Thesis Paper

Discussion

Journal articles selected for this systematic review have proven that the efficacy for

hypothesized somatic pharmacological PTSD prevention should be considered for further

research. Each of the hypothesized somatic pharmacological PTSD preventions discussed in this

review: Ketamine, Oxytocin, Cannabinoids, Opioids, Omega 3, Modafinil, and Albuterol, from

their respective study design proved to be efficacious. However, each of the hypothesized

preventative PTSD pharmaceuticals presented in this review indicated the need for further

research whether it be refined pre-clinical, clinical studies, or larger RCTs.

The systematic review outlined that more preclinical and clinical research needs to be

done before ketamine and other NMDA receptors can be used in large scale RCTs for PTSD

treatment or prevention; they are as follows: collecting more data on long-term ketamine use

before it can be recommended for routine use, studying its intraoperative effects versus sub-

anesthetic doses administered to conscious patients, and identifying its precise mechanism of

action (Ito et al., 2015; Rasmussen, 2016; Westfall & Nemeroff, 2016; Zhang e. al., 2014).

Advances in pre-clinical and clinical technology may be the answer to filling in the data gaps

indicated above. Recently deployed technological advances aim to identify biomarkers of

response to rapid-acting NMDA antagonists such as ketamine and to identify the neurobiological

changes that are involved in this response. Technologies such as structural and functional

neuroimaging, genetics, polysomnography (a type of sleep study) and electrophysiology studies

in patients taking part in clinical trials at this time who are being treated with ketamine could

identify its precise mechanism of action while at the same time identifying the ideal patient

population (Brain & Behavior Research Foundation, 2017). In addition to ketamine, other

medications that regulate the glutamate system are also being studied.

According to the systematic review, oxytocin may affect amygdala reactivity differently

within male and female populations (Frijiling et al., 2015). The review also specified that future

studies should aim to address oxytocin's effect on patient samples, especially sex (Eckstein et al.,

2015; Frijiling et al. 2015). A recent double-blind, randomized, placebo-controlled cross-over

fMRI study utilizing male and female police officers investigated whether IN-OT enhanced

neural sensitivity to social reward in PTSD patients (Nawijn et al., 2016). The study concluded

that by increasing neural sensitivity to social reward, a single intranasal oxytocin administration

may alter salience processing of social reward in both male and female patients with PTSD

(Nawijn et al., 2016). The study also concluded that a single intranasal oxytocin dose could

potentially enhance sensitivity for social support and therapeutic alliance, which in turn may

positively affect treatment response and recovery from PTSD symptoms (Nawijn et al, 2016).

According to the author this is one of the first studies investigating the effects of oxytocin in

PTSD patients and their findings are a promising first step in investigating the therapeutic

potential of intranasal oxytocin in patients with PTSD (Nawijn et al, 2016). Future clinical

studies are needed to investigate whether their findings translate to a clinical setting and to

further substantiate the potential benefits of oxytocin administration in medication-enhanced

psychotherapy to enhance the efficacy of currently available psychotherapy practices (Nawijn et

al, 2016).

The systematic review indicated that cannabinoids may someday be available for clinical

use universally pending FDA deregulation, and more studies are needed to confer optimal time

and dose for treatment with cannabinoids after exposure to a highly stressful event, and in

addition the need for further studies of chronic and therapeutic effects in relevant clinical

populations need to be heightened (Hill & Patel, 2013; Blessing et al., 2015; Gannon-Elazar &

Akirav, 2011). Providence, Rhode Island recently passed legislation and signed into law post-

traumatic stress disorder to the list of conditions that may be treated with medical marijuana

which contains cannabinoids (Medicine and Health Rhode Island, 2016). As more and more

states add PTSD to the list of conditions that can be treated with medical marijuana, scaled up

studies such as prospective studies and retrospective reviews may provide insight into the

chronic and therapeutic effects on prevalence of PTSD among control groups and medical

marijuana user populations, i.e.: young, old, male, female, veteran, etc. The same hypothesis for

scaled up prospective case studies and retrospective reviews should also be implemented in

states that have legalized marijuana use.

The systematic review indicated that opioids made a case of efficacy for pre-symptomatic

prevention of PTSD, finding that morphine administered directly after injury, during

resuscitation and early trauma care was significantly associated with a reduced risk of PTSD

(Melcer et al., 2014; Holbrook et al. 2010). However, risks associated with opioid dependency

along with determining patient selection, route, dose effectiveness, and time need to be tested

before RCTs can be initiated (Howlett & Stein, 2015; Melcer et. al., 2014; Porto et al., 2014;

Holbrook et al. 2010). To date the nature of most studies involving opioids have been

retrospective in nature; more research is needed to separate a specific effect of morphine from a

generic ‘analgesic’ effect. Pain after trauma exposure as noted in the review is a potent predictor

of PTSD. It is unclear, therefore, whether morphine has any preventive value in trauma

survivors without physical pain (Qi et. al., 2016). This would suggest that future studies involve

supplementary technological measurements of opioid effect on pain shortly after experienced

trauma, such as fMRI, to identify its precise mechanism of action on pain response as opposed to

responses recorded on surveys, which are subjective in nature and may be inaccurate due to past

opioid use or non medical abuse.

According to the review Open label studies, pre-clinical, and clinical studies have shown

that omega-3 fatty acids promote hippocampal neurogenesis, which might reduce subsequent

PTSD by facilitating clearance of fear memories (Howlett & Stein, 2015; Matsuoka et al., 2013;

Matsumura et al., 2012; Kawakita et al., 2006; Kitamura et al., 2009). More recent studies are

focusing on the effectiveness of omega 3 and its ability to act as an anti-inflammatory drug by

regulating oxidative unbalance by decreasing lipid peroxidation, which has been shown to

decrease fear response in rodent trials (Balmus et al., 2016). Recognizing the critical role of

nutrition in mental and physical health, all healthcare should prioritize nutrition as an integral

part of treatment, especially for those who are most vulnerable and at risk of developing PTSD

(Schnorr & Bachner, 2016). It is sensible at this time to consider diverse combinations of

nutrients from a variety of natural food sources, although some specific nutrients, such as omega-

3 fatty acids may be isolated as its own modality for hypothetical prevention of PTSD (Schnorr

& Bachner, 2016). Efficacy for selective and possible mandatory use of Omega 3

supplementation by at risk populations such as soldiers, fire fighters, police officers, and other

professions likely to experience high stress situations may decrease the potential for developing

PTSD. A recent secondary analysis study conducted in Tokyo, Japan sought out to determine

whether change in blood levels of eicosapentaenoic acid (EPA) is associated with PTSD

symptoms; the study concluded that increased erythrocyte level of EPA during the trial was

associated with low severity of PTSD symptoms in patients receiving omega3 supplements

(Clinical Research, 2016).

The systematic review indicated that results from a rodent trial suggest modafinil

administered during the first hours following exposure to stress may be a simple but effective

intervention for the secondary prevention of stress-induced pathologies and may be beneficial in

attenuating the traumatic stress-related sequelae (Cohen et al., 2016). A recent rat study utilized

methylphenidate which increases norepinephrine and dopamine activity in the brain much like

modafinil but rather targets attention and behavior as opposed to sleepiness. To test this concept

in rodents they administered cognition enhancing doses of methylphenidate into rats before or

after fear conditioning and measured long-term alterations in their conditioned fear behaviors

and PTSD-like reactions (Ritov & Richter-Levin, 2017). The test revealed that administration of

Methylphenidate before fear-memory formation likely reduced anxiety-like responses during

fear-memory retrieval one month later, and individual profiling analysis revealed that

methylphenidate onset had opposing effects on the risk for PTSD-like classification (Ritov &

Richter-Levin, 2017). These results reveal a possible strategy of using low-dose

methylphenidate for the prevention of PTSD in high risk populations (Ritov & Richter-Levin,

2017).

According to the systematic review albuterol acts as an antagonist of PTSS and one

retrospective case study involving people in MVAs indicated that CAPS scores were much lower

in patients who received the adrenergic receptor agonist and coincidently none of them went on

to develop PTSD (Kobayashi et. al., 2011). At present time there are only a handful of

retrospective case studies involving albuterols effect on acting as an antagonist to the

development of PTSD. Future studies might include pre-clinical studies involving rodents being

administered albuterol before or after fear conditioning to see if there is an association between

conditioned fear behaviors and PTSD-like reactions. Other larger retrospective case studies

should also be considered to validate and duplicate findings from earlier studies.

Conclusion

Pre-clinical, clinical, study designs, models, and reviews utilized in this systematic

review suggest that there is efficacy for further research and development into hypothesized

somatic pharmacologic PTSD interventions. However, research needs to be heightened and

refined so that the exact mechanism of action of hypothesized somatic pharmacologic

interventions is identified. Advances in medical technology may be the answer to identifying

these exact mechanisms of action. Early pharmacologic interventions have potential as

efficacious, cost-efficient methods of preventing or buffering the onset of PTSD.