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Specific Aims
Posttraumatic stress disorder (PTSD) is a psychiatric condition defined by nightmares, flashbacks,
terror, and thoughts about a traumatic event (Nawjin et al., 2015; Koch et al., 2014). Extrinsic symptoms of
PTSD include avoidance, negative feelings, emotional numbness, alertness, and self-destructive behaviors
(Koch et al., 2014). PTSD may develop from the onset of a single traumatic event (Sarren, 2014). However,
people who experience chronic stresses or many traumatic events are more likely to develop PTSD (Sarren,
2014). This explains the high rate of PTSD diagnosis among combat veterans, police officers, Holocaust
survivors, and mothers whose children have cancer (Neylan et al., 2005).
The current recommended treatment for PTSD is cognitive behavioral therapy (CBT). This form of
therapy has been effective in normalizing cortisol levels and increasing dehydroepiandrosterone (DHEA),
which is negatively associated with immune disorders, heart disease, and depression (Olff et al., 2007).
However, a considerable number of PTSD patients fail to complete CBT therapy or relapse after completion. A
Meta-analysis shows that one out of three PTSD patients completing CBT still meet the diagnostic
criteria for PTSD (Carado et al., 2015). Recent literature reviews demonstrate that medication-enhanced
psychotherapy (MEP) with oxytocin is a promising alternative to CBT (Saskia et al., 2014).
Intranasal neuropeptide oxytocin (OT) is a synthetic drug that has anxiolytic properties that may
regulate physiological responsiveness, social bonding and attachment formation (Saskia, 2013; Koch et al.,
2014). Therefore, this may have potentially positive impacts on persons with PTSD who often display signs of
avoidance (Mason, 2001). In addition, the positive effects of OT on the neurological systems for salience
and top-down control overlap with the neurological dysregulations presented in PTSD patients (Koch et
al., 2014; Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In addition, not much is known about the impacts
of OT on different PTSD subgroups. The current body of research on OT suggests that its effects vary
based on sex, stress history, and coping style. Lastly, because all studies on OT have lasted from a single
administration to only a few months, the long-term influence of OT have not been observed.
The proposed research will utilize a longitudinal study that will examine the effectiveness of medication-
enhanced psychotherapy (MEP), cognitive behavioral therapy (CBT), and intranasal oxytocin (OT) for PTSD
patients based on self-reported and objective measurements of therapeutic progress, cortisol level,
neurological changes, and disease susceptibility. This will also provide and compare novel information on the
effects of OT based on sex, history, and personality in PTSD patients. Our specific aims are to:
1. Determine and compare the short-term effectiveness of MEP, CBT, and OT with objective and
subjective measures of symptomatic progression. We predict that MEP will be the most effective
form of treatment for PTSD. Patients under the MEP condition will experience the most amount of
therapeutic progress followed by CBT then OT.
2. Test the long-term impact of MEP, CBT, and OT on neurological functions, cortisol changes,
and disease susceptibility. We predict that the long-term effects of OT will mimic that of short-term
OT use. However, we believe that the CBT and MEP group will experience the most benefits, showing
the most neurological, cortisol, and disease susceptibility improvements.
3. Distinguish the effects of sex, stress history, and coping style of PTSD patients on MEP, CBT,
and OT. We predict that women, people with a history of stressful events, and people with avoidant
styles of coping will react less to OT and CBT treatments. Alternatively, men, people without a history of
stressful events, and people with engagement styles of coping will react more to OT and CBT
treatments. Sex, stress history, and coping styles will not influence the MEP treatment.
The current treatment for PTSD (CBT) only impacts two-third of PTSD patients. Many of those unaffected
patients continue to struggle with interpersonal problems, parenting difficulties, and reductions in household
income (Sarren, 2014). The proposed research will examine the long-term effects of MEP as a potential
alternative to CBT. The sex, stress history, and personality of the PTSD person will be compared because
short-term studies have found that OT acted differently based on these criteria. This, in turn, will distinguish the
specific and long-term influence of OT, which will improve knowledge about OT as a potential alternative
treatment for PTSD.
Research Strategy
A. Significance
Posttraumatic Stress Disorder: An Overview of Prevalence, Clinical Features, Epidemiology, and
Impact
Posttraumatic stress disorder (PTSD) is commonly characterized by reoccurring fear responses to fear-
inducing stimuli that are no longer present. PTSD is a psychiatric disorder that embodies intrinsic symptoms of
nightmares, flashbacks, terror, and thoughts about the traumatic event (Nawjin et al, 2015; Koch et al., 2014).
In addition, PTSD patients show extrinsic signs of avoidance, negative feelings, emotional numbness,
alertness, and self-destructive behaviors (Koch et al., 2014). An estimated 80% of the general population will
experience a traumatic event (TE) with 10% of those persons developing PTSD (Koch et al., 2014). This
means an estimated 8 million people will have PTSD within a given year (National Center for PTSD, 2015).
Furthermore, the diagnosis rate for PTSD differ by gender, as 10 % of women will develop PTSD at some point
during their lifetime as compared to 4% of men (National Center for PTSD, 2015). PTSD symptoms often last
for decades. Shockingly, reports have found that 16% of female rape victims continue to have PTSD 17 years
after their initial diagnosis (Perkoningg et al., 2005).
Exposure to multiple TE is common in clinical populations with PTSD. In the United States, 64% of the
population exposed to TE experienced more than one TE, while 20% of males and 11% females were exposed
to three or more TEs (Sarren, 2014). This is important because persons who experience chronic stresses are
more likely to develop PTSD. Previous studies have found that between 2-17% of veterans will develop PTSD
as compared to the average 10% seen in the general population (Eidelman-Rothman et al., 2015; National
Center for PTSD, 2015). Furthermore, the prevalence rate for developing PTSD in populations who experience
high rates of traumatic events, including physical injuries, combat exposure, peacekeeping, disasters, and rape
show an adjusted developmental rate between 10 to 40%(Sarren, 2014). This information helps us understand
the increased rate of PTSD diagnosis among combat veterans, police officers, Holocaust survivors, and
mothers whose children have cancer (Neylan et al., 2005).
PTSD has substantial impacts on the individual and the society. People with PTSD struggle with
interpersonal problems, parenting difficulties, and reductions in household income (Sarren, 2014). They also
show high rates of mental and physical comorbidities. For instance, epidemiological studies have found that
over 90% of PTSD individuals will develop at least one comorbid mental illness (Sarren, 2014). In addition, the
odds of developing bone joint disease, neurological conditions, cardiovascular conditions, respiratory illnesses,
and metabolic diseases are increased at a rate of 1.5 to 3% in people with PTSD as compared to the general
population (Sarren, 2014). PTSD has a substantial impact on our economy as well. Based on studies of US
Vietnam veterans, posttraumatic stress disorder (PTSD) is associated with increased criminal activities,
violence, alcohol consumption, and drug abuse (Sherman, 2014). Rand Corporation released a report on the
economic impacts of PTSD in 2008. The study found that medical care, productivity, and suicides in PTSD
patients would cost between 4 to 6 billion dollars in the next two years (Tanielian & Jaycox, 2008). In addition,
they found that more than 250,000 veterans received 4.3 billion dollars in PTSD compensation as of 2005
(Tanielian & Jaycox, 2008).
Cortisol Dysfunction and Its Consequences
Individuals with PTSD have altered cortisol levels. However, the direction of impairment has been
bidirectional. In one study, researchers showed that chronic PTSD (duration of at least 1 year) is associated
with lowered cortisol levels (Yehuda, 2000). These results suggest that chronicity may exhaust the
hypothalamic–pituitary–adrenal axis (HPA). Other studies have found higher levels of cortisol. For instance,
Vietnam combat veterans had higher overall cortisol levels (Gotovac, 2003). In a study with Croatian Combat
veterans, lower cortisol circulation was observed. This difference was attributed by the researchers to the
decreases in the number of glucocorticoid receptors that blinds to cortisol. Furthermore, child abuse victims
showed lower levels of cortisol. However, it is interesting to note that when researchers presented those
victims with cues that remaindered them of their TE, their cortisol levels spiked. The studies suggest that their
lower level of cortisol may compensate for the higher levels of cortisol experienced during stress (Elzinga,
2003). Lastly, researches have shown that engagement and non-engagement coping strategies influence
cortisol levels. Specifically, non-engagement has been linked to lower cortisol levels (Mason, 2001). This
finding may explain cortisol variation among PTSD patients.
Cortisol impairment strongly impacts our immune system. Enhanced cortisol activities suppresses
cellular immunity, increases our risk to infections and abnormal tissue growths (Guilliams & Edwards, 2010).
Alternatively, suppressed cortisol activities increased our susceptibility to autoimmune diseases and cancer by
stimulating pro-inflammatory cytokines (Guilliams & Edwards, 2010). Hypercortisoism is also associated with
the onset of mental problems including obsessive-compulsive disorder, panic disorder and melancholic
depression. On the other hand, hypocortisoism is linked to depressed mood, chronic pain, sleep disturbances,
and fatigue (Guilliams & Edwards, 2010).
Current Recommended Treatment Opinion: Cognitive Behavioral Therapy
Researchers have examined the influence of cognitive behavioral therapy (CBT) on PTSD patients.
One study found that CBT alleviated cortisol level and increased the production of dehydroepiandrosterone
(DHEA), which in low quantities is associated with immune disorders, heart disease, and depression (Olff et
al., 2007). Furthermore, another study used 28 trauma individuals from the 9/11 attack on the world trade
center. They found that lower cortisol levels were associated with higher avoidance scores assessed by the
Posttraumatic Stress Symptom-Interview (PSSI) and the PTSD Symptom Scale-Self Report (PSS-SR; Yehuda
et al, 2010). At post-treatment, the researchers found that CBT had improved cortisol levels only for those who
were characterized as highly avoidant. Lastly, a randomized control study with 60 participants showed a 50 %
symptom reduction in Clinician-Administered PTSD Scale (Gerardi et al., 2010). However, a considerable
number of PTSD patients fail to complete CBT therapy or relapse after completion. In addition, a meta-analysis
shows that one out three PTSD patients completing CBT still meet the diagnostic criteria for PTSD (Carado et
al., 2015).
Intranasal Oxytocin: Properties, Strategies, and Potential
Intranasal neuropeptide oxytocin (OT) administration has produced mixed results in healthy individuals.
In some studies, OT has been found to promote empathy for others, improving recognition of facial cues, and
elevating trust in other people by affecting both top-down control and salience processing (Koch et al., 2014;
Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In healthy male participants, OT reduced amygdala
activation to fear-inducing stimuli as compared to a placebo condition (Bakermans-Kranenburg & Van
Ijzendoorn, 2013; Koch et al., 2014). Other researches found results showing that oxytocin administration
curtailed amygdala reactivity towards positive emotional faces, but also increased reactivity to negative faces
in patients with PTSD (Olff et al., 2015). Furthermore, female participants have been found to derive more
positive emotions from infant laughter as OT increased connectivity between the amygdala and the orbital
frontal cortex (OFC) and the caudal anterior cingulate cortex (CACC), which are the reward processing centers
of the brain (Bakermans-Kranenburg & Van-Ijzendoorn, 2013; Eidelman-Rothman et al., 2015). However, a
meta-analysis of 23 empirical papers found positive results in terms of facial recognition (d=0.21) and in-group
trust (d=0.43) with OT vs. placebo condition (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). Therefore, OT
has anxiolytic properties that may improve physiological responsiveness, social bonding, and attachment
formation (Saskia et al., 2014; Koch et al., 2014).
In clinical individuals, OT administration has produced a number of different results regarding its
effectiveness. In an experiment with 43 Vietnam veterans, OT administration did not affect heart rate, skin
conductance or lateral frontalis electromyographic responses to personal combat imagery after 20 international
units (IU) of OT or 40 micrograms (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). However, in a study with
18 participants, a single administration of 24 IU of OT had reduced of the symptoms on the PTSD symptoms
scale (p < .05) and promoted pro-social behaviors (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). Studies
with autism spectrum disorders involving 3 studies with Asperger’s disorder and Prader–Willi syndrome
showed a significant combined effect size (d=0.57) in terms of preventing repetitive behaviors, comprehension
of speech, and emotional recognition (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In addition, three
weeks of 40 IU OT administration, twice a day reduced schizophrenic symptoms and improved cognitive
abilities in schizophrenic individuals (Saskia et al., 2014)
There is currently a gap in knowledge about the influence of coping style, stress history and sex on OT
treatments (Bakermans-Kranenburg & Van Ijzendoorn, 2013). In one study, socially competent individuals with
positive coping styles saw no improvements in social recognition as compared to baseline when they were
asked to rate how positively or negatively they felt during a emotionally positive or negative film, whereas
socially incompetent individuals showed improvements after OT administration as compared to the placebo
group (Bakermans-Kranenburg & Van Ijzendoorn, 2013). Stress history may also be an important factor in OT
effectiveness. Interestingly, OT administration only increased participant’s willingness to donate when they
showed histories of low-levels parental-love withdraw (Bakermans-Kranenburg & Van Ijzendoorn, 2013).
Lastly, two studies with healthy female participants found increased amygdala activities during the presentation
of fearful faces and threatening scenes, which is hypothesized to be the result of higher levels of naturally
circulating OT found in women (Bakermans-Kranenburg & Van-Ijzendoorn, 2013).
Recent reviews show that medication-enhanced psychotherapy (MEP) with OT is a promising
alternative for PTSD patients who exhibit signs of avoidance, negative feelings, emotional numbness,
alertness, and self-destructive behaviors (Koch et al., 2014). OT can promote therapeutic alliance because of
its pro-social anxiolytic properties (Saskia et al., 2014). OT has the ability to inhibit amygdala hyperactivity and
enhance prefrontal control (Saskia et al., 2014). OT may also reduce subjective anxiety. For example, reduced
subjective levels of anxiety have been reported in studies involving public speaking (Saskia et al., 2014).
Although the data are inconsistent, animal studies have also found that OT may facilitate extinction learning
and decrease fear expression (Saskia et al., 2014).
B. Approach
Moving Forward: A Focus on Short-and Long-term Comparison of PTSD Treatment Methods
People with PTSD represent an estimated population of 8 million individuals within a given year
(National Center for PTSD, 2015). In those individuals, only 30 to 40% recover the following year, while
another 30-40% develop chronic PTSD (Perkonigg et al., 2005). PTSD is and has been a burden on the
individual and the society at large. For instance, PTSD has been shown to be associated with increased
participation in criminal activities, violence, alcohol, and drug (Sherman, 2014). Therefore, an effective
treatment for PTSD is necessary. Cognitive behavior therapy has been shown to decrease cortisol level and
reduce PTSD symptoms in the Clinician-Administered PTSD (CAP) Scale by 50% (Gerardi, Rothbaum, Astin,
& Kelly, 2010). However, a considerable number of PTSD patients fail to complete CBT therapy, and one out
of three PTSD patients completing CBT still meet the diagnostic criteria for this disorder (Cardoso et al. 2015).
Oxytocin (OT) has anxiolytic properties that may regulate physiological responsiveness, social bonding,
and attachment formation (Saskia, 2013; Koch et al., 2014). This property may be especially important as a
supplementary tool for CBT, promoting therapeutic alliance and increasing the overall effectiveness of therapy.
In addition, OT regulates both the top-down control and salience-processing portion of our brain, which are
often dysfunctional in PTSD patients (Koch et al., 2014; Bakermans-Kranenburg & Van-Ijzendoorn, 2013).
However, the role and potentials of OT should be examined further as the effects of sex, history, and
personality on OT remains unknown. Furthermore, the long-term effects of OT and MEP as effective
treatments have not been explored. Unless research is conducted on new more effective methods of PTSD
treatment, PTSD will continue to be a substantial individual, interpersonal, and societal burden.
Experimental Design
The Proposed research will measure therapeutic progression by utilizing Structured Interview for PTSD,
Post-traumatic Stress diagnosis test (PDS) and Impact of Event Scale-Revised (IES-R). The study will feature
a repeated measures design, in which scores among treatment conditions will be compared and analyzed for
their effectiveness during the proposed 10-year length of this study. Therapeutic progression, the number of
doctor visits and the reason of that visit, alpha amplitude, and cortisol changes will be measured in this study.
The unique effects of sex, coping style, and stress history of the participants on OT will also be considered.
The main purpose of this study is to compare the effectiveness of MEP, CBT, and OT and the long-term
neurological and immunological consequences.
Study Sample. Participants will be recruited from the University of Virginia and the Virginia
Commonwealth Health System, Psychiatric Institute of Washington, and Fort Belvoir. In addition, the U.S.
Department of Veterans Affairs will help facilitate this recruitment process by promoting this study to qualified
individuals through their already ongoing events such as the creative art festival, adaptive sport programs, and
golden age games. Local and national PTSD programs such as the National Child Traumatic Network,
National Resource Directory, and Real Warrior Campaign will also help the recruitment process by advertising
our study on their website, treatment centers, and headquarters to potential candidates. Subjects interested in
this study must take a post-traumatic stress diagnostic test (PDS). Participants who score zeros will be
excluded from this study. Additionally, all participants must be diagnosed by clinical psychologists blind to the
trauma history while supervised by a psychiatrist using the Clinical interview for DSM-IV Axis I disorders.
Subjects who suffer other mental illness currently or in the past will also be excluded from this study. Because
previous studies support the trend that sex, stress history, and coping styles may be covariates in this study, all
participants must list their appropriate sex as well as completing a background interview (history of chronic
stress vs. history of non-chronic stress) and an avoidant or engagement personality style assessment (Miami
COPE inventory).
This study hopes to recruit a total of 120 participants. This will allow me to randomly assign participants
to one of four treatment groups and still maintain an 80% power. 40 participants have been recruited for our
preliminary trials. This sample includes 24 men (60%) and 16 women (40%). All of the participants have met
both the PDS criteria and the criteria for Clinical interview for DSM-IV Axis I disorder. They also showed no
comorbidity. The mean age of the participants is 35 years old with a range from 16 to 56.
Treatment Condition. Participants will be assigned to one of four treatment conditions. The four
groups are as follow 1) control/placebo: 2) cognitive behavioral therapy: 3) medication-enhanced
psychotherapy with oxytocin: and 4) intranasal administration of oxytocin as shown in Table 1. The control
group (1) will be administered 24 IU or 48 micrograms of PBO. The PBO will be custom designed by a
commercial compounding pharmacy minus the active ingredient. The cognitive behavioral therapy group (2)
will undergo monthly CBT sessions. The session will be conducted with a licensed psychologist specializing in
CBT. The session will consist of identifying thoughts and feeling, confronting fear, and guided discovery. The
medication-enhanced psychotherapy with oxytocin group (3) will administer 24
IU of intranasal oxytocin 5 minutes before CBT because animal studies have
shown that oxytocin was most effective when administered prior to fear
extinction sessions. The oxytocin group (4) will be administered 24 IU. This
measurement is based on an experiment by Bakermans-Kranenburg and Van-
Ijzendoorn (2013), which reported a significant effect of OT on the PDS scale
after a single administration. Furthermore, the subjects in all conditions will be
asked to complete a PDS test and IES after each and every session.
Scales and Interviews. Three scales will be used in this study to
measure the effectiveness of different treatment conditions: Post-traumatic
Stress diagnosis test (PDS), Impact of Event Scale-Revised (IES-R), and
Structured Clinical Interview. The PDS is a 49-item questionnaire that will be
used as a self-reported measurement of clinical progression. The IES-R is a 29-item self-report measurement
that will assess subjective distress as well as hyper-arousal symptoms. A Structured Clinical Interview for
DSM-IV Axis I (SCID-I) is a semi-structured interview that allow clinical or mental health professionals to
assess clinical progression.
Cortisol Measurement. A baseline measure of cortisol level for all subjects will be measured on the
first day of the measurement sessions. The session will measure cortisol level with the Salimetrics Salivary
Cortisol ELISA Kit. ELISA Kit is known as the gold standard in cortisol measurement. Studies have shown that
salivary cortisol level reliably estimates serum cortisol levels. Therefore, this is an important indictor of HPA
functionality. Follow-up sessions aim to compare baseline cortisol measurements with the newly obtained
measurements for directional and magnitudinal changes will be administered every session or months.
Magnetoencephalography. A magnetoencepalography (MEG) recording will be conducted with a
whole-head 248-channel magometer array. This will be adminstred prior to the cortisol measurements
mentioned in the previous paragragh. The scan will be conducted in a magnetically-shilded room. External
noises such as heart beat and mechanical vibrations will be removed from our data. No tasks will be given to
the subjects during measurement. Instead, researchers will instruct subjects to remain relaxed with their eyes
closed. Follow-up sessions will compare statisically significant neurological changes in alpha ampititude. The
areas of interest will be the superior frontal gyrus (SFG), the left middle frontal gyrus (LMFG), and the
amygdala. This will be conducted every six months.
Quanatative Health Measurement. The average number of hospitial and primary care visits during a
six month period will computed by the researchers of this study. Data on the number of visits will be
continously obtained through hosptials and primary care physicans. The types of dieases developed by the
participants will be measured following the frist day of our study. This data will be cumulatively obtained
1-Control
Participants
administer 24 IU
of placebo OT
spray.
2-CBT
Participants
undergo CBT
sessions with
therapist.
3-MEP
Participants
administer 24 IU
of OT 5 min
before CBT
treatment.
4-OT
Participants
administer 24 IU
of OT.
Table 1. Participants will be assigned to
one of four conditions for a duration of 10
years.
throughout the course of this experiment. A ranking of the top 10 most prevelent diagnosis will be computed.
The specific dianosis will be incorperated into broad but defining categories such as bone joint disease,
cardiovascular diseases, respiratory illnesses, and metabolic diseases, malignancy, and autoimmune
conditions.
General Procedure. Participants will be measured on all the methods mentioned above on the first day
of this study. Baseline cortisol and alpha amplitude will be obtained from all participants regardless of
treatment condition. Then, the participants will be randomly assigned to one of the four treatment conditions.
PSD and IES-R Questionnaires will be given before every treatment beginning on the first day. Clinical
Interviews will also begin on the first day, but follow up interviews will be scheduled every three sessions (3
months), follow up cortisol measurements will be scheduled every session (1 month), and follow up MEG
scans every six sessions (6 months).
Analysis. The different scores in the above will be compared with cumulative changes in scores
throughout this study. The measurements obtained will be compared with the control group to determine
statistical significance. The study will use a repeat measures ANOVA. There are four principle goals of such
comparison:
The first and primary goal is to compare the effectiveness of CBT, MEP, and OT on PTSD participants.
This will be achieved by averaging the scores from the PSD scale, IES-R scale, the Structured Clinical
Interview (SCI). All scores will be added and divided by three to obtain an overall PTSD score (PTD+IES-
R+SCI / 3). Therapeutic progression will first be comparable at the third treatment session (3 month), when
data from the second SCI is gathered. A decrease in the overall PTSD treatment score as compared to the
baseline will signal positive progress, whereas as an increase in overall PTSD treatment score will signal
negative progress. A zero score would mark complete recovery. Scores from different groups will be computed
into Z-scores with SPSS for group comparison. It is predicted that the greatest reduction in overall score will be
from the MEP groups, then the CBT, OT, and finally the placebo group.
The second goal is to measure the long-term cortisol changes, neurological differences, and disease
susceptibility. The first part of this goal will be achieved with the Salimetrics Salivary Cortisol ELISA Kit. A
monthly cortisol assessment will be compared against baseline cortisol measurements. Changes in cortisol
level will be marked in SPSS and plotted on a scatter graph. The second part of this goal will be achieved with
magnetoencepalography (MEG) recordings. The change of alpha ampittude will be marked and compared.
The differences will be represented on a bar graph. It is predicted that there will be a overall increase in cortisol
activity because most of the participant are veterans, which as a group have been shown to develop lower
overall levels of cortiosl. In addtion, no task is given to the participants during measurement. Therefore, if
treatment is effective this cortisol direction should be expected. Furthermore, it is predicted that there should
be an increase in prefontal activites (SFG and LMFG) and decrease in salience-processing (amgdala)
activities. The third part of this goal is to record the number and reason of dotor visits. The number of visit and
reason will be divided by treatment groups and updated on a continous bases untill the 10 year mark of this
study. The data will be compared between treatment group and against cortisol and neruological results at 2
month intervals or to the discretion of the researcher. It is predicted that the number and reason of doctor visits
will decrease as cortisol normalize and neruological activities stablize.
The third goal is to test sex, stress history, and coping styles as covariates. The result listed in the
previous goals will be analyzed independently based on sex, history, and personality. The factors will also be
grouped together to find any interactive effects. It is predicted that women will experience the least benefit from
OT, and MEP as shown by the mixed results from Eidelman-Rothman et al (2015) and Bakermans-Kranenburg
and Van-Ijzendoorn (2013). People from a stressful background will benefit more from OT, and MEP as shown
in Eidelman-Rothman (2015) with war veterans. Lastly, subjects with approach-coping styles will benefit most
in all condition based on lower cortisol level found in avoidant approach-coping styles (Mason, 2001). Females
with a non-stressful background and an avoidant approach-coping style will show the least amount of
improvement. However, it is predicted that this amount of improvement will increase when one or more of
these covariates are removed.
Preliminary Study
Results utilizing 40-persons
preliminary sample has been attained. The
participants were randomly assigned into
one of four treatment groups for a period of
6 months. Cortisol changes, neurological
differences, disease susceptibly and
treatment progression has been assessed
by comparing the six-month results with the
baseline results. Treatment progression
scores from all groups are shown in Figure
1. The initial baseline PDS score is 18. As
predicted the MEP group decreased their PDS scores by a total of 33% at 6 months with a PDS score of 12.
The control and OT condition decreased PDS scores by 5% at 6 months with a score of 17. CBT showed a
consistent 10% decrease in PDS scores throughout the study with a stable decrease of 2 points every 3
months. This is constant with the initial prediction.
	
  Cortisol results show an increase in overall cortisol level as compared to
the baseline measurements of 2 mcg/dL (micrograms per deciliter) as shown in
Figure 2.	
   At the final cortisol level, (1) the control condition showed an increase
of 1 mcg/dL, (2) the CBT condition showed an increase of 3 mcg/dL, (3) the MEP
condition showed an increase of 7 mcg/dL, and (4) the OT condition showed an
overall increase of 2 mcg/dL. The overall increase for all groups was 3.25
mcg/dL. The overall increase did not meet the normal cortisol range of 6-23
mcg/dL. This increase is also inversely related to the number of number of doctor
visits as seen in figure 3. The reported cases of chronic pain, sleep disturbance,
and fatigue decreased as cortisol increased. One case of autoimmune diseases
is reported as well. This is also constant with initial predictions.
	
  Neurological results show a baseline average of 3.9 alpha amplitude for
all participants as seen in figure 4. At the 6 months follow-up session, (1) the
control condition showed an increase of .1 alpha amplitudes, (2) the CBT
condition showed a decrease of .2 alpha amplitude, (3) the MEP showed a
decrease of .5 alpha amplitude, and (4) the OT group showed a decrease of .3
alpha amplitude. Statistical significance (p < .05) is observed in conditions (2)
and (4). Lastly, the results here are constant with the initial prediction.
Stress history, and personality style, and sex did not influence the
therapeutic recovery. Even when the variables interacted, the 40 participants in
this study did not show differing measurements based on sex, stress history, or
coping style. It also did not have any significant effect on cortisol level, alpha
amplitude, or disease susceptibility. However, the results here are not constant
with initial predictions.
Implication
We believe that this is a relatively important research study in terms of PTSD treatment. If the effects of
MEP continue as shown in the preliminary trials, then we can expect to see high rates of PTSD recovery. This
could have a substantial impact on the millions of people who suffer from PTSD as well as those who will
develop PTSD during their lifetime. In addition, the cognitive and immunological heath benefits of MEP could
reduce the economic, societal, and individual impact of PTSD. It is imperative that we should continue to
examine the potential impact of sex, stress history, and personality on OT because the preliminary study did
not have enough participants to accurately distinguish the potential positive and negative properties of this
drug on different groups. The role of this study also holds considerable ramifications on the effectiveness of OT
as a supplementary tool for CBT and other psychotherapies. The predicted results would stimulate further
research that will benefit, not only PTSD recovery, but the recovery of other mental illnesses as well.
Fig 1. PTSD score will be compared at
baseline, 3 months, and 6 months among
all treatment groups.
Fig 2. Cortisol level will be compared each
month from 1 month to 6 months for all
treatment groups.
Fig 3. The number and reason of doctor’s
visits monitored each month from month
1 to month 6.
Fig 4. The changes in alpha amplitude in
the amygdala, SFG and MFG based on
different treatment types.
References
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analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Translational
psychiatry, 3(5), e258.
2. Cardoso, C., Kingdon, D., & Ellenbogen, M. A. (2014). A meta-analytic review of the impact of intranasal
oxytocin administration on cortisol concentrations during laboratory tasks: Moderation by method and
mental health. Psychoneuroendocrinology, 49, 161-170.
doi:http://dx.doi.org/10.1016/j.psyneuen.2014.07.014
3. Eidelman-Rothman, Moranne et al. “Oxytocin Affects Spontaneous Neural Oscillations in Trauma-Exposed
War Veterans.” Frontiers in Behavioral Neuroscience 9 (2015): 165. PMC. Web. 8 Aug. 2015.
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PTSD Treatment Comparison of MEP, CBT and OT

  • 1. Specific Aims Posttraumatic stress disorder (PTSD) is a psychiatric condition defined by nightmares, flashbacks, terror, and thoughts about a traumatic event (Nawjin et al., 2015; Koch et al., 2014). Extrinsic symptoms of PTSD include avoidance, negative feelings, emotional numbness, alertness, and self-destructive behaviors (Koch et al., 2014). PTSD may develop from the onset of a single traumatic event (Sarren, 2014). However, people who experience chronic stresses or many traumatic events are more likely to develop PTSD (Sarren, 2014). This explains the high rate of PTSD diagnosis among combat veterans, police officers, Holocaust survivors, and mothers whose children have cancer (Neylan et al., 2005). The current recommended treatment for PTSD is cognitive behavioral therapy (CBT). This form of therapy has been effective in normalizing cortisol levels and increasing dehydroepiandrosterone (DHEA), which is negatively associated with immune disorders, heart disease, and depression (Olff et al., 2007). However, a considerable number of PTSD patients fail to complete CBT therapy or relapse after completion. A Meta-analysis shows that one out of three PTSD patients completing CBT still meet the diagnostic criteria for PTSD (Carado et al., 2015). Recent literature reviews demonstrate that medication-enhanced psychotherapy (MEP) with oxytocin is a promising alternative to CBT (Saskia et al., 2014). Intranasal neuropeptide oxytocin (OT) is a synthetic drug that has anxiolytic properties that may regulate physiological responsiveness, social bonding and attachment formation (Saskia, 2013; Koch et al., 2014). Therefore, this may have potentially positive impacts on persons with PTSD who often display signs of avoidance (Mason, 2001). In addition, the positive effects of OT on the neurological systems for salience and top-down control overlap with the neurological dysregulations presented in PTSD patients (Koch et al., 2014; Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In addition, not much is known about the impacts of OT on different PTSD subgroups. The current body of research on OT suggests that its effects vary based on sex, stress history, and coping style. Lastly, because all studies on OT have lasted from a single administration to only a few months, the long-term influence of OT have not been observed. The proposed research will utilize a longitudinal study that will examine the effectiveness of medication- enhanced psychotherapy (MEP), cognitive behavioral therapy (CBT), and intranasal oxytocin (OT) for PTSD patients based on self-reported and objective measurements of therapeutic progress, cortisol level, neurological changes, and disease susceptibility. This will also provide and compare novel information on the effects of OT based on sex, history, and personality in PTSD patients. Our specific aims are to: 1. Determine and compare the short-term effectiveness of MEP, CBT, and OT with objective and subjective measures of symptomatic progression. We predict that MEP will be the most effective form of treatment for PTSD. Patients under the MEP condition will experience the most amount of therapeutic progress followed by CBT then OT. 2. Test the long-term impact of MEP, CBT, and OT on neurological functions, cortisol changes, and disease susceptibility. We predict that the long-term effects of OT will mimic that of short-term OT use. However, we believe that the CBT and MEP group will experience the most benefits, showing the most neurological, cortisol, and disease susceptibility improvements. 3. Distinguish the effects of sex, stress history, and coping style of PTSD patients on MEP, CBT, and OT. We predict that women, people with a history of stressful events, and people with avoidant styles of coping will react less to OT and CBT treatments. Alternatively, men, people without a history of stressful events, and people with engagement styles of coping will react more to OT and CBT treatments. Sex, stress history, and coping styles will not influence the MEP treatment. The current treatment for PTSD (CBT) only impacts two-third of PTSD patients. Many of those unaffected patients continue to struggle with interpersonal problems, parenting difficulties, and reductions in household income (Sarren, 2014). The proposed research will examine the long-term effects of MEP as a potential alternative to CBT. The sex, stress history, and personality of the PTSD person will be compared because short-term studies have found that OT acted differently based on these criteria. This, in turn, will distinguish the specific and long-term influence of OT, which will improve knowledge about OT as a potential alternative treatment for PTSD.
  • 2. Research Strategy A. Significance Posttraumatic Stress Disorder: An Overview of Prevalence, Clinical Features, Epidemiology, and Impact Posttraumatic stress disorder (PTSD) is commonly characterized by reoccurring fear responses to fear- inducing stimuli that are no longer present. PTSD is a psychiatric disorder that embodies intrinsic symptoms of nightmares, flashbacks, terror, and thoughts about the traumatic event (Nawjin et al, 2015; Koch et al., 2014). In addition, PTSD patients show extrinsic signs of avoidance, negative feelings, emotional numbness, alertness, and self-destructive behaviors (Koch et al., 2014). An estimated 80% of the general population will experience a traumatic event (TE) with 10% of those persons developing PTSD (Koch et al., 2014). This means an estimated 8 million people will have PTSD within a given year (National Center for PTSD, 2015). Furthermore, the diagnosis rate for PTSD differ by gender, as 10 % of women will develop PTSD at some point during their lifetime as compared to 4% of men (National Center for PTSD, 2015). PTSD symptoms often last for decades. Shockingly, reports have found that 16% of female rape victims continue to have PTSD 17 years after their initial diagnosis (Perkoningg et al., 2005). Exposure to multiple TE is common in clinical populations with PTSD. In the United States, 64% of the population exposed to TE experienced more than one TE, while 20% of males and 11% females were exposed to three or more TEs (Sarren, 2014). This is important because persons who experience chronic stresses are more likely to develop PTSD. Previous studies have found that between 2-17% of veterans will develop PTSD as compared to the average 10% seen in the general population (Eidelman-Rothman et al., 2015; National Center for PTSD, 2015). Furthermore, the prevalence rate for developing PTSD in populations who experience high rates of traumatic events, including physical injuries, combat exposure, peacekeeping, disasters, and rape show an adjusted developmental rate between 10 to 40%(Sarren, 2014). This information helps us understand the increased rate of PTSD diagnosis among combat veterans, police officers, Holocaust survivors, and mothers whose children have cancer (Neylan et al., 2005). PTSD has substantial impacts on the individual and the society. People with PTSD struggle with interpersonal problems, parenting difficulties, and reductions in household income (Sarren, 2014). They also show high rates of mental and physical comorbidities. For instance, epidemiological studies have found that over 90% of PTSD individuals will develop at least one comorbid mental illness (Sarren, 2014). In addition, the odds of developing bone joint disease, neurological conditions, cardiovascular conditions, respiratory illnesses, and metabolic diseases are increased at a rate of 1.5 to 3% in people with PTSD as compared to the general population (Sarren, 2014). PTSD has a substantial impact on our economy as well. Based on studies of US Vietnam veterans, posttraumatic stress disorder (PTSD) is associated with increased criminal activities, violence, alcohol consumption, and drug abuse (Sherman, 2014). Rand Corporation released a report on the economic impacts of PTSD in 2008. The study found that medical care, productivity, and suicides in PTSD patients would cost between 4 to 6 billion dollars in the next two years (Tanielian & Jaycox, 2008). In addition, they found that more than 250,000 veterans received 4.3 billion dollars in PTSD compensation as of 2005 (Tanielian & Jaycox, 2008). Cortisol Dysfunction and Its Consequences Individuals with PTSD have altered cortisol levels. However, the direction of impairment has been bidirectional. In one study, researchers showed that chronic PTSD (duration of at least 1 year) is associated with lowered cortisol levels (Yehuda, 2000). These results suggest that chronicity may exhaust the hypothalamic–pituitary–adrenal axis (HPA). Other studies have found higher levels of cortisol. For instance, Vietnam combat veterans had higher overall cortisol levels (Gotovac, 2003). In a study with Croatian Combat veterans, lower cortisol circulation was observed. This difference was attributed by the researchers to the decreases in the number of glucocorticoid receptors that blinds to cortisol. Furthermore, child abuse victims showed lower levels of cortisol. However, it is interesting to note that when researchers presented those victims with cues that remaindered them of their TE, their cortisol levels spiked. The studies suggest that their lower level of cortisol may compensate for the higher levels of cortisol experienced during stress (Elzinga, 2003). Lastly, researches have shown that engagement and non-engagement coping strategies influence
  • 3. cortisol levels. Specifically, non-engagement has been linked to lower cortisol levels (Mason, 2001). This finding may explain cortisol variation among PTSD patients. Cortisol impairment strongly impacts our immune system. Enhanced cortisol activities suppresses cellular immunity, increases our risk to infections and abnormal tissue growths (Guilliams & Edwards, 2010). Alternatively, suppressed cortisol activities increased our susceptibility to autoimmune diseases and cancer by stimulating pro-inflammatory cytokines (Guilliams & Edwards, 2010). Hypercortisoism is also associated with the onset of mental problems including obsessive-compulsive disorder, panic disorder and melancholic depression. On the other hand, hypocortisoism is linked to depressed mood, chronic pain, sleep disturbances, and fatigue (Guilliams & Edwards, 2010). Current Recommended Treatment Opinion: Cognitive Behavioral Therapy Researchers have examined the influence of cognitive behavioral therapy (CBT) on PTSD patients. One study found that CBT alleviated cortisol level and increased the production of dehydroepiandrosterone (DHEA), which in low quantities is associated with immune disorders, heart disease, and depression (Olff et al., 2007). Furthermore, another study used 28 trauma individuals from the 9/11 attack on the world trade center. They found that lower cortisol levels were associated with higher avoidance scores assessed by the Posttraumatic Stress Symptom-Interview (PSSI) and the PTSD Symptom Scale-Self Report (PSS-SR; Yehuda et al, 2010). At post-treatment, the researchers found that CBT had improved cortisol levels only for those who were characterized as highly avoidant. Lastly, a randomized control study with 60 participants showed a 50 % symptom reduction in Clinician-Administered PTSD Scale (Gerardi et al., 2010). However, a considerable number of PTSD patients fail to complete CBT therapy or relapse after completion. In addition, a meta-analysis shows that one out three PTSD patients completing CBT still meet the diagnostic criteria for PTSD (Carado et al., 2015). Intranasal Oxytocin: Properties, Strategies, and Potential Intranasal neuropeptide oxytocin (OT) administration has produced mixed results in healthy individuals. In some studies, OT has been found to promote empathy for others, improving recognition of facial cues, and elevating trust in other people by affecting both top-down control and salience processing (Koch et al., 2014; Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In healthy male participants, OT reduced amygdala activation to fear-inducing stimuli as compared to a placebo condition (Bakermans-Kranenburg & Van Ijzendoorn, 2013; Koch et al., 2014). Other researches found results showing that oxytocin administration curtailed amygdala reactivity towards positive emotional faces, but also increased reactivity to negative faces in patients with PTSD (Olff et al., 2015). Furthermore, female participants have been found to derive more positive emotions from infant laughter as OT increased connectivity between the amygdala and the orbital frontal cortex (OFC) and the caudal anterior cingulate cortex (CACC), which are the reward processing centers of the brain (Bakermans-Kranenburg & Van-Ijzendoorn, 2013; Eidelman-Rothman et al., 2015). However, a meta-analysis of 23 empirical papers found positive results in terms of facial recognition (d=0.21) and in-group trust (d=0.43) with OT vs. placebo condition (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). Therefore, OT has anxiolytic properties that may improve physiological responsiveness, social bonding, and attachment formation (Saskia et al., 2014; Koch et al., 2014). In clinical individuals, OT administration has produced a number of different results regarding its effectiveness. In an experiment with 43 Vietnam veterans, OT administration did not affect heart rate, skin conductance or lateral frontalis electromyographic responses to personal combat imagery after 20 international units (IU) of OT or 40 micrograms (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). However, in a study with 18 participants, a single administration of 24 IU of OT had reduced of the symptoms on the PTSD symptoms scale (p < .05) and promoted pro-social behaviors (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). Studies with autism spectrum disorders involving 3 studies with Asperger’s disorder and Prader–Willi syndrome showed a significant combined effect size (d=0.57) in terms of preventing repetitive behaviors, comprehension of speech, and emotional recognition (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). In addition, three weeks of 40 IU OT administration, twice a day reduced schizophrenic symptoms and improved cognitive abilities in schizophrenic individuals (Saskia et al., 2014) There is currently a gap in knowledge about the influence of coping style, stress history and sex on OT treatments (Bakermans-Kranenburg & Van Ijzendoorn, 2013). In one study, socially competent individuals with positive coping styles saw no improvements in social recognition as compared to baseline when they were
  • 4. asked to rate how positively or negatively they felt during a emotionally positive or negative film, whereas socially incompetent individuals showed improvements after OT administration as compared to the placebo group (Bakermans-Kranenburg & Van Ijzendoorn, 2013). Stress history may also be an important factor in OT effectiveness. Interestingly, OT administration only increased participant’s willingness to donate when they showed histories of low-levels parental-love withdraw (Bakermans-Kranenburg & Van Ijzendoorn, 2013). Lastly, two studies with healthy female participants found increased amygdala activities during the presentation of fearful faces and threatening scenes, which is hypothesized to be the result of higher levels of naturally circulating OT found in women (Bakermans-Kranenburg & Van-Ijzendoorn, 2013). Recent reviews show that medication-enhanced psychotherapy (MEP) with OT is a promising alternative for PTSD patients who exhibit signs of avoidance, negative feelings, emotional numbness, alertness, and self-destructive behaviors (Koch et al., 2014). OT can promote therapeutic alliance because of its pro-social anxiolytic properties (Saskia et al., 2014). OT has the ability to inhibit amygdala hyperactivity and enhance prefrontal control (Saskia et al., 2014). OT may also reduce subjective anxiety. For example, reduced subjective levels of anxiety have been reported in studies involving public speaking (Saskia et al., 2014). Although the data are inconsistent, animal studies have also found that OT may facilitate extinction learning and decrease fear expression (Saskia et al., 2014). B. Approach Moving Forward: A Focus on Short-and Long-term Comparison of PTSD Treatment Methods People with PTSD represent an estimated population of 8 million individuals within a given year (National Center for PTSD, 2015). In those individuals, only 30 to 40% recover the following year, while another 30-40% develop chronic PTSD (Perkonigg et al., 2005). PTSD is and has been a burden on the individual and the society at large. For instance, PTSD has been shown to be associated with increased participation in criminal activities, violence, alcohol, and drug (Sherman, 2014). Therefore, an effective treatment for PTSD is necessary. Cognitive behavior therapy has been shown to decrease cortisol level and reduce PTSD symptoms in the Clinician-Administered PTSD (CAP) Scale by 50% (Gerardi, Rothbaum, Astin, & Kelly, 2010). However, a considerable number of PTSD patients fail to complete CBT therapy, and one out of three PTSD patients completing CBT still meet the diagnostic criteria for this disorder (Cardoso et al. 2015). Oxytocin (OT) has anxiolytic properties that may regulate physiological responsiveness, social bonding, and attachment formation (Saskia, 2013; Koch et al., 2014). This property may be especially important as a supplementary tool for CBT, promoting therapeutic alliance and increasing the overall effectiveness of therapy. In addition, OT regulates both the top-down control and salience-processing portion of our brain, which are often dysfunctional in PTSD patients (Koch et al., 2014; Bakermans-Kranenburg & Van-Ijzendoorn, 2013). However, the role and potentials of OT should be examined further as the effects of sex, history, and personality on OT remains unknown. Furthermore, the long-term effects of OT and MEP as effective treatments have not been explored. Unless research is conducted on new more effective methods of PTSD treatment, PTSD will continue to be a substantial individual, interpersonal, and societal burden. Experimental Design The Proposed research will measure therapeutic progression by utilizing Structured Interview for PTSD, Post-traumatic Stress diagnosis test (PDS) and Impact of Event Scale-Revised (IES-R). The study will feature a repeated measures design, in which scores among treatment conditions will be compared and analyzed for their effectiveness during the proposed 10-year length of this study. Therapeutic progression, the number of doctor visits and the reason of that visit, alpha amplitude, and cortisol changes will be measured in this study. The unique effects of sex, coping style, and stress history of the participants on OT will also be considered. The main purpose of this study is to compare the effectiveness of MEP, CBT, and OT and the long-term neurological and immunological consequences. Study Sample. Participants will be recruited from the University of Virginia and the Virginia Commonwealth Health System, Psychiatric Institute of Washington, and Fort Belvoir. In addition, the U.S. Department of Veterans Affairs will help facilitate this recruitment process by promoting this study to qualified individuals through their already ongoing events such as the creative art festival, adaptive sport programs, and golden age games. Local and national PTSD programs such as the National Child Traumatic Network, National Resource Directory, and Real Warrior Campaign will also help the recruitment process by advertising our study on their website, treatment centers, and headquarters to potential candidates. Subjects interested in
  • 5. this study must take a post-traumatic stress diagnostic test (PDS). Participants who score zeros will be excluded from this study. Additionally, all participants must be diagnosed by clinical psychologists blind to the trauma history while supervised by a psychiatrist using the Clinical interview for DSM-IV Axis I disorders. Subjects who suffer other mental illness currently or in the past will also be excluded from this study. Because previous studies support the trend that sex, stress history, and coping styles may be covariates in this study, all participants must list their appropriate sex as well as completing a background interview (history of chronic stress vs. history of non-chronic stress) and an avoidant or engagement personality style assessment (Miami COPE inventory). This study hopes to recruit a total of 120 participants. This will allow me to randomly assign participants to one of four treatment groups and still maintain an 80% power. 40 participants have been recruited for our preliminary trials. This sample includes 24 men (60%) and 16 women (40%). All of the participants have met both the PDS criteria and the criteria for Clinical interview for DSM-IV Axis I disorder. They also showed no comorbidity. The mean age of the participants is 35 years old with a range from 16 to 56. Treatment Condition. Participants will be assigned to one of four treatment conditions. The four groups are as follow 1) control/placebo: 2) cognitive behavioral therapy: 3) medication-enhanced psychotherapy with oxytocin: and 4) intranasal administration of oxytocin as shown in Table 1. The control group (1) will be administered 24 IU or 48 micrograms of PBO. The PBO will be custom designed by a commercial compounding pharmacy minus the active ingredient. The cognitive behavioral therapy group (2) will undergo monthly CBT sessions. The session will be conducted with a licensed psychologist specializing in CBT. The session will consist of identifying thoughts and feeling, confronting fear, and guided discovery. The medication-enhanced psychotherapy with oxytocin group (3) will administer 24 IU of intranasal oxytocin 5 minutes before CBT because animal studies have shown that oxytocin was most effective when administered prior to fear extinction sessions. The oxytocin group (4) will be administered 24 IU. This measurement is based on an experiment by Bakermans-Kranenburg and Van- Ijzendoorn (2013), which reported a significant effect of OT on the PDS scale after a single administration. Furthermore, the subjects in all conditions will be asked to complete a PDS test and IES after each and every session. Scales and Interviews. Three scales will be used in this study to measure the effectiveness of different treatment conditions: Post-traumatic Stress diagnosis test (PDS), Impact of Event Scale-Revised (IES-R), and Structured Clinical Interview. The PDS is a 49-item questionnaire that will be used as a self-reported measurement of clinical progression. The IES-R is a 29-item self-report measurement that will assess subjective distress as well as hyper-arousal symptoms. A Structured Clinical Interview for DSM-IV Axis I (SCID-I) is a semi-structured interview that allow clinical or mental health professionals to assess clinical progression. Cortisol Measurement. A baseline measure of cortisol level for all subjects will be measured on the first day of the measurement sessions. The session will measure cortisol level with the Salimetrics Salivary Cortisol ELISA Kit. ELISA Kit is known as the gold standard in cortisol measurement. Studies have shown that salivary cortisol level reliably estimates serum cortisol levels. Therefore, this is an important indictor of HPA functionality. Follow-up sessions aim to compare baseline cortisol measurements with the newly obtained measurements for directional and magnitudinal changes will be administered every session or months. Magnetoencephalography. A magnetoencepalography (MEG) recording will be conducted with a whole-head 248-channel magometer array. This will be adminstred prior to the cortisol measurements mentioned in the previous paragragh. The scan will be conducted in a magnetically-shilded room. External noises such as heart beat and mechanical vibrations will be removed from our data. No tasks will be given to the subjects during measurement. Instead, researchers will instruct subjects to remain relaxed with their eyes closed. Follow-up sessions will compare statisically significant neurological changes in alpha ampititude. The areas of interest will be the superior frontal gyrus (SFG), the left middle frontal gyrus (LMFG), and the amygdala. This will be conducted every six months. Quanatative Health Measurement. The average number of hospitial and primary care visits during a six month period will computed by the researchers of this study. Data on the number of visits will be continously obtained through hosptials and primary care physicans. The types of dieases developed by the participants will be measured following the frist day of our study. This data will be cumulatively obtained 1-Control Participants administer 24 IU of placebo OT spray. 2-CBT Participants undergo CBT sessions with therapist. 3-MEP Participants administer 24 IU of OT 5 min before CBT treatment. 4-OT Participants administer 24 IU of OT. Table 1. Participants will be assigned to one of four conditions for a duration of 10 years.
  • 6. throughout the course of this experiment. A ranking of the top 10 most prevelent diagnosis will be computed. The specific dianosis will be incorperated into broad but defining categories such as bone joint disease, cardiovascular diseases, respiratory illnesses, and metabolic diseases, malignancy, and autoimmune conditions. General Procedure. Participants will be measured on all the methods mentioned above on the first day of this study. Baseline cortisol and alpha amplitude will be obtained from all participants regardless of treatment condition. Then, the participants will be randomly assigned to one of the four treatment conditions. PSD and IES-R Questionnaires will be given before every treatment beginning on the first day. Clinical Interviews will also begin on the first day, but follow up interviews will be scheduled every three sessions (3 months), follow up cortisol measurements will be scheduled every session (1 month), and follow up MEG scans every six sessions (6 months). Analysis. The different scores in the above will be compared with cumulative changes in scores throughout this study. The measurements obtained will be compared with the control group to determine statistical significance. The study will use a repeat measures ANOVA. There are four principle goals of such comparison: The first and primary goal is to compare the effectiveness of CBT, MEP, and OT on PTSD participants. This will be achieved by averaging the scores from the PSD scale, IES-R scale, the Structured Clinical Interview (SCI). All scores will be added and divided by three to obtain an overall PTSD score (PTD+IES- R+SCI / 3). Therapeutic progression will first be comparable at the third treatment session (3 month), when data from the second SCI is gathered. A decrease in the overall PTSD treatment score as compared to the baseline will signal positive progress, whereas as an increase in overall PTSD treatment score will signal negative progress. A zero score would mark complete recovery. Scores from different groups will be computed into Z-scores with SPSS for group comparison. It is predicted that the greatest reduction in overall score will be from the MEP groups, then the CBT, OT, and finally the placebo group. The second goal is to measure the long-term cortisol changes, neurological differences, and disease susceptibility. The first part of this goal will be achieved with the Salimetrics Salivary Cortisol ELISA Kit. A monthly cortisol assessment will be compared against baseline cortisol measurements. Changes in cortisol level will be marked in SPSS and plotted on a scatter graph. The second part of this goal will be achieved with magnetoencepalography (MEG) recordings. The change of alpha ampittude will be marked and compared. The differences will be represented on a bar graph. It is predicted that there will be a overall increase in cortisol activity because most of the participant are veterans, which as a group have been shown to develop lower overall levels of cortiosl. In addtion, no task is given to the participants during measurement. Therefore, if treatment is effective this cortisol direction should be expected. Furthermore, it is predicted that there should be an increase in prefontal activites (SFG and LMFG) and decrease in salience-processing (amgdala) activities. The third part of this goal is to record the number and reason of dotor visits. The number of visit and reason will be divided by treatment groups and updated on a continous bases untill the 10 year mark of this study. The data will be compared between treatment group and against cortisol and neruological results at 2 month intervals or to the discretion of the researcher. It is predicted that the number and reason of doctor visits will decrease as cortisol normalize and neruological activities stablize. The third goal is to test sex, stress history, and coping styles as covariates. The result listed in the previous goals will be analyzed independently based on sex, history, and personality. The factors will also be grouped together to find any interactive effects. It is predicted that women will experience the least benefit from OT, and MEP as shown by the mixed results from Eidelman-Rothman et al (2015) and Bakermans-Kranenburg and Van-Ijzendoorn (2013). People from a stressful background will benefit more from OT, and MEP as shown in Eidelman-Rothman (2015) with war veterans. Lastly, subjects with approach-coping styles will benefit most in all condition based on lower cortisol level found in avoidant approach-coping styles (Mason, 2001). Females with a non-stressful background and an avoidant approach-coping style will show the least amount of improvement. However, it is predicted that this amount of improvement will increase when one or more of these covariates are removed.
  • 7. Preliminary Study Results utilizing 40-persons preliminary sample has been attained. The participants were randomly assigned into one of four treatment groups for a period of 6 months. Cortisol changes, neurological differences, disease susceptibly and treatment progression has been assessed by comparing the six-month results with the baseline results. Treatment progression scores from all groups are shown in Figure 1. The initial baseline PDS score is 18. As predicted the MEP group decreased their PDS scores by a total of 33% at 6 months with a PDS score of 12. The control and OT condition decreased PDS scores by 5% at 6 months with a score of 17. CBT showed a consistent 10% decrease in PDS scores throughout the study with a stable decrease of 2 points every 3 months. This is constant with the initial prediction.  Cortisol results show an increase in overall cortisol level as compared to the baseline measurements of 2 mcg/dL (micrograms per deciliter) as shown in Figure 2.   At the final cortisol level, (1) the control condition showed an increase of 1 mcg/dL, (2) the CBT condition showed an increase of 3 mcg/dL, (3) the MEP condition showed an increase of 7 mcg/dL, and (4) the OT condition showed an overall increase of 2 mcg/dL. The overall increase for all groups was 3.25 mcg/dL. The overall increase did not meet the normal cortisol range of 6-23 mcg/dL. This increase is also inversely related to the number of number of doctor visits as seen in figure 3. The reported cases of chronic pain, sleep disturbance, and fatigue decreased as cortisol increased. One case of autoimmune diseases is reported as well. This is also constant with initial predictions.  Neurological results show a baseline average of 3.9 alpha amplitude for all participants as seen in figure 4. At the 6 months follow-up session, (1) the control condition showed an increase of .1 alpha amplitudes, (2) the CBT condition showed a decrease of .2 alpha amplitude, (3) the MEP showed a decrease of .5 alpha amplitude, and (4) the OT group showed a decrease of .3 alpha amplitude. Statistical significance (p < .05) is observed in conditions (2) and (4). Lastly, the results here are constant with the initial prediction. Stress history, and personality style, and sex did not influence the therapeutic recovery. Even when the variables interacted, the 40 participants in this study did not show differing measurements based on sex, stress history, or coping style. It also did not have any significant effect on cortisol level, alpha amplitude, or disease susceptibility. However, the results here are not constant with initial predictions. Implication We believe that this is a relatively important research study in terms of PTSD treatment. If the effects of MEP continue as shown in the preliminary trials, then we can expect to see high rates of PTSD recovery. This could have a substantial impact on the millions of people who suffer from PTSD as well as those who will develop PTSD during their lifetime. In addition, the cognitive and immunological heath benefits of MEP could reduce the economic, societal, and individual impact of PTSD. It is imperative that we should continue to examine the potential impact of sex, stress history, and personality on OT because the preliminary study did not have enough participants to accurately distinguish the potential positive and negative properties of this drug on different groups. The role of this study also holds considerable ramifications on the effectiveness of OT as a supplementary tool for CBT and other psychotherapies. The predicted results would stimulate further research that will benefit, not only PTSD recovery, but the recovery of other mental illnesses as well. Fig 1. PTSD score will be compared at baseline, 3 months, and 6 months among all treatment groups. Fig 2. Cortisol level will be compared each month from 1 month to 6 months for all treatment groups. Fig 3. The number and reason of doctor’s visits monitored each month from month 1 to month 6. Fig 4. The changes in alpha amplitude in the amygdala, SFG and MFG based on different treatment types.
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