title: Alprazolam treatment immediately after stress exposure interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an animal model of PTSD Benzodiazepine use in posttraumatic stress disorder among veterans with substance abuse. Randomized trial of light versus deep sedation on mental health after critical illness* Anti-Intrusion Effect of Lorazepam: An Experimental Study A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care Effects of the benzodiazepine antagonist flumazenil in PTSD Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder? Clonazepam for Treatment of Sleep Disturbances Associated with Combat-Related Posttraumatic Stress Disorder Treatment of recent trauma survivors with benzodiazepines: a prospective study.
abstract: BACKGROUND In light of clinical reports suggesting that early benzodiazepine administration interferes with long-term recovery from traumatic stress , a prospect i ve animal model for PTSD was employed to assess the short- and long-term effects of a brief course of alprazolam following stress exposure . METHOD Animals exposed to stress were treated either 1 h or 7 days later with alprazolam or vehicle for 3-days . Outcome measures included behavior in the elevated plus-maze ( EPM ) and acoustic startle response ( ASR ) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31 . One group was repeatedly exposed to the triggering trauma shortly before and after treatment and assessed as above . Circulating corticosterone levels were assessed 4 h after initiation of alprazolam and post-treatment . Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into ' extreme ' , ' minimal , ' or ' partial ' behavioral response for analysis of prevalence rates . RESULTS Immediate alprazolam treatment was effective in alleviating anxiety at day 4 . No observable anxiolytic effects remained at day 30 . Immediate alprazolam also result ed in significantly greater freezing response to trauma-cue exposure and in extreme responses to double-exposure . Corticosterone levels were significantly suppressed by alprazolam during treatment and rebounded after cessation . CONCLUSION A brief course of alprazolam in the immediate aftermath of stress-exposure is associated with less favorable responses to additional stress-exposure later on . Alprazolam was associated with a significant attenuation of the HPA-response , suggesting a possible link between initial HPA-axis response disruption and the subsequent unfavorable outcomes Veterans with posttraumatic stress disorder ( PTSD ) and substance abuse may abuse benzodiazepines and develop violent dyscontrol when using them . A total of 370 veterans were compared by substance abuse diagnosis ( 50 % ) , benzodiazepine use ( 36 % ) , and their interaction on 1-year outcomes after inpatient discharge . Substance abusers were less likely to be prescribed benzodiazepines ( 26 % vs. 45 % ) . No outcome showed a differential worsening by substance abuse or benzodiazepines , although some baseline differences were noted . Outpatient health care utilization was lower in benzodiazepine users ( 47 vs. 33 visits ) . Among PTSD patients with comorbid substance abuse , benzodiazepine treatment was not associated with adverse effects on outcome , but it may reduce health care utilization Objectives : To investigate if light sedation favorably affects subsequent patient mental health compared with deep sedation . Symptoms of posttraumatic stress disorder are common in patients after they have undergone prolonged mechanical ventilation and are associated with sedation depth . Design : R and omized , open-label , controlled trial . Setting : Single tertiary care center . Patients : Adult patients requiring mechanical ventilation . Interventions : Patients were r and omized to receive either light ( patient awake and cooperative ) or deep sedation ( patient asleep , awakening upon physical stimulation ) . Measurements and Main Results : Self-reported measures of posttraumatic stress disorder , anxiety , and depression were collected at intensive care unit discharge and 4 wks later . The primary outcomes were symptoms of posttraumatic stress disorder , anxiety , and depression 4 wks after intensive care unit discharge . A total of 137 patients were assigned to either the light ( n = 69 ) or the deep sedation ( n = 68 ) group . Seven patients withdrew consent and one patient was r and omized in error , leaving 129 patients ( n = 65 in light sedation and n = 64 in deep sedation ) available for analysis . At the 4-wk follow-up , patients in the deep sedation group tended to have more posttraumatic stress disorder symptoms ( p = .07 ) ; the deep sedation group had more trouble remembering the event ( 37 % vs. 14 % ; p = .02 ) and more disturbing memories of the intensive care unit ( 18 % vs. 4 % ; p = .05 ) . Patients in the light sedation group had an average one day less being ventilated and 1.5 fewer days in the intensive care unit . There were no differences between the two groups in the occurrence of anxiety and depression , and also no difference in mortality or in the incidence of adverse events . Conclusions : These data suggest that a strategy of light sedation affords benefits with regard to reduction of intensive care unit stay and duration of ventilation without negatively affecting subsequent patient mental health or patient safety Objective Easy triggering of trauma-related episodic memory fragments caused by perceptual cues is tied to strong perceptual priming in the implicit memory system . And among benzodiazepines , only lorazepam has been consistently reported to have an atypical suppression effect on perceptual priming processes . The aim of this study was to investigate the effects of single doses of lorazepam , diazepam , and a placebo on intrusive memories after exposure to a distressing videotape and to explore whether the anti-intrusive effect of lorazepam is acquired as a result of the suppression of perceptual but not conceptual priming processes . Methods Under prospect i ve , r and omized , and double-blind conditions , we compared the anti-intrusion effect of a single dose of lorazepam ( n=22 ) with that of diazepam ( n=22 ) and a placebo ( n=21 ) in young healthy Korean college students following exposure to a traumatic videotape . Results We present the first finding for an anti-intrusion effect of lorazepam . One day after the medication , lorazepam , rather than diazepam or the placebo , significantly reduced the extent of intrusion and data -driven processing of the traumatic information . There were no differences among the three conditions in state anxiety , depression , and an arousal scale throughout the experiment . Conclusion Results from this study suggest the possibility of lorazepam as a c and i date anti-intrusion drug , as well as the cautious use of diazepam in the treatment of PTSD patients . The anti-intrusive effect of lorazepam is directly related to its atypical inhibitory effect on implicit perceptual priming processes . The present study provides support for the enhanced perceptual priming hypothesis of PTSD OBJECTIVE The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam , compared with placebo , in reducing  posttraumatic stress disorder ( PTSD ) due to military trauma . METHOD After an introductory session , five sessions of virtual reality exposure were augmented with D-cycloserine ( 50 mg ) or alprazolam ( 0.25 mg ) in a double-blind , placebo-controlled r and omized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD . RESULTS PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3 , 6 , and 12 months . There were no overall differences in symptoms between D-cycloserine and placebo at any time . Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment ; the alprazolam group showed a higher rate of PTSD ( 82.8 % ) than the placebo group ( 47.8 % ) . Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only . At posttreatment , the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes . CONCLUSIONS A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans , although there was no control condition for the virtual reality exposure . There was no advantage of D-cycloserine for PTSD symptoms in primary analyses . In secondary analyses , alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning . D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo , findings that are consistent with those in the animal literature Introduction Post-traumatic stress disorder ( PTSD ) has been identified in a significant portion of intensive care unit ( ICU ) survivors . We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation . Methods Forty-three patients who were mechanically ventilated in the medical and coronary ICUs of a university-based medical center were prospect ively followed during their ICU admission for delirium with the Confusion Assessment Method for the ICU . Additionally , demographic data were obtained and severity of illness was measured with the APACHE II ( Acute Physiology and Chronic Health Evaluation II ) score . Six months after discharge , patients were screened for PTSD symptoms by means of the Post-Traumatic Stress Syndrome 10- Questions Inventory ( PTSS-10 ) . Multiple linear regression was used to assess the association of potential risk factors with PTSS-10 scores . Results At follow-up , six ( 14 % ) patients had high levels of PTSD symptoms . On multivariable analysis , women had higher PTSS-10 scores than men by a margin of 7.36 points ( 95 % confidence interval [ CI ] 1.62 to 13.11 ; p = 0.02 ) . Also , high levels of PTSD symptoms were less likely to occur in older patients , with symptoms declining after age 50 ( p = 0.04 ) . Finally , although causation can not be assumed , the total dose of lorazepam received during the ICU stay was associated with PTSD symptoms ; for every 10-mg increase in cumulative lorazepam dose , PTSS-10 score increased by 0.39 ( 95 % CI 0.17 to 0.61 ; p = 0.04 ) . No significant relationship was noted between severity of illness and PTSD symptoms or duration of delirium and PTSD symptoms . Conclusion High levels of PTSD symptoms occurred in 14 % of patients six months following critical illness necessitating mechanical ventilation , and these symptoms were most likely to occur in female patients and those receiving high doses of lorazepam . High levels of PTSD symptoms were less likely to occur in older patients The authors report a r and om-assignment , double-blind crossover trial comparing alprazolam and placebo in posttraumatic stress disorder ( PTSD ) . Ten patients fulfilling DSM-III criteria for PTSD completed 5 weeks of treatment on each agent . Improvement in anxiety symptoms was significantly greater during alprazolam treatment but modest in extent . Symptoms specific to PTSD were not significantly altered . The impact of nonspecific symptomatic effects on the outcome of drug trials in PTSD is considered Objective This prospect i ve observational study was design ed to explore the relationships between  post-traumatic stress disorder ( PTSD )  ,  patients ' memories of the intensive care unit ( ICU ) and sedation practice s. Design Prospect i ve multi-centre follow-up study out to 3 months after ICU discharge . Setting Two district general hospitals and three teaching hospitals across Europe . Patients and participants Two hundred and thirty-eight recovering , post-ventilated ICU patients . Interventions None . Measurements and results Assessment of patients ' memories of ICU was undertaken at 1–2 weeks post ICU discharge . Patients ' psychological recovery was assessed by examining the level of PTSD-related symptoms and rate of PTSD by 3 months post ICU . The rate of defined PTSD was 9.2 % , ranging from 3.2 % to 14.8 % in the different study ICUs . Independent of case mix and illness severity , the factors found to be related to the development of PTSD were recall of delusional memories , prolonged sedation , and physical restraint with no sedation . Conclusion The development of PTSD following critical illness is associated with a number of different precipitating factors that are in part related to how patients are cared for within intensive care . This study raises the hypothesis that the impact of care within the ICU has an impact on subsequent psychological morbidity and therefore must be assessed in future studies looking at the way patients are se date d in the ICU and how physical restraint is used OBJECTIVE Evidence from pre clinical and clinical studies suggests a role for alterations in the benzodiazepine/GABAA receptor complex in stress and anxiety .  Flumazenil is a relatively pure benzodiazepine/GABAA antagonist with limited intrinsic activity . In panic disorder patients , but not healthy controls , flumazenil has been demonstrated to provoke panic attacks . METHOD Vietnam combat veterans with PTSD ( n = 14 ) received 90-second intravenous infusions of flumazenil 2 mg or placebo in a double-blind , crossover study design . PTSD symptomology was assessed using the PTSD Symptom Scale , and anxiety symptoms were measured with visual analogue rating scales . RESULTS There was no significant difference in PTSD and anxiety symptoms between administration of flumazenil and placebo . CONCLUSION Flumazenil administration does not produce an increase in anxiety and PTSD symptoms in patients with PTSD . This suggests that PTSD and panic disorder are dissimilar in terms of benzodiazepine/GABAA system function OBJECTIVE Benzodiazepines , other anxiolytics , or sedative hypnotics are prescribed for 30%-50 % of posttraumatic stress disorder ( PTSD ) patients . Prior data and theory suggest that these medications may inhibit response to exposure therapy , one of the most effective PTSD treatments . The present post hoc study reanalyzed results from a psychotherapy trial to assess whether benzodiazepine use was associated with reduced response to exposure therapy . METHOD Between August 2002 and October 2005 , 283 female veterans and soldiers meeting DSM-IV criteria for PTSD were r and omly assigned to 10 weekly 90-minute sessions of either prolonged exposure ( n = 140 ) or present-centered psychotherapy ( n = 143 ) . Benzodiazepine use ( n = 57 ) or non-use ( n = 226 ) at intake was not r and omly assigned . Multilevel modeling was used to assess the effects of benzodiazepine status , psychotherapy condition , and their interaction on changes on the Clinician-Administered PTSD Scale and the PTSD Checklist during the treatment and 6-month follow-up periods . RESULTS Consistent with prior reports from these data , prolonged exposure psychotherapy produced greater reductions per week in PTSD symptoms than did present-centered psychotherapy ( b = -0.48 , P = .02 ) . Patients prescribed benzodiazepines did not have weaker response to prolonged exposure , but demonstrated poorer posttreatment maintenance of gains from present-centered psychotherapy ( b = -0.78 , P < .001 ) . CONCLUSIONS Prolonged exposure is a sufficiently robust treatment that patients who are taking benzodiazepines  can benefit from it . It is unclear whether benzodiazepine use or other patient factors accounted for benzodiazepine recipients ' poorer maintenance of gains in  present-centered psychotherapy .  TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00032617 BACKGROUND : Clonazepam is widely used for the treatment of posttraumatic stress disorder (PTSD)—related sleep disturbances  despite very limited published data supporting its use for this indication . OBJECTIVE : We conducted a pilot-controlled trial to provide more data on this clinical practice and lay the foundation for more definitive studies . METHODS : The study was design ed as a r and omized , single-blind ( ie , patient only ) , placebo-controlled , crossover clinical trial involving administration of clonazepam 1 mg at bedtime for one week followed by 2 mg at bedtime for one week . The following week served as a washout period before the alternate treatment was begun . Patients completed sleep diaries each morning upon awakening throughout the study . Parameters included quantity of sleep , quality of sleep , frequency and intensity of difficulty falling or staying asleep , and frequency and intensity of recurrent distressing dreams . RESULTS : Six patients with combat-related PTSD participated in the study . There were no statistically significant differences between clonazepam and placebo for any measure , although clonazepam therapy result ed in mild to moderate numeric improvements in difficulty falling or staying asleep . Adverse effects of clonazepam were generally mild and essentially indiscernible from those attributed to placebo . Only one patient elected to receive further treatment with clonazepam at the conclusion of the trial . CONCLUSIONS : Clonazepam therapy was largely ineffective in improving sleep disturbances , particularly nightmares , associated with combat-related PTSD . The small sample size was a significant limitation of this study , but the prospect i ve design and single-blind , placebo-control parameters were strengths . Further studies are needed to further define the role of this widespread clinical practice BACKGROUND Most types of psychotropic drugs have been tried in the treatment of chronic posttraumatic stress disorder ( PTSD ) , but have yielded limited results . Theory and retrospective research predict that early treatment may be more efficacious . Specifically , high-potency benzodiazepines have been recommended for the treatment of acute responses to trauma and for prevention of PTSD . This study prospect ively evaluates the effect of early administration of benzodiazepines on the course of PTSD and PTSD symptoms . METHOD Thirteen trauma survivors ( the benzodiazepine group ) were treated within 6.7 + /- 5.8 days after the trauma ( range , 2 - 18 ) with either clonazepam ( N = 10 , 2.7 + /- 0.8 mg/day ) or alprazolam ( N = 3 , 2.5 mg/day ) . Thirteen other trauma survivors , pair-matched with subjects in the active treatment group for gender and symptom severity in the first week after the trauma , constitute the control group . Both groups were reevaluated 1 and 6 months after the trauma for PTSD symptoms ( Horowitz Impact of Event Scale ; Mississippi Rating Scale for Combat-Related PTSD-civilian trauma version ) , PTSD status ( Clinician Administered PTSD Scale ) , state anxiety , depression , and resting heart rate . RESULTS Subjects in the benzodiazepine group did not differ from controls in 1-month and 6-month PTSD and anxiety scores . Repeated measures ANOVA showed no group or group-by-time effect on psychometric measures . A trend toward group-by-time interaction in resting heart rate was noted ( progressive decrease in the benzodiazepine group ) . Nine benzodiazepine subjects and 3 controls met PTSD diagnostic criteria 6 months after the trauma . CONCLUSION Contrary to expectations , the early administration of benzodiazepines to trauma survivors with high levels of initial distress did not have a salient beneficial effect on the course of their illness , while reducing physiologic expression of arousal
target: RESULTS BZDs are ineffective for PTSD treatment and prevention , and risks associated with their use tend to outweigh potential short-term benefits .
  In addition to adverse effects in general population s , BZDs are associated with specific problems in patients with PTSD : worse overall severity , significantly increased risk of developing PTSD with use after recent trauma , worse psychotherapy outcomes , aggression , depression , and substance use .
  The results of this systematic review suggest that BZDs should be considered relatively contraindicated for patients with PTSD or recent trauma .
background: OBJECTIVE Although benzodiazepines ( BZDs ) are commonly used in the treatment of posttraumatic stress disorder ( PTSD ) , no systematic review or meta- analysis has specifically examined this treatment .
  The goal of this study was to analyze and summarize evidence concerning the efficacy of BZDs in treating PTSD .