Download Posttraumatic Stress Disorder: in search of new treatments

COGNITIVE NEUROSCIENCE
Posttraumatic stress
disorder
In search of new treatments
Aaron Gehan
12/7/2011
Posttraumatic stress disorder: In search of new treatments
Abstract
Contemporary cognitive behavioral therapies may be a lost cause for treatment of severe
posttraumatic disorder (PTSD) patients due to a decreased ability to become desensitized to a
conditioned stressor. This creates a need for novel treatment procedures. This paper surveys
relevant literature of the past few decades that seem to be culminating in a novel
pharmacological treatment structure for PTSD patients. Research indicates that modulation of
endogenous glucocorticoid levels decreases the recall of emotionally salient memories. Future
treatments of PTSD may take advantage of this effect. A possible future treatment structure may
involve a combination of pharmacological modulation of endogenous glucocorticoid levels and
forced recall of past trauma in psychiatrically guided sessions in an attempt to disrupt the
recoding of traumatic memories.
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Posttraumatic stress disorder: In search of new treatments
Introduction
Posttraumatic stress disorder, or “PTSD”, is an anxiety disorder. More specifically, it is
an anxiety disorder that can develop in a person after being exposed to a traumatic event or series
of events (eg.: war, rape, domestic violence). PTSD is most commonly characterized in
individuals by intrusive recollections of the traumatic event, difficulties with emotion regulation,
avoidance of stimuli that provoke the intrusive thoughts and emotions, hyperarousal or extreme
sensitivity to normal life experiences, and/or disrupted sleep cycles, and will befall about 6.8%
of Americans within their lifetimes (Kessler, et al., 2005). PTSD is especially prevalent in rape
victims, child abuse victims, and war veterans with lifetime prevalence rates as high as 30%
(Price, 2007).
The most effective contemporary treatments for PTSD are individual trauma-focused
cognitive behavior therapy and eye movement desensitization and reprocessing (Ehlers, et al.,
2010). In cognitive behavioral therapies such as exposure therapy, patients learn how to confront
stressors in a controlled, therapeutic environment. Over time and various treatments, usually
gradually increasing in intensity, the patient becomes slowly desensitized to former stressors.
The brain is slowly trained to react differently through manipulations of the patient’s
environment.
However, a study by Milad et al. (2008) points to the possibility that cognitive behavioral
therapies may not be enough to treat PTSD, due to the nature of the disorder. According to Milad
et al.’s study conducted with identical twins, PTSD leads to a reduced recall for fear extinction.
This means that after going through a cognitive behavioral therapy meant to habituate the PTSD
patient to the formerly fear-inducing stimulus, the fear response to that stimulus may later exhibit
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Posttraumatic stress disorder: In search of new treatments
a spontaneous recovery to its original state.
Milad et al.’s (2008) study recruited 14 pairs of monozygotic twins, one of each pair
having been exposed to combat in the Vietnam War (N=18). Of the 14 war-exposed participants,
7 developed PTSD and 7 did not. The participants were asked to view a color LCD screen with a
photograph of a room with a lamp in it that could either light up with a red or blue illumination.
Participants completed three phases: acquisition, fear extinction learning, fear extinction recall;
skin conductance responses (SCRs) were measured as an indication of stress during all phases.
The first two phases were completed on the first of two days of testing. In the acquisition
phase, the participants were conditioned to be afraid of one of the colors by receiving a shock
whenever the lamp illuminated with that specific color. In the fear extinction learning phase,
participants were presented with a photograph of a different room, also with a lamp that
illuminated with either red or blue light. They were told there would be no shocks administered,
and there were none. All participants exhibited an average of 70% fear extinction learning at this
phase.
The fear extinction recall test was done the next day. The experimental set-up was
identical to the fear extinction learning phase the day before; the electrodes were applied and the
stimuli (illuminations of the lamp) were delivered in the context of the same room used in the
fear extinction learning phase. Participants were told that they may or may not receive shocks;
however, no shocks were delivered. While the non-PTSD participants did not differ significantly
from the average of 70% fear extinction measured the prior day, the PTSD-positive participants
showed a significant return of fear response to the stimuli as measured by SCRs.
Exposure therapy depends on the ability of the patient to learn and retain fear extinction
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Posttraumatic stress disorder: In search of new treatments
in regards to the stressor being desensitized, the very ability shown to be inhibited in PTSD
patients by Milad et al. (2008). The relative ineffectiveness of contemporary cognitive behavioral
therapies such as exposure therapy for the treatment of PTSD leaves the field of psychiatry in
need of novel forms of treatment in order to address it effectively. This paper will review
relevant literature of the past few decades that indicate the potential for a promising future
treatment of PTSD, and outline a proposal of such a potential treatment structure.
Investigations of the brain structures correlated with PTSD will first be presented and the
nature and implications of such correlations discussed. Literature investigating the strong
relevance of endogenous cortisol levels to memory performance will then be presented and
potential relevance and implications of such findings to PTSD will be discussed. A proposal of a
potential future treatment of PTSD will be then presented and discussed. Finally, a critical
evaluation of the feasibility of such a treatment structure will be presented.
Neurophysiological correlations of PTSD
PTSD is largely characterized by traumatic memories, and the part of the brain most
associated with long-term memories is the hippocampus. Interestingly, one neurophysiologically
salient discovery of PTSD's effects on the brain suggests that PTSD results in decreased
hippocampal volumes in traumatized children. In their longitudinal study, Carrion, Weems and
Reiis (2007) evaluated the levels of PTSD in 15 children, imaged their brains with magnetic
resonance imaging (MRI), and measured salivary cortisol levels as a measure of stress. The
Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA) was used to
determine total posttraumatic stress symptoms and hyperarousal symptoms in the children.
Salivary cortisol samples were collected at home over a period of three days, taken four times
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Posttraumatic stress disorder: In search of new treatments
daily, resulting in 12 total samples per child. The brains of each child were then imaged via MRI
and image analysis was performed by staff blind of the goal of the study or condition of the
participants. Behavioral, endocrinological, and neuroanatomical analyses were done at the
beginning of the study, and then again 12 to 18 months later.
By comparing the data from initial measurements to those obtained 12 to 18 months later,
it was found that severity of PTSD and stress levels effectively predicted the relative amount of
reduction in hippocampal volume with more severe symptoms and higher cortisol levels
predicting larger decreases in hippocampal volume. This seems to agree with the researchers'
hypothesis that stress changes the structure of the brain, and they even went so far as to posit an
additional hypothesis as to how exactly the process takes place in the brain. The researchers
posited that because cortisol is toxic to neurons in high concentrations (Sapolsky, 1993;
Watanabe, Gould & McEwen, 1992; as cited in Carrion, Weems & Reiis, 2007, p. 510), and
PTSD was correlated with increased general cortisol levels in the children, that these increases in
cortisol due to the PTSD are what caused the decreases in hippocampal volume in those with
PTSD (Carrion, Weems & Reiis, 2007, p. 513-515). Cortisol is known to be especially damaging
to the glucocorticoid receptor-rich hippocampus (Sapolsky, Uno, Rebert & Finch, 1990;
Magarinos, McEwen, Flugge & Fuchs, 1996; Sapolsky, 2000; as cited in Carrion, Weems &
Reiis, 2007, p. 515).
This 'neurotoxicity hypothesis' involves the hypothalamic-pituitary-adrenal axis (HPA
axis) which is involved in the response to stressful stimuli. In the neurotoxicity hypothesis,
PTSD is seen as being a potentially self-perpetuating problem in which symptoms of hyperarousal lead to an over-activation of the stress-response system. This over-activation leads to
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Posttraumatic stress disorder: In search of new treatments
cortisol secretion and may strain the HPA axis into a state known as an 'allostatic load' (McEwan,
2000a; as cited in Carrion, Weems & Reiis, 2007, p. 514). The allostatic load is essentially a state
in which the HPA axis is primed for excitatory post-synaptic potentials. While in this heightened
state, there is an increase in the sensitivity of the stress-response system and a decrease in the
specificity of stimuli required to elicit a response (McEwan, 2000b; as cited in Carrion, Weems
& Reiis, 2007, p. 514). This sets the stage for the HPA axis to become increasingly sensitive and
create increasingly more cortisol, eventually leading to toxic levels of cortisol in the
glucocorticoid receptor-rich hippocampus, causing damage to the area (Carrion, Weems & Reiis,
2007, p. 515).
There is some debate over the causal direction of the findings of relatively lower gray
matter densities in individuals with PTSD. One stance is that the PTSD itself creates these
abnormalities, as proposed in the neurotoxicity hypothesis. Another possibility is that lower
hippocampal gray matter densities act as a biological, perhaps genetically heritable,
predisposition to the acquisition of PTSD. There are findings to support both theories and thus it
remains an open question; meta-analyses of PTSD studies conducted by Karl et al. (2006) and
Karl & Werner (2010) revealed such mixed findings that the authors proposed that both theories
may theories may be true and both proposed processes may interact to give rise to the over-all
effects observed on the brain.
Prior studies had failed to find lowered gray matter densities in the hippocampi of PTSD
diagnosed children (Bellis et al., 1999; Carrion, et al., 2001; Tupler & De Bellis, 2006). Perhaps
the fact that Carrion, Weems and Reiis' (2007) study was longitudinal in nature is the reason they
were able to find differences where other studies had not. This could be seen as an affirmation of
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Posttraumatic stress disorder: In search of new treatments
their conclusion that PTSD related stress causes reduction in hippocampal gray matter density in
traumatized children. It may be due to the young age of children, and therefore the short amount
of time for such density reductions to manifest, that other studies were unable to detect the
differences. Along the same lines, the fact that it is difficult to detect lower hippocampal gray
matter densities in children with PTSD, combined with the findings of lowered densities in
adults with PTSD (Kasai, Yamasue, Gilbertson, Rauch & Pitman, 2008), may suggest that there
is not a preexisting density abnormality to blame.
However, a similar argument could be made for a theory proposing genetic/biological
predisposition. Such a genetic predisposition may not become apparent until later adulthood, but
could still play a role in modulating the function of the hippocampus during childhood.
Currently, the jury is still out on the casual connection between hippocampus abnormalities and
PTSD.
The hippocampus isn't the only brain structure implicated in PTSD; in fact, Kasai,
Yamasue, Gilbertson, Rauch and Pitman (2008) found seven separate areas of the brain with
significant decreases in gray matter density related to PTSD. The study involved 41 pairs of
identical, monozygotic twins in which one of each pair of twins was a Vietnam veteran (N=82).
Of the 41 participants that were veterans of the Vietnam War, 18 were diagnosed with PTSD at
the time of the study; none of the other participants were diagnosed with PTSD. Upon
observation of brain regions via MRI, the researchers found that PTSD-positive veterans had
lower gray matter densities than non-PTSD veterans in seven areas of the brain: right midinsula;
left middle temporal gyrus; right hippocampus; left anterior insula; pregenual anterior cingulate
cortex (ACC); left inferior frontal gyrus; and left superior temporal gyrus (Kasai, Yamasue,
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Posttraumatic stress disorder: In search of new treatments
Gilbertson, Rauch & Pitman 2008, p. 551-552).
These results seem to implicate that the limbic and paralimbic structures are the major
sites of gray matter density reduction in combat-related PTSD. Symptom Cluster B
(reexperiencing) of the Clinician-Administered PTSD Scale (CAPS) were correlated with
decreased gray matter densities in the pregenual ACC (r=-.57), left anterior insula (r=-.53), and
right midinsula (r=-.59); all of which are closely connected to one another and compose the
anterior paralimbic belt which is highly involved in emotional aspects of brain function (Kasai,
Yamasue, Gilbertson, Rauch & Pitman, 2008, p. 553).
The most informative finding of the study was that a significant interaction of diagnosis
and combat exposure was found in the pregenual ACC as well (z=3.32) (Kasai, Yamasue,
Gilbertson, Rauch & Pitman 2008, p. 552). This implies that pregenual ACC gray matter
reduction is an acquired sign of PTSD, meaning that PTSD causes the reduction in the gray
matter density in this area of the brain (Kasai, Yamasue, Gilbertson, Rauch & Pitman 2008, p.
554).
It was also pointed out that the findings are consistent with a 'neurocircuitry model' of
PTSD: “The neurocircuitry model of PTSD posits that the ventromedial prefrontal cortex,
including pregenual ACC, inhibits the expression of classically conditioned fear responses by the
amygdala” (Kasai, Yamasue, Gilbertson, Rauch & Pitman 2008, p. 553; in reference to Rauch,
Shin & Phelps, 2006). In the neurocircuitry model of PTSD, impairment of function in the
pregenual ACC would likely increase scores on the Symptom Cluster B (reexperiencing) of the
CAPS in patients with PTSD; symptoms B.4 (intese physiological distress) and B.5
(physiological aversiveness/reactivity to stimuli similar to traumatic event) of the CAPS would
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Posttraumatic stress disorder: In search of new treatments
be expecially predicted. This is exactly what was observed in the PTSD participants (Kasai,
Yamasue, Gilbertson, Rauch & Pitman 2008, p. 553).
In this study, other than the pregenual ACC, none of the other differences in gray matter
densities could be said to be caused by PTSD or not, as they may have existed as predispositional
influences to the acquisition of PTSD in the first place. This study leaves the cause of the other
six known loci of the brain known to exhibit lowered gray matter densities as open questions.
Thus far, lowered gray matter densities in the hippocampus, right midinsula, left middle
temporal gyrus, right hippocampus, left anterior insula and the pregenual ACC are known to
correlate with PTSD. The causal connections between these areas of the brain and PTSD remain,
for the most part, open questions.
Endogenous glucocorticoid (cortisol) levels and declarative memory performance
Nearly eight years before Carrion, Weems and Reiis (2007) published their research on
traumatized children and posited the neurotoxicity hypothesis involving high levels of cortisol,
Newcomer et al. (1999) had found that high cortisol levels have an effect on memory processes.
More specifically, they found that pharmacologically induced levels of cortisol similar to those
normally present during high stress conditions (trauma) decreased performance on a verbal
declarative memory task.
Newcomer, et al. (1999) recruited fifty-one participants using local advertisements and
screened them for general health, including psychiatric disorders, using the Diagnostic Interview
for Genetic Studies. The participants were then randomly assigned to one of three groups: a
placebo-control group (10 men, 10 women); a low-dose group (8 men, 8 women); and a highdose group (7 men, 8 women). All participants took two pills a day for four consecutive days:
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Posttraumatic stress disorder: In search of new treatments
placebo-control group took two sugar pills identical to glucocorticoid pills; low-dose group took
40mg of hydrocortisone in two daily doses; high-dose group took 160mg of hydrocortisone in
two daily doses. Participants completed cognitive tests before treatment, after one day of
treatment, after four days of treatment, and after a six-day ‘washout’ of treatment. The
participants were tested on cognitive skills such as verbatim recall, nonverbal recognition
performance, selective and sustained attention, verbal executive function and nonverbal spatial
recall (Newcomer, et al., 1999, p. 528).
By the fourth day of treatment, the high-dosage group was scoring significantly lower
than the low-dose and placebo-control groups (F2, 48= 3.82) on verbal declarative tasks that tested
both immediate (F2, 48= 4.04) and delayed (F2, 48= 3.29) recall. Participants in the low-dose and
placebo-control groups actually improved their scores over the duration of the treatment, while
the high-dose group did not. None of the other cognitive tests revealed any differences in
performance between the groups. The decreases in verbal declarative memory performance were
reversible, meaning that the abilities came back to the high-dose group after the six-day
‘washout’ of the drug treatment (Newcomer, et al., 1999, p. 529-530).
The results of this study were suggested to generalize to fairly high stress conditions,
meaning that the cortisol levels maintained in the high-dose group were only similar to those
found in normal individuals when under highly stressful conditions, and that the effects would
most likely not manifest in most individuals under mildly stressful circumstances. The results
suggest that glucocorticoids have specific effects on memory encoding processes and/or retrieval
mechanisms involved with immediate and delayed recall. The hippocampus, a glucocorticoidreceptor rich area of the brain, is highly implicated in these functions; and, as discussed earlier, is
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Posttraumatic stress disorder: In search of new treatments
structurally correlated with PTSD, making its functional involvement with stress to be expected.
It was also suggested that the glucocorticoids could be interfering with the ‘practice
effect’ or ‘procedural memory effect.’ This would imply that glucocorticoids also have an effect
on procedural memory as well as verbal declarative memory. A future study could possibly
determine whether this is true or not. By implementing the same experimental design as this
study, but postponing any testing until four days of treatment have passed, the practice effect
could be eliminated as a possible confound. Since none of the participants would be getting any
practice, therefore removing the possibility of the practice effect as a confound. If results are the
same, then the practice effect could be said to not be playing a large role in the original results. If
the results differ, then that difference could presumably be attributed to the relative role that the
practice effect, and therefore procedural memory, had played in the original study.
Whatever the underlying process, pharmacologically-induced heightened levels of
glucocorticoids over extended periods (4 days or so) seem to decrease verbal declarative memory
abilities while leaving other cognitive functions intact (Newcomer, et al., 1999, p. 530-532).
Also, these effects dissipate after a six-day withdrawal from treatment.
Rather than pharmacologically inducing heightened glucocorticoid levels, Kuhlmann,
Piel and Wolf (2005) demonstrated that a psychosocial stressor can induce similar effects in
healthy young men. In their study, 19 young healthy males each completed two two-day trials.
On the first day of each trial, the participants learned a list of thirty words (10 emotionally
neutral, 10 emotionally negative, and 10 emotionally positive). On the second day, they were
either subjected to the Trier Social Stress Test (TSST) or completed a control test with no stressor
before being asked to recall the words learned the previous day. The second trial was done four
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Posttraumatic stress disorder: In search of new treatments
weeks after the first and employed the remaining condition (control or TSST) for each
participant; participants were then measured against their own recall performance in the prior
condition (“cross-over study”). Salivary cortisol samples were taken before treatment, five
minutes after treatment, five minutes before recall testing, and five minutes after testing to ensure
successful cortisol modulation by the TSST.
A significant main-effect was found for condition (control or TSST) on the retrieval of
emotionally negative words, while a quasi-significant main effect was found of condition on
emotionally positive words; when combined, ‘arousing words’ (positive and negative together)
were found to be highly affected by condition. Recall was affected such that the TSST condition
(57% recall) resulted in lower recall scores for arousing words than the control condition (66%
recall). Neutral word recall was not significantly affected by condition. These results show that
high levels of psychosocial stress can induce memory impairments, especially regarding
emotionally salient material.
This study was the first to demonstrate a negative effect of psychosocial stress on
memory, but not the first to attempt it. Two previous studies failed to observe an effect of
psychosocial stress on memory retrieval (Wolf et al., 2002; Domes et al., 2004). Kuhlmann, Piel
and Wolf (2005) suggest this is due to methodological issues in these studies; the greatest
difference being that others included large delays (two weeks) between learning and recall of the
material in their studies.
Kuhlmann, Piel and Wolf (2005) were also one of the first to demonstrate that cortisol has
particular effects on emotionally salient memories while leaving emotionally neutral memories
fairly unaffected. This may prove to be very important to the subject of PTSD since the
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Posttraumatic stress disorder: In search of new treatments
memories that haunt PTSD sufferers are often highly emotional in nature. Given the two
previously outlined studies, cortisol increases, whether pharmacologically or
environmentally/experientially induced, seem to decrease memory in a way that is specific to
emotionally salient material.
The apparent effects of stress on the recall and/or reconsolidation of emotionally salient
memories seem to present a paradox when considered in the context of PTSD. Given that stress
interferes with recall of emotionally salient material, shouldn't the stress of the emotionally
traumatic memories of PTSD patients therefore interfere with the those memories that are
causing the stress? There seems to be a discrepancy that may cast doubt on whether or not the
findings of Kuhlman, Piel and Wolf (2005) and Newcomer et al. (1999) can be generalized to
PTSD patients. Future studies should attempt to address this by employing PTSD patients in
studies similar to Kuhlman, Piel and Wolf (2005) and Newcomer et al. (1999).
But, what if the same results were found when lowering cortisol levels in participants?
This would do away with the apparent paradox of the earlier studies. A study by Lupien and
McEwan (1997) seems to suggest that this is indeed possible. The notion that cortisol levels
seem to have an optimal level of concentration in the brain that allows memory processes to
occur, while deviating from this zone in either direction seems to impair memory processes was
investigated by Lupien and McEwen (1997). They found that the effect of cortisol on memory
performance follows a pattern similar to that of the Yerkes-Dodson law, or an inverted-U shaped
graph of efficacy. This suggests that there are optimal levels of cortisol concentration for
memory performance, and suboptimal levels above and below these levels (see figure 1).
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Posttraumatic stress disorder: In search of new treatments
Fig. 1: Yerkes-Dodson Law (Diamond et al., 2007)
A 2011 study done with mice may provide some insight as to why differing levels of
cortisol have the different effects that they do. Yau, Noble and Seckl (2011) used two different
groups of mice: one control group, and one group genetically engineered to be 11β Hydroxysteroid Dehydrogenase Type 1 Deficient (11β-HSD1). The study had the mice learn
mazes first, then treated them (or not) with a glucocorticoid receptor (GR) antagonist or a
mineralocorticoid receptor (MR) antagonist before having them run the mazes again. The mice
were measured against themselves.
The aged control mice showed initial/untreated spatial memory loss, while the aged 11βHSD1 mice did not. Further, when injected with the GR antagonist, the aged control mice
improved their maze/spatial memory performance, while the MR antagonist had no effect on
them. In contrast, 11β-HSD1 mice were impaired by the MR antagonist, where the GR
antagonist had no effect on them.
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Posttraumatic stress disorder: In search of new treatments
This suggests that MRs are activated by lower levels of glucocorticoids and are
conducive to spatial memory performance, whereas GRs are activated when MRs become
saturated with glucocorticoids and therefore spill over onto the GRs. Activation of GRs seems to
be detrimental to spatial memory performance. In terms of the Yerkes-Dodson law, too little
glucocorticoid (cortisol) will fail to activate MRs which are conducive to memory performance,
whereas too much cortisol will activate GRs which is detrimental to memory performance.
Something similar could be happening in the human hippocampus and other brain
structures due to cortisol modulation. This suggests that reducing cortisol levels would produce
similar results as increasing them in humans. With the Yerkes-Dodson model of cortisol efficacy
on memory performance, it was just a matter of time before researchers investigated the effects
of reduced cortisol levels on emotionally salient memory in the same PTSD-salient way that they
investigated the effects of increased levels of cortisol.
In a recently published study, Marin, Hupbach, Maheu, Nader and Lupien (2011)
investigated the effects of reduced cortisol levels on the strength of emotional memories. Men
aged between 18 and 35 years were recruited through online ad postings at the local university
(University of Montreal). They were screened by phone for cardiovascular, neurological,
psychiatric, drug use, and general health problems; all chosen participants were non-smokers and
free of medication. Through the administration of metyrapone, they pharmacologically reduced
levels of endogenous glucocorticoids in the participants, and then tested their performance on
memory tasks.
The participants were divided into three groups: placebo/control, single-dose, and doubledose. One the first day of the study, participants viewed a computer-narrated series of 11 pictures
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Posttraumatic stress disorder: In search of new treatments
presenting a story. The beginning and end of which (slides 1-4 & 9-11) were emotionally neutral,
and the middle of which (slides 5-8) was emotionally negative. Salivary samples of cortisol were
taken four times throughout.
Three days were left to pass with no interference and on the fourth day of the study,
participants received their respective treatments. The placebo group received sugar pills designed
to be identical to those of the experimental groups. The single-dose group received one 750mg
administration of metyrapone, and the double-dose group received two 750mg administrations of
metyrapone. After receiving their treatments, the participants were asked to recall the story they
had seen three days earlier. Salivary cortisol samples were taken ten times throughout.
On the eighth day of the study, participants were asked to recall the story again. Salivary
cortisol samples were taken twice throughout. All of the memory assessments were taperecorded and transcribed for rating by two independent scorers. Recall of neutral scenes was
scored together and recall of the negative scenes was scored together, each as a separate measure
(Marin, Hupbach, Maheu, Nader & Lupien, 2011, pgs. 2-3).
They found that their decrease of cortisol with the metyrapone was successful, with the
double-dose group having significantly lower cortisol levels than the placebo group. A
significant effect of recall time was found, in that memory performance was better at session 3
(day 8) than at session 2 (day 4). It was also found that, similar to heightened cortisol levels,
lowered cortisol levels significantly affected recall of emotionally salient information but not
emotionally neutral information. The double-dose group recalled significantly less emotionally
negative material than the placebo group at both recall sessions (Marin, Hupbach, Maheu, Nader
& Lupien, 2011, pgs. 3-4).
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Posttraumatic stress disorder: In search of new treatments
Not only does this show that modulation of cortisol in either direction has the effect of
inhibiting recall of emotionally negative material, it shows that decreasing cortisol levels seems
to make for a more long-lasting effect than increasing cortisol during recall and reconsolidation.
In the Newcomer et al. (1999) study, which pharmacologically increased cortisol levels, the
verbal declarative memory capabilities came back after a six-day 'washout' of the drug; whereas,
in this study, the participants were tested four days after pharmacological reduction of cortisol
(when cortisol levels returned to normal) and the memory of the material was still impaired. It is
hard to directly compare the two in any meaningful way at this point due to methodological
differences, but a future study could mimic the methodology of Marin, Hupbach, Maheu, Nader
and Lupien's (2011) metyrapone study in a way that pharmacologically increases cortisol to see
if similar results are observed.
Also, this study seems to suggest that decreasing cortisol levels interferes with the
retrieval of an emotional memory, which is then rewritten into memory in this impaired state.
This could make subsequent retrievals void of the emotional valence that was stripped from it by
the modulated cortisol levels at the time of the initial recall. What this study does not show is
whether or not cortisol modulation has an effect on reconsolidation of memory. In order to do
this, the information would have to be recalled before treatment, and then recalled while under
the effects of the treatment (short-term memory performance), and again long after the treatment
subsided (long-term memory performance). If reconsolidation was being affected, the short-term
performance would not be affected, but the long-term performance would be. Therefore, at this
point, the best explanation of the effects of cortisol on memory performance in this study is the
former explanation of its effect on retrieval and recall processes.
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Posttraumatic stress disorder: In search of new treatments
This study is very promising for the possible future of a pharmacological treatment of
PTSD. In contrast to earlier studies that increased cortisol levels in their participants, inducing
stress, this study reduced cortisol levels. Also, the findings of this study were in keeping with
other similar studies (Maheu, Joober, Beaulieu, Lupien, 2004; Lupien et al., 2002a; Lupien et al.,
2002b), where studies of increased cortisol levels found relatively mixed results (Marin,
Hupbach, Maheu, Nader & Lupien, 2011, pg. 2). Possibly the only discouraging thing about this
study is that metyrapone is a rare chemical that is not manufactured by any pharmaceutical
companies at this time. As a possible solution to this, and as a way of investigating the effects of
cortisol reduction further, Marin, Hupbach, Maheu, Nader and Lupien (2011) suggest similar
studies to be conducted with other cortisol reducing chemicals like dexamethasone, which is
much more currently available than metyrapone.
Possible future treatment
The research outlined in this paper makes me optimistic as to the possibility of a novel
treatment for PTSD in the near future. This treatment could combine pharmacologically lowering
levels of cortisol with professionally-guided personal therapy that would require the patient to
recall their stress-inducing memories while under the influence of the lowered cortisol levels.
This could, perhaps, interfere with the recall and subsequent re-storage of the memories in a way
that may remove large portions of the emotional valence originally associated with them.
Repeated sessions may, over time, mute or distort those memories enough to render them nonthreatening.
One potential obstacle to this treatment plan is the non-availability of metyrapone. As
mentioned, dexamethasone may provide a more available alternative, but research must first be
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Posttraumatic stress disorder: In search of new treatments
done to see if it actually has the same effects as metyrapone. The research behind such a
treatment is also far from complete. The biggest problem I see with the current state of the
literature is the failure to investigate actual PTSD patients themselves to see if different cortisol
levels have the same or similar effects on them as they did on the non-PTSD participants. This is
a huge generalizability issue that must be addressed. Also, Marin, Hupbach, Maheu, Nader and
Lupien (2011) claimed “long-lasting” effects of metyrapone, but operationally defined “longlasting” as a span of four days. A follow-up study should investigate longer periods of time to see
if the memory modulations are more-or-less permanent or not.
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Posttraumatic stress disorder: In search of new treatments
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Carrion, V.G., Weems, C.F. & Reiss, A. L. (2007) Stress Predicts Brain Changes in Children: A
Pilot Longitudinal Study on Youth Stress, Posttraumatic Stress Disorder, and the
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