Pharmacological Prevention of Combat-Related PTSD: A Literature Review

MILITARY MEDICINE, 177, 6:649, 2012 Pharmacological Prevention of Combat-Related PTSD: A Literature Review Cristina P. Searcy, MSN, FNP-C*; Leonardo Bobadilla, PhD ; Winford A. Gordon, PhD ; Sharon Jacques, PhD*; Lydia Elliott, DNP, FNP-BC* ABSTRACT Preventing posttraumatic stress disorder (PTSD) could have a significant positive impact on military readiness and quality of life. Few studies have examined whether pharmacological agents may prevent PTSD, and there has not been a systematic and critical review of these studies in order to guide future research efforts. We performed a literature review of articles examining the use of pharmacological agents for the prevention of PTSD. A total of 27 articles met inclusion criteria for the review and their results are summarized. The review points to corticosteroids and propranolol as the most promising agents for future research. g-amino butyric acid mimetic drugs received the least support. Complementary approaches using psychotherapy and pharmacological agents could also yield good results. Research aimed at determining the potential efficacy of these agents could start being carried out in the field with smaller numbers of personnel that has not been personally injured but have witnessed traumatic events. In addition, psychological interventions immediately after postdeployment could be used in large numbers of soldiers. Preliminary studies regarding the use of pharmacologic agents for the secondary prevention of PTSD are promising. However, much larger studies are needed before implementation in generalized practice. INTRODUCTION Posttraumatic stress disorder (PTSD) is a significant cause of morbidity in military and veteran personnel in the United States. It is more prevalent among combat veterans than in the general population, with rates reaching 19% postdeployment and 30% across lifetime, compared to 7.8% among civilians. 1 Currently, 18% of veterans returning from Iraq and 11% from Afghanistan have been diagnosed with PTSD, and it remains to be seen what the lifetime prevalence rates will be for veterans of the current conflicts. 2 In addition, approximately 75% of military personnel diagnosed with PTSD have a co-occurring substance abuse disorder, and many of these patients report abusing psychoactive substances to self-medicate PTSD symptoms. 3,4 Finally, recent data show that between 6% and 8% of active duty personnel who completed or attempted suicide had a diagnosis of PTSD. 5 These statistics are particularly worrisome given that the suicide rate for persons serving in all 4 military service branches has risen since 2002, and in 2009 surpassed the national average. 6 PTSD involves three main categories of symptoms: physiological hyperarousal, thought intrusion, and avoidance or emotional numbing in response to actual or threatened death or serious injury to oneself or others. 7 These symptoms have fixation on the trauma as a unifying theme, and the traumatic event dominates the patient s life. Sufferers may experience vivid flashbacks or nightmares and avoid stimuli that remind them of the trauma indicating that memory synthesis and fear conditioning play a central role in the development of PTSD. 8 Recent technological advances such as magnetic *School of Nursing, Western Carolina University, 1459 Sand Hill Road, G-33 Candler, NC 28715. Department of Psychology, Western Carolina University, 91 Killian Building Lane, Room 301, Cullowhee, NC 28723. resonance imaging (MRI), and better assessment tools such as the Clinician-Administered PTSD scale, 9 have allowed researchers to elaborate on the observable characteristics of PTSD with an eye toward using these characteristics for early intervention. These characteristics include dysregulation of neuronal and hormonal homeostasis and possible neurological deficits that lead to a failure of physiologic and psychologic coping in response to a traumatic event. 10 Although it is unclear if these psychoneuroendocrinological differences are a pre-existing condition or the consequence of trauma exposure and PTSD, preventing the dysregulation and structural changes associated with the disorder may prevent a traumatic event from leading to PTSD. Military populations are uniquely exposed to risk factors and might be particularly susceptible to PTSD. Combat personnel witness events, including death and violence that challenge their worldview. They may also experience protracted periods of autonomic arousal in response to a constant threat. 2 Moreover, these stressors are often repeated and last for a longer period of time than those found in civilian samples. 11 Prevention of PTSD among military populations could have a major positive impact on the rates of this disorder and on related negative outcomes including suicide and substance abuse. This change could enhance combat readiness and improve the quality of life of military personnel and their families. A significant amount of research has been dedicated to the treatment of PTSD, but research into the prevention of the disorder is still in its early stages and to our knowledge, no systematic review of pharmacological interventions for PTSD prevention have been performed. Thus, the objective of this article is to bridge this gap by outlining major nervous system structures and neurotransmitters implicated in the development of PTSD and summarize studies that have examined pharmacological agents that affect activity in these MILITARY MEDICINE, Vol. 177, June 2012 649

areas to prevent the development of PTSD. Then, we comment on the most promising pharmacological approaches, including special considerations for their use in military populations. Finally, although not the main focus of the review, there are some data suggesting that psychosocial treatments may also be effective in the prevention of PTSD in military populations. 12 Although some complimentary medicine approaches for the prevention of PTSD have been proposed, the current review is limited to pharmacological agents supported in the medical literature through rigorous research methods. METHODS A literature review was performed through the assistance of the Department of Veteran Affairs via a search of the Cumulative Index of Nursing and Allied Health, PsychINFO, U.S. Department of Defense, Medline, and Cochrane Databases. Key words used in the search included but were not limited to, PTSD, prevention, pharmacology, neuroanatomy, and pathophysiology. Article selection was limited to articles that focused on diagnosis, epidemiology, pathophysiology, neuroanatomy, neurochemistry, and secondary prevention of PTSD. A total of 27 articles were included in the final literature review and were used to assess both current knowledge of the pathophysiology of PTSD and to address potential biological targets for the use of pharmacological agents in the secondary prevention of PTSD. REVIEW Hypothalamic Pituitary Adrenal Axis, Limbic System, and Cortisol Physiological responses to stress are well known and involve several mechanisms including an increase in sympathetic tone, along with the release of catecholamines. Exposure to a stressor triggers the activation of the paraventricular nucleus located in the hypothalamus which causes a release of corticotrophin-releasing factor (CRF) and vasopressin. This release stimulates pro-opiomelanocortin products including adrenocorticotrophin hormone, which interacts with the immune system. These changes lead to autonomic arousal including increase in heart rate, blood pressure, respiration, and skin conductance. 10 An important factor in this process is the negative feedback mechanism initiated by cortisol, which returns the body to homeostasis. It is thought that in some persons with PTSD, the inhibitory effect of cortisol fails or does not sufficiently return the organism to a normal hormonal state. 13 Moreover, cortisol has been linked to structural abnormalities in the limbic system pointing to the interaction between cortisol and limbic structures as a target area for prevention. Animal studies have found that hippocampal size is decreased by the presence of glucocorticoids, and corticotrophin-releasing hormone. 14 The hippocampus mediates working memory and memory of episodic events. Human studies have linked elevated cortisol levels to reduced hippocampal volume. 15,16 However, in humans, there has been a failure to consistently find reduced hippocampal volume following trauma, or exposures to a stressful event. Further, controversy remains as to whether lower hippocampal volume associated with PTSD is the result of a neurotoxic effect of trauma or a pre-existing structural abnormality. 17 A meta-analysis by Karl et al 18 grouped different studies according to anatomical boundaries and measurement tools and found significantly smaller bilateral hippocampal volumes in PTSD relative to healthy controls. However, these findings do not show a causal link between PTSD and lower hippocampal volume. In an effort to resolve this issue, Gilbertson et al 19 conducted an MRI study with male monozygotic twin pairs discordant for combat (i.e., only one brother had combat exposure) during the Vietnam War. The final sample included a group with 19 twin pairs in which one sibling was affected with PTSD (PTSD+) and a group with 24 twin pairs in which neither sibling had PTSD (PTSD ). Results indicated that combat exposed and unexposed members of the PTSD+ group had significantly smaller hippocampi than members of the PTSD group. A later study by Gilbertson et al 20 with these same samples found that the PTSD+ group also had lower scores on neurocognitive tests than the PTSD twins. These two studies suggest that pre-existing differences in hippocampal volumes and neurocognitive functioning are a potential risk factor for PTSD rather than a result of PTSD. In a similar fashion, the amygdala, anterior cingulate cortex (ACC) and glucocorticoids have been implicated in the pathophysiology of PTSD. The amygdalae are located in the temporal regions of the brain in close proximity to the hippocampus. It is thought that fear conditioning occurs in the lateral nucleus of the amygdala and that the activation of this area transmits the fear response to the central amygdala which relays the information to the brainstem and hippocampus. Following trauma, glucocorticoids cause these areas to hypertrophy. 10 However, findings regarding amygdala size in persons with PTSD vary, and smaller amygdala volumes have also been observed with chronic PTSD. 18 Meanwhile, the ACC is closely associated anatomically with subcortical components of what is commonly called the central fear system. 21 Neuroimaging studies have shown reduced grey matter density and volume of the ACC in patients with PTSD relative to healthy controls. Notably, a twin study of monozygotic twins disconcordant for combat exposure revealed that the combat-exposed PTSD twin had smaller ACC volumes than their combat-unexposed co-twin. 22 This finding suggests that the reduction in ACC volume and grey matter is most likely an acquired structural change. Glucocorticoid Pharmaceutical Interventions Although findings regarding the effects of cortisol and its effect on the limbic system are somewhat mixed, several studies analyzing cortisol administration to prevent PTSD 650 MILITARY MEDICINE, Vol. 177, June 2012

have found some promising results. Although human experimental evaluation of pharmacological agents, such as cortisol, is difficult and limited under the best circumstances, fortunately, several valid, translatable animal models are available for such studies. 23,24 For example, a study by Cohen et al 13 examined whether corticosterone injections could temper and decrease PTSD-like behaviors in three groups of rats in response to a stressor. The rats were prescreened for the intensity of their startle and fear responses. The extreme behavioral response (EBR) rats displayed increased startle response and fear behaviors compared to control and minimal behavioral response (MBR) rats. Subsequently, the EBR rats were given corticosterone injections before a stressful event. After the injection, the stress responses in the EBR rats were significantly reduced and fear behaviors were less than both the MBR and control rats. The results from this study suggest that corticosterone supplementation reduced the catecholamine response to the stressor. Thus, corticosterone could moderate the central fear response, and perhaps prevent PTSD. In humans, Schelling et al 25 performed one of the first studies using cortisol in the secondary prevention of PTSD. The participants were 20 patients admitted to the intensive care unit (ICU) with a diagnosis of sepsis. Patients with septic shock are often exposed to intense physical and psychological stress during the course of their treatment. Eleven study participants received placebo and nine received the stress doses of hydrocortisone. The groups did not differ in traumatic experiences or treatment complications. At the 31-month post-treatment interval, only 1 of the hydrocortisone treatment group patients met a diagnosis of PTSD, whereas seven of the patients in the placebo group developed PTSD. These findings are important because they demonstrated for the first time that cortisol supplementation in humans could bring about a significant decrease in the number of patients later diagnosed with PTSD. These findings were replicated by Schelling et al 26 with postcardiac surgery patients. In this study, 91 patients were randomized to receive hydrocortisone or the standard treatment following surgery. Forty-five patients were lost to follow-up either as a result of death or inadequate completion of assessment questionnaires and forms. Of the 48 remaining patients, 26 had received the stress dose of hydrocortisone and 22 had received the standard treatment. Six months after cardiac surgery, patients who received hydrocortisone had lower chronic stress scores. Schelling et al s findings support the use of cortisol as a secondary prevention for PTSD in an ICU setting; however, further research is needed to determine the utility of corticosteroid use in trauma victims or military personnel. Sympathetic Nervous System and Catecholamines The primary catecholamines involved in the stress response are norepinephrine (NE) and epinephrine (Epi), which are released by the sympathetic nervous system during emotionally arousing events. NE is produced by neurons located in the locus coeruleus and is the predominant catecholamine in the central nervous system (CNS). The locus coeruleus is located in the center of the brain stem with projections into the amygdala, hypothalamus, thalamus, median prefrontal cortex, and hippocampus. These structures have been implicated in the pathophysiology of PTSD. Epi on the other hand is created by the adrenal cortex and is found in greater concentrations in the periphery. 27 Levels of circulating catecholamines vary throughout the day in healthy individuals, with a noticeable decline during sleep. Persons with PTSD have higher levels of catecholamines in urine at night compared to healthy controls, suggesting a connection between elevated catecholamines and non-nightmare distressed awakenings, a salient symptom of PTSD. 27 Combat-related PTSD in contrast to other forms of PTSD involves more symptoms of hyperarousal, re-experiencing, and sleep disturbances, which could be attributed to the action of the catecholamines. Also, elevated catecholamines in persons with PTSD correlate with findings of decreased cortisol levels, despite elevations in CRF. This indicates that the body s attempts to counter-regulate the catecholamine release are exhausted, allowing more circulating catecholamines. 28 Therefore, interventions aimed at regulating catecholamine dysfunction could lead to prevention avenues for some of the most prevalent and distressing PTSD symptoms in military personnel. The primary NE and Epi adrenergic receptors are the a- and b-adrenoreceptors. Adrenergic blockading drugs act on these receptors in both selective and non-selective manners. Of the adrenergic-acting medications Prazosin (a-1 blocker), clonidine (a-2 agonist), and Propranolol (nonspecific b- blocker) are lipophilic and have the ability to cross the blood brain barrier and exert effects on the NE receptor sites in the CNS. 29 Of these drugs, only propranolol has been studied as possible PTSD prevention agent. O Carroll et al 30 studied the administration of metoprolol (noradrenergic antagonist), yohimbine (a noradrenergic agonist), and placebo in 36 healthy participants. The participants viewed a narrated slide show with emotionally neutral and arousing material. After 1 week, the subjects who received the yohimbine overall had higher recall scores for the emotionally arousing material over that of placebo, whereas the metoprolol group had a lower recall of the details than the placebo group. This study showed that noradrenergic pharmacological agents do modulate the retention of emotionally arousing material. Therefore, it could be postulated that treatment with propranolol could potentially modulate memory of a stressful event thus preventing PTSD. Vaiva et al 31 examined the effects of propranolol administration immediately following a motor vehicle accident. The 23 patients involved in the study were recruited from an Emergency Department in Douai and Lille, France. The participants were individuals in good physical health between 21 and 30 years of age. Those with traumatic brain injuries and MILITARY MEDICINE, Vol. 177, June 2012 651

active cardiovascular disease or asthma were excluded. The participants also had sustained tachycardia of at least 90 beats per minute after 20 minutes of rest in a supine position. Sustained tachycardia represents a potential risk factor of PTSD as it represents an increase in the adrenergic response following trauma. Propranolol administration time posttrauma was 2 to 20 hours following the traumatic event. The findings showed that of the eleven patients who agreed to the administration of propranolol, only one reported PTSD symptoms, whereas out of eight patients who agreed to participate in the study but refused propranolol, three developed symptoms of PTSD. Although the studies by O Carroll et al 30 and Vaiva et al 31 have a small number of participants, the results are promising and suggest that administration of a catecholamine antagonist, such as propranolol, could prove beneficial in the secondary prevention of PTSD (for a review on the relationship between adrenergic function and PTSD see Strawn and Geracioti, 2008). Beyond the qualified results of these three studies, research into combat-related trauma victims is necessary before firm conclusions can be drawn regarding the use of these agents for secondary prevention in patient military populations. It is also worth repeating that using a b-blocker, such as propranolol, does include the risk factors of decreased blood pressure and heart rate. These factors could become particularly problematic in the treatment of soldiers who have suffered significant blood loss or physical trauma. However, as with cortisol administration, among soldiers exposed to psychological trauma without personal injury (e.g. witnessing death of other soldiers or civilians) who have sustained elevations in heart rate above baseline, propranolol could help prevent PTSD. g-amino Butyric Acid Another inhibitory agent that has received some research attention is g-amino butyric acid (GABA). GABA is a global inhibitory neurotransmitter and has been implicated in the pathogenesis of anxiety, insomnia, depression, and potentially PTSD. 32 GABA antagonizes the actions of glutamate, which is the primary excitatory neurotransmitter in the brain. The interaction between glutamate and GABA are thought to be involved in the process of factual memory registration, emotion, and fear memory. 21 Vaiva et al 32 conducted a double-blind study with 108 trauma victims admitted to the hospital following a motor vehicle accident and had their blood collected after the trauma and upon admission to the hospital. The researchers found that patients who had significantly lower mean plasma GABA levels immediately after the trauma were more likely to have developed PTSD at a 6-week follow-up. Therefore, it could be postulated that if GABA levels are low when trauma occurs this may predispose an individual to develop PTSD. As such, benzodiazepines, gabapentin (a GABA mimetic), or other GABA agonists could be used as possible preventative therapy for PTSD. However, there are two significant potential confounding variables in Vaiva et al that should be considered. First, women s GABA levels vary with their menstrual cycle and in this study there were 37 female participants. Future studies should control for this variable in their results. Also the blood sample assayed for GABA levels was collected 24 hours after the trauma, and GABA reserves could have been exhausted by then. Thus, lower levels at the time of collection may not necessarily reflect lower basal rates at the time of the trauma before the development of PTSD. 32 Nonetheless, even with the potential confounding variables, these findings point to GABA and GABA agonists as prophylactic PTSD treatments and provide clues regarding the high rates of comorbid alcohol/substance abuse among PTSD sufferers. Alcohol and benzodiazepines are GABA agonists and thus suppress the excitatory glutamatergic function. Therefore, persons with PTSD who self-medicate with these substances may do it to compensate for a lower level of GABA suggesting that GABA agonists could also help reduce substance abuse related to PTSD. Of the GABA mimetic drugs, gabapentin has been studied with regards to PTSD prevention. Gabapentin is an anticonvulsant structurally similar to endogenous GABA. Gabapentin binds to the GABA-B receptor and does not appear to interfere with endogenous GABA. Therefore, gabapentin could be used to supplement endogenous GABA among those with vulnerability for PTSD and inhibit the excitatory neurotransmissions following a trauma and decrease traumatic memory formation. In a double-blind proof-of-concept trial, Stein et al 33 gave 48 patients either the b-blocker propranolol (n = 17), gabapentin (n = 14), or placebo (n = 17) within 48 hours postinjury. The medications were administered for a total of 14 days, which included initial dosing, up-titration, acute treatment, and taper. Patients were compliant with the medication protocol. Outcomes were assessed at 1, 4, and 8 months post-treatment using standardized questionnaires, such as the Acute Stress Disorder Scale, 34 and Comprehensive International Diagnostic Interview. 35 During the 1-month follow-up, there were no differences between the three groups in the number of stress disorder symptoms. At the 4-month follow-up, the rate for PTSD was 25% in the propranolol group, 20% for gabapentin, and 25% for placebo. The differences between the groups were not statistically significant, and the effect size for the difference was very small. The researchers noted that, given the effects sizes, a sample of at least 600 subjects per group would be needed to show a significant difference between propranolol and placebo and 9,000 subjects would be needed to show a difference between gabapentin and placebo. In this study, of the 5,062 patients screened, 905 were eligible for participation, but only 48 were participated in the study. Stein et al state that this low rate of participation is probably typical for this type of research and will be a major obstacle for future studies. The researchers also noted that the delay between the trauma and the first medication administration 652 MILITARY MEDICINE, Vol. 177, June 2012

(24 48 hours postinjury) may have been too long to see an effect. Given the realities of medically managing post-trauma injuries, a shorter delay may not often be possible. This casts some doubt on the practical utility of this approach to preventing PTSD. Future Directions The field of secondary prevention of PTSD is a promising area of study. Pharmaceutics, while helpful as a secondary prevention method, will most likely be more efficacious when combined with psychosocial interventions. Currently, the military is testing Battlemind, a psychological debriefing technique taught to the military population immediately postdeployment with promising results. Battlemind is defined as a soldier s inner strength to face fear and adversity in combat with courage. 12 Battlemind training involves a cognitive and skills-based approach that educates military personnel about their postdeployment transition and emphasizes that skills learned to survive during combat need to be refocused upon return home. Battlemind also emphasizes that bonds formed with comrades during deployment should be replaced with bonds to their families and loved ones limiting emotional withdrawal and numbing. Finally, the symptoms of PTSD are considered in a positive light in order to destigmatize them and present them as a normal response to an abnormal situation. 12 The authors tested Battlemind against standard postdeployment stress education on 2,188 participants with high levels of combat exposure, with a final number of 1,060 participants. The findings showed that soldiers trained in Battlemind experienced fewer PTSD symptoms at a 4-month follow-up than those who received traditional stress education. An interesting future approach would be to examine the effects of predeployment Battlemind training at a battalion scale with prophylactic pharmaceutical interventions for squads or individuals who experience acute trauma during deployment. CONCLUSION PTSD is a significant cause of morbidity in military personnel and it is emotionally, physically, and financially burdensome for soldiers and their families. PTSD is a complex disorder and we need to learn more about the pathophysiology and treatment of the disorder. Recent advances in the knowledge of neural pathways involved in learning and traumatic memory formation suggest potential pharmaceutical interventions that may counteract the post-trauma pathological changes in the brain to prevent PTSD. Of the pharmacological agents discussed, the two drug classes with the most potential are b-blockers and corticosteroids. Of the b-blockers, propranolol is of particular interest as it readily crosses the blood brain barrier to exert its effects in the CNS. However, the side effects including decreased heart rate and blood pressure could be limiting factors for its use in populations suffering from traumatic injury or blood loss. Nonetheless, since PTSD can develop in patients even if they do not suffer a major medical injury, perhaps propranolol can best be utilized in patients who have witnessed traumatic events in the battlefield but did not sustain an injury. Corticosteroids have also been shown to significantly decrease in PTSD rates during pilot studies in an ICU setting. However, a significant difference exists between the ICU environment and the battlefield, and so further research into this is warranted. An advantage of corticosteroids is that they can be given parenterally or orally, in similar fashion to the parenteral administration of morphine already in use on battlefields. However, further study in acute trauma settings is required before their use becomes routine in the battlefield. Further, these medications are already used postoperatively and in patients with severe illnesses. However, with severe traumatic injuries, these drugs could cause medical complications. Additionally, further study is needed to determine the corticosteroid dose and length of treatment time. Although gabapentin has not proven as successful in the secondary prevention of PTSD, this medication still warrants further study. Its pharmacokinetics, pharmacodynamics and clinical effects may still prove to be helpful in the prevention of PTSD or related problems such as substance abuse. 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