Home
Clinical
Research
Education
Grand Rounds
Faculty

Informatics
Links

 

 

 

      QUEST - Posttraumatic Stress Disorder  

 

AUTHOR
 Sampath Kumar 

Intimate Partner Violence

Chairman’s Rounds, January 29, 2007

Reference: Miriam K. Ehrensaft, Terrie E. Moffitt, and Avshalom Caspi Am J Psychiatry 2006; 163: 885-92.                                                                                       

Clinical Question:  Does intimate partner violence lead to increased mental illness?  Is there a difference based on gender? 

Clinical Case or Background Info: Phone call from wife of a veteran to commit patient over the phone as he was threatening to hurt her. Wife was asked to petition vet. Vet “broke all things breakable in my house before he got to the hospital” according to wife. 

Question Type: Predicting harm. 

Validity Criteria: Both groups were treated equally and assessed at the same intervals, follow-up was not complete: there were 1037 to start, so follow up was 90% at age 18 and 95% at age 26.  However, this is remarkably good for a study lasting 23 years! This rate of follow-up, although not complete, should be sufficient to meet validity criteria. There is a reasonable temporal relationship between exposure and outcome.

Study Design Type: Longitudinal Cohort Study

Sample: cohort of 1,037 children (52% boys, 48% girls) was constituted at age 3, 91% of consecutive births, April 1972 and March 1973 in Dunedin, New Zealand. Across all socioeconomic status.

 

Assessment:

Diagnostic interview Schedule was used at both points. Depression, Alcohol dependence, MJ dependence was analyzed at 18 &26. Anxiety disorders at 18 were analyzed with PTSD at 26. Abuse was measured with Partner Conflict Calendar which was laid beside Life history Calendar to cue memories. 

Analysis: Hierarchical Logistic regression modeling. Separate models for men and women, and for each disorder studied. : Psychiatric disorder at 26 was regressed onto same disorder at 18, juvenile conduct disorder, and abuse between 24 and 26

Main Results: 

I- Adolescents with a history of mental illness have a higher chance of getting into abusive relationships.

II- Men and women reported equal mean numbers of events in the clinical abuse group

III- In women aged 26 years, even after correcting for previous diagnosis of the same disease and lifetime conduct disorder, being in an abusive relationship within the last 3 years

1)       Increases the odds of having a depressive disorder by 2.46 times

2)       Increases the odds of being dependant on Marijuana by 10.14 times

3)       Increases the odds of having PTSD by 6.42 times

However, in men aged 26 yrs, being in an abusive relationship does not seem to predict an increase in the odds of having a mental illness after correcting for past history of the same mental illness and lifetime conduct disorder. Please refer to table 1. 

Limitations: Recall bias, the range of age in the group is small and minor cases of abuse were not included.

Conclusions:  

Partner abuse contributes to increase in psychiatric morbidity among the reproductive age group in women. Though one of the explanations for  increase prevalence of abuse among mentally ill people was that patients with mental illness are more prone to getting involved in abusive relationships (which is also shown in this study), by establishing a temporal relationship between the exposure and event, this study also shows that abuse can also cause an increase in psychiatric illness

Teaching Point:  Asking about intimate partner abuse in psychiatric patients will help one pick up important etiological information and intervention by abuse prevention might alter the prognosis of the illness. 

Table 1 

 

Risk factors predicting disorder at age 26 after regressing abuse, past history of same disorder, & conduct disorder (CD); odds ratios in parenthesis

Disorder 

Women

Men

Major depressive episode (MDD)

MDD at 18   (1.93**)

Abuse (2.46*)

MDD at 18 (3.38**)

Marijuana dependence (MJ)

MJ at 18 (10.26**)

CD (3.36*)

Abuse (10.14**)

MJ at 18 (3.72**)

CD (4.44**)

Alcohol dependence (ETOH)

ETOH at 18 (3.45**)

CD (4.09**)

ETOH at 18 (3.47**)

CD (1.78*)

Post-traumatic stress disorder (PTSD)

Abuse (6.42**)

Anxiety disorder at 18 (3.04*)

CD (3.15*)

Generalized anxiety disorder (GAD)

___

 

GAD at 18 (2.90*)

* p<0.05

** p< 0.01

Sites that give information about sources for referring patients in abusive relationships:

http://www.nccadv.org/ or http://durhamcrisisresponse.org/

 Return to top of the page

AUTHOR
Harold Hong

Brief CBT Treatment of Acute PTSD

Chairman’s Rounds, January 29, 2007

Reference:  Sijbrandij, Marit et al.  Treatment of Acute Posttraumatic Stress Disorder with Brief Cognitive Behavioral Therapy: A Randomized Controlled Trial. American Journal of Psychiatry.  164:1, January 2007. 

Clinical question:

Background And Objectives: Persons that experience trauma carry considerable risk of developing PTSD.  Various efforts have been made to evaluate the hypothesis that psychological intervention in the early post-traumatic period can prevent the development of PTSD.  However, results thus far for various interventions have been somewhat mixed – with studies showing both positive and negative outcomes.  This particular study was designed to test the hypothesis that a brief course of therapy tailed around cognitive-behavioral principles444

Methods:

Design / Setting – Randomized control trial in an academic clinic setting

Patient Population – predominantly Dutch, HS level of education, and had previously experienced another trauma.

Inclusion Criteria – 1. Met dx criteria for acute PTSD (DSM-IV, minus time criterion), 2. Trauma occurred between 2wks and 3 months prior to inclusion 3. Traumatic event is finished at time of inclusion 4. 18 yrs old or greater 5. Proficient in Dutch

Exclusion Criteria – 1. Presence of SI  2.  Meet dx criteria for a psychotic disorder, organic disorder, substance abuse, or chronic PTSD

Enrollment method – Trauma victims were referred from the community care setting

Number screened vs. Number enrolled –278 screened, 143 enrolled (102 did not meet inclusion criteria, 135 met exclusion criteria, 33 refused)

Intervention – CBT format adapted from CBT for female victims of rape by Foa et al.  There were four 120 minute sessions spaced 1 wk apart.  Session 1 – information gathering, education, and noting of cognitive distortions, and situations that were avoided.  Session 2  - list of avoided situations completed and ranked by degree of anxiety caused by each situation, and deep muscle relaxation exercises practiced and audio taped for homework, use of imaginal exposure audio taped, discussed cognitive distortions.  In-between sessions 2 and 4, pt’s told to relive the experience by listening to tapes of imaginal exposure and confront avoided, but safe, situations.  Session 3 – review of homework assignment, imaginal exposure, and cognitive restructuring. Session 4 – homework reviewed, imaginal exposure and cognitive restructuring, discuss progress of the patient.

Control – assessed at same follow-up times as the patients.  Pt’s then referred to therapy if found to meet criteria for PTSD.

Analysis – intention to treat

Primary Outcomes – Pt’s assessed at baseline, 1 week, and 4 months.  PTSD sx severity was measured via Structured Interview for PTSD

Secondary and Additional Outcomes –  Hospital Anxiety and Depression Scale scores, SCID-I for dx of co-morbid axis I disorders  pt satisfaction with CBT group. 

Validity: Randomized?  Yes

Blinding – randomization was blinded. 

Treatment groups similar at baseline? Yes, no significant differences between intervention and control groups

Patients starting trial accounted for at conclusion?  Yes

Patients analyzed in groups to which they were randomized?

Intention to treat analysis? yes

Patients and clinicians blinded to treatment? Not explicitly stated if assessors were blinded

Groups treated similarly outside of intervention? Yes

Results
 Primary outcomes –  Structured Interview PTSD scores significantly lower at week 1 compared to control group (total, re-experiencing, hyperarousal).  However, there were no significant differences in Structured Interview PTSD scores between treatment and control groups at 4 months follow up.

Additional outcomes – there were no significant differences between groups on Hospital Anxiety and Depression Scale scores.

There were significant differences between rate of diagnosis of PTSD at week 1 and follow-up – 38.1% in Tx group 61.1% in control, and then 26.4% in Tx group and 43.8% in control group at 4 months. 

Adverse effects – none reported 

Comments
Strengths: This study has a considerable sample size. This study evaluates a specific area of PTSD treatment

Weaknesses: No power calculations were stated regarding subgroup analysis.  Exclusion criteria of those that have co-morbid substance abuse marks out a particular subset of PTSD pt’s

Next steps for further study: study of brief courses of CBT involving different methods than the ones employed here.  Study of brief courses of CBT for the treatment of non-civilians 

CLINICAL BOTTOM LINE: A brief course of CBT can be helpful in reducing symptom severity in the short term following trauma, however, it has not been shown to reduce symptom severity in the longer term (4 months).

Return to top of the page

AUTHOR:
Victoria Carroll

Efficacy And Tolerability Of Mirtazapine And Sertraline In Korean Veterans With Posttraumatic Stress Disorder

Chairman’s Rounds, November 20, 2006

Reference: Chung, MY et al.  Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: A randomized open label trial.  Hum Psychopharmacol Clin Exp 2004; 19:489-494.

Clinical Question: In terms of efficacy and tolerability, how does mirtazapine compare to sertraline in the treatment of combat veterans with Post Traumatic Stress Disorder? 

Background: 30.9% of male and 26.9% of female Vietnam veterans in the U.S. have PTSD.  The medication mirtazapine increases both noradrenergic and serotonergic signaling by its antagonism at central presynaptic α2-receptors.  The resultant
increase in serotonergic signaling affects primarily 5HT1 receptors, as mirtazapine antagonizes 5HT2 and 5HT3 receptors.  This 5HT2 and 5HT3 antagonism is thought to result in mirtazapine’s anxiolytic and pro-sleep effects, as well as its lower incidence of serotonin-induced side effects. 

Question Type: Therapy

Validity Criteria: Complete follow-up? All subjects were accounted for, with 13 patients dropping out of the study (reasons given for dropouts).  Randomized?  Yes, but it is unclear if randomization was concealed.  Intention to treat: Subjects were analyzed in the groups they were randomized to; data from subjects who dropped out were not analyzed.  Similar groups?  Please see Tables 1 & 2, p. 491.  The groups appear quite similar, but the mirtazapine group (M group) had more subjects with a h/o hospitalizations and suicide attempts, though this may not have been statistically significant.  Blinding?  This was an open-label study; it is unclear whether analyzers were aware of subjects’ allocations.  Equal treatment?  Yes.

Study Design: Randomized, open label trial; funded by a grant from Organon and Janssen.

Duration: 6 week study

Setting: Seoul Veterans Hospital

Population: 113 veterans of the Korean or Vietnam Wars (95 outpatient and 18 inpatient) with PTSD and possible comorbid depressive d/o (if depressive sx for > 3 months).  It is unclear how many subjects were enrolled.

Intervention: Subjects were randomized to receive either mirtazapine (n=51) or sertraline (n=49).  After a 7-day washout period, subjects were started on mirtazapine 15 mg qd or sertraline 50 mg qd; doses could be adjusted after weeks 1, 2 and 6. 

Outcomes: Outcome measures were not explicitly stated.  Subjects in each group were identified as “responders” or “nonresponders” based on improvement as measured by clinician administered PTSD scale (CAPS-2), the Hamilton rating scale for depression (HAMD-17) or the clinical global impression scale (CGI), each measured at baseline and weeks 1, 2 and 6.  A psychiatrist assessed side effects through “direct inquiry.”

Results: See Tables 3 and 4 (over).

--Statistically significant reductions (vs. baseline) in CAPS-2, HAMD-17, and CGI in both groups at week 6.  The differences b/t both groups in these reductions were not statistically significant.

--CAPS-2 Total: 43.4% in M group v. 37.4% in S group (p=0.467)

--CAPS-2 Clusters: Reductions from baseline to week 6 were similar in both groups

--HAMD-17: 58.5% in M group v. 59.1% in S group (p=0.319)

--CGI-S: 49.2% in M group v. 49.2% in S group (p=0.809)

--Percentage responders, as measured by:

            CAPS-2: statistical significance by week 6 (88.24% in M group v. 69.39% in S group, p=0.039)

            HAMD-17: no statistically significant difference b/t groups at weeks 1, 2 and 6

            CGI-S: ?trending toward intergroup difference by wk 6 (96.08% in M gr v. 87.76% in S gr, p=0.156)

 

Risk of CAPS2 Response*

RR of CAPS2 Response

Risk of HAMD-17 Response

RR of HAMD-17 Response

Risk of CGI-S Response

RR of CGI-S Response

Mirtazapine

45 / 51 = 0.88

0.88 / 0.69 = 1.28

38 / 51 = 0.75

0.75/0.78=0.96

49 / 51 = 0.96

0.96/0.88=1.10

Sertraline

34 / 49 = 0.69

 

38 / 49 = 0.78

 

43 / 49 = 0.88

 

*Risks calculated in this table are from data collected at 6 weeks. 

Comments: This 6-week study found that a group of Korean combat veterans with PTSD treated with mirtazapine (vs. sertraline) had a higher proportion of responders as measured by the CAPS-2.  There were no differences between groups in magnitude of improvement as measured by the CAPS-2, CGI-S, and HAMD-17 scales; both groups did, however, show significant improvement on all scales from baseline to week 6.  Strengths: study assessed both PTSD and depressive sx; study directly compares two interventions.  Weaknesses: short duration of study (would some of the differences observed extinguish or increase with time?; if mirtazapine has been noted to have a shorter time of onset, does that bias the results because of the short duration of the study?); study was designed so subjects could have comorbid depressive dx, but all the subjects in this study didàhow would the results vary (e.g. on the HAMD-17) in subjects without a depressive dx?; the M group had higher scores on the scales at baseline—how did this affect the results (e.g. is it easier to show response with more severe pathology than it is less severe?); study was sponsored by manufacturer of mirtazapine; small population size.         

Bottom Line: In a 6-week randomized, open label trial involving 61 Korean combat veterans with PTSD, a higher proportion of subjects receiving mirtazapine responded to treatment as measured by the CAPS-2 than subjects receiving sertraline; there was no difference in the proportion of responders as measured by the HAMD-17 and CGI-S.  There were also no differences between groups in magnitude of symptom improvement as measured by the CAPS-2, HAMD-17, and CGI-S, though both groups did show significant improvement on all scales from baseline to week 6. 

 

Return to top of the page

AUTHOR:
Seamus Bhatt-Mackin

Comparison of Sertraline And Placebo In The Treatment Of PTSD

Chairman’s Rounds, August 7, 2006

Citation:   Multicenter, Double-blind Comparison of Sertraline and Placebo in the Treatment of PTSD. Davidson et al.   Archives of General Psychiatry   May 2001, Vol 58 pp. 485-92.  

Clinical Question:  Compared to placebo, is sertraline an effective acute treatment for PTSD?

Clinical Case or Background Info:  It is routine in PEC to start patients with PTSD on SSRIs and the word on the street suggests that setraline has the best evidence for such practice.

Question Type:  Therapy

Validity Criteria:

Follow-up: unclear

Randomization:  pts were randomized, method not described

Intention to treat: claimed in methods section, but unclear

Similar groups: yes, except for small difference in percentage of women

Blinding: not well described (“double-blind” likely refers to patients and clinicians, but not made explicit and also treating clinicians = assessors?)

Equal treatment: both groups had same treatment throughout trial

Study Design Type:  Randomized Controlled Trial

Allocation:  randomized (no description of method)

Blinding:  double-blind

Follow Up Period:  12 weeks

Setting:  outpatient clinic

Patients/Population:  ~80% women, ~80% white, ~age 36, ~60% physical or sexual assault as traumatic event, ~25% hx alcohol dependence,

Intervention/exposure:  treatment with flexible-dose sertraline 50-200mg

Primary Outcomes:  responder 30% decrease in score on CAPS-2 (Clinician Administered PTSD Scale), IES (Impact of Event Scale), CGI-S (Clinical Global Impression-Severity Scale)

Patient Follow Up: not well described (see Follow-up above)

Main Results:  There is a specific treatment effect of sertraline (60% responder rate on CAPS-2)  that distinguishes it from the placebo arm (38% responder rate) with a number-needed-to-treat of 4. 

Conclusions: Unfortunately, the patient characteristics in this study do not match well with the patient population at the DVAMC.  There is a significant difference between treatment with sertraline and the placebo arm, demonstrating a specific effect of the medication.  This study will not change my current clinical practice. 

Two Teaching Points: 

1)  Nonspecific effects of treatment are powerful in the treatment of this illness (as demonstrated by the 38% responder rate in the placebo arm of the trial), but also note visits at weeks 1, 2, 3, 4, 6, 8, 10 and 12.

2)  Response in this study was defined as a 30% decrease on CAPS-2 scale; does this represent improvement in level of function?  Is this a clinically significant improvement?

Two Questions for Discussion:

1) 70% of the improvement in PTSD symptoms occurred during the first 4 weeks of treatment (we don’t know how the dosage was titrated).  Is that consistent with attendings’ clinical experience?  Do PTSD symptoms consistently respond like this?

2) In schizophrenia, cognition matches better with functional outcome than the diagnostic symptoms of the illness.  Is there a clear relationship with a particular symptom or aspect of PTSD and level of function? 

Return to top of the page

VIRTUAL REALITY EXPOSURE TREATMENT FOR VETERANS WITH PTSD

Author:
Rosario Hidalgo, MD

Bottom Line: Virtual reality exposure (VRE) may represent a useful adjuvant treatment for veterans suffering from chronic PTSD.

Background: VR integrates computerized devices to immerse a participant in a computer generated visual environment. VRE has showed to be effective in treatment of specific phobias (i.e. flying, heights, etc). In this paper VRE is proposed as an alternative to typical imaginal exposure treatment for Vietnam combat veterans with PTSD.

Search terms: PTSD, virtual reality, therapy.

Clinical case: 48 yo 100% service connected (PTSD) AAM with chronic severe PTSD who has hx of poor response to numerous antidepressants. Pt is currently taking Fluoxetine 80mg po qd but continues to experience daily intrusive memories, weekly flashbacks and chronic insomnia due to frequent nightmares about his Vietnam experiences. Pt would like to know if there is something else he could try to ease his sxs. 

Reference: Rothbaum BO et al. Virtual reality exposure therapy for the Vietnam veterans with PTSD. J Clin Psychiatry 62:617-622.

Methods: open clinical trial. Conducted at the Atlanta VA hospital on an outpatient basis. (N=16; Male veterans). Inclusion crit: chronic PTSD, treatment refractory pts who are able to provide informed consent, and have enrollment approval from treating physicians. Exclusion crit: current substance addiction, serious heart condition, psychosis, bipolar d/o, unstable medication regimen (in the past 3 mo), planned departures from the Atlanta area, uncontrolled suicidal intention. Pts were recruited using publicity and referral resources. 31 pts were screened and 16 pts were enrolled.

Intervention: 8 to 16, 90min sessions conducted twice weekly over 5-7 wks.

Analysis: authors didn't specify which statistical models they used. There was no intent-to-treat analysis; authors included only the data from the 9 participants who completed the treatments and post-treatment f/ups.

Outcomes: % change in different scales used (CAPS: clinician administered PTSD scale (primary); IES: impact of event scale; BDI: Beck depression inventory).

Follow up: authors evaluated pt pretreatment, after completion and did a 3 and 6 months f/u eval. At 3 months f/u only 5 pts were evaluated and at 6m 8pts participated of the f/u. Authors did not account for the lost to f/u.

Validity: limited by the fact that is a small open trial, group of pt may be not completely homogeneous (they had different comorbidities, were taking different medications, etc). However, the study population pretty much resembles the characteristics of our pt and many pts we may encounter at the VA. 

Results:
For 1ry outcomes: CAPS. There was an overall statistically significant reduction from baseline (from 15% to 67%) at 6 mos. This decrease was seen in all 3 symptom clusters of PTSD.

2ry outcomes: IES. Pt self reported intrusion symptoms were significantly lower at 3 months than at baseline but not at 6 mo, although there was a trend towards fewer intrusive thoughts and somewhat less avoidance. BDI. There was a statistically significant reduction at 6 mos. There were no adverse effects reported.

Comments:
The strengths of the study are related to the fact that this is a treatment that is feasible with just minor equipments and can be done in an office setting. Another clear strength is the fact that the population treated is very similar to many of the pts that we see at the VA, although pts with current substance abuse and serious medical conditions were excluded.

The major weaknesses of the study are being non-controlled, open label and with a very small sample. Other weaknesses are that the authors didn't account for pts lost to follow up and did not do an intent to treat analysis. Not all the pts were treated equally (while standard treatment was 10 sessions, some pts received 8 and another 16). There are other factors that can also act as confounders (i.e. pts were taking different medications in non-reported doses for an unknown total time, were seeing their doctors, etc and all these interventions may affect the outcome). Another possible confounder is the fact that the l' two authors disclosed that they share sales royalties in one of the companies who provided the equipment for VRE.

Regardless these limitations, VRE may still be a useful component of a comprehensive treatment program for severe cases of PTSD. There is need for controlled studies and the authors reported that there is one currently underway at the VA Nat Ctr for PTSD in Boston, Mass.

Return to top of the page

BENZODIAZEPINES IN THE TREATMENT OF PTSD

Author:
Julie Adams, MD

Bottom Line: The use of benzodiazepines in the treatment of PTSD shows no significant improvement of outcome in recent trauma survivors when compared to no pharmacotherapy.

Background: Up to 94% of recent trauma survivors will experience PTSD symptoms in the first week post trauma. Most patients will experience remission of symptoms over 9 months, but between 15% and 25% will be left with a pervasive disorder.

Clinical Question: Can early use of benzodiazepines in recent trauma survivors prevent development of chronic PTSD?

Reference: Gelpin E, Bonne 0, Peri T, Brandes D, Shalev A. "Treatment of recent trauma survivors with benzodiazepines: a prospective study," J Clin Psych 57:9, September 1996.

Methods: Subjects recruited for this study were all admitted to an ED following a traumatic event. Those who met DSM-III-R PTSD Criterion A were invited for inclusion. Those who were currently taking psychotropics were excluded, as were those with head injury, coma or loss of consciousness. Of 162 subjects, only 13 were started on a benzodiazepine (10 with clonazepam, 3 with alprazolam) based on evaluation of symptoms. All used the medication for at least a month and 9 used medication for the study duration. Those in the treatment group were matched with 13 controls based on gender and initial Horowitz Impact of Event Scale (IES) score. At the initial interview, subjects were assessed using the IES, the Spielberger State-Trait Anxiety Inventory (STAI-State), and the Beck Depression Inventory (BDI). Interviews at the 1- and 6-month follow up included, in addition, the Mississippi Rating Scale for Combat-Related PTSD-civilian trauma version (MISS), the Structured Clinical Interview for DSM-III-R (SCID) and the Clinician Administered PTSD Scale (CAPS). Resting heart rate was also measured.

Validity: The subjects in this study were not randomized and not blinded to their treatment. Likewise the controls were not blinded. The interviewer "was not involved with clinical management" but it is unclear from the article if this meant the person was blinded. The psychiatrist who prescribed benzodiazepines was blinded to the patients' psychometric scores.

Results: ANOVA showed a significant main effect of time for STAI (F=4.8, df=2,24; p<.03) and MISS (F=4.8, df=1,25; p<.04) and no other statistically significant effects. At the 6-month follow up 9 subjects in the treatment group (69%) and 2 controls (15%) met CAPS-PTSD diagnostic criteria.

Comments: Rates of PTSD were higher in the treatment group than in either the control group or the larger study group. Rates between the controls and larger study group did not differ significantly. A possible explanation could be that those treated were sicker at baseline and therefore possibly at greater risk for developing PTSD in the first place. And while treatment may have improved their symptoms, it did not prevent development of PTSD in 69% of these patients. Another explanation could be that early treatment with benzodiazepines might actually worsen outcome. While benzos are theorized to inhibit memory acquisition, the effect is anterograde. Given after the fact, benzos could interfere with adaptation, reappraisal and learning which could be helpful in recovery. While this study is clearly flawed, the results are still alarming.

Return to top of the page

RISK FACTORS FOR DEVELOPING PTSD AFTER TRAUMA EXPOSURE

Author:
Heidi Harrom, MD

Clinical Question: What factors may predict the likelihood for developing PTSD in a patient who has been exposed to a trauma?

Citation: Brewin, CR, Andrews, B and Valentine, JD. Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. Journal of Counseling and Clinical Psychology 68(5):748-766,2000.

Clinical Bottom Line: Certain risk factors are shown consistently to predict PTSD but to varying extents, others with more demonstrated homogenous effects, and those that seem to predict PTSD in some populations only. Factors operating during or after the trauma appear to show more effect than pre trauma factors.

Search Methods: The evaluators used bibliographic databases, recent journal articles, review articles, and book chapters. The Social Science Citation Index and PILOTS databases were searched using the words PTSD and risk, predictor, prediction, or predisposition.

General Methods: English-written studies from 1980-present which analyzed predictive or risk factors for PTSD were searched, excluding those which didn't assess avoidance/arousal/re experiencing sx, those that included both fully dx PTSD and "partial" PTSD subjects, those whose subjects all already had PTSD or other Ψ sx, those studies which didn't report analysis of all pts exposed to similar adulthood trauma, and those with insufficient data to calculate relevant effect size. 77 articles were ultimately selected. Risk factors that were studied in 4+ articles were analyzed, which included 14 factors. Researchers then looked at the impact that certain study/sample characteristics may have on risk factor effect sizes (military vs civilian, gender, study design, analysis based on diagnosis vs continuous sx scores, interview vs. questionnaire, presence of childhood or adult trauma vs adult only). Regardless of statistical design used in original studies (t(F/chi­square in group designs or Pearson's r/Spearman's P in co-relational studies), these were converted to correlation coefficient r for a common measure for effect size, then combined using Fisher's Z transformation and converted back to r for a weighted average effect size. Higher r values indicate a stronger positive association of a factor with PTSD.

Validity: A focused clinical question was addressed and inclusion criteria was appropriate. The authors specifically analyzed the potential effect an omitted relevant study may have on their conclusion . Separate analysis was performed for those study/sample characteristics which could possibly skew results. Interrator reliability was stated as high. The degree of heterogenicity between the included studies was notable and could indicate that the risk factors don't always predict equally well. Details about the included studies were not sufficient to determine certain characteristics such as follow-up.

Comments: The study had access to a large sample size and made effort to control for the effects of certain study/sample characteristics on the studies. There were too many studies included for detailed data regarding individual studies. Results are comprehensive and factors generally consistent predictors, but only certain characteristics were found to be homogenous. Attempts to identify a common set of pre trauma predictors valid across groups may be premature. Unclear at this point why civilian women are at greater risk for PTSD. Not enough prospective studies. Many pre trauma predictors may not be independent of each other.

Return to top of the page

PREVENTION OF SECONDARY PREVENTION OF POSTTRAUMATIC STRESS DISORDER WITH PROPRANOLOL

Question: In a patient who presents to the emergency room after a traumatic event, does administration of a centrally-acting B-blocker prevent subsequent development of post-traumatic stress disorder? (Pre clinical studies have shown that epinephrine strengthens memory consolidation and fear conditioning; and, propranolol abolishes this effect-)

Pilot study of secondary prevention of post-traumatic stress- disorder with propranolol. Pitman, RK et al. BiologicalPsychiartry, 2002. Vol 51, pp 189-142.

Study: 41 emergency room patients who had just experienced a-traumatic event then received a 3-week course of either propranolol or placebo. Patients were assessed for PTSD at 1 and at 3 months post-trauma, using a clinician administered PTSD scale. Also at 3 months, a "psychophysiological"assessment was done: patients listened to a taped script (in their own words) describing the trauma and were asked to imagine the event for 30 seconds while HR, skin conductance, and EMG responses were measured.

Validity:
Randomization- Patients were randomized to either study group.
Follow-up- The attrition rate was high, particularly in the treatment group. This loss was not accounted for. (Of 18 propranolol patients, 50% dropped out by the end of the study; only I I completed the 1-month assessment and only 9 completed the 3-month assessment. Of 23 placebo patients, about 35% dropped out; only 20 completed the 1-month assessment and only 15 completed the 3-month assessment. Only 8 propranolol and 14 placebo patients completed the physiological measure.)
Analysis- Patients were analyzed in the groups to which they were randomized.
Blinding- A blinded clinician assessed the patients. A separate research nurse provided supportive counseling and monitoring of medication side effects.
Baseline characteristics- Groups were similar at the start of the trial. There were no significant differences in: overall percentage of trauma due to MVA, sex, age, self-rated response intensity, time to first dose of medication, and heart rate in the ED.
Treatments- Aside from the treatment intervention, the two groups night NOT have been treated equally. The paper does not report contact with the research nurse, and the authors suggest that perhaps the treatment group had more contact secondary to having had more side effects.

Results:
The most statistically significant result was at the one month assessment: 9 (out of 11) of the propranolol patients had scores below the median for treatment group, p=.03. 

How does this apply to the patient?
It is difficult to tell whether these patients are comparable to those we see in the ED. Not much detail is given about patient characteristics other than sex (about half male, half female), mean age (about 34), and the fact that 70% of the traumas were due to MVA.

As for the treatment outcomes measured, one thing to note is that the psychophysiological measure is correlated with PTSD in a previous lab study, this measure is not used clinically. Furthermore, the B blocker may be affecting physiology apart from any psychological effect, ie just because the propranolol group has for example, less reactive heart rates, does not mean that this is because they don't have PTSD -- it could be a direct physiological effect of the medication.

The most concerning flaw of this study is that the treatment dropouts were not accounted for in the statistics. Given the very high attrition rate in the treatment group, and the potential side effects, I would not use propranolol for prevention of PTSD.

Return to top of the page

PHARMACOTHERAPY FOR TREATMENT OF PTSD

Author:
Sandeep Vaishnavi, MD

Bottom Line: In a systematic review of 13 RCTs of pharmacotherapy for PTSD, the data support the use of medications for reducing the severity of core PTSD symptoms and comorbid anxiety and depression, and for significantly improving PTSD symptoms. There was no data to support one class of medication over another, and it was not possible to predict response to medications.

Background: PTSD, by definition, involves prior psychological trauma, and psychotherapy has long been a mainstay of treatment. However, there has been increasing recognition that PTSD is characterized by specific neurobiological dysfunctions, dysfunctions that could conceivably be treated by pharmacotherapy.

Clinical Case/Questions: 1) Is there evidence for the use of medications in PTSD?; 2) If so, are there particular classes of medications more efficacious than others?; 3) Are there clinical or methodological factors that predict response to medications?

Methods: This was a Cochrane Review of all RCTs of PTSD pharmacotherapy (including both placebo controlled and comparative trials, whether published or unpublished) completed prior to the end of 1999. Electronic bibliographic databases (MEDLINE 1966 to 1999, PSYCHLIT, The National PTSD Center Pilots database, Dissertation Abstracts, and The Cochrane Collaboration Depression, Anxiety & Neurosis Controlled Trials Register) were searched. Additional RCTs were requested from researchers and from pharmaceutical companies, but conference proceedings were not systematically utilized. RCTs were selected which were of 12 weeks or less duration and had enough data for analysis. Each included study was assessed for quality by using the CCDAN Quality of Research Scale; this scale was completed for each study by two reviewers.

Validity: The present overview did address a specific clinical question, albeit it is a broad one (use of pharmacotherapy in PTSD). This study used rather broad inclusion criteria; no attempt was made to include or exclude studies based on different diagnostic criteria for PTSD, duration and severity of PTSD symptoms, presence of comorbid disorders, or age and gender of subjects. It is easily conceivable that the studies chosen for inclusion varied drastically in the type of patient population studied and perhaps even the form of PTSD (with comorbidities or without). Including all these types of studies might limit the ability to form a strong conclusion. On the other hand, these broad inclusion criteria do allow a conclusion to be applied to a larger patient population. Interestingly, the overview focused on short term trials (less than 12 weeks) and did not look for longer term trials (perhaps including the requirement for short term trials was too stringent). This overview included both published and unpublished data; unpublished data may be of lesser quality and may dilute the strengths of the conclusions. MEDLINE searches were from 1966, and the earlier studies suffered from methodological problems such as low power and imprecise patient outcome measures (often self-report); including these trials may dilute the strengths of the conclusions. It is unlikely that important, relevant studies were missed precisely because the inclusion criteria were so broad. The validity of the included studies was appraised with the CCDAN Quality of Research Scale, but appraisals did not affect the overall data analyses since data were pooled. Assessments of studies were done by two independent raters and then a consensus was reached; it is unclear if these assessments were reproducible within and across raters. It is unclear if the results were similar across the trials.

Results: Fifteen short term RCTs were found, of which 13 were included because they provided post-treatment medication and placebo categorical response rates or dimensional symptom means/standard deviations (enough data to put into an analysis). Based on Clinical Global Impressions scale change item (CGI-C) and Clinical Global Impressions scale severity item (CGI-S), patients who received medication were significantly less likely to be non­responders and had decreased severity of symptoms compared to placebo (RR=0.72, 95% CI=0.64;lower severity by 0.74 units, CI=0.87, 1.12; CAPS-2 score lower by 0.46 SD units, CI=0.20, 0.71). There was no significant difference between types of trials (non-combat trauma vs. combat trauma - CI 0.60, 0.81 and CI 0.66, 0.86 respectively) on CGI-C score and trials that included clinician-rated scales and those that did not (CI 0.66, 0.86 and 0.29, 0.74). There was no significant difference when types of medications were compared: SSRIs (0.75, CI=0.65, 0.88), older non-SSRI antidepressants (0.62, CI=0.45, 0.86), and TCA/MAOI trials (0.48, CI=0.32, 0.72). Core PTSD symptoms were improved with medication more than placebo based on the Impact of Events Scale. The medications were also more effective than placebo for comorbid depression and anxiety. Medications improved quality of life more than placebos (by 0.44 units, CI=0.03, 0.85). Drop out rates for medication vs. placebo were not significantly different (RR=0.85, CI=0.63, 1.14) and drop out rates did not vary by type of medication: SSRI (0.99, CI=0.68, 1.44), non-SSRI (0.70, CI=0.43, 1.14), and TCA/MAOI (0.70, CI=0.32, 1.41)

Comments: This study meets most criteria for validity for a meta-analysis. The study is useful in providing evidence for the use of pharmacotherapy for PTSD. Future studies need to compare pharmacotherapy with psychotherapy, and compare across medications.

Return to top of the page

SINGLE SESSION PSYCHOLOGICAL DEBRIEFING FOR MANAGEMENT OF PSYCHOLOGICAL DISTRESS AFTER TRAUMA

Author:
Alyson Kuroski, DO

Bottom Line: At this time, the routine use of single session psychological debriefing given to non selected trauma victims cannot be recommended.

Background: Debriefing has been defined as a psychological treatment intended to reduce the psychological morbidity that arises after exposure to trauma (Hodgkinson & Stewart, cited in Rose, 1997). It involves promoting some form of emotional processing, catharsis, or ventilation by encouraging recollection, ventilation, and reworking of the traumatic event led by an experienced mental health professional. Furthermore, it has been broken down into seven specific portions, by Mitchell, 1983 and Dyregov, 1989, including an introduction, the facts, thoughts and impressions, emotional reactions, normalization, planning for the future, and disengagement. Of note, these stages have been described and quantified differently by various authors. Debriefing has been used in recent years in a myriad of circumstances and has become a compulsory practice for some organizations. The assumption is naturally that debriefing can decrease acute distress and prevent the onset of PTSD that follows traumatic incidents. The data surrounding this assumption is very controversial and, thus, a review of the current literature was completed.

Search Method: The evaluators utilized an electronic searching of MEDLINE, EMBASE, PsychLit, PILOTS, Biosis, Pascal, Occ. Safety and Health, SOCIOFILE, CINAHL, PSYCINFO, PSYNDEX, SIDLE, LILACS, CCTR, CINAHL, NRR, hand search of Journal of Traumatic Stress, and contact with leading researchers.

Clinical Question: Is single session psychological debriefing effective for the management of psychological distress after trauma, specifically assault in regards to this writer's pt, and prevention of PTSD?

Reference: Rose, S; Bisson, J; Wessely, S. Psychological debriefing for preventing PTSD (Cochrane Review). The Cochrane Library, Issue 3, 2002.

Methods: 11 randomized trials were chosen for evaluation that focused on persons recently (one month or less) exposed to a traumatic event, consisted of only a single session, and involved some form of emotional processing/ventilation by encouraging recollection/reworking of the traumatic event accompanied by normalization of emotional reaction to the event. These trials were reviewed and agreed upon for inclusion by the three reviewers individually according to three standard quality assessments. The three quality assessments included the methods described in the Cochrane Collaboration Handbook (A-C levels of evidence), the quality ratings scale devised by Churchill. 1996 (QC) with max of 37 for studies of psychiatric interventions, and the quality ratings scale devised by Kenardy & Carr,1996 (QK) with max of 26 for studies of debriefing. Additionally, the principal continuous measure used in all the modern trials was the Impact of Events Scale (IES). Lastly, for categorical outcomes the Peto method for computing the pooled odds ratio was used.

Results: Single session individual debriefing did not reduce psychological distress nor prevent the onset of PTSD. Those who received the intervention showed no significant short term (3-5 months) decrease in the risk of PTSD (odds ratio 1.22 (95% CI 0.06 to 2.46)). At one year, one trial reported that there was a significantly increased risk of PTSD in those receiving debriefing (odds ratio 2.88 (95% CI 1.11 to 7.53)).

Comments: The study populations are reasonably comparable apart from the three studies involving childbirth/miscarriage and the Bunn,1979 study focusing on relatives of trauma victims. Also, most studies showed an excess of males, reflecting the epidemiology of trauma. Of note, the analyzable data in the Bordrow, 1979 study compares brief with prolonged treatment and, thus, can not be compared to the other trials. The most significant problems are the small sample sizes, high attrition rates, the varying forms of debriefing, pt led aspect of the two obstetric papers, lack of comparison with other data sources (many positive uncontrolled studies), and interventions/follow up may have been too short. Those at most risk of developing PTSD are unlikely to be helped by a single PD session, and it is possible that in some individuals it serves as further trauma without the assistance in emotional processing. Thus, emphasis should be placed on early detection of those at risk for developing further psychiatric illness and early interventions should be aimed at this group. Overall, there is a continuing need for more research on this and related topics.

Return to top of the page

ADJUNCTIVE ANTIPSYCHOTIC TREATMENT FOR SSRI-RESISTANT PTSD

Clinical Question: Is it effective to use adjunctive anti psychotic treatment for SSRI­-resistant PTSD?

Reference: Stein MB, line NA. Matloff JL. Adjunctive olanzapine for SSRI-resistant combat - related PTSD: a double-blind, placebo-controlled study.[comment]. [Clinical Trial. Journal Article. Randomized Controlled Trial] American Journal of Psychiatry. 159(10):1777-9, 2002 Oct

Methods
Design - RCT randomization by a random-numbers table prepared by pharmacy.
Setting - VA San Diego Healthcare System
Patient Population - SSRI resistant PTSD, Typical duration of illness in the range of 20-25 years.
Inclusion criteria: DSM-IV PTSD (psychotic Sx is not determination factor).
Exclusion criteria: Not concurrently using anti psychotics.
Screening/enrollment methods: Minimally responsive to 12 or more weeks (4 weeks or more at maximally tolerated doses) with SSRI; who agreed to participate. 21 enrolled, two failed to return for the thirst medication and lost to f/u. Total of 19.
Intervention / Control: Olanzapine vs placebo on top of SSRI.
Blinding: Double-blind. Code for randomization maintained in the pharmacy. Analysis ; Student-t test.

Longitudinal Interval Follow-Up Evaluation of PTSD Sx for 8 weeks:
Clinician-Administered PTSD Scale for DSM-IV
Center for Epidemiologic Studies Depression Scale [CES-D Scale] Self-report Pittsburgh Sleep Quality Index fro sleep Clinical Global Impression (CGI) scale

Validity
Randomized? Randomization list concealed? yes
Treatment groups similar at baseline? yes
Patients starting trial accounted for at conclusion? yes
Patients analyzed in groups to which they were randomized? Yes. Patients and clinicians blinded to treatment? yes
Groups treated similarly outside of intervention? yes
Do the study population characteristics describe your patient? Yes

Early termination: 3 from Olanzapine grp (for somnolence) and 2 from placebo (for lack of efficacy) Side-effect: significant Wt gain.

CONCLUSIONS: This is most likely the first double-blind, placebo-controlled study of an adjunct to SSRIs for PTSD. Despite the small group size, the findings suggest a role for olanzapine or other atypical anti psychotics in treating SSRI-resistant PTSD. Sleep symptoms may especially benefit.

Comments
Strengths and Weaknesses of Study (internal and external validity) RCT. Sample size to small. F/u not detailed. Undetermined SSRIs effects. Sample and fast report to ...
Study in context of other available literature and/or current standard-of care: First study for this issue.
How will this study affect your management of the putative patient? Not much.
Next steps for further study of this problem. Contracted therapy - Large sample, longer f/u, well designed.

Return to top of the page

LAMOTRIGINE IN PTSD

Author:
Simone Litsch, MD

Clinical Question: Is there evidence that lamictal might be helpful in treating symptoms of PTSD?

Reference: Michael A. Hertzberg, Marian I. Butterfield et al.: A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder, Biol Psychiatry, 1999;45:1226-1229

Methods
Design - RCT 12 week long, randomized in a ratio of 2 to 1 to either lamotrigine or placebo
Setting - DUMC and the PTSD outpatient treatment and the Women's Veteran Health Programs at DVA 
Patient Population - patients with combat or civilian PTS, Caucasian and African American, both genders Inclusion criteria DSM IV criteria for PTSD based on clinical interview and the Structured Interview for PTSD (SIP)
Exclusion criteria no concomitant psychotropic medication was permitted, otherwise no comment Screening/enrollment methods no comment
Number screened vs. number enrolled no comment
Intervention / Control Lamotrigine vs. placebo: lamotrigine 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/d for 1 week, then increase by 100 mg every 1 to 2 weeks until achieving maximal response, reaching a maximum dosage of 500 mg/day. A 2 week medication taper was begun at week 10, with medication being reduced by 50% per week. Mean lamotrigine dosage at endpoint (week 10) was 380 mg/day, with a range of 50 to 500 mg.
Blinding double blind
Analysis - intention-to-treat with one exception of 1 patients who moved away and was not included 
Outcomes - primary: Symptoms were assessed by clinician ratings at each visit using the SIP Structured Interview for PTSD (SIP) and the physician administered Duke Global Rating Scale for PTSD scale (DGRP). The DGRP for PTSD measures severity and improvement for each of the three PTSD symptom domains (re experiencing, avoidance, numbing, hyperarousal) as well as overall PTSD severity. Final DGRP-I (improvement) scores were used as the basis for distinguishing treatment responders (DGRP-I of 1=very much improved; 2=much improved) and non responders (DGRP>2). No secondary outcomes 
Follow-up - Patients were seen at 2-week intervals throughout the 12-week study. Not all patients completed 10 weeks.

Validity
Randomized? Yes Randomization list concealed? No comment
Treatment groups similar at baseline? yes
Patients starting trial accounted for at conclusion? 1 lamotrigine pt moved away and was not included Patients analyzed in groups to which they were randomized? yes
Patients and clinicians blinded to treatment? yes
Groups treated similarly outside of intervention? yes

Results
For primary outcomes: 15 patients entered treatment, 14 of whom returned for subsequent visits.
10 Patients in lamotrigine completed study, 4 in placebo. Mean DGRP severity scores for total PTSD symptoms as well as re experiencing, avoidance/numbing, and hyperarousal clusters were compared pre and post-treatment for lamotrigine and placebo patients. In the lamotrigine group 5 of 10 (50%) responded as measured by changes in DGRP-I (much or very much improved) compared to 1 of 4 (25%) in the placebo group. Improvement on re experiencing, avoidance/numbing symptoms was seen in the lamotrigine group with mean (± SD) changes of 0.7 ± 1.4 and 0.6 ± 1.6, respectively, where no changes were noted in the placebo group (.00 ±.0 change for both). OR=3, RR=2, NNT= 4
Adverse Effects Somatic symptoms during tx were assessed using a 34-item checklist rated on a 4-point Likert scale. Patients completed this checklist at baseline and each subsequent visit. 2 of 10 lamotrigine pts had rash leading to discontinuation from the study and were non responders. 2 of 4 of placebo had rash and did not complete study. Otherwise, treatment was well tolerated, only minor side effects were reported (sweating, drowsiness, poor concentration, thirst, urge to move about, forgetfulness, bad taste in mouth).

Comments
Weaknesses of Study (internal and external validity) small sample size
Next steps for further study of this problem: larger double-blind, placebo-controlled studies of lamotrigine are warranted

Return to top of the page

PRAZOSIN IN PTSD

Author:
Kerry Landry

Clinical Question: 55yo AAM 100% SC Vietnam veteran with PTSD presents complaining of persistent nightmares of combat experiences, despite numerous medication trials with which patient has been compliant. Will prazosin be of any help?

Reference: Raskind MA, Peskind ER, et al. Reduction of Nightmare and Other PTSD Symptoms in Combat Veterans by Prazosin: A Placebo-Controlled Study. Am JPsychiatry, Feb 2003, vol 160: 371­373.

Background: Prazosin substantially reduced trauma-related nightmares and globally rated severity of PTSD in open-label studies. Prazosin is a centrally active al adrenergic antagonist that should counteract in part the excessive brain noradrenergic activity reported in PTSD. PTSD nightmares appear to arise from light sleep and /or disrupted REM sleep. Prazosin reduces light sleep and normalizes REM sleep

Methods
Design - RCT, 2-period, 2-treatment crossover study.
Setting - VA outpatient clinic
Patient Population - 10 male Vietnam combat veteran outpatients. All met DSM-IV criteria for PTSD and reported experiencing symptoms since return from Vietnam. Five patients had remote history of alcohol abuse, but all subjects had been alcohol and substance-free for at least 6 months. All had frequent & severe combat-trauma related nightmares (Clinician-Administered PTSD Scale recurrent distressing dreams item score >= 6 out of 8), despite trials of psychoactive medications. Nine of ten receiving disability compensation for PTSD. Seven subjects on one or more PTSD medications, including SSRI's, trazodone, benzodiazepines, anticonvulsants, hydroxyzine, and risperidone.
Intervention / Control - Prazosin / Placebo. Other medications and psychotherapy were maintained unchanged during the study.

Baseline 1-*randomization to Prazosin or Placebo- Period 1 (9 wks total: 3 weeks of prazosin/placebo titration, 6 weeks maintenance treatment)-)' Endpoint 14 Washout period (2 weeks)-Baseline 24 "Crossover of Groups" -)'Period 2 (9 wks total) Endpoint 2.

Titration: Prazosin started at lmg/d QHS x 3 days to avoid possible "first-dose" orthostatic syncope- 2mg QHS x 4 days. If nightmares not markedly improved and AE's clinically acceptable, dose was increased to 4mg QHS x 7 days. If still no marked improvement or AE's, dose increased to 6mg QHS x 7 days, then to 6mg QHS and 4mg Q 1600.

Blinding - Patients blind to medication condition. Clinicians and raters blind to medication condition and blood pressure.
Outcomes -Clinician-Administered PTSD Scale completed at baselines and endpoints. CGI of change was administered at endpoints.
Primary: C-A PTSD Scale recurrent dream item, difficulty falling asleep item, and CGI of change for overall PTSD severity and functional status
Secondary: C-A PTSD Scale total score, 3 symptom cluster scores (re experiencing/intrusion, avoidance/numbing, & hyperarousal)
Follow-up - 20 week period total. All 10 patients completed all conditions except for those in second placebo condition. Five patients experienced rapid return of distressing nightmares during post-prazosin washout, 4 experienced no benefit from second placebo treatment and insisted on discontinuing study. LOCF was selected to impute conservative endpoint 2 values for these subjects. 
Analysis, - ITT with LOCF. Differences between baseline & endpoint for all outcome measure were calculated for each treatment condition regardless of order and compared between treatment conditions by 2-taile paired t test. Effect sizes calculated as (mean post-prazosin score minus mean post-placebo score)/ standard deviation of mean post-placebo score.

Validity
Randomized and Randomization list concealed? yes Treatment groups similar at baseline? yes
Patients starting trial accounted for at conclusion? yes
Patients analyzed in groups to which they were randomized? yes Patients and clinicians blinded to treatment? yes Groups treated similarly outside of intervention? yes
Do the study population characteristics describe your patient? very much so

Results
For primary outcomes - "very large" to "huge" effect sizes for recurring nightmares, sleep disturbance, and global change in PTSD severity and functional status.
For secondary outcomes - "medium" to "very large" effect sizes for reduction of re experiencing/ intrusion, avoidance/numbing, & hyperarousal symptom cluster scores, and C-A PTSD Scale total score. Compliance with Therapies - No confirmation of compliance.
Adverse Effects - Prazosin was well tolerated. 2 patients experienced mild orthostatic SBP decreases and dizziness early during prazosin titration, which resolved as dose was increased.

Comments
Strengths: conservative study design, yet still demonstrated significant effect
Weaknesses: small number of subjects, only combat-experienced PTSD, all men, no long-term follow up beyond 20 weeks, no mention of other adverse effects
How will this study affect your management of the putative patient? will likely try
Next steps for further study of this problem: Long term study, broaden subject pool to assess effectiveness in civilian trauma PTSD, improved monitoring/ reporting of AE's

Verbal Study Synopsis
Our question about therapy was "does prozain vs placebo reduce persistent nightmares of combat experiences in Vietnam veterans with PTSD?" The best evidence we found was a small randomized crossover trial of prazosin vs placebo for male, Vietnam veteran VA outpatients with PTSD, which showed a 650% relative reduction in recurrent distressing dreams as measured by the Clinician-Administered PTSD Scale recurrent distressing dreams item over 20 weeks,. corresponding to an effect size of 1.9 and NNT of 4 (95% CI 2-infinity). The trial's validity was limited by small number of subjects, no long term follow up, and drop out of 4 subjects, which may have biased the results in the direction of underestimating and overestimating the true treatment effect. Given these limitations, this study provides good quality of evidence of a moderate benefit, and therefore does support cautious clinical use of prazosin in similar patients.

Return to top of the page

Chairman's Rounds 6/7/04 - Anandhi Narasimhan

Clinical Question: Does olanzapine vs. placebo improve the outcome in patients with SSRI-resistant combat-related PTSD?

Reference: Stein, MB, Kline, NA, Matloff, JL. Adjunctive Olanzapine for SSRI-Resistant Combat-Related PTSD: A Double-Blind, Placebo-Controlled Study. Am J of Psychiatry, Oct. 2002, 159:10

Methods:

Design-randomized, cohort, double-blind, placebo controlled study

Setting-VA San Diego Healthcare system

Patient Population-21 patients enrolled in study

Inclusion criteria- 1) male patients from the VA San Diego Health care system with a clinically predominant diagnosis of DSM-IV PTSD 2) Patients whose PTSD symptoms were prospectively judged to be minimally responsive to 12 or more weeks (4 weeks or more at maximally tolerated doses) of treatment with an SSRI 3) Subjects had chronic military-related PTSD 4) Duration of illness in the range of 20-25 years 4) Comorbid mood disorders

Numbers screened vs. enrolled- did not give number screened, 21 enrolled, 2 failed to return for first medication assessment and were lost to follow-up. Out of remaining 19 patients, 5 were taking fluoxetine (median dose 40mg/day), 7 taking paroxetine (median dose 40mg/day), 7 were taking sertraline (median dose 200mg/day)

Intervention- Subjects continued to take maximally tolerated stable dose of SSRI throughout the study and were randomly assigned to take adjunctive olanzapine (10mg) or placebo at bedtime for the first 2 weeks, which could be increased to 20mg at the next visit, if felt necessary and medication was tolerated

Blinding- double-blinded

Analysis- Two-tailed tests were used, with p<0.05 deemed statistically significant, ITT done wherever possible for non-completers, Pittsburgh Sleep Quality Inventory scores available only for completers, so no ITT in regards to sleep symptoms

 Outcomes- Primary-change in 3 symptom domains-1) Posttraumatic stress (Clinician­Administered PTSD Scale for DSM-IV 2) Depressive (self-rated Center for Epidemiologic Studies Depression Scale (CES-D Scale) 3) Sleep (self-report Pittsburgh Sleep Quality Index). Secondary- changes in these measures compared across treatments; number of responders defined by CGI scale of change as "much improved" or "very much improved" since start of treatment

Follow-up- no follow-up after 8 week trial period

Validity­

Randomized-yes

Treatment groups similar at baseline-yes in regards to having PTSD, but do not know about similarities in regards to comorbid disorders

Patients starting trial were accounted for at conclusion-yes, except in regards to sleep measurements

Patients analyzed to groups to which they were randomized-yes Patients and clinicians blinded to treatment- yes

Groups treated similarly outside of intervention-don't know

Results-

Primary Outcomes­

Olanzapine was associated with a greater reduction than placebo in PTSD symptoms, as measured by total score on the Clinician-Administered PTSD Scale for DSM-IV corresponding to a Cohen's d of 1.04(large effect)
Olanzapine was associated with a greater reduction than placebo in sleep disturbance, as measured by the global score on the Pittsburgh Sleep Quality Index corresponding to a Cohen's d of 1.75 (huge effect). The change in Pittsburgh Sleep Quality Inventory Score was moderately correlated with change in Clinician-Administered PTSD Scale for DSM-IV score (r=0.66, df15, p=0.01)
Olanzapine was associated with a greater reduction than placebo in depressive symptoms, as measured by the CES-D Scale corresponding to Cohen' d of 1.33(very large effect)

Secondary Outcomes- for responders on the CGI scale- 30% on olanzapine vs. 11% on placebo
RRR: 173%; 95% CI (-2455%-71%) ARR: 0.19; 95% CI (-0.19-0.5745)
Odds Ratio: 3.47; 95% CI(0.23-50.66) NNT: 5; 95% CI(2-infinity)
The mean dose of olanzapine was 15mg/day (SD=5.25) compared to the mean dose of placebo, 20mg/day (SD=0.00)(t=2.83, df=17, p<0.02)
Weight gain was significantly greater with olanzapine than placebo (p=0.001).
In the treatment group, 2 patients were terminated from protocol because of somnolence, 1 for unspecified reasons, and 2 patients were terminated in the placebo arm (lack of efficacy)

Comments:
Strengths- randomized, patients were similar in regards to absence of psychotic symptoms. Weaknesses- the improvement in symptoms could be related to the sedation effect of olanzapine, we do not know if patients were treated similarly outside of intervention, did not exclude comorbid mood disorders, CGI may not be the best way to measure overall improvement, no ITT for sleep symptoms, no follow-up after 8 week trial period, small sample size

Verbal Synopsis:
Our question about therapy was "does olanzapine vs. placebo improve the outcome in patients with SSRI-resistant combat-related PTSD?" The best evidence we found was a small randomized double blind study of olanzapine vs. placebo for patients with SSRI­resistant combat-related PTSD, which showed 19% absolute risk reduction in symptoms as measured by the CGI over 8 weeks, corresponding to a NNT of 5 (95% CI 2-infinity). The trial's validity was limited by a small sample size, the improvement of symptoms possibly related to sedation effect, no ITT for sleep symptoms and lack of long-term follow-up which may have biased the results in the direction of overestimating the treatment effect. Given these limitations, this study provides fair quality evidence of a small benefit, and therefore does support the cautious clinical use of olanzapine in similar patients.

Return to top of the page
Matthew Rosa
Chairman's Rounds 6/6/04

Cohen H., Kaplan Z.,Kotler M., Kouperman I. , Moisa R.,Grisaru N. "Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex in Posttraumatic Stress Disorder: A Double Blind, Placebo-Controlled Study" Am J Psychiatry 161:3. March 2004

Background:

PTSD is a generally difficult psychiatric disorder to treat. Pharmacotherapy for symptoms of PTSD and/or associated anxiety and depression have included most of the standard psychotropic medications including MAOI's, TCA's and more recently SSRI's (for which Sertraline and Paroxetine are FDA approved) as well as mood stabilizers, b­blockers, anticonvulsants and benzodiazepines.

Transcortical magnetic stimulation (TMS) is a noninvasive technique for directly stimulating cortical neurons. Electrical energy crosses the brain almost painlessly, without causing convulsions or cognitive impairment but causing depolarization of neurons with resultant changes in monoamines. The authors cite prior pilot studies that lend credence to the idea that repetitive TMS (rTMS) may be an effective alternative for treating patients with PTSD.

They note a number of structural and functional neuroimaging studies which have shown that abnormalities in the prefrontal cortex can be found in patients with PTSD. Low metabolism was found at baseline in temporal and prefrontal cortical areas according to PET scans. PTSD patients showed increased regional cerebral blood flow (rCBF) in the amygdala and decreased rCBF in prefrontal cortex in response to provocation of symptoms by script driven imagery. Also proton magnetic resonance spectroscopy (MRS) measurement of medial temporal lobe neural density in Vietnam combat veterans with PTSD and in healthy controls showed the ratio of N-acetyl-L-aspartic acid to creatinine ratio was lower in the right hemisphere vs. left as well as in comparison with healthy control subjects. This lower ratio is suggestive of neuronal loss.

Additionally, prefrontal and limbic abnormalities is suggested by neuropsychological testing sensitive to frontal lobe damage., which demonstrate impaired performance on tests reflecting abnormalities of the dorsolateral prefrontal cortex, the orbitofrontal cortex as well as the limbic system generally.

Taken together these studies suggest that the right limbic and paralimbic structures are involved in the pathophysiology of PTSD and that stimulation of the right dorsolateral prefrontal cortex may result in improvement of symptoms.

Methods:
29 patients satisfying DSM IV criteria for PTSD (as assessed by SCID) were recruited from inpatient and outpatient programs at Beer Sheeva Mental Health Center . 24 of the patients completed daily rTMS sessions over the course of 10 days. They were divided into three treatment arms, a sham placebo arm, low frequency (1 Hz) and a high frequency (10 Hz) treatment arm. The subjects were rated on a number of parameters. Ham-D, Ham-A, Treatment outcome PTSD scale and PTSD checklist were taken by subjects at days 0, 5,10 and 24 (14 days after finishing rTMS). The Clinician­Administered PTSD Scale was performed at day 0 and 24.
Exclusion criteria included substance use disorder, cardiac pacemaker implant, history of epilepsy, neurosurgery, brain trauma or any "chronic medical condition".
Regarding the validity of this study:
It is a randomized placebo controlled trial. The randomization was by number generator and all parties were blinded. All subjects, including 5 dropouts are accounted for in the study.
As to whether all participants are accounted for in the results, 29 patients were recruited and randomized but only 24 patients were analyzed. There were 5 dropouts who are not accounted for in the analysis despite being randomized. 2 patients who received sham treatment asked to be pulled after the first TMS, 1 receiving low frequency refused to continue secondary to dizziness and another because of "unrelated side effects". One patient in the high frequency group was excluded at the end because of "problems with device calibration".
Also, despite the randomization there were clinically important differences between the groups regarding polypharmacy and other therapy modalities which subjects were receiving. The follow drugs were being used by different subjects in various quantities (not discussed): clomipramine, SSRI's, benzodiazepines, mood stabilizers and anti psychotics. Drug treatment was neither stopped nor changed in the 3 weeks before the study or during the study. Also the patients all continued to receive whatever individual and group therapies they were receiving prior to the intervention.
As far as equal treatment, aside from the experimental arm, there is no difference in the way groups were treated by investigators evident in the study.
Results:
With respect to the various rating scales, the mean change in scores were calculated within and between groups using ANCOVA, ANOVA and post hoc Sheffe tests.
Two way repeated measures ANCOVA for the PTSD checklist showed significant effect of rTMS. Post hoc Sheffe tests showed significant effect of RTMS 10HZ vs. sham and
lHz with regard to the checklist. The mean PTSD check list score decreased by 29.3% in the 10Hz by day 10 (table 3)
Two way repeated-measures ANCOVA for the Treatment Outcome PTSD Scale showed a significant effect of rTMS. Post hoc Sheffe tests showed significant effect of RTMS 10HZ vs. sham and 1Hz with regard to PTSD scale as well (see table 3). The mean scores decreased by 39% in the 10Hz on this parameter between day 1 and day 10.
Two way repeated measures ANCOVA for the Ham-A showed significant effect of rTMS. Post hoc Sheffe tests showed significant effect of RTMS 10HZ vs. sham and 1 Hz with regard to Ham-A (see table 3). The mean score for Ham-A decreased by 44.1% in 10 Hz group by day 10.
Two way repeated measures ANCOVA for the Ham-D showed no significant effect of rTMS on this scale, nor did post hoc testing reveal differences between groups.
With regard to the Clinician administered PTSD Scale, two way measured ANOVA for the various subscales were significant. (See table 4) and these were significant between groups by post hoc analysis as well. On the re-experiencing subscale, the 10Hz score dropped by 32.2% at day 24 from baseline. On the avoidance subscale, the score dropped 32.7% With regard to hyperarousal, the score dropped by a mean of 30.5% and the total score dropped by 32.5%. That compares to a 7.7% drop in the sham arm an a 2.2% drop in the 1 Hz arm, both statistically significant.
Unfortunately the authors only provide the mean scores on rating scales for the various arms and do not offer raw data as to the percent of patients who actually improved using rTMS. They also do not provide confidence intervals. This limits the ability of readers to analyze the results of this study, nor can we calculate the NNT for this mode of therapy.

Conclusions:
Given the relatively positive findings of this study, it is certainly possible to conclude that rTMS may be of benefit to patients with PTSD. However that conclusions must be tempered by the lack of validity of this study regarding analysis of all subjects who were randomized, five of whom dropped out but are not included as treatment failures. Had they been, the results may have been quite different. Also, the small size of this study reduces its power while the use of multiple modes of therapy which differed among subjects introduces multiple elements of confounding which are not stratified in the results.
As a result, the authors rightly suggest that their study must be considered merely "preliminary" and that future more rigorous studies are warranted.
Despite this 10 days of daily right prefrontal high frequency rTMS may have therapeutic effects for PTSD patients above those for low frequency rTMS or placebo.

 

Return to top of the page