Editorial

Toward Rational Pharmacotherapy for

Posttraumatic Stress Disorder: Reprise

wenty-ve years ago, I wrote a special article for the Journal with the same title
as this one (1). Posttraumatic stress disorder (PTSD) was only 8 years old as a DSMIII diagnosis, and research on PTSD-related psychobiological alterations was in its
infancy. As for randomized controlled trials in PTSD patients, none had been
published, although a few were in progress at that time. Instead, the sparse
literature on pharmacotherapy for PTSD consisted entirely of open trials and case
reports on tricyclic antidepressants, monoamine oxidase inhibitors, antiadrenergics (clonidine and propranolol), lithium, and benzodiazepines. I concluded that
article optimistically, stating that there was every reason to hope that emerging
psychobiological research would lead to rational pharmacotherapy for PTSD.
Since that time, we have learned that individuals with PTSD exhibit dysregulation
in a number of key psychobiological systems; most research has focused on the
adrenergic and hypothalamic-pituitary-adrenocortical systems, although there
have also been studies of serotonergic, dopaminergic, opioid, glutamatergic, GABAergic, cannabinoid, and other mechanisms (2). Unfortunately, it is only recently
that such discoveries have stimulated a search for novel pharmacological
treatments. Instead of a rational approach, focusing on agents designed to address
the unique pathophysiology of PTSD, most randomized controlled trials have
followed an industry-dominated empirical approach in which medications with
proven effectiveness in other disorders have been tested for their efcacy in PTSD.
Randomized controlled trials with antidepressants, most notably selective
serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake
inhibitors (SNRIs), dominate the list of published trials. Indeed, two SSRIs have
been approved by the U.S. Food and Drug Administration as indicated treatments
for PTSD (sertraline and paroxetine), although the remission rate after 12 weeks of
treatment is only about 30% (3). This compares quite unfavorably with the
remission rates achieved with cognitive-behavioral approaches, such as prolonged
exposure and cognitive processing therapies (4). There are probably good reasons
for the inferior performance of SSRIs and SNRIs. First of all, they are too nonspecic.
Given the number and various (sometimes antagonistic) actions of the many
different serotonin (5-HT) receptors, it is probably remarkable that any efcacy at all
has been demonstrated with these drug classes. Second, these agents appear to
have an overall permissive utility that addresses a transdiagnostic irregularity in
5-HT functionhence their efcacy in a variety of mood, anxiety, obsessivecompulsive spectrum, and trauma- and stress-related disorders. Belated recognition of this fact has recently led to clinical trials with much more selective actions at
specic 5-HT receptors. Likewise, clinical trials with antiepileptic drugs acting at
glutamatergic or GABA-ergic receptors have been even more disappointing, with the
possible exception of topiramate (3). To summarize, the hope expressed in my 1988
article has not disappeared but has been laced with a strong dose of disappointment,
caution, and a healthy appreciation for the psychobiological complexity of PTSD.
One thing seems clear: dusting off medications developed for other disorders

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(depression, cardiovascular illness, seizure disorders, schizophrenia, and so on) and

giving them to PTSD patients is unlikely to lead to a major breakthrough. A rational
rather than an empirical approach is much more likely to produce the results we all
hope for.
In that regard, the randomized controlled trial of prazosin conducted by Raskind
and colleagues and reported in this issue (5) is an important and refreshing
exception to the many previous clinical trials in PTSD recounted above. Raskind
et al. began from the theoretical perspective that adrenergic dysregulation has been
one of the most robust ndings in all PTSD research (2). Narrowing their focus to
solid evidence regarding adrenergic disruption of rapid eye movement (REM) sleep
(6), these investigators predicted that an adrenergic alpha-1 antagonist, prazosin,
would reduce traumatic nightmares and possibly ameliorate other PTSD symptoms as well. Starting with small clinical trials and culminating in this successful
randomized controlled trial with 67 recently deployed soldiers with war zonerelated PTSD, they have shown that prazosin treatment not only reduces traumatic
nightmares but also reduces total PTSD symptom severity. Questions remain about
these ndings, which I will address shortly. For me the biggest question is why
adrenergic antagonists have received so little attention over the years. Weve known
about adrenergic dysregulation in PTSD since 1987 (7), and case reports by Kolb
et al. (8) regarding successful PTSD treatment with clonidine and propranolol rst
appeared even earlier, in 1984. Although there have been two negative randomized
controlled trials of guanfacine in
Vietnam veteran cohorts with chronic
PTSD (3), one would have expected It is exciting that a large and successful
a much more aggressive attempt
theory-driven randomized controlled
among PTSD investigators to test
trial has nally been conducted
adrenergic antagonists. Part of the
and published.
answer, no doubt, relates to a lack of
interest on the part of industry to
support research on medications whose patents have expired. Indeed, the prazosin
trial was supported by federal funding from the Departments of Veterans Affairs
and Defense. Had it not been, it is doubtful that this important clinical trial could
have taken place.
As for the results themselves, it is exciting that a large and successful theorydriven randomized controlled trial has nally been conducted and published.
Given the moderate success achieved with SSRIs and SNRIs, it is important that
clinicians have the option of prescribing a medication for PTSD that acts through
a different mechanism. There are still too few evidence-based pharmacological
alternatives available (9). It is noteworthy that average reductions in symptom
severity following prazosin treatment are considerable. A reduction of 10 points on
the Clinician-Administered PTSD Scale (CAPS) is considered clinically signicant;
in this trial the average CAPS improvement was over 25 points in the prazosin
group, compared with 13.3 points for the placebo group. On the other hand, only
three of 32 prazosin patients (10.7%) achieved full clinical remission, which is
poorer than the 30% remission rates achieved among mostly civilian cohorts
treated with sertraline and paroxetine (3). Other questions concern the poorer
outcomes of prazosin patients who were also taking SSRIs. Does this indicate that
these patients had more chronic and severe PTSD, or that there is an interaction
between SSRIs and prazosin that produces poorer outcomes? As the authors point
out, this result was found with secondary analyses among a handful of patients.
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But it is a nding that demands further investigation since it suggests that

adjunctive use of prazosin in patients receiving SSRIs (or vice versa) may be
counterproductive.
To summarize, these results represent an important advance. I hope that other
investigators will turn their attention to other theory-driven novel medications for
PTSD as well as to replication of the present ndings. I am glad to report that federal
funding agencies are supporting such research. Indeed, more than 30 randomized
controlled trials are currently under way to test novel medications for the
prevention and treatment of PTSD as well as to enhance psychotherapy for the
disorder (10). In addition to targeting adrenergic, specic serotonergic (e.g., 5-HT2)
and glutamatergic (both NMDA and AMPA) mechanisms, other medications
under investigation act on corticotropin-releasing factor, neuropeptide Y, oxytocin,
neurokinins, dopamine, dopamine-beta-hydroxylase, allopregnanolone, hydrocortisone, endocannabinoids, and other psychobiological systems.
And so, 25 years later, I end on an optimistic note with the hope that there will be
a greater and more aggressive search by investigators for rational approaches to
PTSD pharmacotherapy. I also hope that these investigators will receive the federal
and industry support that will be needed for them to succeed.
References
1. Friedman MJ: Toward rational pharmacotherapy for posttraumatic stress disorder: an interim report. Am J
Psychiatry 1988; 145:281285
2. Shiromani PJ, Keane TM, LeDoux JE (eds): Post-Traumatic Stress Disorder: Basic Science and Clinical Practice.
New York, Humana Press, 2009
3. Friedman MJ: PTSD: pharmacotherapeutic approaches. Focus 2013; 11:315320
4. Cahill SP, Rothbaum BO, Resick PA, Follette VM: Cognitive-behavioral therapy for adults, in Effective Treatments for PTSD: Practice Guidelines From the International Society for Traumatic Stress Studies. Edited by
Foa EB, Keane TM, Friedman MJ, Cohen JA. New York, Guilford, 2009, pp 139222
5. Raskind MA, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, Homas D, Hill J, Daniels C, Calohan J, Millard
SP, Rohde K, OConnell J, Pritzl D, Feiszli K, Petrie EC, Gross C, Mayer CL, Freed MC, Engel C, Peskind ER: A trial
of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and
Afghanistan. Am J Psychiatry 2013; 170:10031010
6. Germain A: Sleep disturbances as the hallmark of PTSD: where are we now? Am J Psychiatry 2013; 170:
372382
7. Kosten TR, Mason JW, Giller EL, Ostroff RB, Harkness LL: Sustained urinary norepinephrine and epinephrine
elevation in post-traumatic stress disorder. Psychoneuroendocrinology 1987; 12:1320
8. Kolb LC, Burris BC, Grifths S: Propranolol and clonidine in treatment of the chronic post-traumatic stress
disorders of war, in Post-Traumatic Stress Disorder: Psychological and Biological Sequelae. Edited by Van der
Kolk BA. Washington, DC, American Psychiatric Press, 1984, pp 97105
9. Watts BV, Schnurr PP, Young-Xu Y, Mayo L, Weeks WB, Friedman MJ: Meta-analysis of the efcacy of treatments for posttraumatic stress disorder. J Clin Psychiatry (in press)
10. Dunlop BW, Mansson E, Gerardi M: Pharmacological innovations for posttraumatic stress disorder and
medication-enhanced psychotherapy. Curr Pharm Des 2012; 18:56455658

MATTHEW J. FRIEDMAN, M.D., PH.D.

From the National Center for PTSD, U.S. Department of Veterans Affairs and the Departments of Psychiatry
and Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, N.H. Address
correspondence to Dr. Friedman (matthew.j.friedman@dartmouth.edu). Editorial accepted for publication
June 2013 (doi: 10.1176/appi.ajp.2013.13060768).
Dr. Friedman reports no nancial relationships with commercial interests.

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