NEI’s Master Psychopharmacology Program

Facing Fear: On the Frontlines of Development

for Novel Treatments for PTSD
Sabrina K. Segal, Ph.D.

ABSTRACT

Posttraumatic stress disorder (PTSD) is an intense physical and emotional response to thoughts and reminders
of a traumatic event that lasts for many weeks or months after the event. The symptoms of PTSD fall into three
broad types: re-living, avoidance, and increased arousal. Approximately 70% of adults in the United States will
experience some type of traumatic event at least once in their lifetime. Up to 20% of these individuals progress
to develop PTSD, which equates to approximately 44.7 million Americans who are struggling with the disorder.
Some populations are particularly at risk for PTSD, such as combat military personnel. Nearly 20% of military
veterans who return from Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) are diagnosed with
PTSD. Research suggests that PTSD is frequently misdiagnosed or underdiagnosed, leading to patients who may
not be receiving alleviation from painful and debilitating symptoms. Recent research efforts have focused on the
development of novel evidence-based pharmacological and non-pharmacological treatments for PTSD.

Novel Pharmaceutical Therapeutic Approaches Cyclobenzaprine Phase III Trials Halted

Ganaxolone Cyclobenzaprine (CBP), a muscle relaxant, is a serotonin
2A (5HT2A) antagonist and an alpha-1-adrenergic
Ganaxolone is a synthetic 3β-methylated derivative of
antagonist. The 5HT2A antagonism is associated with
allopregnanolone, a GABAergic neuroactive steroid.
increased restorative slow wave sleep (SWS), and alpha-
In a recent proof-of-concept trial, 112 veterans and
1-adrenergic antagonism is associated with reduced
non-veterans were randomized to placebo or biweekly
trauma-related nightmares and sleep disturbances.
escalating doses of 200, 400, and 600 mg twice-daily
The sublingual form of CBP results in faster absorption,
for 6 weeks to examine whether ganaxolone could have
bypassing liver “first pass” metabolism, and decreasing
significant effects on reducing symptoms associated
norcyclobenzaprine, a persistent psychoactive metabolite.
with PTSD. The multi-site, double-blind, randomized
In a Phase II clinical trial (AtEase Study), 5.6 mg of
controlled trial was followed by an open-label 6-week
sublingual CBP resulted in a significant decrease in
extension phase, where the placebo group crossed over to
military-related PTSD symptoms at 12 weeks compared
ganaxolone. There were no significant differences between
to baseline. However, in a follow-up Phase III clinical trial
placebo and ganaxolone on Clinician-Administered PTSD
(HONOR Study), the results reflected the AtEase study
Scale for DSM-5 (CAPS-5) scores, global well-being,
findings at week 4, but not at week 12. Specifically, a
negative mood, or sleep. However, trough blood levels
significant reduction in CAPS-5 scores were reported in
of ganaxolone at the end of the double-blind phase were
week 4, but not in week 12. The results emphasize the
lower than the anticipated therapeutic level of ganaxolone
challenges that come with designing clinical studies for
in more than 35% of participants on active drug. The
military-related PTSD (Tonix Pharma, data on file).
results suggest that higher dosing, rigorous monitoring of
dosing adherence, and longer length of placebo-controlled
Brexpiprazole
testing will improve future studies.1
A recent Phase II clinical trial was conducted to examine
whether the antipsychotic brexpiprazole could significantly

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reduce symptoms associated with PTSD, either as a scripts.3 Transcranial magnetic stimulation (TMS) is a
monotherapy or as adjunctive therapy. Brexpiprazole noninvasive procedure that utilizes magnetic fields to
actions may be mediated through a combination of partial induce a current in the brain to stimulate neurons in order
agonist activity at 5HT1A and dopamine D2 receptors to treat mental health conditions. Low frequency (1 Hz)
and antagonist activity at 5HT2A receptors. Brexpiprazole pulses are thought to be inhibitory and high frequency
exhibits high affinity (sub-nanomolar) for these receptors pulses (≥ 10 Hz) are considered excitatory. Studies
as well as for norepinephrine alpha1B/2C receptors. have shown that both low- and high-frequency repetitive
Thus, the drug could be targeting neurocircuitry that transcranial magnetic stimulation (rTMS) significantly
is often disrupted in PTSD. In the study, 321 patients reduce PTSD symptoms when applied to the right DLPFC
with PTSD were randomized to placebo, flexible-dose (Table).3,4,5,6 Negative alterations in mood and cognition
sertraline, brexpiprazole, or sertraline and brexpiprazole related to PTSD are thought to involve neurocircuitry in the
in combination. Only the combination of sertraline and prefrontal cortex. Low-frequency rTMS to the right PFC is
brexpiprazole significantly reduced scores on the CAPS- thought to decrease activity in the cortical areas of the right
5 (p<0.01). Results suggest that brexpiprazole may be hemisphere that could be contributing to persistent and
an effective adjunctive therapy for the treatment of PTSD exaggerated negative beliefs, feelings of guilt, and inability
(Otsuka Lundbeck, data on file). to experience positive emotions. High-frequency rTMS
to the right PFC is thought to help inhibit the overactive
Cannabinol and Cannabidiol amygdala activation seen in PTSD, by enhancing PFC
There is evidence that the endocannabinoid (eCB) activation. Hyperactivity of the amygdala is related to
system is involved in emotional memory processing. hypervigilance, irritability, anger, sleep disturbances,
Cannabidiol (CBD) is a phytocannabinoid constituent of reckless behavior, and exaggerated startle responses.
cannabis without the psychoactive component of delta- Future research is needed to better characterize specific
9-tetrahydrocannabinol. Preclinical studies in a variety of protocols for the treatment of PTSD symptoms with
rodent behavioral models have demonstrated that CBD rTMS.3,4,5,6
can facilitate the extinction of aversive memories and
block reconsolidation, presumably through potentialization Transcranial Magnetic Stimulation Combined with Neu-
of the eCB system. Recent human studies suggest that roimaging to Predict Treatment Response to Exposure
CBD alters important aspects of aversive memories and Therapy in PTSD
significantly reduces PTSD symptomatology. A recent In a recent study, patients with PTSD underwent functional
retrospective case study found that CBD resulted in a 91% magnetic resonance imaging (fMRI) while completing three
decrease in PTSD symptom severity at 8 weeks compared tasks assessing emotional reactivity and regulation: (1)
to baseline. Future randomized controlled trials are needed emotional reactivity task, (2) emotional conflict task, and
with much larger sample sizes in order to more effectively (3) emotional reappraisal task. Participants were randomly
investigate whether cannabinol and/or CBD result in assigned to immediate prolonged exposure treatment
significant reduction of PTSD symptoms.2 (n=36) or a waiting list condition (n=30). A random subset
of the prolonged exposure group (n=17) underwent single-
Novel Non-Pharmacological Therapeutic pulse transcranial magnetic stimulation (TMS) concurrent
Approaches with fMRI to investigate whether predictive activation
Transcranial Magnetic Stimulation patterns reflect causal influence within circuits. Among
individuals receiving immediate treatment, those who
Neuroimaging studies have revealed that patients with
showed the largest reductions in left amygdala activation
PTSD exhibit hypoactivation of the medial prefrontal
(versus controls) in response to right posterior middle
cortex (mPFC) and dorsolateral prefrontal cortex (DLPFC).
frontal TMS single pulses also demonstrated greater
Studies involving positron emission tomography (PET)
reductions in PTSD symptoms (p=.003). The results
imaging have demonstrated increased blood flow to the
suggest that high-frequency TMS applied to the right
right-sided limbic/paralimbic regions when participants
DLPFC has an inhibitory effect on the left amygdala and
were presented with traumatic scripts compared to neutral

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Table. TMS for PTSD.

Sample Number of
Authors Procedure Effects
size (N) sessions

HF-rTMS resulted in
significant improvement in
LF (1 Hz)-, HF (10
re-experiencing subscale
Cohen et al., 20044 24 Hz)-rTMS to right 10
of CAPS-5 and a 44.1%
DLPFC (80% RMT)
reduction in symptoms on
HAM-A

LF (1 Hz)-rTMS
to right DLPFC Significant reduction in
Osuch et al., 20093 9 combined with brief 20 hyperarousal symptoms of
exposure therapy PTSD
(80% RMT)

Both resulted in significant

decrease in PTSD
HF (20 Hz)-rTMS
symptoms on PTSD
Boggio et al., 20105 30 to left and to right 10
Checklist. Right side had
DLPFC (80% RMT)
greater effect (44.6%
decrease vs. 36%)

Deep TMS to mPFC

Significant improvement
at 120% RMT
Isserles et al., 20136 30 12 in intrusive component of
combined with brief
CAPS-5
exposure therapy

LF: low frequency. HF: high frequency. RMT: resting motor threshold. HAM-A: Hamilton Anxiety Rating Scale.

may have led to greater reductions in PTSD symptoms moving toward them through a virtual reality exposure
during emotional reactivity after exposure therapy.7 therapy (VRET). In this trial treatment paradigm, patients
walk on a treadmill while listening to music and interacting
Military Motion Memory Desensitization (3MDR) with self-selected emotional images related to their specific
A novel approach to the treatment of combat-related trauma that are displayed on a large screen. Exposure
posttraumatic stress disorder (cr-PTSD) could play a therapy and other psychological therapies, such as eye
significant role in helping British veterans overcome PTSD, movement desensitization and reprocessing (EMDR), can
a new Cardiff University research project suggests. The be very effective; however, these types of therapies are
ongoing two-year study is investigating the effectiveness of typically met with much resistance from patients because
a relatively new therapy known as Military Motion Memory reliving the traumatic memories can be very painful.
Desensitization, or 3MDR. The study, led by Professor The novel approach of combining physical movement
Jonathan Bisson of the Institute of Psychological Medicine with VRET allows patients to regain a sense of control
and Clinical Neurosciences at Cardiff University’s School of over their well-being and their traumatic memories. The
Medicine, is being conducted on veterans with researchers hope that the combination of the exposure
cr-PTSD to help them learn how to move through the to traumatic memories within the context of walking will
avoidance of painful traumatic memories, by literally eliminate cognitive avoidance, which is a coping strategy

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that is detrimental to recovery for patients with PTSD. of 40 mg propranolol HCL (noradrenergic beta-blocker)
Researchers are regularly assessing symptoms of PTSD that was expected to disrupt the memory restabilization
throughout the duration of the study. Preliminary results process. In three of the four cases, results demonstrated
with the first 42 patients suggest that 3MDR may be an a steep decline of fear symptoms after only one or
effective treatment for cr-PTSD in British military veterans. two intervention sessions. In the one case where the
The study is based on previous research studies that intervention was not successful, the fear memory was
utilized 3MDR.8,9 not reactivated and destabilized. Treatment effectiveness
depends on whether the memory reactivation actually
Novel Combined Pharmacological and triggers memory reconsolidation. Specifically, the
Non-Pharmacological Therapeutic Approaches memory trace must become labile through the process
Reconsolidation and Propranolol for the Treatment of reactivation in order for reconsolidation to occur. The
of PTSD results reflect previous studies on reconsolidation of fear
memories (Figure). 10
Reconsolidation is a two-phase process in which retrieval
of a memory initiates a transient period of memory
3,4-Methylenedioxymethamphetamine (MDMA) for the
destabilization, followed by a protein synthesis-dependent
Treatment of PTSD
restabilization phase. The process of reactivation of a
memory trace and reconsolidation of that fear memory MDMA-assisted psychotherapy for the treatment of
can weaken or even erase the emotional expression from PTSD has recently progressed to Phase III clinical trials
specific fear memories. A recent study examined four and received Breakthrough Therapy designation by
uncontrolled case descriptions of patients with PTSD who the Food and Drug Administration (FDA). Used as an
underwent a reconsolidation intervention. The procedure adjunctive treatment during psychotherapy sessions,
involved a brief reaction of the trauma memory aimed to MDMA has demonstrated effectiveness and acceptable
trigger memory destabilization followed by administration safety in reducing PTSD symptoms. In Phase II trials,

Figure. Reconsolidation in combination with propranolol as treatment for PTSD.

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68% achieved durable remission and it was reported 10. Kindt M, van Emmerik A. New avenues for treating emotional
to be effective after just 2–3 therapy sessions. MDMA memory disorders: towards a reconsolidation intervention for

enhances the release of monoamines, hormones, and posttraumatic stress disorder. Ther Adv Psychopharmacol
2016;6(4):283-95.
other downstream signaling circuits to modulate emotional
memory circuits. It may allow for reprocessing of traumatic 11. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for
memories in a safe environment via reconsolidation of fear PTSD: are memory reconsolidation and fear extinction underlying
memories into more positive memories. Dopamine may mechanisms? Prog Neuropsychopharmacol Biol Psychiatry

underlie the destabilization of memory reactivation during 2018;8(84)221-8.

reconsolidation processing. Enhanced serotonin may allow

for the positive affective states and prosocial effects that
present a safe environment for reconsolidation to occur.11

References
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2. Bitencourt RM, Takahashi RN. Cannabidiol as a therapeutic

alternative for post-traumatic stress disorder: from bench research
to confirmation in human trials. Front Neurosci 2018;12(502). doi:
10.3389/fnins.2018.00502.

3. Osuch EA, Benson BE, Luckenbaugh DA et al. Repetitive TMS

combined with exposure therapy for PTSD: a preliminary study. J
Anxiety Disord 2009;23(1):54-9.

4. Cohen H, Kaplan Z, Kotler M et al. Repetitive transcranial magnetic

stimulation of the right dorsolateral prefrontal cortex in posttraumatic
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5. Boggio PS, Rocha M, Oliviera MO et al. Noninvasive brain

stimulation with high-frequency and low-intensity repetitive
transcranial magnetic stimulation treatment for posttraumatic stress
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6. Isserles M, Shalev AY, Roth Y et al. Effectiveness of deep

transcranial magnetic stimulation combined with brief exposure
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7. Fonzo GA, Goodkind MS, Oathes DJ et al. Brain activation during

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8. Nijdam MJ, Vermetten E. Moving forward in treatment of

posttraumatic stress disorder: innovations to exposure-based
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9. Van Gelderen MJ, Nijdam MJ, Vermetten E. An innovative framework

for delivering psychotherapy to patients with treatment-resistant
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fpsyt.2018.00176.

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