Recent Progress in Understanding the Pathophysiology of Post-Traumatic Stress Disorder

Abstract

Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can result after exposure to a traumatic event. Though our understanding of the aetiology of PTSD is incomplete, several neurobiological systems have been implicated in the pathophysiology and vulnerability towards developing PTSD after trauma exposure. We aimed to provide a concise review of benchmark findings in important neurobiological systems related to the aetiology and maintenance of PTSD symptomology. Specifically, we discuss functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. This article provides a succinct framework to appreciate the current understanding of neurobiological mechanisms related to the pathophysiology of PTSD and how these findings may impact the development of future, targeted pharmacological treatments for this debilitating disorder.

1 Introduction

Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can develop following exposure to a traumatic life event such as military combat, a natural disaster, and/or physical or sexual assault. PTSD occurs in approximately 8–14 % of the population in the USA [1-3], and rates of PTSD among women in the USA (12—18 %) are approximately twice than in men [3, 4].

PTSD presents a significant burden not only to individuals but society at-large. The majority of people with PTSD meet the diagnostic criteria for other psychiatric disorders [4, 5], including major depression [6, 7] and anxiety disorders [8]. Individuals with a PTSD diagnosis are more likely than the general population to use drugs and experience impairments in psychosocial functioning [9] and to engage in suicidal behaviours [1]. Not only does this population have increased psychiatric treatment needs, but when compared with the general population, people with PTSD also require greater healthcare utilization, have more costs attributed to co-morbid medical conditions such as heart problems, diabetes and peptic ulcers [10], and gastrointestinal problems [11], and have increased rates of surgery and visits to the physician [12, 13].

Despite the deleterious impact of PTSD, our current understanding about the human pathophysiology governing the divergent paths associated with extreme stress response is lacking [14, 15], and these models have failed to provide effective therapeutic targets. US-based practice guidelines for PTSD have recommended cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) or selective noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) as first-line treatments [16, 17]. However, PTSD response rates to pharmacological treatments such as the two US FDA-approved SSRIs paroxetine and sertraline rarely exceed 60 %, and even fewer patients (20–30 %) achieve clinical remission [18]. Several placebo-controlled trials of other medications in PTSD have failed, and even recent studies of approved medications (e.g. sertraline) have failed to show efficacy in specific subgroups of PTSD patients such as combat veterans [19]. The recent review of treatments for PTSD by the United States Institute of Medicine, located in Washington, DC, concluded there was not sufficient evidence for any drug or class of drug for the treatment of PTSD [20]. To date, drug development in PTSD has been opportunistic, building almost solely on empirical observations with drugs approved for other indications, and not surprisingly, treatment options for the often chronically symptomatic PTSD patients remain limited.

This paper reviews our current understanding of the pathophysiology underlying PTSD with evidence suggesting functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid, and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. Other systems, for example glutamate, are also relevant and important, but have been reviewed extensively elsewhere [21] [22]. By revealing the neurobiological mechanisms that play a role in the aetiology of PTSD, we aim to identify novel targets that offer potential therapeutic value in developing future evidence-based PTSD pharmacological interventions.

2 Noradrenergic System

The adrenoreceptors (ARs) are a group of G protein-coupled receptors consisting of three major classifications: α₁, α₂ and β with associated subtypes [23]. The AR system stimulates CNS activity and sympathetic autonomic responses through cell bodies located in the locus coeruleus and projects to the prefrontal cortex and limbic system structures (e.g., amygdala, hypothalamus) [24], which implicate it in selective attention to rewarding and aversive stimuli [25] and stress and fear-related responses [26] [27]. Through dysregulation of physiological mechanisms, hyperadrenergic activity has been linked to psychiatric conditions such as major depression [28] [29], traumatic brain injury [30] and anxiety disorders [31-33] [23, 34].

The AR system has held a preeminent role in PTSD research, as it influences amygdala functioning and associated fear signalling [27, 35, 36]. Table 1 lists evidence of altered peripheral and central AR functioning in PTSD populations suggesting state and trait alterations in AR functions.

Table 1.

Evidence for altered noradrenergic function in PTSD^a

Physiological observations	Study results
Baseline/resting state measures
Increased resting heart rate and blood pressure	+/−
Increased resting urinary noradrenaline (norepinephrine) and adrenaline (epinephrine)	+
Decrease in basal and stimulated activity of cAMP	+/−
Decreased binding to platelet α2 receptors	+
Decrease in platelet MAO activity	+
Increased resting plasma noradrenaline or MHPG	+/−
Challenge test markers
Increased plasma noradrenaline with traumatic reminders/panic attacks	+
Increased heart rate and blood pressure response to traumatic reminders/panic attacks	+++
Increased orthostatic heart rate response to exercise	+
Increased symptoms, heart rate and plasma MHPG with yohimbine noradrenergic challenge	++
Differential brain metabolic response to yohimbine	+

^aThe evidence for altered noradrenergic functioning in PTSD is stronger in challenge test designs (i.e., incorporating threat responses, trauma reminders) in comparison to baseline/resting state studies

cAMP cyclic adenosine 3′5′-monophosphate, MAO monoamine oxidase, MHPG 3-methosy-4-hydroxyphenylglycol, PTSD post-traumatic stress disorder, +/− indicates an equal number of studies support this finding and do not support this finding, + indicates at least one study supports this finding and no studies do not support the finding, or the majority of studies support the finding, ++ indicates two or more studies support this finding, and no studies do not support the finding, +++ indicates three or more studies support this finding, and no studies do not support the finding

Early studies using the α₂ selective antagonist yohimbine, which acts on both pre- and post-synaptic receptors and increases noradrenaline activity, helped form a model suggesting that increased noradrenaline activity leads to impaired medial prefrontal cortex functioning [27, 37] and fear extinction [38, 39], explaining increases on behavioural measures of anxiety and PTSD symptom severity [40, 41]. β-AR antagonists (i.e., propranolol) have produced mixed results in animal models, with some evidence for inhibiting fear memory reconsolidation and responding [35]. However, post-trauma administration of propranolol has not yielded significant effects on preventing fear conditioning [42] or inhibitory avoidance reconsolidation [43]. Clinical evidence has shown a similar trend regarding propranolol as a PTSD prophylactic [44, 45] with several contrary findings [46, 47]. However, clinical trials to date have not yet provided conclusive results given small sample sizes, difficulties recruiting for these trials and heterogeneous patient cohorts.

The noradrenaline transporter (NET) is a potential noradrenaline target for studying the pathophysiology of PTSD and may emerge as a target for treatment development in the future. The NET is a part of the Na+/Cl− neurotransmitter transporters [48] that has high concentrations in the locus coeruleus and moderate levels within cortical regions including the frontal cortex, hippocampus, amygdala, thalamus and cerebellar cortex [49]. Besides acting as a noradrenaline plasma membrane monoamine transporter and maintaining presynaptic noradrenaline storage [50], the NET has been connected to the regulation of dopamine reuptake, and its dysregulation may be involved in mood and stress disorders [37, 51-53].

There is ongoing work suggesting NET involvement in PTSD. Preclinical evidence has demonstrated that chronic stress exposure may lead to AR system dysregulation and can decrease NET availability in the locus coeruleus and increase noradrenaline synaptic availability in cortical areas [54], while the selective noradrenaline reuptake inhibitor (NRI) reboxetine can antagonize noradrenaline synaptic availability and decrease foot shock stress reactivity [55]. These preclincial findings have been recently substantiated in a human positron emission tomography (PET) study in humans showing decreased NET availability in patients with PTSD [194]. This alteration in homeostatic stress responding could trigger anxious and depressive phenotypes [56], which characterize PTSD [23, 29, 31-34, 57]. Recent clinical research [58] used a combination of naltrexone and either the SSRI, paroxetine, or the NRI, desipramine, in treating veterans with PTSD and alcohol dependence. The desipramine group performed equivalently in PTSD symptom reduction compared with the standard SSRI treatment and was more effective in reducing alcohol consumption and study attrition and therefore improving overall clinical presentation.

The NET may inform the development of future PTSD treatments. Trauma exposure can cause impaired impulse control and emotional dysregulation [59-61]. Early clinical evidence suggests that atomoxetine, which has a high affinity for the NET, increases inhibitory response control [62] and reduces attention-deficit hyperactivity disorder (ADHD) symptoms with co-morbid anxiety [63] and PTSD [64] diagnoses. This drug may be effective in treating phenotypes exhibiting pronounced hyperarousal and impulsive behaviours. Venlafaxine, an SNRI, has shown clinical utility in reducing re-experiencing and avoidance/numbing symptoms [65, 66] and can improve fear extinction in rats, thus suggesting its utility for supplement PTSD exposure therapy [67]. As the NET interacts with other stress systems such as dopaminergic [37, 51-53] and serotonergic [65, 66] systems, combination drugs (i.e., SNRIs) and combination treatments that affect NET functioning [58] may lead to improved PTSD treatment modalities.

3 Serotonergic Receptors: 5-HT_1A, 5-HT_1B

The serotonergic (5-HT) receptors are a group of G protein-coupled receptors and one identified ligand-gated ion channel (5-HT₃) that encompass seven classifications, ranging from 5-HT₁ through 5-HT₇ with associated subtypes [68]. The 5-HT system is involved in cognition, emotional processing and behavioural regulation [69]. Animal and human models have demonstrated that 5-HT receptor systems are implicated in the pathophysiology of several psychiatric disorders, including depression [70] [71], alcoholism [72, 73] and PTSD [74, 75].

Fear regulation and threat responsiveness have been linked to 5-HT signalling in the amygdala [76], a brain region integral to understanding the fear response and PTSD aetiology [77-80]. 5-HT agonists can selectively induce anxiety attacks and trauma-related flashbacks in PTSD populations [41, 81, 82]. The 5-HT_1A and 5-HT_1B receptors have been identified in the study of stress disorders [74, 83, 84] and could provide new clinical understanding of PTSD phenotypes. The 5-HT_1A receptors are located presynaptically on 5-HT cell bodies in the raphe and postsynaptically in other brain regions [85]. The density of 5-HT_1A receptors in humans and monkeys appears highest in the raphe, hippocampal formation, hypothalamus, and insula, temporal, cingulate and ventral prefrontal cortices [86], [87, 88]. Postsynaptic 5-HT_1A receptors are expressed mainly in the astroglia of the frontal and limbic cortices [85], [89] and stimulate the release of trophic-factor S-100β, which promotes serotonergic system development [85], [90] and cytoskeletal maintenance [91]. Therefore, the neuropathological abnormalities exhibited in limbic and paralimbic cortical areas in mood disorders (i.e., reduced cortex volume, reduced synaptic proteins, increased neuronal density, reduced glial counts) may be attributed to impaired 5-HT_1A receptor functioning [92, 93]. Preclinical evidence has shown 5-HT_1A receptor knockout mice display increased anxiety and fear responses [94]. Relevant to stress regulation and PTSD, mice administered the 5-HT_1A agonist 8-OH-DPAT demonstrated anxiogenic responses to the elevated plus maze (EPM) test, which could modulate glutamatergic and GABAergic systems located in the medial prefrontal cortex [95].

The 5-HT_1B receptors have the highest expression in the striatum, pallidum, nucleus acumbens, substantia nigra and the ventral tegmental area and to a lesser extent in the dorsal raphe nucleus, the amygdala, hippocampus and cortical areas [96]. These receptors operate presynaptically as autoreceptors on the axon terminals of 5-HT-containing neurons and as heteroreceptors on non-5-HT-containing neurons [71, 96]. As a heteroreceptor, the 5-HT_1B receptor is involved in regulating the activity of multiple neurobiological systems in the brain including gamma-aminobutyric acid (GABA) [96, 97], noradrenaline [98], dopamine [99], acetylcholine [100] and glutamate [97, 101] in areas of a cortico-striato-pallido-thalamic-limbic circuit that have been implicated in the pathogenesis of PTSD. Animal studies have yielded behavioural pharmacological results indicating 5-HT_1B receptor involvement in locomotor activity, reinforcement learning, appetitive behaviours (i.e., sexual, feeding), sleep and aggression [96, 102]. PTSD patients and healthy trauma-exposed individuals have demonstrated reduced 5-HT_1B binding potentials in the caudate, amygdala and anterior cingulate cortex with positive correlations observed according to trauma history and symptom severity [74]. Recently, alterations in 5-HT_1B receptor density have been shown to be linked to specific PTSD symptomology suggesting that these changes may be responsible for certain features of the clinical phenotype of PTSD [193] (Fig. 1). This evidence suggests that trauma exposure can have long-term effects on 5-HT_1B receptor functioning and could explain some of the enduring behavioural, neurological and psychological changes observed in PTSD phenotypes.

Fig. 1.

Post-traumatic stress disorder (PTSD) patients, overall, have lower serotonin 5-HT_1B receptor density in the anterior cingulate cortex (ACC), hippocampus (HC) and pallidum as well as other regions implicated in PTSD [70]. Specific alterations in 5-HT_1B receptor density in PTSD have been shown, using the 5-HT_1B selective radioligand [11C]P943, to be linked to specific domains of PTSD symptomology. Decreased 5-HT_1B receptor binding in the ACC has been shown to increase re-experiencing symptoms. Decreased 5-HT_1B receptor binding in the HC has been shown to increase numbing symptoms. Decreased 5-HT_1B receptor binding in the pallidum has been shown to increase anxious arousal, re-experiencing, and numbing symptoms [193]

5-HT_1A and 5-HT_1B receptor modulators may help in future treatment development. Animal [95] and human [103, 104] models suggest that further inquiry into the influence of 5-HT_1A agonists on anxiety regulation could inform new forms of PTSD treatments. Drugs targeting 5-HT_1B receptors may have clinical utility in treating PTSD, which are possible efficacious treatments for co-morbid mood disorders [70, 84]. A recent clinical trial utilizing coadministration of the now discontinued 5-HT_1B antagonist, elazsonan (CP-448187), with sertraline yielded 14.9 % and 15.7 % treatment response rates for reducing depressive symptoms by at least half during weeks 2 and 3, respectively, compared with 3.3 % and 7 % for sertraline alone [105]. These symptom reductions were sustained throughout the 8-week trial, which suggests that 5-HT_1B antagonists may have expediting therapeutic properties in PTSD.

4 Endocannabinoids and the Cannabinoid CB₁ Receptor

Various lines of evidence suggest that the endogenous cannabinoids (eCB), anandamide (AEA) and 2-arachidonolyflycerol (2-AG) [Fig. 2], which exert much of their actions through the two known cannabinoid (CB) receptors (CB₁, CB₂), play an important role in the development [106] and function of the PTSD circuit, specifically in stress responses [107-112].

Fig. 2.

Chemical structures of endogenous compounds that bind to cannabinoid receptors

First, animal studies [113] show that chronic stress is associated with significantly decreased AEA levels in all brain areas studied. Furthermore, inhibiting the metabolism of AEA leads to a reduction of anxiety in rodents [114]. In our own work in PTSD we found decreased plasma AEA levels in PTSD patients relative to healthy control subjects (0.72 ± 0.12 vs. 2.74 ± 0.85 pmol/mL, t = 2.47, degrees of freedom [df] = 17, p = 0.024; Fig. 3, personal unpublished observations), providing additional evidence for an important role of altered eCB signalling in PTSD. Notably, these findings agree with results of human studies in depression [112] reporting that female outpatients with major depressive disorder (MDD) have lower serum 2-AG levels than controls, and the magnitude of the decrease was associated with the length and severity of the depressive episode. While AEA was not associated with major depression per se, an inverse relationship was found between serum AEA content and Hamilton Anxiety Rating Scale scores, suggesting that AEA content may relate to the anxiety dimension of the depression phenotype. In addition, earlier age at first trauma was correlated with lower AEA levels in PTSD and the magnitude of the decrease was associated with the length of illness, providing additional evidence for an important role of dysfunctional eCB signalling in PTSD.

Fig. 3.

Plasma anandamide (AEA) levels are decreased in post-traumatic stress disorder (PTSD) patients (0.72 ± 0.12 pmol/mL) relative to healthy control subjects without trauma history (hippocampus [HC]; 2.74 ± 0.85 pmol/mL, t = 2.47, degrees of freedom [df] = 17, p = 0.024)

The CB₁ receptors are of particular interest as recent studies demonstrate a specific and primary [115] role for the CB₁ receptor in mediating the neurobiological underpinnings and behavioural consequences of stress exposure. The first CB₁ receptor was discovered relatively recently by Allyn Howlett’s laboratory in 1988 [116, 117], and since then there has been substantial attention devoted to this neuromodulatory system.

CB₁ receptors are found in moderate to high levels throughout forebrain limbic structures and have been shown to modulate a variety of behaviours, including mood, stress, anxiety, learning, memory [118-120] and notably the extinction of fear [121-123]. They are the most abundant G protein-coupled receptors in the CNS, [124, 125] and are found in high concentrations in a fear circuit of cortical and subcortical brain regions that are consistently implicated in PTSD. Moreover, genetic or pharmacological disruption of CB₁ receptor signalling, which is required for normal fear extinction [121-123], results in an anxious PTSD phenotype [126, 127], and brain CB₁ receptor signalling controls extinction of aversive memories [121-123]. Mice lacking CB₁ receptors exhibit heightened indices of anxiety and depression, reinforcing the concept that eCBs are required to maintain emotional homeostasis [117, 119, 126]. While the eCB system is highly reactive in response to acute stress, there is evidence to suggest that chronic stress causes a breakdown in eCB signalling, thus compromising an endogenous buffer system to stress in the brain [113, 117]. Therefore, CB₁ receptor function is a mechanism that seems to play an important role in the neurobiology of emotional behaviour with specific implications in PTSD.

Additionally, animal studies have shown gender disparities in the stress-induced regulation of CB₁ receptors in male and female animals [109, 113, 128, 129] with elevated CB₁ receptor expression in female but not male animals. Additionally, impaired CB₁ receptor-mediated eCB signalling [130] was identified as a key mechanism explaining the increased vulnerability of female animals to develop an anxious phenotype in chronic stress models (for a review see Palanza [131]). This evidence may help explain why women are at higher risk for developing PTSD symptoms following exposure to various types of trauma [132-140] (odds ratio approximately 5), even when sexual trauma, which predominates in women, was excluded (odds ratio approximately 3) [141].

To further understand the neuromodulatory role of the eCBs and their corresponding receptors, we look to PET imaging as it is the most direct, sensitive and straightforward means of probing the functional neurochemistry of humans and assessing molecular targets in the brain in vivo, provided the proper tracer and modelling approaches are available. Due to the recent development of CB₁ receptor-selective radiotracers, it is now possible for the first time to conduct an in vivo assessment of CB₁ receptor density using PET.

Given the overwhelming evidence that the eCBs and their attending receptors play a key role in the aetiology of PTSD, pharmacological interventions specifically designed to target eCB signalling could emerge as a novel, potentially breakthrough treatment for PTSD. Conversely, the development of CB₁ receptor antagonists, such as SR-141716 (rimonabant), has been associated with the emergence of negative mood symptoms and an increased risk of suicidality. Therefore, direct modulation of the CB1 receptor may not be the most appropriate point of intervention for therapeutic drug development. Fatty-acid amide hydrolase (FAAH) is an integral membrane enzyme primarily responsible for the degradation of the eCBs in the brain[142] and may yield a safer alternative treatment. FAAH activity has been linked with aversive memory processing [143] and arousability [142]. In addition to these findings, a single nucleotide polymorphism of FAAH was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex [142]. Therefore, FAAH inhibition may point to a novel treatment mechanism with unique therapeutic potential in the treatment of PTSD.

5 Hypothalamic-Pituitary-Adrenal Axis and Corticotropin-Releasing Factor

The eCB system is believed to be strongly tied to the HPA axis, another neurocircuit implicated in stress responding [144]. The HPA axis is a stress-responsive neuroendocrine system that ties the CNS to the endocrine system. The HPA axis assists with the adaptation to stress and the maintenance of homeostasis after challenge, yet is also vital in supporting baseline functioning [145]. A dysfunctional HPA axis is associated with numerous psychosomatic and psychiatric disorders [146-154].

Corticotropin-releasing factor (CRF) is a neuronal signalling molecule produced by cells in the hypothalamus in response to physical or psychological stress. Increased levels of CRF in the hypothalamus in response to stress results in the activation of the HPA axis and increased release of cortisol. CRF acts at the G protein-coupled receptors CRF-1 and CRF-2. It is believed that high CRF levels at the time of trauma may facilitate encoding of traumatic memory and enduring anxiety effects via direct action at CRF-1 receptors [155-158].

Animal models provide further evidence for the role of CRF in the development and maintenance of stress-induced behaviours. Mice deficient in the G protein-coupled receptor CRF-1 display an impaired stress response and decreased anxious behaviours [159, 160], while mice deficient in the G protein-coupled CRF-2 receptor display increased anxious phenotypes and hypersensitivity to stress [159, 161]. Regulation of the relative contributions of the two CRF receptor subtypes may be essential to regulating physiological and psychological responses to stress [160]. In a mouse-predator stress model of PTSD, CFR-1 receptor antagonism prevented the initiation of stress effects [157, 158], suggesting a potential therapeutic target for the primary prevention of stress-induced symptoms.

PTSD patients exhibit increased cerebrospinal fluid levels of CRF [162, 163] and abnormalities in other HPA axis systems [164], indicating the utility of compounds that dampen the CRF system or other HPA axis hormones in the treatment of PTSD [158, 165]. CRF-1 receptor antagonism is a treatment modality that has been explored for the treatment of MDD [166], While an initial open-label study suggested promising efficacy data, these results were not confirmed in follow-up placebo-controlled trials [167]. Testing of CRF-1 receptor antagonists in the treatment of chronic PTSD is currently underway, but the potential role for CRF-1 antagonists as a method of primary prevention has not yet been explored.

Recently, much attention has been devoted to furthering our understanding of the relationship between the eCB system and the HPA axis in response to stress. Animal models showed that (1) in vivo exposure to stress was capable of modulating eCB content in the hypothalamus, and (2) eCB signalling in vivo exerted negative regulation over the HPA axis [117, 168]. It is believed that a functional crosstalk exists between eCB signalling and the HPA axis, and changes in one system have a ripple effect on the other [117]. This relationship poses the opportunity for further development and understanding of unique therapeutic targets in the treatment of PTSD.

6 Opioid System

Multiple lines of evidence connect opioid systems in the pathophysiology of PTSD. Opioid receptors (ORs) belong to the superfamily of G protein-coupled receptors and are generally classified into at least three subtypes: δ (encephalin preferring), κ (dynorphin preferring) and μ (morphine preferring) [169]. The dynorphin/κ opioid receptor (κ-OR) is of particular interest, as it has been implicated in several brain disorders including substance (particularly psychostimulant) abuse [170], epilepsy [171], Tourette’s syndrome [172] and Alzheimer’s disease [173]. Moreover, recent evidence suggests a role for the dynorphin/κ-OR in the expression of stress-induced behaviours [174].

Relevant to the aetiology of PTSD, is the expression pattern of the κ-OR with high receptor levels in a ventral medial, prefrontal, cortex-hippocampal-limbic circuit (see Fig. 4) [175, 176] where they mediate anxiety-like behaviours [177]. These brain regions are also implicated in the aetiology of PTSD [27].

Fig. 4.

MRI scans and positron emission tomography (PET) images of kappa opiate receptors in the brain of a healthy individual. For both left and right panels, the left column shows the axial slice, the middle column shows the coronal slice and the right column shows the sagittal slice. The PET images of the receptors confirm their known distribution in the human brain, with high levels in a circuit implicated in post-traumatic stress disorder, which includes the amygdala, hippocampus and ventromedial prefrontal cortex. Left panel: Top row: MRI images. Middle row: 0–10 min summed PET image. Bottom row: 60–120 min summed PET image. Right panel: Top row: MRI images. Middle row: corresponding binding potential (BPND images estimated using a simplified reference tissue model [SRTM]). Bottom row: corresponding BPND images estimated using the SRTM2; it is slightly less noisy than the SRTM, as would be expected.

There is a growing body of basic science data [178] showing that although κ-OR signalling during acute stress may create the physical ability and motivation to escape a threatening situation, κ-OR signalling in response to chronic and inescapable stress can lead to persistent depressive and anxious behaviours [179], which resemble important components of the phenotype of PTSD [180].

Recent preclinical evidence suggests that κ-ORs may emerge as targets for treatment development for patients with anxious-depressive phenotypes [179]. This would be an important step forward in the treatment of PTSD because current FDA-approved medication treatments (SSRIs) offer relatively little benefit to most PTSD patients [181, 182]. A recent study showed that κ-OR antagonists, in contrast to the SSRI fluoxetine, possess unique antidepressant-anxiolytic properties in models of unlearned and learned fear [183], which are informative models to our further understanding of trauma-related psychopathology leading to the development of new treatment approaches [184].

Clinical evidence implicating opioid systems in the aetiology of PTSD are three-fold. First, survivors of intimate partner violence can exhibit persistent pain syndromes [185]. Second, there is an association between childhood sexual trauma and exaggerated rate of opioid use later in life [186]. Lastly, the use of morphine during trauma care may reduce the risk of subsequent development of PTSD after traumatic injuries in military personnel [187], burn victims [188], and children [189] and adult [190] patients.

The ability to image the κ-OR would be important in allowing us to further understand the circuitry of the κ-OR and characterize the involvement of κ-OR transmission in PTSD. A greater understanding of the neuromodulatory role the κ-OR plays in the aetiology and course of PTSD may provide a basis and justification for the development of experimental drugs targeting the κ-OR. In vivo functional imaging using PET is currently the sole method for providing a quantitative measurement of κ-OR-mediated signalling in the brain [191], and novel imaging approaches are currently under development.

To date, data suggest direct involvement of the κ-OR system in the maladaptive stress response resulting in the phenotype of PTSD. The implications of these lines of evidence are that the κ-OR system could emerge as a system of interest for targeted evidence-based treatment development for this patient population, either alone or as combined pharmacotherapy with behavioural exposure, a therapeutic strategy that has recently been validated to enhance extinction of conditioned fear in PTSD patients [192]. Pharmacological therapies targeting the κ-OR might be particularly effective in the management of depression and co-morbid anxiety, the typical phenotype of PTSD. Such developments would be critical steps forward in the clinical care of this severely ill patient population.

7 Conclusion

In a sharp distinction from other medical disorders such as cancer, coronary artery disease and diabetes, which have objective biological tests for diagnosis, severity of illness and response to treatment, biological markers cannot yet independently confirm the assessment of PTSD. Current procedures for diagnosing PTSD rely on self-report screening measures and clinical interviews. Treatment has been limited to symptom management rather than targeting the biological aetiology. To date, drug development in PTSD has been opportunistic, building almost solely on empirical observations with drugs approved for other conditions. As of today, not a single pharmacological treatment has been developed specifically for PTSD. Utilizing our existing knowledge of the circuits and substrates underlying the development and maintenance of PTSD, and the critical importance of forthcoming research findings, we are now able to guide future PTSD treatments altering brain mechanisms with proven relevance to PTSD.