Investigational drugs under development for the treatment of PTSD.

Review

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Investigational drugs under development for the treatment of PTSD 1.

Introduction

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Cannabinoids

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Glutamate

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Opioids

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Brain-derived neurotrophic factor

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Oxytocin

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Conclusion

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Expert opinion

Benjamin J Ragen, Jordan Seidel, Christine Chollak, Robert H Pietrzak & Alexander Neumeister† †

New York University School of Medicine, Department of Radiology, Molecular Imaging Program for Anxiety and Mood Disorders, New York, NY, USA

Introduction: Posttraumatic stress disorder (PTSD) is a prevalent, chronic and disabling anxiety disorder that may develop following exposure to a traumatic event. There is currently no effective pharmacotherapy for PTSD and therefore the discovery of novel, evidence-based treatments is particularly important. This review of potential novel treatments could act as a catalyst for further drug investigation. Areas covered: In this review, the authors discuss the heterogeneity of PTSD and why this provides a challenge for discovering effective treatments for this disorder. By searching for the neurobiological systems that are disrupted in individuals with PTSD and their correlation with different symptoms, the authors propose potential pharmacological treatments that could target these symptoms. They discuss drugs such as nabilone, D-cycloserine, nor-BNI, 7,8dihydroxyflavone and oxytocin (OT) to target systems such as cannabinoids, glutamate, opioids, brain-derived neurotrophic factor and the OT receptor, respectively. While not conclusive, the authors believe that these brain systems include promising targets for drug discovery. Finally, the authors review animal studies, proof-of-concept studies and case studies that support our proposed treatments. Expert opinion: A mechanism-based approach utilizing techniques such as in vivo neuroimaging will allow for the determination of treatments. Due to the heterogeneity of the PTSD phenotype, focusing on symptomology rather than a categorical diagnosis will allow for more personalized treatment. Furthermore, there appears to be a promise in drugs as cognitive enhancers, the use of drug cocktails and novel compounds that target specific pathways linked to the etiology of PTSD. Keywords: evidence-based, neurobiology, posttraumatic stress disorder, treatment Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

Posttraumatic stress disorder (PTSD) is a major public health concern. According to US population-based studies such as the National Comorbidity Survey (NCS) [1], NCS-Replication [2], and the National Epidemiologic Survey on Alcohol and Related Conditions [3], the lifetime prevalence of PTSD ranges from 6.4 to 7.8%. Furthermore, PTSD is the most prevalent, chronic and disabling psychiatric disorders in veterans of Operations Enduring Freedom, Iraqi Freedom and New Dawn. A study of 18,305 US army personnel found that 23.6% of active component soldiers and 30.5% of National Guard soldiers screened positive for DSM-IV PTSD 12 months after returning from deployment to Iraq [4]. Unfortunately, the majority of civilians and veterans with PTSD receive poor treatment or no treatment at all. The etiology and risk factors for PTSD in the civilian versus military 10.1517/13543784.2015.1020109 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Multiple novel neural mechanisms have been studied in PTSD recently which lend promise to the development of mechanism-based treatments. Endocannabinoid-derived novel compounds are currently entering the clinical arena to be tested in first clinical trials. Efforts focus on secondary prevention of PTSD to prevent the development of most disabling symptoms, i.e., emotional numbing or suicidality.

This box summarizes key points contained in the article.

populations overlap and are also unique in nature as different circumstances can result in variances in symptoms and their severity. This is important to take into account when treating PTSD. In civilian and military populations, early childhood abuse, and particularly childhood sexual abuse in women, is a reliable predictor of PTSD [5,6]. Differences in exposure to early childhood adversity can affect the course of PTSD especially in regard to the type and severity of symptoms. Individuals who experienced childhood abuse as their worst trauma experience symptoms such as affect dysregulation, self-guilt and difficulties in interpersonal attachment. These symptoms are not observed in adults who undergo certain types of acute traumas such exposure to the 9/11 attacks (i.e., 9/11 survivor) [7]. Consequently, the age of onset for the development of PTSD also affects how the disorder impacts the functionality of an individual. In adult populations, symptoms of avoidance and numbing are predictive of PTSD severity and functionality [8]. This symptom functionality relationship can differ in adolescents with PTSD. Unlike adults, symptoms such as intrusive memories, psychological reactivity and irritability are significant predictors of impaired functioning. Furthermore, the impact of these symptoms can change over time during adolescents [9]. While childhood adversity is one of the key predictors of developing PTSD in both civilian and military populations, [6], there are some differences in the predictors of military personnel in developing PTSD compared to civilians. A meta-analysis performed by Brewin et al. [6] revealed that trauma at a younger age was a risk factor for military PTSD and not civilian PTSD and gender was not a factor for military PTSD compared to civilians [6]. The triggers and severity of PTSD can also be unique to the military population. High combat exposure and killing, particularly that of specific individuals (e.g., children) and context (e.g., anger or revenge) predict severe PTSD [10,11]. Military sexual trauma is also unique in that development of PTSD is four times more likely compared to any other military trauma, including combat [12]. Furthermore, women who experience military sexual trauma are more likely to develop PTSD compared to sexual trauma 2

experienced as a civilian [13]. These distinct sources of trauma and their resulting symptoms could impact the selection of which pharmacological treatment could be best for a military versus civilian with PTSD. PTSD diagnosis and phenotype One challenge to identifying successful pharmacotherapies for PTSD is due to the heterogeneous nature of the disorder. While PTSD is often characterized as a unitary disorder, recent research has suggested that the disorder is composed of heterogeneous symptom clusters and each may have its separate neurobiological correlates. The complexity of PTSD may limit pharmacotherapies in having the ability to only target certain symptoms. The DSM-IV originally had PTSD separated into three dimensions, which included re-experiencing (Criterion B: e.g., intrusive thoughts, flashbacks), avoidance and emotional numbing (Criterion C: e.g., avoidance of places, detachment), and hyperarousal (Criterion D: e.g., hypervigilance, irritability) [14]. Later research by Simms et al. [15], and King et al. [16] performed further factor analyses on the DSM-IV symptoms and discovered a superior four-factor model, which included an intrusion/re-experiencing factor, an avoidance factor, a numbing/ dysphoria factor and a hyperarousal factor. Recent confirmatory factor analyses in veterans [17-19] and civilians [20-22] have revealed that PTSD is best characterized as being composed of five distinct symptom clusters -- re-experiencing (e.g., intrusive thoughts, flashbacks), avoidance (e.g., avoiding thoughts of trauma), emotional numbing (e.g., loss of interest, detachment, restricted affect), dysphoric arousal (e.g., sleep difficulties, concentration problems, anger/irritability) and anxious arousal (i.e., hypervigilance, exaggerated startle); this same symptom structure was recently confirmed using DSM-5 data [23]. This five-factor model of PTSD symptoms has been driven by PTSD-specific assessments such as the ClinicianAdministered PTSD Scale (CAPS). One issue with this five-factor model is that PTSD is commonly comorbid with other psychological disorders such as anxiety disorders and major depressive disorder [24]. In order to address this, our lab has approached clustering via a transdiagnostic approach through the use of the CAPS, Montgomery--A˚sberg Depression Rating Scale (MADRS; [25]), and Hamilton Anxiety Rating Scale (HAM-A; [26]), as well as self-report instruments such as the behavioral inhibition system (BIS)/behavioral activation system (BAS) [27] scales that assess component aspects of behavioral inhibition and behavioral approach/reward responsiveness. We have used these tools to specifically cluster systems implicated in negative and positive valence implicated in threat, loss and reward responsiveness. Although the CAPS, MADRS and HAM-A were designed to provide categorical diagnoses of PTSD, major depression disorder (MDD) and generalized anxiety disorder [28], respectively, they also provide a rich dimensional assessment of component aspects of negative valence systems implicated in threat and loss, as 1.1

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Investigational drugs under development for the treatment of PTSD

well as a more refined characterization of transdiagnostic aspects of these systems. Accordingly, the BIS/BAS scales provide a rich dimensional assessment of negative valence implicated in behavioral inhibition, as well as positive valence systems implicated in reward responsiveness, behavioral drive and fun-seeking. Due to the high comorbidity of PTSD with MDD and generalized anxiety disorder (GAD), Forbes et al. [29] took a transdiagnostic approach using the various symptoms measured in CAPS as well as scores for MDD, GAD and phobias to form two latent factors. Phobic disorders and PTSD symptoms hypervigilance and re-experience loaded onto to a fear factor. MDD, GAD and PTSD symptoms numbing and dysphoric arousal loaded onto an anxious-misery/distress factor. There is already evidence that different clusters are driven by different neural circuits, which could have implications for PTSD drug discovery. Positron emission tomography (PET) studies lend support to the idea that neural mechanisms are related to different PTSD symptoms. Norepinephrine transporter availability in the locus coeruleus is positively correlated with the severity of anxious arousal (i.e., hypervigilance and exaggerated startle response) response [30]. Serotonin (5-HT) 1b receptors in the pallidum are negatively correlated with anxious arousal and 5-HT1b receptors in the hippocampus are negatively correlated with emotional numbing symptoms (e.g., detachment, restricted range of affect) [31]. The pharmacological treatments we propose will take into account the heterogeneous nature of PTSD with the idea that different symptom clusters are driven by dysfunctions in specific neurotransmitters and neural circuits. Therefore, we will address which symptoms each treatment and/or system would be able to target. This view of treatment is of the same vein as the Research Domain Criteria project set up by the National Institute of Mental Health whose goal is to improve mental health treatments based on behavioral and neurobiological measures rather than a single diagnosis [32]. The current review will discuss cannabinoids, glutamate, opioids, brain-derived neurotrophic factor (BDNF), and oxytocin (OT) and which components of PTSD they could treat. Since we want to specifically discuss novel treatments we will review drugs that have only been studied in animal models, utilized in proof-of-concept studies or used in case studies. 2.

Cannabinoids

The cannabinoid system is made up of two receptor types CB1 and CB2. CB1 receptors are primarily found in the CNS, while CB2 receptors are primarily found in the periphery particularly in the immune system. CB1 receptors act as presynaptic heteroreceptors that are tonically activated to regulate the release of neurotransmitters [33]. The cannabinoid system has at least five endogenous cannabinoids (eCB), including a variety of endogenous ligands: anandamide, 2-arachidonoylglycerol (2-AG), noladin ether, virodhamine and N-arachidonoyldopamine [34]. The cannabinoid system

has been implicated in mood, pain regulation, appetite, memory, emesis and cognition [35]. Recent studies have also pointed to disruptions of the cannabinoid system in individuals with PTSD, thereby making it a target system for treatment. We recently published the first translational in vivo molecular imaging study using PET and the CB1-selective radioligand [11C]OMAR in individuals with PTSD (n = 25), and healthy controls (HC) with lifetime histories of trauma exposure (trauma controls [TC]) (12) and those without such histories (HC; n = 23) [36]. As shown in Figure 1, the PTSD group, relative to the HC and TC groups, had significantly elevated brain-wide [11C]OMAR VT values (F(2,53) = 7.96, p = 0.001; 19.5 and 14.5% higher, respectively). Peripheral anandamide concentrations were additionally reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Further, three biomarkers examined collectively -- OMAR VT, anandamide and cortisol -- correctly classified nearly 85% of PTSD cases. Taken together, these results suggest a relationship between abnormal CB1 receptor-mediated anandamide signaling and PTSD. A decrease in the eCB, 2-AG, has also been observed in survivors of the 9/11 attacks [37]. In trauma survivors, an association between increased CB1 receptor availability in the amygdala and abnormal threat processing has been observed. This increase in CB1 receptors in the amygdala was also associated with an increased severity of a threat symptomology factor, which included sleep disturbances and hyperreactivity, but not loss symptomatology, which included emotional numbing and dysphoria [38]. Furthermore, there was a negative correlation between peripheral anandamide levels and CB1 binding in the amygdala. CB1 agonists Recent discovery of neurological disruption of this system in individuals with PTSD provides an opportunity to target both the anxious arousal and dysphoric arousal symptoms of PTSD. Several recent pilot studies have tested direct CB1 agonists in individuals with PTSD. These studies show promise for sleep disturbances, which are a hallmark of PTSD [39]. Underactivation of the cannabinoid system induced by cannabis withdrawal results in sleep problems as well as vivid dreams [40]. This suggests that the cannabinoid system could be a target to aid in the treatment of sleep disturbances in individuals with PTSD. Two studies have used the synthetic CB1 agonist, nabilone, to treat PTSD-related sleep disruptions and nightmares [41,42]. Compared to pre-nabilone treatment, nabilone administration was able to significantly increase hours of sleep and reduce the number of nightmares. This suggests that CB1 activation may aid in alleviating some of the dysphoric arousal symptoms. It is important to note that these were not placebo-controlled studies and one involved prison inmates, many of who were comorbid with other psychological disorders [41,42]. However, a recent double-blind, cross-over placebo-controlled study found that 2.1


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Composite value Orbitofrontal cortex Anterior cingulate Amygdala Hippocampus Trauma control


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Effect size difference relative to HC group (Cohen’s d and 95%CI) 3

0 PTSD

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Figure 1. Cannabinoid receptor type 1 availability in posttraumatic stress disorder. Top: Cohen’s d and 95% CIs of effect size differences in [11C]OMAR volume of distribution (VT) values in PTSD and trauma controls (TC) groups relative to healthy controls (HC). Bottom: The figure has been partially reproduced [36] with permission of Nature Publishing Group. PTSD: Posttraumatic stress disorder.

a 7-week treatment of nabilone improves CAPS scores, particularly the Recurring and Distressing Dream Item [43]. The direct CB1 agonist D9-tetrahydrocannabinol (THC) may also be a potential treatment. THC is found in cannabis and is a large contributor to its psychoactive effects [44]. It has been found that individuals with PTSD are more likely to use cannabis to help with coping as well as sleep disturbances [45]. One study also administered THC to PTSD-affected patients and found an improvement specifically in the CAPS arousal score and sleep disturbances [46]. CB1 agonists also have the potential to act as an adjunct to psychotherapy. PTSD has been considered to be a problem with fear extinction to the traumatic event. In most individuals, the responses to a trauma such as re-experiencing, avoidance and hyperarousal are extinguished over time. This does not occur in individuals with PTSD indicating difficulties in fear extinction [47]. Currently, an effective treatment for PTSD is exposure therapy, which utilizes fear extinction. Exposure therapy involves repeated exposure to a fear-related cue until the subject no longer associates that cue with an aversive event. This type of therapy has been shown to be effective in people with PTSD [48]. There has been some research done utilizing drugs as ‘cognitive enhancers’ to strengthen this process. Research in animals has shown that administration of a CB1 agonist aids in fear extinction [49]. Furthermore, recent studies in healthy humans have shown that administration of 4

synthetic THC prior to extinction in a fear conditioning paradigm also improves fear extinction [50,51]. Fatty acid amide hydroxylase inhibitors One particularly noteworthy development in recent years has been the identification of the fatty acid amide hydroxylase (FAAH) enzyme as a critical mediator of anandamide metabolism and thus a potential target for novel, mechanism-based pharmacotherapy development for PTSD and related disorders [52,53]. Inhibition of the hydrolysis of fatty acid amides, including anandamide, results in their accumulation and potentiates their pharmacological effects. Anandamide is a weak partial agonist at both of the two known cannabinoid receptors -- CB1 [54] and CB2 [55]. Under conditions of FAAH inactivation, fatty acid amides accumulate markedly, but concentrations exhibit a plateau, suggesting alternative mechanisms of clearance. However, these pathways have yet to be conclusively demonstrated. FAAH inhibitors may help mitigate PTSD symptoms via multiple mechanisms: i) restoring low levels of anandamide back to normal -- possibly by decreasing FAAH activity -which represent a vulnerability factor to developing PTSD and have been linked to increased anxiety and hyperarousal symptoms [37,38,56]; ii) suppressing amygdala hyperreactivity, thereby facilitating the mitigation of anxious arousal and more rapid habituation to threat [57]; iii) restoring the 2.2.1




PTSD-characteristic hypothalamic--pituitary--adrenal (HPA) axis dysregulation [58]; iv) promoting sleep and suppressing of rapid eye movement sleep [59], which can increase re-experiencing and hyperconsolidation of traumatic memories during sleep; v) reducing anxious arousal and sympathetic tone via activation of CB1 receptors on noradrenergic nerve terminals [60]; and/or vi) modulating other eCBs, such as palmitoylethanolamide or oleoylethanolamide, which are anti-inflammatory and analgesic, and regulate satiety, respectively. In addition to FAAH inhibitors having the potential to reduce PTSD symptoms, particularly anxious arousal, they may also help mitigate altered pain sensitivity [61], as well as low-grade inflammation [62], which have been documented in military-related PTSD [61-64]. FAAH inhibitor versus CB1 receptor agonists In light of increasing legalization of marijuana for medical and recreational purposes, there is a popular notion that direct agonism of the CB1 system with drugs such as marijuana is harmless and can even help mitigate anxiety and related symptoms. However, a recent review in the New England Journal of Medicine by Volkow et al. [65] presents a preponderance of evidence highlighting the substantial adverse health effects of marijuana use. For example, short-term marijuana use has been linked to impaired short-term memory, learning difficulties, impaired motor coordination, altered judgment, and in high doses, paranoia and psychosis. Long-term or heavy marijuana use has been linked to substantially elevated risk of addiction to marijuana as well as other drugs of abuse, altered brain development, cognitive impairment, poor educational outcomes, diminished life satisfaction and achievement, chronic bronchitis, increased risk of motor vehicle accidents, and increased risk of depression and anxiety, as well as psychotic disorders, including schizophrenia, among persons predisposed to such disorders. Several lines of evidence demonstrate the superiority of FAAH inhibitors over direct CB1 receptor agonists for the treatment of PTSD and related disorders. These include: i) anandamide is a weak, partial CB1 agonist [66] and unlike D9-THC has no reinforcing effects [67,68]; ii) FAAH inhibitor treatment is not associated with adverse cognitive side effects [69]; iii) cardiovascular liabilities (tachycardia, orthostasis, syncope) [70]; or iv) hyperphagia [71]; v) the pharmacology of FAAH inhibitors can be localized to active pathways [72,73]; and vi) FAAH inhibitors exhibit polypharmacology by influencing multiple eCBs in their metabolism [74], possibly resulting in complementary positive effects in mitigating anxiety, as well as pain and inflammatory responses [75]. New FAAH inhibitors are starting to be created and patented, and their chemical structures have also been published [76-78]. These compounds work in a similar fashion to those used in animal studies, and some of these compounds are currently undergoing human trials. Research in animal models, including nonhuman primates, has demonstrated that these compounds are safe [68,79]. Research using FAAH 2.2.2

inhibitors in rodents offer promise for use in humans. AM3506 has been shown to be a potent inhibitor of FAAH, increases anandamide levels and promotes fear extinction in a mouse strain prone to impairment in fear extinction [80]. URB597 and URB532 are other FAAH inhibitors that have been used in mice to show anxiolytic effects that are blocked via the CB1 antagonist, rimonabant [71,81], suggesting a key effect of the CB1 receptor in mediating the effects of enhanced anandamide signaling. The efficacy of FAAH inhibitors has also been demonstrated in rodent models of anxiety [81] and depression [82] and FAAH inhibition has been described to produce enhancement of learning ability [83] or minimal effects on working memory [84]. Based on recent research done there is evidence that there are disruptions in eCB in individuals with PTSD, particularly a decrease in eCBs such as anandamide and 2-AG and a possible compensatory upregulation of CB1 receptors potentially due to CB1 underactivation [36,37]. Deficits in the cannabinoid system appear to be related to arousal symptoms in PTSD, including both anxious arousal and dysphoric arousal, and either direct (e.g., nabilone) or indirect (e.g., FAAH inhibitor) CB1 agonists appear to be a promising treatment for these factors of PTSD. Furthermore, CB1 agonists may also be a potential cognitive enhancer for treatment with exposure therapy. 3.

Glutamate

Glutamate is considered to be the primary excitatory neurotransmitter in the CNS. The glutamatergic system consists of both ionotropic glutamate receptors (iGlu) receptor and metabotropic glutamate receptors (mGlu). iGlu receptors consist of NMDA, AMPA and kainite receptors, which have ion channels and allow for rapid synaptic transmission [85]. The glutamate system also consists of three groups of metabotropic receptors, which are couple to second messengers. Group I mGlu consists of mGlu1 and mGlu5; Group II mGlu consist of mGlu2 and mGlu3; and Group III mGlu consist of mGlu4, mGlu6, mGlu7 and mGlu8 [85]. NMDA receptors have been shown to be involved in fear extinction and that activation of NMDA receptors can enhance fear extinction [86]. Therefore, NMDA agonist could aid in fear extinction in individuals with PTSD. D-cycloserine (DCS) is a partial agonist of the NMDA receptor and has been shown to be beneficial in fear extinction in rodents and humans with phobias [87,88]. Recent studies have been administering DCS both alone and in conjunction to exposure therapy to treat individuals with PTSD and results have varied. Attari et al. [89] performed an 11-week, double-blind, randomized study administering DCS in conjunction with other medications. DCS was able to reduce the intensity of the numbing and avoidance symptoms in males who had combat-related PTSD, but findings were weak. Heresco-Levy et al. [90] also found that DCS


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improved numbing and avoidance symptoms, but placebo had similar effects. The effectiveness of DCS appears to be better when given immediately prior to exposure therapy to enhance extinction learning. However, the efficacy of this kind of treatment does vary. Results using DCS in conjunction with virtual reality exposure therapy appears to be better than imaginal exposure therapy. The use of DCS in conjunction with imaginal therapy results in small improvements or impairments in symptoms compared to placebo [91,92]. Studies utilizing virtual reality exposure therapy find that DCS results in improvements in CAPS measurements [93], and Difede et al. [94] found improvements specifically among factors such as avoidance, re-experiencing and hyperarousal, especially sleep disturbances. Paradoxically the NMDA antagonist, ketamine, has been found to be helpful in some instances of PTSD although results are mixed. There have been a few case studies that have found temporary improvements, but also other studies that have found a worsening of symptoms. Two case studies of individuals with severe chronic PTSD experienced a temporary decrease in symptoms after an acute administration of ketamine [95,96]. Burn victim soldiers who received ketamine during surgical procedures experienced a decrease in PTSD symptoms compared to those who did not receive ketamine during operations [97]. Furthermore, study by Feder et al. [98] found that a single intravenous administration of ketamine provided a temporary reduction in symptoms compared to baseline [98]. It also performed better compared to the benzodiazepine midazolam; however, no inactive control was used in this study. Despite these preliminary positive observations, one study examining the effects of peritraumatic administration of ketamine found an increase in future PTSD symptoms [99]. Glutamatergic neurotransmission via mGlu receptors may also play a role in PTSD. During periods of extreme chronic stress, there are mGlu2/3 receptor regulatory changes in key brain regions implicated in stress regulation [100-102]. Specifically, mGlu2/3 receptors are highly localized in key cortical and subcortical (limbic) brain structures that are relevant to the etiology of PTSD, including the amygdala, hippocampus, nucleus accumbens (NAcc), and prefrontal cortex, which collectively function to regulate glutamatergic neurotransmission [103]. This unique distribution pattern and approach to suppressing stress-induced glutamate release through mGlu receptors [104] have motivated efforts to explore mGlu2/3 receptors as potential targets for treatment development for individuals with stress-related psychopathology. mGlu receptors are a family of glutamate G-protein-coupled receptors that are commonly separated into three classes based on their pharmacologic and signal transduction pathways (for review [104,105]). mGlu2/3 are negatively coupled to cAMP formation and are thought to function as inhibitory presynaptic autoreceptors that may play a role in synaptic plasticity [104,106] and suppress excitation [107-111]. Further, mGlu2/3 receptor agonists have demonstrated efficacy in preclinical models of anxiety by 6

reducing anxiety-like behaviors in fear-potentiated startle paradigms [112-116]; and stress-induced hyperthermia [117]; increasing open-arm time in an elevated plus maze [112,118,119]; preventing lactate-induced panic-like responses in panic-prone rats; and attenuating certain physiological, behavioral and neurochemical consequences of acute stress in rodents [120]. mGlu2/3 activation in the amygdala appears to be particularly effective at reducing fear-potentiated startle, which could indicate benefits to individuals with PTSD [87,114]. In addition to preclinical trials with rodents, there has been one clinical trial using mGlu2/3 agonists in humans. High doses of the mGlu2/3 agonist, LY544344 showed improvements in the Hamilton Anxiety Scale in individuals with generalized anxiety disorder [121]. These recent studies suggest that drugs targeting the glutamate system have promise. In particular, using NMDA agonists as cognitive enhancer to use in conjunction to the correct type of exposure could aid in the cognitive impairments of PTSD and the resulting avoidance and arousal factors. mGlu2/3 agonists may be able to act more as a novel anxiolytic and provide relief to the anxious arousal symptoms. 4.

Opioids

The opioid system is composed of three main receptors: d (enkephalin-preferring) opioid receptor, k (dynorphin-preferring) opioid receptor (KOR) and µ (b-endorphin-preferring) opioid receptor [122]. One role of the opioid system is to regulate stress physiology. The dynorphin/KOR system is involved in the dysphoric components of stress, particularly after exposure to chronic stress [123]. In rats, KOR blockade attenuates the dysphoric components of forced swim stress test [124]. Additionally, exposure to both acute and chronic stressors increases KOR immunoreactivity in the NAcc in rats [125]. In humans, KOR mRNA is found in limbic-striatal frontal cortical neural circuitry, which is associated with PTSD [126]. Research from our group has provided further evidence of KOR distribution in the human brain via PET using the novel radioligand [11C]LY2795050 [127]. A recent study has examined KOR distribution in the brains of individuals who experienced trauma. KOR distribution was particularly focused on amygdala-anterior cingulate cortex-ventral striatal neural circuitry. KOR binding was negatively correlated with loss symptomology, which included cognitive anxiety, psychic anxiety, dysphoria, and so on, but not threat symptomology, which included avoidance and hyperarousal. Of the loss symptomology, KOR binding was specifically correlated with dysphoria. This corroborates recent research from our group showing that the dynorphin/ KOR system drives the dysphoric component of stress in trauma survivors [127]. The downregulation of KOR may be due to chronically high levels of dynorphin, which happens upon chronic stress [125,128]. This study did not distinguish individuals who were just exposed to trauma and those who developed PTSD. This study suggests that targeting the




dynorphin/KOR system may aid in the dysphoric arousal symptoms of PTSD. Despite this relationship, the use of a KOR antagonist still needs to be studied in humans. There are currently several studies that demonstrate KOR antagonists have anxiolytic and antidepressant properties [129,130]. However, systemic administration of these drugs have a delayed onset of action (i.e., 24 h) and a surprisingly long duration of action that can last up to 3 weeks after a single dose even though drug is no longer detectible in plasma [131,132]. This family of KOR antagonists includes GNTI, JDTic, and nor-BNI [131]. These drugs have been used in rodents and nonhuman primates with little to no side effects [124,132,133]. Novel fastacting and short-lasting KOR antagonists, such as zyklophin, have recently been produced and show anxiolytic potential but these studies have only been done with rodents [134]. Of the discussed systems, the KOR system and the possible future use of KOR antagonists appear to be a promising target to target loss symptomology, specifically the symptoms of dysphoria and numbing. 5.

Brain-derived neurotrophic factor

BDNF is a neurotrophic factor that is involved in neuroplasticity and learning [135]. BDNF and its high-affinity receptor, tropomyosin-related kinase B (TrkB) has been implicated in stress and components of fear learning including fear extinction [136]. There is an increase in TrkB mRNA in animal exposed to chronic stress, which may reflect an upregulation due to lower levels of BDNF [137]. Modulating BDNF activity in animals provides evidence that BDNF plays an important role in fear extinction. Inhibiting BDNF gene expression in the dorsal hippocampus of mice results in impaired fear extinction but not fear acquisition or fear expression [138]. Heterozygous BDNF knockout mice have impaired fear extinction and these transgenic mice have decreased levels of BDNF in the hippocampus, amygdala and prefrontal cortex compared to wild-type mice [139]. Disruptions in the BDNF system have been observed in individuals with PTSD such as lower levels of serum BDNF [140]. Additionally, individuals with the BDNF Val66Met polymorphism, which results in decreased secretion of BDNF [141] have less success with exposure therapy [142]. Activation of TrkB can be achieved through the use of the small molecule 7,8-dihydroxyflavone (7,8-DHF). 7,8-DHF acts as a direct TrkB agonist, crosses the blood--brain barrier, and can be administered systemically to activate TrkB receptors in the brain [143]. It has been demonstrated that 7,8-DHF can improve fear extinction in female mice [144]. Additionally, systemic administration of 7,8-DHF also rescues impaired fear extinction in mice that experienced a 2-h immobilization [145]. This novel compound shows promise in rodent models to improve fear extinction. 7,8-DHF could be a drug used in the future as another

cognitive enhancer for individuals with PTSD undergoing exposure therapy. 6.

Oxytocin

OT is a nonapeptide that has recently received a great amount of interest in treatment of psychological disorders. OT is involved in smooth muscle contractions, social bonding, orgasm, labor and lactation (for review [146]). OT release has also been found to result in anxiolysis and reduction in HPA activity [147]. OT is well known for its pro-social effects. Intranasal administration of OT has been utilized to treat social deficits in individuals with schizophrenia [148] and autism [149]. The effect of OT on anxiety and fear extinction provides a possibility for a treatment or an adjunct treatment for individuals with PTSD. In fact, there is some evidence that disruption of the OT system could contribute to the development of PTSD. Israeli children exposed to war who have certain single nucleotide polymorphisms in the OT and vasopressin systems are more prone to developing chronic PTSD [150]. Studies done with rats and humans have provided evidence that OT administration does not affect fear conditioning but has the potential to facilitate fear extinction and attenuate fear expression. Timing of administration appears to be important in whether intranasal OT has the ability to aid in fear extinction. Intrahippocampal or intracerebroventricular administration of OT in rodents facilitates fear extinction [151,152]. Imaging studies in human studies have found that intranasal OT has the ability to dampen amygdala activity in response to threatening visual stimuli, which is overactivated in individuals with PTSD [153]. A study in humans showed that administering intranasal OT to healthy humans during a fear conditioning task aids in very specific components of fear extinction [154]. Frijling et al. [155] have designed a study to utilize intranasal OT as a pharmacological tool to prevent or attenuate later development of PTSD symptoms. The study will utilize a randomized controlled study and recruit individuals who go to the Emergency Department in Amsterdam after they undergo a traumatic experience. Subjects will be administered either intranasal OT or placebo twice a day for a week posttrauma. PTSD symptoms and physiological measures will then be tracked. More research must be done with intranasal OT particularly placebo-controlled studies with individuals with PTSD. It is possible that OT could either be used alone or in conjunction with other therapies such as exposure therapy. OT could also possibly be used as a prophylactic. 7.

Conclusion

It also possible, of course, that the novel treatments that are currently entering the clinical arena for being tested in patient populations will not be associated with clinically significant improvements relative to placebo, in which case it is unlikely


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that they will undergo further evaluation and would not have any sustained short- or long-term impact. Nevertheless, even with negative trials, it is possible that some patients will respond to the intervention and responder analyses can be conducted to evaluate baseline predictors of treatment response that can help inform the design of future clinical trials (e.g., sample enrichment strategies). An additional short- and long-term impact of these trials is that it will increase knowledge of the etiology of PTSD. By employing a multi-modal assessment approach that includes clinical interviews, neuroimaging and functional endophenotypic measures of emotional reactivity, hypervigilance, and fear processing mechanisms, results of these trials will provide much-needed insight into the etiology of PTSD. This information can also be used to predict response to treatments, which can inform strategies for personalizing treatment for veterans and other trauma survivors with PTSD. Fortunately, there are some evidence-based treatments for PTSD, including selective serotonin reuptake inhibitors [156], cognitive behavioral therapy [157] and prazosin for sleep disturbances [158]. Unfortunately, some of these treatments have small effect sizes. It is possible that if the experimental treatments discussed in this review actually do show promise, they can replace those that only provide weak-to-moderate success. 8.

Expert opinion

Studies exploring potential pharmacotherapies for PSTD have began to broaden the range of systems that can be targeted to provide faster and better symptom relief. One weakness of the current research is the lack of focus on how treatments help different symptom clusters. The authors believe that it is particularly important to utilize the current standardized five-factor model that is currently being used in the DSM-5 since that is the most up-to-date and widely used diagnostic tool that both clinical and research psychiatrists would use. In reviewing different studies in this paper, the authors attempted to determine which symptom clusters a certain pharmacotherapy could improve. However, although promising to some extent, limitations in the study designs, relatively small sample sizes and the often preliminary nature of these novel studies do not provide conclusive results yet. In order to identify effective treatments for PTSD, more research is needed to determine which neurotransmitters and neural circuits are involved in PTSD in general but most importantly which symptoms they are related to. This will then allow the field to determine which symptom factors are related to which disrupted neural mechanism. This would then allow for the determination of which drugs to utilize and develop. One promising approach to gather this information is via in vivo neuroimaging, that is, PET scans that enables the visualization of neurochemical processes in the 8

brain in vivo. Studies like these have already been performed for CB1 receptors [36,38], 5-HT1b receptors [31], KOR or norepinephrine transporters [30]. Unfortunately, radioligands for receptors such as OT receptors, TrkB and mGlu2/3 do not currently exist. A promising direction that the field is pursuing and gaining momentum has been the use of drugs as cognitive enhancers. These are drugs that would be given in conjunction with psychotherapy. For PTSD, this therapy would specifically involve exposure therapy. In this paper, the authors discussed manipulations of the glutamate system via DCS [94], cannabinoids such as synthetic THC (e.g., dronabinol) [50], BDNF [145], and OT [155] could all have the potential to act as cognitive enhancers. Two systems that show promise for specific symptom clusters are the KOR and CB1 receptor. Blocking KOR could help with the numbing symptom class of PTSD specifically those symptoms that are shared with MDD such as loss of interest and detachment. Unfortunately, the current KOR antagonists (e.g., nor-BNI, GNTI, etc.) have not been used in humans. CB1 agonists, both direct and indirect, show promise for targeting the dysphoric and anxious arousal symptom clusters related to PTSD. One possible treatment approach for this complex disorder may be the use of a drug cocktail due to the heterogeneity of the PTSD phenotype. When determining the appropriate drug or drugs to be prescribed, clinicians should consider which symptom clusters are most prevalent and severe in an individual. This would be taking an Research domain criteria approach to the treatment of PTSD rather than a diagnostic approach. It may also be important to consider a patient’s history and demographics such as age, type of trauma, severity of trauma, age at first trauma, and whether the individual is a veteran or civilian. Currently, FAAH inhibitors are receiving considerable attention as representing a class of compounds that could emerge as novel, evidence-based treatment for PTSD. There have been recent studies suggesting benefits of direct CB1 agonists on both PTSD symptoms and also when used as cognitive enhancers. The use of a FAAH inhibitor presents greater promise since it would both restore the appropriate eCB tone, which appears to be deficient in individuals with PTSD [36], as well as activate CB1 receptors without the potential unwanted negative effects that have been linked to direct CB1 receptor activation with THC. Nevertheless, CB1 agonists appear to treat both the anxious arousal and dysphoric arousal symptom domains of PTSD that is important since arousal symptoms including hyperarousal have found to predict the more disabling symptoms of PTSD such as numbing, which are symptoms that may facilitate the emergence of suicidal behaviors in people with PTSD [159-163]. Therefore, FAAH inhibitors lend promise for the reduction of impaired functioning and sociality among people with PTSD, which can range between 18 and 20% [164,165].




Declaration of interest This project was supported by the National Institutes of Health through the following awards: R21MH096105, R21MH085627, R34MH102871, RO1MH096876 and RO1MH102566; the Office of the Assistant Secretary of Defense for Health Affairs under Award No. W81XWH-141-0084. The Clinical Neurosciences Division of the United States Department of Veterans Affairs National Center for Posttraumatic Stress Disorder. Opinions, interpretations, conclusions and recommendations are those of the author and are Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Benjamin J Ragen1, Jordan Seidel1, Christine Chollak1, Robert H Pietrzak2,3 & Alexander Neumeister†1,4 MD † Author for correspondence 1 New York University School of Medicine, Department of Psychiatry, New York, NY, USA 2 VA Connecticut Healthcare System, Clinical Neurosciences Division, United States Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, USA 3 Yale School of Medicine, Department of Psychiatry, New Haven, CT, USA 4 Professor of Psychiatry and Radiology, Director, New York University School of Medicine, Department of Radiology, Molecular Imaging Program for Anxiety and Mood Disorders, One Park Avenue, 8th floor, room 225, New York, NY 10016, USA Tel: +1 646 754 4827; E-mail: [email protected]

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