Post-traumatic stress disorder (PTSD) is a severe anxiety disorder which can occur in people who experience fear, helplessness, or horror following threat of injury or death. The first section of this review discusses the epidemiology and the risk factors for PTSD. The second section discusses the DSM-IV criteria for diagnosis of PTSD. Adrenergic dysfunction is responsible for most of the hyperarousal and reexperiencing symptoms seen in patients suffering from PTSD. Reduced cortisol and increased levels of corticotrophin releasing hormone also contribute to the adrenergic dysfunction. The third section discusses the role of the dysfunction of the central as well peripheral adrenergic nervous system and how it may be contribute to the reexperiencing and hyperarousal symptoms seen in patients with PTSD.
Dysregulation of the hypothalamus-pituitary-adrenocortical axis results in exaggerated suppression of cortisol levels in PTSD patients and contributes to hyperfunctioning of the adrenergic nervous system seen in those patients. Adrenergic antagonists have emerged as a promising therapeutic intervention to treat the adrenergic dysfunction seen in patients with PTSD. Clinical studies carried out so far have shown that propranolol, clonidine and prazosin have a beneficial role in alleviating some of the symptoms of PTSD. Clonidine and prazosin can be useful for treating traumatic nightmares and hyperarousal symptoms seen in patients with PTSD. Propranolol by blocking the consolidation of memory for traumatic events can be useful for secondary prevention of PTSD in patients who suffered a traumatic event. There is a great need for large scale clinical trials to further evaluate these and newer agents for the growing need for pharmacological treatment of patients with PTSD.
Table of Contents
List of Tables
List of Figures
List of Abbreviations
I) Introduction
A) Risk Factors
B) Structural Abnormalities
II) Diagnostic Criteria for PTSD
III) Role of Norepinephrine
A) Cathecholamine Receptors
B) Peripheral Norepinephrine in PTSD
C) Central Norepinephrine in PTSD
D) Catecholamines and Memory
E) Relation between Catecholamines and the Sleep Cycle
F) Norepinephrine Mechanisms in Hyperarousal Symptoms
IV) Deregulation of the Hypothalamic –Pituitary-Adrenocortical
System
V) Use of Adrenergic Agonists & Antagonists
A) Clonidine
B) Prazosin
C) Propranolol
D) Summary
VI) Current Pharmacotherapy.
VII) Conclusions
VIII) References
IX) Abstract
List of Tables
Table 1 – Factors contributing to intensity of trauma. Page
Table 2 – DSM-IV criteria for PTSD Page
Table 3 – Classification of alpha-1 adrenergic receptors Page
Table 4 – Norepinephrine levels in plasma and urine in PTSD patients Page
Table 5 – Prazosin effects on primary outcome measures Page
Table 6 – Between group comparisons of participants who agreed versus refused to take propranolol In the aftermath of trauma. Page
Table 7 – Common adverse effective, doses, half lifes of the adrenergic drugs with a potential use in treatment of PTSD Page
List of Figures
Figure Page Number
1 Prevalence of trauma and PTSD by gender
2 Synthesis and metabolism of NE in the CNS
3 Noradrenergic projections in the CNS
4 Classification of alpha adrenergic receptors
5 Mechanism of action of adrenergic receptors
6 Role of NE in acquisition and maintenance of reexperiencing symptoms of PTSD
7 Recognition test results for three phases of arousal Story in different drug groups
8 Proposed NE mechanisms of hyperarousal symptoms
9 Response to stress in a normal subject (A),a patient With major depressive disorder (B), and a patient with PTSD (C)
10 Conceptual model of the pathogenesis of PTSD..
List of Abbreviations
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Introduction –
Post-traumatic stress disorder (PTSD) is a severe anxiety disorder which can occur in people who experience fear, helplessness, or horror following the threat of injury or death. People who are exposed to such events are not only at a high risk for developing PTSD but also major depression, panic disorders, generalized anxiety disorder, and substance abuse compared with those individuals who have not experienced traumatic events. (Yehuda, 2002) Symptoms of PTSD have been observed in up to 94% of trauma survivors one week following the trauma and persist in 15 to 25% of trauma survivors.
PTSD is characterized by the presence of three distinct, but coexisting symptom clusters.
These are:
1) Reexperiencing symptoms – These are often insuppressible intrusions of the traumatic memory in the form of images or nightmares that are accompanied by intense physiological distress.
2) Avoidance symptoms - These involve restricting thoughts and distancing oneself from reminders of the event.
3) Hyperarousal symptoms - These symptoms reflect more overt physiological manifestations such as insomnia, irritability, impaired concentration, hypervigilance and increases startle response.
The above mentioned symptoms must be severe enough to impair social, occupational, or interpersonal function. They co-occur for at least 1 month. (Yehuda, 2007) PTSD is
a pathological response. Eighty to 90% of the people who experience a traumatic event adapt to it and lead a regular life. The remaining 10 to 20% of people do not adapt and develop a pathological fixation on the traumatic event; the most common pathological fixation is PTSD. (Brunello, 2000)
The incidence of PTSD in USA is very high. Lifetime prevalence of PTSD in the USA is between 8 to 9%. Ten to 14% of women and 5 to 6% of men develop PTSD during their lifetime. (Yehuda, 2004)
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Figure 1 (Kessler, 1995; Yehuda, 2004)
The data in Figure 1 show the prevalence of trauma and post-traumatic stress disorder by gender from the National Comorbidity Survey. The Survey consisted of a total sample size of 5814 people (2812 men and 3065 women) aged between 15 to 54 years. Data from the National Comorbidity Survey indicated that about 60.7% of men and 51.2% of women in the survey were exposed to a traumatic event that could potentially result in the diagnosis of PTSD. Ninety-two percent of men and 79.6% of women exposed to a trauma did not suffer from PTSD. Eight point one percent of men and 20.4% of women exposed to a trauma were at a risk for developing PTSD. From these data we can see that some individuals are more prone to develop PTSD after trauma while others are more resistant. (Yehuda, 2002) Kessler noted that traumas like rape, sexual molestation, physical attack, childhood physical abuse have a higher probability of resulting in the diagnosis of PTSD. Data from the National Comorbidity survey indicated that women have a higher occurrence of the above mentioned traumatic events. This could result in a higher incidence of PTSD in them. (Kessler, 1995)
A) Risk Factors - The severity of the trauma is responsible for differences in the prevalence of PTSD. (Kessler, 1995) The various factors which contribute to the intensity of the response to the trauma and may affect the development of PTSD in certain individuals are listed in Table 1 below. Factors such as loss of a loved one or property can also influence the intensity of the response. (Lane, 1992) Exposure to heat, cold or pain can also contribute to the intensity of the response. (Schreiber, 1993)
Table 1. (Yehuda, 2002)
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David Tomb created a list of potential vulnerability risk factors for PTSD based on a retrospective analysis. The pre-trauma risk factors for PTSD include: previous psychiatric history, genetics, a history of trauma, low intelligence, poor education, limited coping abilities, youth, low socio-economic status, a genetic predisposition to poor stress tolerance and limited social supports. These vulnerability factors in general seem to be most true for PTSD due to minor traumas. (Tomb, 1994) The chances of developing PTSD are low if an attempt is made to minimize the stressful event. (Lane, 1992)
B) Structural abnormalities – Abnormalities in brain structure have been found in patients with PTSD. A study was carried out by Gurvtis to further investigate these structural changes in patients with PTSD. Three groups were studied. One group included Vietnam War combat veterans who had PTSD; the second group included non veterans while the third group included war veterans who did not have PTSD. Magnetic resonance imaging revealed a decrease in hippocampal volume in combat veterans when compared with veterans without PTSD or non veterans. (Gurvits, 1996) The authors suggested that a smaller hippocampal volume may have been a pre-existing risk factor for the development of PTSD in response to combat exposure. (Gurvits, 1996)
Positron emission tomography scan studies done on PTSD patients have shown increased blood flow to the limbic and the paralimbic areas. The blood flow was increased increased especially to the right amygdala and the ventral anterior singulate gyrus. (Friedman, 2000) There was a reduced blood flow to the Broca’s area in the left temporal lobe suggesting an impaired language function and linguistic processing. (Rauch, 1996) These abnormalities in hippocampal volume and altered brain blood flow may be related to the reduced cognitive abilities of patients with PTSD. (Friedman, 2000)
II) Diagnostic Criteria -Individuals can develop PTSD only if they suffer from a traumatic event. Table 2 given below lists the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria published by the American Psychiatric Association for the diagnosis of PTSD. This includes various criteria classified as A, B, C and D. All adverse events are not traumatic. Things like divorce, lawsuits, and financial problems don’t satisfy the DSM-IV A1 criteria for diagnosis of PTSD.
Table 2 – DSM-IV criteria for PTSD (Friedman, 2000)
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The criterion listed under B in Table 2 includes the re-experiencing of symptoms. These symptoms are the most distinctive symptoms of PTSD. In individuals suffering from PTSD, the traumatic event remains as a dominating psychological experience that can evoke panic, terror, dread, grief, or despair as daytime intrusive recollections or as traumatic nightmares. It can also provoke psychotic enactments known as PTSD flashbacks.
The criterion listed under C in Table 2 consists of symptoms reflecting behavioral, cognitive, or emotional strategies. Behavioral strategies include avoiding any situation in the patients they perceive a risk of confronting such stimuli. These strategies help PTSD patients to reduce the likelihood that they will expose themselves to trauma-related stimuli and if exposed it will minimize the intensity of their psychological response.
The criterion listed under D in Table 2 includes symptoms of arousal such as insomnia, irritability and inability to concentrate. The symptoms included in criterion D are also found in other anxiety disorders such as generalized anxiety disorder or panic disorder. Hypervigilance and an exaggerated startle response are diagnostic of PTSD.
III) Role of Norepinephrine
PTSD is a condition characterized by a chronic stress following a traumatic event. Symptom-linked hyper noradrenergic derangements have been observed in patients with PTSD. (Strawn, 2008) The catecholamine NE plays a critical role as one of the principal mediators of the mammalian response to stress. Its potential role in the pathophysiology of PTSD has been under direct investigation for more than two decades. (Strawn, 2008)
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Figure 2 – Synthesis and metabolism of norepinephrine in the central nervous system. (Strawn, 2008)
Figure 2 above shows the synthesis and metabolism of NE in the CNS. Tyrosine hydroxylase catalyzes the conversion of tyrosine to DOPA. DOPA is converted to dopamine by L-aromatic amino acid decarboxylase. Dopamine is then converted to NE by dopamine beta hydroxylase in the presynaptic vesicles. The arrival of an action potential at the presynaptic neuron terminal results in opening of the voltage-dependent calcium channels resulting in a infux of Ca2+ ions from the extracellular fluid into the presynaptic neuron's cytosol. This results in the fusion of the presynaptic vesicles with the presynaptic membrane and causes a calcium-mediated exocytosis of NE into the synaptic cleft. NE then acts on postsynaptic alpha and beta adrenergic receptors. NE released into the synaptic cleft can also act on the presynaptic alpha-2 adrenergic receptors. The presynaptic alpha-2 receptors have an inhibitory action and prevent further release of NE.
The action of NE within the synaptic cleft is primarily terminated by its reuptake through presynaptic NE transporters. The NE transporter pumps NE from the synaptic cleft, back into the neuron where it may enter presynaptic vesicles or it may be metabolized to MHPG via MAO. MHPG is the principal metabolite of NE in the brain. Studies measuring 24-hour urine levels of MHPG have been carried out in patients with PTSD. These results are described in detail in the section on peripheral NE and PTSD.
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Figure 3 – Noradrenergic projections in the human central nervous system. (Strawn, 2008)
NE is the major CNS neurotransmitter. It is primarily derived from the neurons whose cell bodies primarily reside in the locus ceruleus (LC). This pontine collection of neurons (Figure 3) projects to a variety of structures in the brain including the thalamus, hypothalamus, prefrontal cortex, amygdala and the periaqueductal grey matter. All of these structures have been implicated in the pathology of PTSD. (Strawn, 2008)
A) Catecholamine Receptors –
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Figure 4 - The basic classification of adrenergic receptors. (Bylund, 1992)
Alpha Receptors - Alpha adrenergic receptors can be subdivided into alpha-1 and alpha-2 receptors. Alpha-1 receptors are further divided into alpha-1A, alpha-1B and alpha-1C receptor subtypes. All the alpha-1 receptors are G protein coupled receptors and act via the IP3 PLC pathway. The alpha-1 adrenergic receptor antagonist prazosin which has a potential role in the treatment of PTSD has similar affinity for the different alpha-1 adrenergic receptor subtypes. (Bylund, 1992)
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Figure 5. (www.wikipedia.com) – Mechanism of action of adrenergic receptors.
Epinephrine or NE are receptor ligands to either α1, α2 or β-adrenergic receptors. α1 couples to Gq, and acts via the IP3 PLC pathway. α2, on the other hand, couples to Gi, which causes a decrease of cAMP activity, resulting in vascular smooth muscle constriction. Βeta-2 receptors couple to Gs, and increases intracellular cAMP thus causing smooth muscle relaxation.
Table 3 – Classification of α1 adrenergic receptors. ( Bylund, 1992)
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Table 3 summarizes the classification of alpha-1 adrenergic receptors. The structure of the three alpha-1 adrenergic receptor subtypes is consistent with the seven transmembrane spanning model that has been developed for the G-protein coupled receptors. The alpha-1 adrenergic receptor antagonist prazosin has similar affinities for all the three subtypes of the alpha-1 adrenergic receptor.
Alpha-2 adrenergic receptors are Gi-coupled receptors and they act by inhibiting production of cellular levels of AMP (Figure 5). There is a high density of alpha-2 receptors in the LC. Activation of these receptors exerts a strong inhibitory influence on the firing of the LC neurons. Antagonism of alpha-2 receptors by yohimbine stimulates the LC neurons and increases NE release in target brain regions as the inhibitory effect of the alpha-2 receptors on neurotransmitter release is lost. Blockade of alpha-2 receptors increases the response of LC neurons to excitatory stimuli. (Southwick, 1999)
The biochemical sensitization of NE release induced by chronic stress may be partially due to the reduced sensitivity of the presynaptic alpha-2 adrenergic receptors. A local infusion of an alpha-2 adrenergic agonist like clonidine into the hippocampus produced a great reduction in NE levels in chronically stressed animals by stimulating the presynaptic alpha-2 adrenergic receptors which inhibit neurotransmitter release when compared with the native control rats. On the other hand local infusion of an alpha-2 antagonist like idazoxan produced significantly greater increase in NE in chronically stressed rats when compared with the naive control rats. From these data it was concluded that NE release via alpha-2 adrenergic receptor stimulation may be altered in conditions of chronic uncontrollable stress. Since PTSD is a chronic stress condition, modulation of alpha-2 adrenergic receptors can be responsible for increased levels of NE seen in patients with PTSD. (Southwick, 1999)
Beta adrenergic receptors are also G protein-coupled receptors and act by increasing cellular levels of AMP. They are present in the CNS as well as the periphery. Beta adrenergic receptors can be further classified as beta-1, beta-2 and beta-3 receptor subtypes. Beta receptors in the human brain have the highest density in the hippocampus. (Reznikoff, 1986)
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