An Exposition Of Ptsd: Past To Present From A Psychopharmacological Perspective

Abstract

With the sheer amount of information and the broad range of approaches that clinicians take in PTSD treatment, this review serves as a concise summary, bringing together a multitude of research to give a look at where we stand today with the disorder. Post traumatic stress disorder is a chronic response to a traumatic experience that has a broad spectrum of symptoms that vary greatly from patient to patient With the rising prevalence of PTSD, we look back to examine a brief history from ancient Mesopotamia up till present day, and then explore current pharmacological therapies and research methods behind them. As there’s no drug therapy which was initially developed and designed for PTSD, we examine the limitations of the current mainstream options, as well as look forward into possibilities which could not only treat PTSD but also prevent its occurrence.

Introduction

Posttraumatic stress disorder, or PTSD, is currently one of the most prevalent mental health disorders in the United States, it’s estimated that about 8 million adults have PTSD during any given year, and 7 or 8 adults out of 100 will have PTSD at some point in their lives. Women are twice as likely to have PTSD at some point in their lives as compared to men. While there have been no comprehensive studies of prevalence in children and adolescents, recent surveys have estimated it to effect a greater percent of those exposed to traumatic events as compared to the adult population. We commonly see PTSD in veterans returning from armed conflict, assault and sexual assault survivors, first responders, and medical professionals. However, anyone who experiences a traumatic event is potentially at risk. PTSD is classified as a chronic disorder which develops after the individual experiences a traumatic event in person, or learns of a traumatic event that occurred to a loved one. The traumatic event is characterized by exposure to threatened or actual death, serious injuries, or sexual violence. PTSD can occur after a single traumatic event, as is often seen in survivors of sexual assault, or as a result of multiple traumatic events, as is seen in many returning veterans or in domestic first responders and medical personnel.

PTSD is a disorder which has been documented in one form or another for as long as there has been recorded history, although it was not given the name of “post traumatic stress disorder” until the 1980’s in the American Psychiatric Association’s release of DSM 2. From as early as 1300 BCE in ancient Mesopotamia, there’s evidence that soldiers, upon returning to war, experienced much the same symptoms then as they do today, in what would be classified as PTSD (Scurlock & Andersen, 2010). As history progresses, up until very recently when it was given its formal name, we have seen PTSD being referred to as “soldier’s heart”, “war neurosis,” “shell shock,” and “battle fatigue”. Today, treatment usually consists of behavior therapy combined with drug therapy. We will focus on the drug therapy for purposes of this review.

Symptomatology

The symptoms of PTSD can have a large variance from patient to patient, some with overlap, and some without. Individuals can express wildly different symptoms following similar traumatic experiences. In general though, there are three domains of symptoms exhibited by patients. These domains encompass the same symptoms any person could experience after a traumatic event, and are referred to as acute stress reaction, disorder, or just “shock”, but what differentiates those with PTSD is a persistence of the symptoms for longer than 1 month following the event. Furthermore, patients must experience symptoms from each of the three domains, and said symptoms must be of the severity that quality of life is impaired, be it social, professional, or interpersonal function (Yehuda, 2003). It’s worth noting that individuals who go through a traumatic event and experience an acute stress reaction are not correlated with those individuals who end up with PTSD, meaning PTSD isn’t, in many circumstances, a continuation of an initial acute response, but is something that can develop much later in time after the incident.

The first of the three domains is the ‘reexperiencing’ cluster of symptoms. This can include vivid nightmares, mental imagery, flashbacks of the event, and are typically accompanied by a physiological response such as sweating, heart palpitations, feelings of nausea, or other panic symptoms. The second domain is avoidance. This includes distancing oneself from any stimuli which may remind the patient of the traumatic experience. Stimuli is commonly overgeneralized as well, so that the even distantly related stimuli may trigger a strong aversive or panic reaction (Yehuda, 2003). The final domain is hyperarousal, which refers to an unhealthy, overactive state of vigilance which can lead to insomnia, paranoia, irritability, and increased startle response. The combination of symptoms from these three domains lead to patients who become increasingly detached, have trouble functioning in their professional and social lives, and suffer from instability at work and broken marriages. Furthermore, these PTSD symptoms correlate strongly with other psychiatric disorders, such as depression. Beyond higher rates of depression, PTSD affected individuals have been found to be up to 13 times more likely to commit suicide.

Pathophysiology

Brain Structures

Research has pointed out many correlations between behavioral symptoms of PTSD and changes within the brain, including volume, density, and hormonal function. It’s important to note that despite much contemporary research providing us better directions for future studies, we still largely do not know the exact pathophysiology of PTSD (Zhang et al., 2016). Significant changes to brain volume of specific regions in sufferers of PTSD has been discovered. We see abnormality in the anterior cingulate cortex, the left and right insulae, amygdala, and the hippocampal region in those suffering from PTSD. It’s somewhat unclear, however, if these reduced volumes and densities were pre-existing, and were signs that these patients were predisposed to developing PTSD or were changes brought about by the PTSD itself. In a study by Kasai et al. (2008) of identical twins, one of whom went to combat in the Vietnam war and suffered PTSD, and the other did not go to combat and suffer PTSD, it’s clear that at the minimum, the medial prefrontal cortex is affected with the anterior cingulate cortex volume reduced.

In the cortex, the changes in size to the anterior cingulate are thought to have the effect of impairing the extinction of fear response. Additionally in the cortex, we see a pattern of reduced volume in the prefrontal cortex. With the prefrontal cortex playing such a large role in so many functions, from complicated planning, decision making, personality expression, and even social behavior control, the effect of a size reduction can be far reaching.

The hippocampus is involved in memory processes and fear encoding, and significant interaction with the amygdala occurs during the encoding of emotional memories (Shin et al., 2006). The reduced hippocampal volume and abnormal functioning seen in PTSD patients may explain why they fail to be able to identify safe situations or associate the affect of the traumatic event to only the event itself and not other other stimuli in their lives. In animals, we see that cell damage and memory impairment occurs when they are exposed to traumatic events or high levels of stress hormones (Shin et al., 2006). Furthermore, we see a relationship between hippocampal volume and severity of symptoms, with a more reduced volume the more severe the symptoms, as well as seeing an increase in volume in those with PTSD who are recovering and experiencing diminishing symptoms at lesser frequences. We see abnormal functioning of another structure within the limbic system; the increase of activity in the amygdala has been theorized to be the main contributor to the sufferer’s increased sense of vigilance and their poor ability to discriminate between harmless and dangerous stimuli.

Neurochemical

Across the nervous system, we see some significant changes in activity. In the catecholamines, we see increased dopamine and norepinephrine levels. The dopaminergic system has influence in the mesolimbic system which plays a prominent part in fear conditioning (Sherin & Nemeroff, 2011). Increases in activity and levels of norepinephrine lead to symptoms such as elevated blood pressure, increased sweating, heart palpitations, increased nervousness and anxiety, and headaches. Serotonin or 5 HT are found in lower than normal concentrations, specifically in the dorsal and median raphe nuclei in the brain stem. It’s theorized that this throws the balance and communication between the amygdala and hippocampus into abnormal and could be responsible for the many of the hyperarousal symptoms, including increased vigilance, increased startle response, and memory intrusions.

Among the amino acids, we see decreased GABA activity alongside an increase of glutamate activity. Because Glutamate and GABA are such abundant neurotransmitters, the effects of an alteration to their balance would be far reaching. Primarily, this would be a likely explanation of the increased general anxiety levels, and the derealization and dissociation related symptoms. Low levels of GABA have been shown to be strongly correlated with sleep disorders, depression, and alcohol addition as well. Finally, but arguably most importantly, from the hypothalamus and associated structures we see hypercortisolism, which, being primarily a glucocorticoid ‘stress’ hormone, has broad reaching effects across the body including effects on memory and various other physiological functions. The role of changes in cortisol levels, or sustained exposure to high levels, in the development of PTSD may be at the root of the development of many of the other symptoms and physiological changes we see.

Animal Model(s) of Disorder

There’s a vast variety of animal models currently in use for PTSD, and while none of the models are perfect, they do an excellent job of different aspects of the condition. Due to the complexity of the brain and the vast array of symptoms which can present with PTSD, it’s currently impossible to model for every aspect, all in one model. A good model should have, at the minimum, a phenomenological resemblance, or face validity. Furthermore, they should share construct validity, or go some way in theoretical explanatory fashion. They also should share a predictive validity, meaning that the model will respond to treatment in a similar way as a human with PTSD will respond to the same treatment. The best models in use will display a wide variation of symptoms from animal to animal, similar to how the symptoms manifest in humans.

The most straightforward of the ways of creating an animal model is through subjecting an animal to an extreme physical stressor. One method, called the Single-Prolonged Stress puts rats through a procedure that begins with being restrained for 2 hrs, then forcing them to swim for 20 minutes, and then being knocked unconscious with ether. Animals conditioned in this fashion will display a failure to retain extinction memory, increased acoustic startle.

Another way of creating an animal model is through the underwater trauma paradigm. Rats are placed in water that’s too deep to stand, forced to swim until exhaustion, then held underwater for 30 s. The procedure greatly induces PTSD like symptoms and anxiety behavior in rats. If reminded of the underwater trauma, memory related changes are seen in the rats amygdala, hippocampus, and dentate gyrus, consistent with humans with PTSD. Behavioral markers are assessed by the elevated plus maze, acoustic startle, and freezing to cues. Physical markers, such as volume of the hippocampus and the anterior cingulate cortex can also be measured, and neuroimaging can examine changes in brain activity. While these animal models, and the many others that have been developed have shown some use in examining some of the symptoms of PTSD, it’s hard to distinguish between these symptoms and those of other psychiatric disorders because there’s so much overlap.

Drug Treatments

Drug treatments for PTSD span the spectrum, with many practitioners prescribing off label to address the many symptoms that PTSD can manifest. It’s an extremely difficult disorder to treat as the intricacy of interrelated symptoms and broad biological impact not only varies drastically from patient to patient, but is difficult to ascertain empirically by the practitioner. The most commonly prescribed medications fall under the anxiolytic and sedative hypnotic category, followed by atypical antipsychotics. Benzodiazepines, which I won’t be discussing any further, are unfortunately prescribed quite commonly (estimated 30% of PTSD patients), despite a lack of efficacy, risk of developing physical dependence, and potentially life devastating side effects, and are no longer recommended by the medical and psychiatric community for PTSD treatment.

SSRIs, or selective serotonin reuptake inhibitors, such as Praxil or Zoloft are some of the most commonly prescribed antidepressants available, and are currently the only FDA approved drugs for PTSD treatment. SSRIs have been clinically shown to have the broadest effect covering all the domains of symptoms. Unfortunately, while studies show a 60% response rate, less than 30% of patients treated will show complete remission of symptoms. It’s also debated whether those 20-30% would have achieved remission without the drug, as the numbers are close to that of those who advieve remission taking a placebo. Side effects can be mild to severe, ranging from sleep disturbances, weight gain, sexual dysfunction, and various GI symptoms but also can paradoxically include an overall increase of anxiety, mainly when the drug is not in the system. This can be counterproductive to a long term goal of rehabilitation of the patient to a functioning level without need for lifelong medication plan.

Prazosin, which is a norepinephrine (Alpha-1) receptor antagonist, is prescribed to alleviate the nightmares and insomnia associated with PTSD. Clinical studies have shown statistically significant reductions of trauma related nightmare symptoms versus a placebo. It’s worth noting that, while there is some improvement in sleep quality to those prescribed, there are no effects on any of the other symptoms of PTSD, and the improvement of sleep quality is seen in some of the other drugs which address multiple symptoms as well. The side effects can include dangerous hypotension as well as the expected fatigue and sedation. Guanfacine and Clonidine, both norepinephrine (Alpha-2) receptor agonists are prescribed to help manage patients’ agitation. Studies have shown that both of these antiadrenergic drugs significantly reduce aggressive outbursts, hypervigilance, and startle reactions among PTSD patients. Unfortunately, their side effects include hypotension, like Prazosin, so being prescribed both medications can put you at high risk.

Finally, it’s common for atypical antipsychotics, such as quetiapine to be prescribed off label. This drug, usually reserved for treating schizophrenia or bipolar manic episodes acts as an antagonist to the Serotonin (5-HT2) and dopamine (d2) receptors as well as a reuptake inhibitor. Clinical studies have shown effectiveness in reduction of symptoms from all three domains, mostly with mild side effects, but considerably more investigation is required to be conclusive as to its efficacy in terms of complete remission. Typical side effects include lethargy, sedation, weight gain, and increased risk of developing type 2 diabetes.

Discussion

With the prevalence of PTSD on the rise today, developing a better understanding of the underlying cognitive and physiological processes that underlie it are critical in maintaining a healthy populace, especially within veterans returning from conflict. Because PTSD is a disorder with such a broad spectrum of varied symptoms there are significant challenges to both designing a comprehensive animal model, and a drug therapy with a high level of effectiveness. Current drug therapies all show significant limitations, and unfortunately all are focused on symptom control as a means to treatment. The future could hold the development of novel drug therapies solely focused on PTSD, or could shift more towards prevention of PTSD development.

Limitations

The primary limitation to drug therapy for PTSD veterans is the lack of ability to treat the full spectrum of symptoms, due in no small part to the range and variation of symptoms from patient to patient. We see medications that have been designed to treat other disorders being prescribed to PTSD patients for one set of symptoms, many times in conjunction with other medications to address the other symptoms. There’s no drug on the market that was developed with PTSD as the primary focus. Currently, as many as half of those who are diagnosed with PTSD will not fully respond to prescribed medications. The sometimes severe side effects of the common pharmacological treatments, especially when multiple are prescribed simultaneously, lead to an early discontinuation or lack of adherence by the the patient. Another struggle is the focus on treating the symptoms as opposed to the underlying causes, or upon prevention, consequently it’s not uncommon for PTSD patients’ symptoms to return upon discontinuation of the drug therapy.

Future Directions

Some studies have experimented with the use of “forgetting” drugs, such as propranolol, a beta adrenoreceptor agonist (beta blocker) that could be administered within 24 hours of experiencing a traumatic event and has been shown to lessen the salience of powerful memories compared to that in a control group, which in theory would prevent the development of PTSD in the first place. This is an interesting concept, although use of this drug would certainly bring up a slew of ethical dilemmas, especially if made available to a broader populace. Emphasis on research in the prevention of PTSD in those populations who are especially at risk may well be the best direction to focus in the future. Investigation into glucocorticoid receptor antagonists that could be administered prior to exposure to traumatic events, for example, may help prevent the formation of PTSD since this hormone seems to play such an integral part in the development of PTSD and formulation of memory.

Conclusion

Fundamentally, PTSD is an extreme response to an extreme event. We could describe it as an extremely salient stimuli which creates an incredible learning response within a single exposure. It’s important to remember, that while we have labelled PTSD a disorder, and those that suffer it: “diseased,” it could be considered a completely normal, albeit extreme, survival response of the human mind in an effort to prevent itself from ever going through such an extreme experience again. It may well be that the best we can do is control some of the symptoms of sufferers of PTSD while they go through behavioral and cognitive therapy in order to relearn about the safety of their everyday environment. Hopefully the future will hold deeper research into PTSD and ultimately allow us to prevent its occurrence in populations that are especially at risk. Novel therapies developed specifically for PTSD could address shortcomings in the current mainstream treatment options.

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