onset and offset of blockade. As predicted by the model, the estimated reverse rate was independent of blocker concentration while the forward rate increased with concentration. Changing the level of positively charged ketamine (pKa 7.5) tenfold by changing pH from 6.5 to 8.5 caused a corresponding change in the forward rate while having no effect on the reverse rate. Most of the voltage dependence of the blockade could be accounted for by reduction of the reverse rate by depolarization. 4. Estimated forward rate constants for ketamine, PCP and MK-801 were similar to one another when measured under similar conditions and were 3 x 10(4) - 3 x 10(5) M-1 S-1. Most of the differences in potency of the three blockers could be accounted for by differences in the reverse rate constants which were approximately 0.2, 0.03 and 0.003 s-1 for ketamine, PCP and MK-801, respectively. The estimated rate constants actually are the product of the rate constants and 1/Po. Suggestions that maximum Po is much less than 1 for NMDA channels imply that both forward and reverse rate constants of blockade may in fact be larger than we have calculated. However, their magnitudes, relative to one another, are unaffected by this consideration. 5. The reverse rate constant of blockade increased at positive potentials. This increase was prevented when the neurone was loaded with N-methyl-D-glucamine, an impermeant cation which prevented outward currents.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
N-Methyl-D-aspartate (NMDA)-induced translocation of protein kinase C (PKC) from cytosol to membrane fractions was examined by the methods of [3H]phorbol 12,13-dibutyrate binding and western blotting in rat hippocampal slices. NMDA and L-glutamate induced translocation of PKC from cytosol to membrane fractions in immature rat hippocampal slices, but not in mature ones. The NMDA-induced translocation of PKC was dependent on Ca2+. It was inhibited by the NMDA receptor antagonists, 2-amino-5-phosphonovaleric acid and ketamine, but not by Mg2+ and Zn2+. These results suggest that stimulation of NMDA receptors enhances Ca2+ influx and thereby induces translocation of PKC in immature rat hippocampus.
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The degree to which patients hospitalized for a major burn displayed symptoms of post-traumatic stress disorder or met the full criteria for this disorder was assessed during the course of hospitalization. Fifty-four consecutive patients were screened weekly for symptoms of post-traumatic stress disorder. Sixty-three percent showed intrusive recollections of the initial trauma (partial diagnostic criteria) and 16 (29.6%) of the sample met full criteria for post-traumatic stress disorder at some point during the hospitalization. None of the patients met the full diagnostic criteria at discharge from the hospital, although one did at follow-up. Post-traumatic stress disorder was found to be related to patients' total body surface area burn, length of hospital stay, sex (female patients), and lack of responsibility for the injury. The results suggest that although post-traumatic stress disorder in patients with burn injuries generally resolves without interventions other than standard hospital care, it might be preventable if patients who are at risk for developing it receive appropriate psychologic treatment soon after the injury.
Article
The present investigation was conducted to study the relationship between intracellular Ca2+ and inhibition of large conductance Ca(2+)-activated K+ (BK) currents by ketamine using excised patches from GH3 cells. Five ketamine concentrations were studied in the presence of six Ca2+ concentrations. The half-maximal inhibition for BK channel block by ketamine was increased from 4.1 +/- 0.7 microM at 0.1 microM intracellular Ca2+ to 230 +/- 74 microM at 100 microM intracellular Ca2+. Open probability (Po), Ca2+ concentration, and ketamine concentration data were best described by a competitive inhibition model. The inhibition constant for ketamine was 20.5 +/- 5.2 microM, and the Michaelis-Menten constant (Km) value for Ca2+ was 3.58 +/- 0.49 microM, which was not different from Km for Ca2+ in the absence of ketamine (3.33 +/- 0.37 microM). Taken alone, these data would suggest that Ca2+ and ketamine were competing for the same site on the channel protein. However, examination of open and closed interval data from patches containing only one channel show that ketamine primarily produces a decrease in the frequency of long-lived open events, suggesting that the effect of ketamine on BK channels may not be by a direct effect on channel proteins.
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Among 39 patients with burns evaluated a mean of 12 months after hospital discharge, 38% met DSM-III-R criteria for post-traumatic stress disorder (PTSD) for at least 1 month. With proposed DSM-IV criteria, 43% met criteria for past or current PTSD. Analysis of specific symptom clusters of PTSD revealed that 74% of patients had been affected by a reexperience symptom for at least 1 month, but only 30% were currently experiencing flashbacks. No correlation was found between several clinical correlates (TBSA, length of hospitalization, and age) and development of PTSD. There was no correlation between presence of a DSM-III-R psychiatric diagnosis at the time of hospitalization and later development of PTSD and no correlation between whether or not a psychiatric diagnosis emerged during hospitalization and later development of PTSD. Finally, patients who had injuries that they could not prevent were no more likely to experience PTSD.
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The psychometric properties of the PTSD Checklist (PCL), a new, brief, self-report instrument, were determined on a population of 40 motor vehicle accident victims and sexual assault victims using diagnoses and scores from the CAPS (Clinician Administered PTSD Scale) as the criteria. For the PCL as a whole, the correlation with the CAPS was 0.929 and diagnostic efficiency was 0.900 versus CAPS. Examination of the individual items showed wide ranging values of individual item correlations ranging from 0.386 to 0.788, and with diagnostic efficiencies of 0.700 or better for symptoms. We support the value of the PCL as a brief screening instrument for PTSD.
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The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is blocked by ketamine, and this action likely contributes to ketamine's anesthetic and analgesic properties. Previous studies suggest that ketamine occludes the open channel by binding to a site located within the channel pore. This hypothesis was examined by investigating the effects of ketamine on single-channel currents from NMDA receptors. The cell-attached and outside-out configurations of the patch clamp technique were used to study NMDA-activated currents recorded from cultured mouse hippocampal neurons. In cell-attached patches, NMDA evoked currents that had an apparent mean open time (tau o) of 3.26 ms. The probability of at least one channel being open (Po') was 0.058. The addition of ketamine (0.1 microM or 1 microM) to the pipette solution decreased Po' to 53% and 24% of control values, respectively. At 1 microM ketamine, this reduction was due to a decrease in both the frequency of channel opening and the mean open time (44% and 68% of control values, respectively). Ketamine did not influence channel conductance and no new components were required to fit the open- or closed-duration distributions. Ketamine (50 microM), applied outside the recording pipette, reduced the opening frequency of channels recorded in the cell attached configuration. This observation suggests that ketamine gained access to a binding site by diffusing across the hydrophobic cell membrane. In outside-out patches, ketamine potency was lower than that observed in cell-attached patches: 1 microM and 10 microM ketamine reduced Po' to 63% and 34% of control values, respectively, and this reduction was due primarily to a decrease in the frequency of channel opening with little change in mean open time. These observations are consistent with a model whereby ketamine inhibits the NMDA receptor by two distinct mechanisms: (1) Ketamine blocks the open channel and thereby reduces channel mean open time, and (2) ketamine decreases the frequency of channel opening by an allosteric mechanism.
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This article describes the relationship between post-traumatic morbidity, anxious anticipation of pain and pain perception in 33 adult burn patients. Burn patients were assessed, on average, 7 days after admission to the hospital. Five times a day nurses asked the patients to provide pain ratings. The more patients suffered from post-traumatic stress, the more their anxiety state was elevated. The association between post-traumatic stress and pain perception was, controlling for the effects of anxious anticipation, spurious.
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Common sequelae following a traumatic event include chronic pain and posttraumatic stress disorder (PTSD). Over the last decade, the literature relating to PTSD has become progressively more sophisticated, resulting in well-supported theories and treatments for sufferers. Equivalent research relating to chronic pain has more recently gathered momentum. However, to date there has been minimal attention devoted to the concurrence of the two disorders, even though high comorbidity has been noted. This review begins by briefly summarizing the literature relating to the two disorders in terms of symptoms, prevalence and comorbidity. It explicates the major psychological theories of chronic pain and PTSD and reviews the evidence relating what factors maintain the disorders. A number of pathways by which chronic pain and PTSD may be mutually maintaining are highlighted. We conclude that chronic pain and PTSD are mutually maintaining conditions and that there are several pathways by which both disorders may be involved in the escalation of symptoms and distress following trauma. Treatment implications are considered, as are issues for future research.
Article
It is common for individuals with symptoms of posttraumatic stress disorder (PTSD) to present with co-occurring pain problems, and vice versa. However, the relation between these conditions often goes unrecognized in clinical settings. In this paper, we describe potential relations between PTSD and chronic pain and their implications for assessment and treatment. To accomplish this, we discuss phenomenological similarities of these conditions, the prevalence of chronic pain in patients with PTSD, and the prevalence of PTSD in patients with chronic pain. We also present several possible explanations for the co-occurrence of these disorders, based primarily on the notions of shared vulnerability and mutual maintenance. The paper concludes with an overview of future research directions, as well as practical recommendations for assessing and treating patients who present with co-occurring PTSD or chronic pain symptoms.
Article
There has been growing empirical examination of the co-occurrence of pain and post-traumatic stress disorder (PTSD) symptoms, and existing evidence suggests that the symptoms associated with each have a close association. To date, however, the association has only been examined within samples of mostly male participants. In the present study, pain and PTSD symptoms were examined in a sample of 221 female veterans who utilised the VA Healthcare System between 1998 and 1999. Women who visited the clinic between 1998 and 1999 were mailed a self-report questionnaire package designed to elicit information regarding general health (including pain experiences), military and trauma history, childhood abuse and neglect, and PTSD symptoms. Analyses were conducted to identify differences in pain experience between those women classified as having PTSD, subsyndromal PTSD, and no PTSD. Analyses were also conducted to determine the degree to which pain-related (e.g., current pain, interference with activity) variables predicted PTSD symptom cluster scores. The three groups differed significantly on a number of pain-related variables. Analyses suggested that pain-related variables were significant predictors of PTSD symptom cluster scores. These results indicate that the association between pain and PTSD symptoms, previously observed in primarily male samples, is generalisable to females. Clinical implications and possible mechanisms of association are discussed.
Article
This study examined rates, predictors, and course of probable posttraumatic stress disorder (PTSD) and depression among seriously injured soldiers during and following hospitalization. The patients were 613 U.S. soldiers hospitalized following serious combat injury. Standardized screening instruments were administered 1, 4, and 7 months following injury; 243 soldiers completed all three assessments. Cross-sectional and longitudinal analyses of risk factors were performed. PTSD was assessed with the PTSD Checklist; depression was assessed with the Patient Health Questionnaire. Combat exposure, deployment length, and severity of physical problems were also assessed. At 1 month, 4.2% of the soldiers had probable PTSD and 4.4% had depression; at 4 months, 12.2% had PTSD and 8.9% had depression; at 7 months, 12.0% had PTSD and 9.3% had depression. In the longitudinal cohort, 78.8% of those positive for PTSD or depression at 7 months screened negative for both conditions at 1 month. High levels of physical problems at 1 month were significantly predictive of PTSD (odds ratio=9.1) and depression at 7 months (odds ratio=5.7) when the analysis controlled for demographic variables, combat exposure, and duration of deployment. Physical problem severity at 1 month was also associated with PTSD and depression severity at 7 months after control for 1-month PTSD and depression severity, demographic variables, combat exposure, and deployment length. Early severity of physical problems was strongly associated with later PTSD or depression. The majority of soldiers with PTSD or depression at 7 months did not meet criteria for either condition at 1 month.
Predictors of posttraumatic stress disorder after burn injury Ketamine: its mechanism(s) of action and unusual clinical uses
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Chronic pain and posttraumatic stress disorder: mutual maintenance?
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Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psychol Rev. 2001;21:857– 877.