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A GUIDE TO THE LITERATURE ON
PHARMACOTHERAPY FOR PTSD
Matthew J. Friedman, MD, PhD
National Center for PTSD and
White River Junction VAM&ROC
Dartmouth Medical School
We are beginning to reap the benefits of the
upsurge in multi- and single-site clinical trials with
newer pharmacological agents that began in the
mid-1990s. Although we eagerly await publications
on large industry-sponsored trials currently in
progress, this is a good time to take stock of the
current and older literature on pharmacotherapy
for PTSD. The two major developments are publica-
tion of guidelines on best pharmacotherapeutic prac-
tices in PTSD and recent approval by the Food and
Drug Administration (FDA) of sertraline as a treat-
ment for PTSD.
Best practices. Two recent publications address the
question of best practices in pharmacotherapy from
somewhat different perspectives. The empirical
evidence on drug efficacy is thoroughly evaluated
in a chapter by Friedman et al. (in press) that will
appear in the forthcoming treatment guideline com-
missioned by the International Society for Trau-
matic Stress Studies (ISTSS). This comprehensive
overview evaluates results from both randomized
and open label trials and determines the level of
evidence for the efficacy of each medication that has
been the focus of an article in the PTSD treatment
literature. A very different kind of overview is
represented in a recent monograph summarizing
the responses of an expert consensus panel of 57
international experts to a questionnaire on prescrib-
ing preferences for PTSD (Foa et al., 1999). There are
some very interesting differences between these
two practice guidelines. Conclusions in the ISTSS
chapter (Friedman et al., in press) are based on
empirical data derived from monotherapy efficacy
studies. In contrast, the panel of experts (Foa et al.,
1999) offer opinions based on clinical experience on
complex treatment questions about treatment strat-
egies for partial and non-responders to medication
treatment as well as on questions about what to
prescribe for patients with co-morbid psychiatric,
medical, and chemical abuse/dependency disor-
ders.
Selective serotonin reuptake inhibitors (SSRIs). FDA
approval of sertraline as the first medication indi-
cated for treating PTSD patients is an important
milestone in our field. The data that convinced the
FDA to take this action came from two large multisite
trials in which approximately 200 subjects (in each
trial) were randomly assigned to either sertraline or
placebo, respectively. A description of the first of
these studies is currently in press (Brady et al., in
press). Since results of the second trial are still being
prepared for publication, I have included an ab-
stract of the data that were presented at a scientific
meeting (Davidson, Londborg, et al., 1997). Both
studies demonstrate what others have previously
reported from single-site trials with sertraline,
paroxetine, fluvoxamine, and fluoxetine: that selec-
tive serotonin reuptake inhibitors have a broad spec-
trum of action on all three (re-experiencing,
avoidant/numbing, and hyperarousal) clusters of
PTSD symptoms (Davidson, Malik, et al., 1997;
Marmar et al., 1996; Marshall et al., 1998; Rothbaum
et al., 1996). Van der Kolk and associates (1994), who
conducted the first randomized clinical trial with
the SSRI fluoxetine, also found clear evidence for the
efficacy of this agent, although their results suggest
a more constricted spectrum of action since it re-
duced numbing and hyperarousal, but not re-expe-
riencing or avoidant PTSD symptoms.
Randomized clinical trials (RCTs). I have presented
abstracts of all the randomized clinical trials con-
ducted with PTSD patients since I believe that that
is the best and most valuable data in this field.
Citations on SSRI trials have already been discussed.
Chronologically speaking, the first trials were with
older antidepressants, tricyclic antidepressants
(TCAs), and monoamine oxidase inhibitors (MAOIs).
Three studies with TCAs, all with Vietnam veteran
subjects, report positive results with imipramine
(Kosten et al., 1991), mild-to-moderate effects with
amitriptyline (Davidson et al., 1990), and negative
results with desipramine (Reist et al., 1989). Two
trials with the MAOI phenelzine report very posi-
tive results in one study (Kosten et al., 1991) and
negative results in a methodologically flawed inves-
tigation (Shestatzky et al., 1988). Although interest
in these older agents has waned because of the more
recent interest generated by SSRIs and other new
agents, it is important to consider the fact that nei-
ther TCAs nor MAOIs have been systematically
evaluated and that there may be good reasons to
include them in future drug trials.
Other RCTs worth noting are a negative trial with
the benzodiazepine, alprazolam (Braun et al., 1990),
a negative trial with the second messenger, inositol,
which had previously shown promise in treatment
of depression and panic disorder (Kaplan et al.,
1996), and a negative trial with the serotonin antago-
nist cyproheptadine, which had previously appeared
Address for Dr. Friedman: National Center for PTSD (116D), VA
Medical & Regional Office Center, White River Junction, VT
05009. E-mail: matthew.friedman @dartmouth.edu.
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to reduce PTSD flashbacks and traumatic nightmares
(Jacobs-Rebhun et al., in press). The published results from
two large multi-site trials with brofaromine must be men-
tioned. This interesting medication combines an SSRI ac-
tion with reversible MAO-A inhibition. Findings with
brofaromine were modestly promising in one study (Katz
et al., 1994/1995) and negative in another (Baker et al.,
1995). This is only of academic interest, however, since its
manufacturer has withdrawn brofaromine from the mar-
ket and it is not available to clinicians.
Results from open trials. The remainder of the literature
consists of open trial and case reports on a number of
medications that are often utilized by practitioners despite
the fact that there is little published evidence to support
such prescribing practices. The best study of this sort is
with the adrenergic beta receptor antagonist, propranolol,
which was administered to 11 sexually and physically
abused children with good results. Propranolol was ad-
ministered according to an A-B-A design: six week baseline-
six week active treatment-six week post-treatment after
discontinuation of treatment (Famularo et al., 1988). Other
open trials worth noting are a successful open trial of the
SSRI sertraline for patients with co-morbid PTSD and
alcohol dependence (Brady et al., 1995); this study stands
out as a model for clinical trials designed to treat PTSD and
a comorbid psychiatric disorder simultaneously. Given
the high prevalence of comorbid disorders in PTSD pa-
tients, this strategy needs to be emulated in future re-
search. Positive results with the reversible MAO-A inhibi-
tor moclobemide (Neal et al., 1997) are of great interest,
since this agent is much easier to prescribe than traditional
MAOIs such as phenelzine. Only one small open trial with
nefazadone has been published (Hertzberg et al., 1998),
despite the fact that this antidepressant is widely pre-
scribed by clinicians and greatly favored by the expert
consensus panel mentioned earlier (Foa et al., 1999). Rep-
resentative open trials with a variety of medications are
also cited for the sake of completeness, although in every
case much more research is needed. These include reports
concerning the anticonvulsant carbamazepine (Lipper,
1990); the antidepressant trazadone (Hertzberg et al., 1996);
the adrenergic alpha-2 agonist, clonidine (Harmon & Riggs,
1996); and an interesting report on dramatically mixed
results with the experimental narcotic antagonist,
nalmafene (Glover, 1993).
Treatment of recently traumatized individuals. As the PTSD
field begins to emphasize early intervention for popula-
tions at risk, three studies are worth noting concerning
pharmacotherapy. The most exciting of these is a success-
ful prospective trial of the TCA imipramine for pediatric
burn patients with Acute Stress Disorder (Robert et al.,
1999). Second, a prospective trial of Israeli emergency
room patients with benzodiazepines was not successful
(Gelpin et al., 1996)-further evidence that there is little
evidence supporting the use of this class of medications to
prevent or ameliorate core PTSD symptoms. Third, a pilot
study in which the hypnotic temazepam was adminis-
tered specifically to promote better sleep among patients
with Acute Stress Disorder suggested that such an ap-
proach might reduce the development of PTSD after expo-
sure to traumatic stress (Mellman et al., 1998). Friedman
and colleagues (1993) present guidelines for pharmaco-
therapy for recently evacuated medical and psychiatric
casualties during war.
Review articles. There are also a number of review articles
that should be useful for anyone who wishes to understand
this literature. Davidson et al. (1997) consider response
characteristics of patient cohorts treated with antidepres-
sants in randomized clinical trials; important questions
such as predicting responsivity, latency of detectable thera-
peutic effect, and other matters are thoughtfully addressed.
Donnelly et al. (1999) review the disappointingly small
literature on medication treatment for children and adoles-
cents. Friedman (in press) reviews the psychobiology of
PTSD and predicts new classes of pharmacological agents
that need to be developed and tested in the future.
There are also a number of older reviews that should not
be forgotten because they discuss clinical trials that tend to
be overlooked in more recent reviews. The most compre-
hensive review on TCAs is by ver Ellen and van Kammen
(1990); on MAOIs by DeMartino et al. (1995); and on
ethnopharmacology and the treatment of PTSD by Lin et
al. (1996). Southwick et al. (1994) provide a quantitative
review of older (randomized and open) trials with TCAs
and MAOIs showing the effectiveness of both classes of
drugs on global improvement and PTSD reexperiencing
symptoms. Friedman and Southwick (1995) remains the
most detailed and comprehensive review of the literature
up to 1995, but does not contain more recent studies with
SSRIs and newer agents.
Interpreting the data. There are many questions about the
published data regarding gender, type of trauma,
comorbidity, and chronicity. Most clinical trials with women
include women exposed to sexual trauma. Most clinical
trials with men involve Vietnam veterans exposed to war-
zone trauma. Furthermore, the male cohorts have tended
to have more comorbid disorders and greater chronicity
and severity of their PTSD. Therefore, it would be a serious
mistake to interpret the findings of van der Kolk et al.
(1994) as demonstrating greater responsivity of women
than men, or greater responsivity of sexual trauma than of
war-zone trauma survivors to Drug X or Drug Y. Future
research must systematically evaluate the importance of
gender, type of trauma, comorbidity, chronicity, and other
factors as predictors of response to medication.
Conclusion. After a five-year hiatus, research on pharma-
cotherapy for PTSD began to increase in the mid-1990s.
Much of this activity was spurred by the interest of phar-
maceutical companies in testing the efficacy of SSRIs and
related agents on patients with PTSD. Such activity has not
only resulted in FDA approval of sertraline and multisite
trials with other agents such as nefazadone but has also
stimulated the development of new classes of drugs, such
as corticotropin releasing factor antagonists, substance P
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antagonists, and new anticonvulsants such as lamotrigine
and gabapentin (see Friedman, in press) that may eventu-
ally prove efficacious in PTSD. As we are swept along by
this exciting momentum, however, we should not neglect
to consider that older agents such as antiadrenergic agents,
MAOIs, anticonvulsants, and possibly TCAs may yet find
their niche in PTSD pharmacotherapy after they have been
evaluated systematically.
SELECTED ABSTRACTS
BAKER, D.G., DIAMOND, B.I., GILLETTE, G.M., HAMNER,
M.B., KATZELNICK, D., KELLER, T.W., MELLMAN, T.A.,
PONTIUS, E.B., ROSENTHAL, M., TUCKER, P., VAN DER KOLK,
B.A., & KATZ, R.J. (1995). A double-blind, randomized, pla-
cebo-controlled, multi-center study of brofaromine in the treat-
ment of post-traumatic stress disorder. Psychopharmacology, 122,
386-389. A large multi-center, double-blind, parallel trial to assess
the efficacy of brofaromine in the treatment of PTSD failed to
show a significant difference between the brofaromine and pla-
cebo treatment groups. The placebo response rate in this study
was higher than that in previously published double-blind, pla-
cebo-controlled studies of PTSD.
BRADY, K., PEARLSTEIN, T., ASNIS, G.M., BAKER, D.,
ROTHBAUM, B., SIKES, C.R., & FARFEL, G.M. (in press). Double-
blind, placebo-controlled study of the efficacy and safety of
sertraline treatment of posttraumatic stress disorder. Journal of
the American Medical Association. CONTEXT: Despite the high
relevance, chronicity, and associated comorbidity of PTSD in the
community, few placebo-controlled studies have evaluated the
efficacy of pharmacotherapy for this disorder. OBJECTIVE: To
determine if acute treatment with sertraline hydrochloride can
effectively treat symptoms of PTSD of moderate-to-marked se-
verity. DESIGN: Patients completed a 2-week single-blind, pla-
cebo lead-in prior to being randomized to 12 weeks of double-
blind treatment with either sertraline or placebo. SETTING:
Outpatient psychiatric clinics in 8 academic medical centers and
6 clinical research centers. INTERVENTION: Acute treatment
with sertraline hydrochloride in flexible daily doses in the range
of 50-200 mg, following one week at 25 mg, or placebo. PA-
TIENTS: A total of 187 outpatients with a DSM-III-R diagnosis of
PTSD and a Clinician Administered PTSD Scale part 2 (CAPS-2)
minimal total score > 50 at baseline (73% were female, mean age
40 years, mean duration of illness 12 years, 61% were the victims
of physical or sexual assault). MAIN OUTCOME MEASURES:
Baseline-to-endpoint change in CAPS-2 total severity score, the
Impact of Event Scale total score (IES), and Clinical Global Im-
pression Severity (CGI-S), and CGI-Improvement (CGI-I) ratings
at endpoint. RESULTS: Sertraline treatment yielded significantly
(p < 0.02) greater improvement on 3 out of the 4 primary outcome
measures, with the fourth measure, the IES, showing a trend
toward significance (p = 0.071). Using a conservative LOCF
analysis, treatment with sertraline resulted in a responder rate of
53% at study endpoint compared to 32% for placebo (p = 0.008;
with responder defined as > 30% reduction from baseline in
CAPS-2 total severity score and a CGI score of 1 (very much
improved), or 2 (much improved). Significant (p < 0.05) efficacy
was evident for sertraline from week 2 on the CAPS-2 total
severity score. Sertraline had significant efficacy vs. placebo on
the PTSD symptom clusters of avoidance/numbing (p = 0.015)
and increased arousal (p = 0.027) but not on the reexperiencing/
intrusion (p = 0.143). The beneficial effect of sertraline was con-
firmed by a highly significant improvement both on the patient-
rated Davidson Trauma Scale (DTS; p = 0.003), as well as on
functional and quality of life measures. Sertraline was well-
tolerated, with insomnia being the only side effect significantly
different from placebo (16% vs. 4%). CONCLUSIONS: The re-
sults of this study suggest that sertraline is a safe, well-tolerated,
and effective treatment for PTSD.
BRADY, K.T., SONNE, S.C., & ROBERTS, J.M. (1995). Sertraline
treatment of comorbid posttraumatic stress disorder and alco-
hol dependence. Journal of Clinical Psychiatry, 56, 502-505. BACK-
GROUND: PTSD often co-occurs with alcohol dependence, yet
little is known about treatment of this comorbidity. The serotonin
selective reuptake inhibitors have been shown preliminarily to be
effective in decreasing symptoms of PTSD but have not been
studied in individuals with comorbid alcohol dependence. This
is of particular interest as the SSRIs also have a modest effect in
decreasing alcohol consumption. METHOD: In this preliminary
trial, 9 subjects with comorbid PTSD and alcohol dependence
were treated in an open-label trial with sertraline for a 12-week
period. Symptoms of PTSD and depression were monitored
monthly with the Impact of Event Scale and the Hamilton Rating
Scale for Depression (HAM-D). Alcohol consumption was moni-
tored by a self-report instrument (Time-Line Follow-Back). RE-
SULTS: There were significant decreases in all 3 symptom clus-
ters of PTSD measured by overall PTSD symptom scores (p < .001)
and in HAM-D scores (p < .001) during the follow-up period.
Days of abstinence increased and average number of drinks
decreased during the follow-up period. 4 subjects claimed total
abstinence during the follow-up period. CONCLUSION: While
limited by small sample size and the open-label, nonblinded
study design, this study suggests that sertraline may be useful in
the treatment of PTSD complicated by alcoholism. The medica-
tion was well tolerated and subjects showed improvement in
PTSD symptoms as well as decreased alcohol consumption. A
controlled trial of sertraline in this population would be of
interest.
BRAUN, P., GREENBERG, D., DASBERG, H., & LERER, B.
(1990). Core symptoms of posttraumatic stress disorder unim-
proved by alprazolam treatment. Journal of Clinical Psychiatry, 51,
236-238. The authors report a random-assignment, double-blind
crossover trial comparing alprazolam and placebo in PTSD. 10
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.
DAVIDSON, J.R.T., KUDLER, H.S., SMITH, R.D.,
MAHORNEY, S.L., LIPPER, S., HAMMETT, E.B., SAUNDERS,
W.B., & CAVENAR, J.O. (1990). Treatment of posttraumatic
stress disorder with amitriptyline and placebo. Archives of Gen-
eral Psychiatry, 47, 259-266. Amitriptyline hydrochloride was
compared with placebo in 46 veterans with chronic PTSD. Treat-
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ment continued up to 8 weeks, and efficacy was measured by five
observer and two self-rated scales. Percent recovery rates were
higher for amitriptyline than placebo on two measures. In pa-
tients who completed 4 weeks (n = 40), better outcome with
amitriptyline was noted on the Hamilton depression scale only.
In the group completing 8 weeks of treatment (n = 33), the drug
was superior to placebo on Hamilton depression, Hamilton anxi-
ety, Clinical Global Impression severity, and Impact of Event
scales. There was no evidence for drug effects on the structured
interview for PTSD. Drug-placebo differences were greater in the
presence of comorbidity in general, although recovery rates were
uniformly low in the presence of major depression, panic disor-
der, and alcoholism. At the end of treatment, 64% of the amitrip-
tyline and 72% of the placebo samples still met diagnostic criteria
for PTSD.
DAVIDSON, J.R.T., LONDBORG, P.D., PEARLSTEIN, T.,
WEISLER, R., SIKES, C., & FARFEL, G.M. (1997). Double-blind
comparison of sertraline and placebo in patients with posttrau-
matic stress disorder (PTSD). American College of Neuropsycho-
pharmacology Abstracts, 36th Annual Meeting, 147. The lifetime
prevalence of PTSD has been reported to be 7.8% in the general
population and twice as common in females as in males. Symp-
toms can persist for years after the traumatic event. A multi-
center, 12-week, double-blind, flexible dose study of adult outpa-
tients (n = 208) with a DSM-III-R diagnosis of PTSD was con-
ducted at 12 U.S. centers to evaluate the safety and efficacy of
sertraline (50-200 mg/day) compared to placebo in the treatment
of PTSD. The primary efficacy ratings were the Impact of Event
Scale (IES), the Clinician Administered PTSD Scale (CAPS) and
the Clinician Global Impression ratings of severity and improve-
ment. At endpoint, sertraline patients exhibited significantly (p <
.05) greater improvement than placebo patients on all primary
efficacy measures. Sertraline-treated patients experienced mean
decreases of approximately 49% and 44% in IES and CAPS scores
respectively, compared to approximately 35% mean reductions
on both the IES and CAPS scores in placebo-treated patients. The
Davidson Self-Rating Trauma scale (DTS) was administered as a
secondary efficacy measure, and at endpoint sertraline-treated
patients exhibited a mean decrease of approximately 43% com-
pared to 27% in the placebo group (p < .01). Sertraline was
generally well tolerated. The most frequently reported adverse
events (>10%) that occurred significantly more in sertraline-
treated patients than placebo-treated patients were insomnia,
diarrhea, nausea, fatigue, and anorexia. Treatment
discontinuations due to adverse events occurred in approxi-
mately 10% of the sertraline-treated patients compared to 5% of
the placebo-treated patients, and this difference was not statisti-
cally significant. There were no clinically meaningful changes in
laboratory values nor any significant changes in vital signs or
ECGs between treatment groups. In this study, sertraline in doses
of 50-200 mg/day was shown to be a safe and effective treatment
for patients with PTSD.
DAVIDSON, J.R.T., MALIK, M.L., & SUTHERLAND, S.N.
(1997). Response characteristics to antidepressants and placebo
in post-traumatic stress disorder. International Clinical Psycho-
pharmacology, 12, 291-296. Characteristic response patterns are
described for 2 antidepressant drugs and placebo in PTSD. Early
onset and steady improvement occurred on a global rating scale
for both drugs and placebo in those who ultimately met re-
sponder criteria at the end of treatment. In certain cases, the
magnitude of global response was greater for drug than for
placebo. At weeks 2 or 4, the Clinical Global Impressions score for
fluoxetine, but not for amitriptyline, served as a good predictor of
eventual response. In a review of numerous completed placebo-
controlled trials, antidepressants were superior to placebo in 7
out of 8 comparisons using the Clinical Global Impressions,
although specific effects on PTSD scales were more variable.
Drug response rates are similar for combat and civilian trauma
samples, but placebo response rates may be higher in the latter.
Effect sizes suggested a moderate-to-good effect for drug therapy.
FAMULARO, R., KINSCHERFF, R., & FENTON, T. (1988).
Propranolol treatment for childhood posttraumatic stress dis-
order, acute type. American Journal of Diseases of Children, 142,
1244-1247. We report 11 cases of PTSD. Each child had been
physically abused or sexually abused or both and presented in an
agitated, hyperaroused state. Using a B-A-B (off-on-off) medica-
tion design in a clinical setting, the children were treated with the
beta-adrenergic antagonist propranolol. Scores on an inventory
of symptoms of PTSD indicated that patients exhibited signifi-
cantly fewer symptoms while receiving medication than either
before or after they received medication.
FOA, E.B., DAVIDSON, J.R.T., & FRANCES, A.J. (1999). Treat-
ment of posttraumatic stress disorder [Expert consensus guide-
line series]. Journal of Clinical Psychiatry, 60 (Supplement 10). The
Expert Consensus Guidelines for the treatment of PTSD are based
on surveys of 52 experts on the psychotherapy treatment and 57
experts on the medication treatment of PTSD. We first created a
skeleton algorithm based on the existing research literature and
other guidelines to identify key decision points in the everyday
treatment of patients with PTSD. We then developed two written
questionnaires, one on medication treatments and one on psy-
chotherapy treatments. The actual questions and results of the
medication and psychotherapy treatment surveys are presented.
These guidelines can be viewed as an expert consultation, to be
weighed in conjunction with other information and in the context
of each individual patient-physician relationship. [Adapted from
Text]
FRIEDMAN, M.J., DAVIDSON, J.R.T., MELLMAN, T.A., &
SOUTHWICK, S.M. (in press). Guidelines for pharmacotherapy
and position paper on practice guidelines. In E.B. Foa, T.M.
Keane, & M.J. Friedman (Eds.), Effective treatments for post-trau-
matic stress disorder: Practice guidelines from the International Society
for Traumatic Stress Studies. New York: Guilford. PTSD appears to
be a very complex disorder that is associated with stable and
profound alternatives in many psychobiological systems that
have evolved for coping, adaptation, and survival of the human
species. The most substantial available evidence supports the use
of the broad category of antidepressant medications, especially
SSRIs, which appear to promote global improvement in most, but
not all, randomized clinical trials. Antiadrenergic agents such as
clonidine, guanfacine, and propanolol may prove to ameliorate
arousal and reexperiencing symptoms by reducing the excessive
adrenergic activity associated with PTSD. Unfortunately there is
very little clinical data to substantiate this speculation at this time.
There is a great deal of evidence suggesting that pharmaco-
therapy will successfully reduce most disorders comorbid with
PTSD. There is good reason to anticipate exciting breakthroughs
in the foreseeable future that should equip clinicians with a
greater variety of effective drugs that will benefit patients with
PTSD. [Adapted from Text]
FRIEDMAN, M.J., & SOUTHWICK, S.M. (1995). Towards
pharmacotherapy for post-traumatic stress disorder. In M.J.
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Friedman, D.S. Charney, & A.Y. Deutch (Eds.), Neurobiological
and clinical consequences of stress: From normal adaptation to post-
traumatic stress disorder (pp. 465-481). Philadelphia: Lippincott-
Raven. We review the current literature on the clinical psycho-
pharmacology of PTSD. With our growing appreciation of the
complexity of PTSD, we are beginning to understand why we
may have failed to discover a single drug that will significantly
reduce PTSD symptoms. There have been too few published
randomized clinical trials. Even among these few published
RCT's, there are enough questions about methodology, instru-
mentation, and sample selection to suggest the need for expan-
sion and extension of RCT programs to include testing and
retesting of more drugs. Despite these concerns, it does appear
that certain drugs may be helpful in alleviating specific PTSD
symptom clusters. A rational approach to pharmacotherapy for
PTSD may require a multisystem approach in which multiple
drugs, each one with a unique and distinct action, are adminis-
tered simultaneously. [Adapted from Text]
GELPIN, E., BONNE, O.B., PERI, T., BRANDES, D., & SHALEV,
A.Y. (1996). Treatment of recent trauma survivors with benzo-
diazepines: A prospective study. Journal of Clinical Psychiatry, 57,
390-394. BACKGROUND: Most types of psychotropic drugs
have been tried in the treatment of chronic PTSD, but have
yielded limited results. Theory and retrospective research pre-
dict 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 prospectively evaluates the effect of early
administration of benzodiazepines on the course of PTSD and
PTSD symptoms. METHOD: 13 trauma survivors (the benzodi-
azepine 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). 13 other trauma survivors, pair-
matched with subjects in the active treatment group for gender
and symptom severity in the first week after the trauma, consti-
tute 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 Adminis-
tered 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). 9 benzodiazepine sub-
jects 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 expres-
sion of arousal.
KATZ, R.J., LOTT, M.H., ARBUS, P., CROCQ, L., HERLOBSEN,
P., LINGJAERDE, O., LOPEZ, G., LOUGHREY, G.C.,
MACFARLANE, D.J., MCIVOR, R., MEHLUM, L., NUGENT, D.,
TURNER, S.W., WEISAETH, L., & YULE, W. (1994/1995). Phar-
macotherapy of post-traumatic stress disorder with a novel
psychotropic. Anxiety, 1, 169-174. This was a multicenter, ran-
domized, double-blind, parallel trial conducted in outpatients in
three countries. Following screening and placebo washout, pa-
tients received brofaromine (a combined MAO-A inhibitor/5-
HT transport inhibitor) or placebo in a flexible dosing design.
Based upon the CAPS, a standardized PTSD interview, findings
from a cohort involving both subchronic and chronic traumatic
stress marginally favored brofaromine over placebo; however,
not to a statistically significant degree. With a more conservation
[sic] definition of the syndrome, employing a primary cohort of
patients with PTSD of one year or greater duration, brofaromine
significantly reduced PTSD symptoms in comparison with pla-
cebo. In all analyses a substantial proportion of patients in both
drug and placebo groups remained symptomatic throughout.
Findings were supported by an analysis of secondary measures.
Brofaromine may be of benefit in the therapy of PTSD.
KOSTEN, T.R., FRANK, J.B., DAN, E., MCDOUGLE, C.J., &
GILLER, E.L. (1991). Pharmacotherapy for posttraumatic stress
disorder using phenelzine or imipramine. Journal of Nervous and
Mental Disease, 179, 366-370. 60 male veterans with PTSD partici-
pated in an 8-week, randomized trial comparing phenelzine (n =
19), imipramine (n = 23), and placebo (n = 18). Mean treatment
retention was better on phenelzine (7.4 weeks) than on imi-
pramine (5.6 weeks) or placebo (5.5 weeks). By week 5, both
medications significantly reduced PTSD symptoms, as assessed
by the Impact of Event Scale (IES), but the 44% improvement on
phenelzine was greater than the 25% improvement on imipramine.
The intrusion, but not the avoidance, subscale of the IES showed
significant improvement, and the initial mild to moderate de-
pressive symptoms did not significantly improve.
LIN, K., POLAND, R.E., ANDERSON, D., & LESSER, I.M.
(1996). Ethnopsychopharmacology and the treatment of PTSD.
In A.J. Marsella, M.J. Friedman, E.T. Gerrity, & R.M. Scurfield
(Eds.), Ethnocultural aspects of posttraumatic stress disorder: Issues,
research, and clinical applications (pp. 505-526). Washington: Ameri-
can Psychological Association. In this chapter, we first review the
principles of how ethnicity may interact with drug metabolism
and drug action. Next, the role that ethnicity plays in relation to
the specific classes of medications that are commonly used to
treat PTSD - antidepressants, neuroleptics, benzodiazepines, and
lithium - is covered. Finally, we briefly discuss future research
directions and the applicability of this research to clinical prac-
tice.
REIST, C., KAUFFMANN, C.D., HAIER, R.J., SANGDAHL, C.,
DEMET, E.M., CHICZ-DEMET, A., & NELSON, J.N. (1989). A
controlled trial of desipramine in 18 men with posttraumatic
stress disorder. American Journal of Psychiatry, 146, 513-516. 18
male U.S. veterans meeting DSM-III criteria for PTSD completed
a 4-week double-blind, crossover study comparing administra-
tion of 200 mg/day of desipramine with placebo. Response was
measured by using the Beck Depression Inventory, the Hamilton
Rating Scale for Depression, the Hamilton Rating Scale for Anxi-
ety, and the Impact of Event Scale. Overall, the only apparent
response to desipramine was in some symptoms of depression;
there were no changes in anxiety and other PTSD symptoms.
ROBERT, R., BLAKENEY, P.E., VILLARREAL, C.,
ROSENBERG, L., & MEYER, W.J. (1999). Imipramine treatment
in pediatric burn patients with symptoms of acute stress disor-
der: A pilot study. Journal of the American Academy of Child and
Adolescent Psychiatry, 38, 873-878. OBJECTIVE: Pediatric burn
patients often exhibit acute stress disorder (ASD) symptoms.
Information on psychopharmacological treatment of ASD symp-
toms in children is scarce. This pilot study used a prospective,
randomized, double-blind design to test whether thermally in-
jured children suffering ASD symptoms benefit from imipramine.
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METHOD: 25 children, aged 2 to 19 years, received either imi-
pramine or chloral hydrate for 7 days. A structured interview
(clinically useful, but validity and reliability not yet established)
was used to assess the presence and frequency of ASD symptoms
both before treatment and 3 times during the treatment period.
RESULTS: 11 females and 14 males participated, with a mean
total burn surface of 45% (SD = 23%) and mean age of 8 years (SD
= 6). Imipramine was more effective than choral hydrate in
treating ASD symptoms ( 2 [1, n = 25] = 5.24, p < .02). Five of 13
were positive responders to chloral hydrate (38%). Ten of 12 were
positive responders to low-dose imipramine (83%). CONCLU-
SIONS: This pilot study suggests a place for cautious initial use of
imipramine to reduce ASD symptoms in burned children. Care
must be taken to minimize cardiovascular risks in an off-label
application of imipramine in children, especially those receiving
additional medications.
SHESTATZKY, M., GREENBERG, D., & LERER, B. (1988). A
controlled trial of phenelzine in posttraumatic stress disorder.
Psychiatry Research, 24, 149-155. 13 patients meeting DSM-III
criteria for PTSD participated in a random-assignment, double-
blind crossover trial comparing phenelzine (45-75 mg/day) and
placebo. 10 patients completed at least 4 weeks of each treatment
phase. Clinical response to phenelzine did not differ from pla-
cebo, and overall improvement by the end of the study could not
be attributed to the active drug. The findings are discussed in the
light of preliminary reports suggesting that phenelzine may be an
effective treatment for PTSD.
VAN DER KOLK, B.A., DREYFUSS, D., MICHAELS, M.J.,
SHERA, D., BERKOWITZ, R., FISLER, R.E., & SAXE, G.N. (1994).
Fluoxetine in posttraumatic stress disorder. Journal of Clinical
Psychiatry, 55, 517-522. Background: This study was designed to
establish the efficacy of the serotonin reuptake blocker fluoxetine
in the treatment of PTSD. Method: 64 subjects (22 women and 42
men; 31 veterans and 33 nonveterans) with PTSD entered a 5-
week randomized double-blind trial comparing fluoxetine (n =
33) and placebo (n = 31). Results: By Week 5 fluoxetine, but not
placebo, significantly reduced overall PTSD symptomatology, as
assessed by the Clinician-Administered PTSD Scale (CAPS) score.
Changes were most marked in the arousal and numbing symp-
tom subcategories. Non-VA patients responded much better
than VA patients. Fluoxetine was an effective antidepressant
independent of its effects on PTSD. Conclusion: Fluoxetine is an
effective pharmacotherapeutic agent for treating PTSD and its
associated features, particularly in patients without chronic treat-
ment histories.
ADDITIONAL PUBLICATIONS
Annotated by the Editor
DEMARTINO, R., MOLLICA, R.F., & WILK, V. (1995).
Monoamine oxidase inhibitors in posttraumatic stress disor-
der: Promise and problems in Indochinese survivors of
trauma. Journal of Nervous and Mental Disease, 183, 510-515.
Discusses the existing findings on the use of monoamine oxidase
inhibitors for treating PTSD and presents 5 cases in which MAOIs
were used to treat Indochinese refugees with PTSD. The authors
suggest the use of a dose lower than that typically used for
Caucasians.
DONNELLY, C.L., AMAYA-JACKSON, L., & MARCH, J.S.
(1999). Psychopharmacology of pediatric posttraumatic stress
disorder. Journal of Child and Adolescent Psychopharmacology, 9,
203-220.
Provides the only comprehensive review of information about
the pharmacological treatment of PTSD in children. The authors
conclude that pharmacotherapy may be effective for children,
but caution that there are few controlled trials.
FRIEDMAN, M.J. (in press). What might the psychobiology of
PTSD teach us about future approaches to pharmacotherapy?
Journal of Clinical Psychiatry.
Discusses the implications of the pathophysiology of PTSD for
the development of pharmacological interventions, such as cor-
ticotrophin releasing factor antagonists, neuropeptide Y enhanc-
ers, anti-adrenergic compounds, more specific serotonergic agents,
and anticonvulsants.
FRIEDMAN, M.J., SOUTHWICK, S.M., & CHARNEY, D.S.
(1993). Pharmacotherapy for recently evacuated military ca-
sualties. Military Medicine, 158, 493-497.
Presents a rationally derived set of recommendations for using
psychoactive medications to treat recent military psychiatric
casualties. All medications should be withheld for at least 2 days
prior to initiating new treatment, and then drugs such as clonidine,
propanolol, lorazepam, and antidepressants should be used,
depending on symptoms.
GLOVER, H. (1993). A preliminary trial of nalmefene for the
treatment of emotional numbing in combat veterans with
post-traumatic stress disorder. Israel Journal of Psychiatry and
Related Sciences, 30, 255-263.
Administered nalmefene, an opiate antagonist, to 18 male veter-
ans with combat-related PTSD. Eight of the participants showed
notable improvements in numbing and other PTSD symptoms.
Case descriptions are provided.
HARMON, R.J., & RIGGS, P.D. (1996). Clonidine for posttrau-
matic stress disorder in preschool children. Journal of the
American Academy of Child and Adolescent Psychiatry, 35, 1247-
1249.
Administered clonidine to 7 preschool children who had PTSD
due to severe abuse or neglect and who had not responded to
psychological or behavior therapy. The treatment, delivered in
patch form, was well-tolerated. All children showed improve-
ment in aggression and interpersonal function. Most children
also showed improvements in other symptoms.
HERTZBERG, M.A., FELDMAN, M.E., BECKHAM, J.C., &
DAVIDSON, J.R.T. (1996). Trial of trazodone for posttrau-
matic stress disorder using a multiple baseline group design.
Journal of Clinical Psychopharmacology, 16, 294-298.
Administered trazodone to 6 male Vietnam veterans with com-
bat-related PTSD. Four of the 6 were much improved following
treatment. Statistical tests are not reported. The authors describe
improvements in PTSD and sleep, but not in depression or social
and occupational functioning.
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HERTZBERG, M.A., FELDMAN, M.E., BECKHAM, J.C.,
MOORE, S.D., & DAVIDSON, J.R.T. (1998). Open trial of
nefazodone for combat-related posttraumatic stress disor-
der. Journal of Clinical Psychiatry, 59, 460-464.
Administered nefazodone to 10 male veterans with combat-
related PTSD. Most symptoms showed improvement after 12
weeks, and treatment gains generally were maintained at 16
weeks. Symptoms of hyperarousal showed the most improve-
ment.
JACOBS-REBHUN, S., SCHNURR, P.P., FRIEDMAN, M.J.,
PECK, R., BROPHY, M., & FULLER, D. (in press). Cyprohep-
tadine for treating PTSD [Letter to the Editor]. American
Journal of Psychiatry.
Conducted a double-blind, randomized, placebo-controlled trial
of cyproheptadine for treating sleep problems in 60 male Vietnam
combat veterans with PTSD. Treatment did not improve sleep or
PTSD outcomes, and poorer outcomes were associated with
higher blood levels of cyproheptadine. The results reinforce the
need for skepticism about open label or anecdotal findings and
for careful scientific trials to replicate uncontrolled studies.
KAPLAN, Z., AMIR, M., SWARTZ, M., & LEVINE, J. (1996).
Inositol treatment of post-traumatic stress disorder. Anxiety,
2, 51-52.
Administered inositol, a second messenger system precursor, to
13 patients with PTSD due to either combat or civilian trauma,
drawn from two clinics. Using a double-blind placebo-controlled
cross-over design, the authors found no effects of treatment on
PTSD symptoms. Patients at one site showed some improve-
ments in depression.
LIPPER, S. (1990). Carbamazepine in the treatment of post-
traumatic stress disorder: Implications for the kindling hy-
pothesis. In M.E. Wolf, & A.D. Mosnaim (Eds.), Posttraumatic
stress disorder: Etiology, phenomenology, and treatment (pp. 184-
203). Washington: American Psychiatric Press.
Administered carbamazepine to 10 male veterans with military-
related PTSD. There were significant reductions in PTSD symp-
toms, depression, anxiety, and violence.
MARMAR, C.R., SCHOENFELD, F.B., WEISS, D.S., METZLER,
T.J., ZATZICK, D.F., WU, R.M., SMIGA, S., TECOTT, L., &
NEYLAN, T.C. (1996). Open trial of fluvoxamine treatment
for combat-related posttraumatic stress disorder. Journal of
Clinical Psychiatry, 57 (Supplement 8), 66-72.
Administered fluvoxamine to 10 male Vietnam veterans with
PTSD. There were large changes in PTSD symptoms from pre- to
posttreatment. Depression, anxiety, and other symptoms also
improved, although to a somewhat lesser extent.
MARSHALL, R.D., SCHNEIER, F.R., FALLON, B.A., KNIGHT,
C.B.G., ABBATE, L.A., GOETZ, D., CAMPEAS, R., &
LIEBOWITZ, M.R. (1998). An open trial of paroxetine in
patients with noncombat-related, chronic posttraumatic stress
disorder. Journal of Clinical Psychopharmacology, 18, 10-18.
Administered paroextine to 17 patients with PTSD due to civilian
trauma. There were significant improvements in PTSD and other
symptoms, and 65% of the patients were judged to be much or
very much improved.
MELLMAN, T.A., BYERS, P.M., & AUGENSTEIN, J.S. (1998).
Pilot evaluation of hypnotic medication during acute trau-
matic stress response. Journal of Traumatic Stress, 11, 563-569.
Administered temazepam to 4 trauma survivors with 1-3 weeks
of traumatic exposure. Treatment was administered for 7 nights.
There were significant improvements from baseline to 1 week
after the medication was discontinued for total sleep time and
PTSD symptoms.
NEAL, L.A., SHAPLAND, W., & FOX, C. (1997). An open trial
of moclobemide in the treatment of post-traumatic stress
disorder. International Clinical Psychopharmacology, 12, 231-237.
Administered moclobemide, a reversible inhibitor of monoam-
ine oxidase-A, to 20 patients with PTSD due to military or civilian
trauma. There were large improvements in PTSD and function-
ing, and 11 patients no longer met PTSD criteria when tested after
12 weeks of treatment.
ROTHBAUM, B.O., NINAN, P.T., & THOMAS, L. (1996).
Sertraline in the treatment of rape victims with posttraumatic
stress disorder. Journal of Traumatic Stress, 9, 865-871.
Administered sertraline to 5 female rape victims with PTSD.
After 12 weeks, PTSD symptoms were reduced by 53% and 4 of
the 5 were substantially improved. Initial severity was related to
poorer treatment response.
SOUTHWICK, S.M., YEHUDA, R., GILLER, E.L., & CHARNEY,
D.S. (1994). Use of tricyclics and monoamine oxidase inhibi-
tors in the treatment of PTSD: A quantitative review. In M.M.
Murburg (Ed.), Catecholamine function in posttraumatic stress
disorder: Emerging concepts (pp. 293-305). Washington: Ameri-
can Psychiatric Press.
Combined data from studies that evaluated the efficacy of antide-
pressant treatment for PTSD in order to compare the relative
efficacy of tricyclic antidepressants and monoamine oxidase
inhibitors. Overall, MAOIs were found to be more effective than
tricyclic antidepressants for PTSD symptoms. Efficacy of both
treatments varied across types of symptoms.
VER ELLEN, P., & VAN KAMMEN, D.P. (1990). The biologi-
cal findings in post-traumatic stress disorder: A review. Jour-
nal of Applied Social Psychology, 20, 1789-1821.
Presents one of the earliest reviews of the literature on the
pharmacological treatment of PTSD. The authors also review
psychophysiological and neurobiological studies on PTSD.
IMPORTANT NOTICE TO OUR VA
SUBSCRIBERS:
KEEP YOUR RESEARCH QUARTERLY
COMING
If you are receiving a copy of the PTSD Research
Quarterly personally addressed to you at your VA
address, and the code 98 appears on the mailing
label on your copy of this issue, you need to let us
know that your address is correct and that you wish
to continue receiving the Research Quarterly. To do
this, just photocopy page 8, which includes the
mailing label, and return it to us. If you need to
correct your VA address, please type or print the
new address next to the old one.
Prev Page 8 Next
PILOTS UPDATE
Last November, the Dutch organization ICODO hosted
an "expert meeting" of traumatic stress bibliographers
from eight countries. This meeting, titled "From Spider's
Web to World Wide Web," brought eighteen of us to the
lovely city of Utrecht, for three days of extensive consul-
tation and planning. From this emerged the beginnings
of a cooperative program to improve the indexing of
traumatic stress literature and the provision of informa-
tion services on PTSD and related disorders.
The meeting had three goals:
* to develop a social/personal network on
psychotrauma
* to work toward a joint collection policy for infor-
mation on psychotrauma
* to build a joint clearinghouse for information on
psychotrauma.
These are ambitious goals to set, and it will be some
time before we can assess our success in meeting them.
Nevertheless, substantial progress is being made.
The first product of our meeting was the Psychotrauma
Documentation Network, an organization of libraries
and documentation working with the traumatic stress
literature. Its initial membership is drawn from the insti-
tutions represented in Utrecht, and its purpose is to
provide a mechanism for communication among these
institutions and the people on their staff who work with
the literature.
One of the first items to be communicated is a compila-
tion of members' collection, access, and information poli-
cies. This will serve as the starting-point for discussions
on ways to ensure comprehensive coverage of the world-
wide psychotrauma literature while avoiding unneces-
sary duplication of effort. Among the ideas brought up at
the Utrecht meeting were:
* a division of responsibility for identifying and
collecting various portions of the literature
* a joint format for the recording of bibliographic
information, to facilitate the use by PDN members of
each other's work
* the development of a single thesaurus to standardize
the indexing vocabulary used by traumatic stress
bibliographers.
These are not issues that can be decided quickly. A joint
format for bibliographical information cannot be estab-
lished without careful consideration of the needs of each
participating organization, and the users of its bibliographi-
cal records. A common thesaurus may not be practical
when the participating organizations cover somewhat dif-
ferent subject matter. (Some PDN members focus on the
problems of refugees, or war veterans, or torture survivors,
and concern themselves with medical, legal, and educa-
tional issues of their constituencies. Others focus on PTSD
and other aspects of mental health, their concern for the
psychotrauma literature extending across the various
groups affected by traumatic events.) But cooperation in
these technical areas is not an all-or-nothing proposition. If
a single thesaurus cannot meet the needs of everyone, we
can agree upon a concerted effort to unify the terminology
among psychotrauma thesauri wherever possible. If we
cannot agree upon a standard format for recording the
bibliographical facts of a publication, perhaps we can de-
sign our individual formats so as to minimize the difficulty
of transferring information from one format to another.
These are technical issues, likely to interest nobody but
librarians and bibliographers. But if they can be resolved,
we shall be able to improve the service that we render to
researchers and clinicians. If we can reach our goal of
establishing a joint clearinghouse for psychotrauma infor-
mation on the World Wide Web, it will be easier for
information seekers to know exactly where to turn for the
material that they need. Thanks to the initiative of ICODO,
the eleven organizations of the Psychotrauma Documenta-
tion Network are taking the first steps toward achieving
this goal.
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