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Neuropharmacology 62 (2012) 539–541

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Neuropharmacology

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Editorial

Neuropharmacology special issue on posttraumatic stress disorder (PTSD): Current state of the art in clinical and preclinical PTSD research

Posttraumatic stress disorder (PTSD) is unique among mental disorders in that the primary eliciting factor is explicitly environ- mental: the experienceofa severe,life threatening trauma. According to the National Comorbidity Survey Replication (NCS-R) conducted in 2001–2003 in the United States, the lifetime prevalence of PTSD among men is 3.6% and among women is 9.7% (Kessler et al., 2005). The twelve month prevalence is 1.8% among men and 5.2% among women. The effects of PTSD on normal functions are myriad, charac- terized by unrelenting memories of the traumatic event, consequent behavioral adaptations to avoid trauma reminders which often severely impinge on work and family functions, increased vigilance, sleep disturbances and arousal symptoms as well as high co- morbidity with depression, substance abuse, and chronic pain. PTSD is also a strong risk factor for suicide attempts (Nock et al., 2010).

Although there are extant treatments for PTSD, including phar- macological interventions (e.g. serotonin reuptake inhibitors) as well as effective psychological therapies (e.g. a variety of cognitive behavioral and other therapies), many patients (as high as 40–50%) do not respond to these treatments and develop a chronic course of the illness (IOM, 2007). With war, natural disasters and other trau- matic events unlikely to be curbed in the foreseeable future, a great deal of effort in the last decade has gone toward understanding the etiology of this disorder and development of novel treatment strate- gies and prevention measures. The main approaches revolve around understanding the root cause(s) of the disorder and consequent pathology in order to aid development of more effective therapeu- tics, identification of biomarkers of risk, and development of prophy- lactic treatments at various points in the biological and psychological trajectory of traumatic exposure to trauma-related disorder.

Due to the growing awareness of the need for better PTSD treat- ment and prevention modalities, partly due to the large influx of new combat trauma-exposed veterans from the Iraq and Afghanistan wars, funding for PTSD research has increased substantially within the last 5 years resulting in an increase in PTSD-related research. This PTSD special issue of Neuropharmacology embodies many of the current research approaches (imaging, pharmacology, genetics, animal models) that have been used to understand the etiology of PTSD and its symptom domains, how to model the disorder, and novel treatment approaches that are under pre-clinical and clinical investigation.

1. PTSD symptom domains and common co-morbidity

One of the difficulties of studying the etiology of PTSD is that it is often present with other common co-morbid disorders including

0028-3908/$ – see front matter � 2011 Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2011.08.021

depression, substance abuse, sleep disorders, and in veterans of recent wars, traumatic brain injury. Understanding these common co-morbid disorders, including their biological mechanisms, neural circuitry, functional impairments, specific biomarkers and genetics iscritical in understanding how these disordersmay mask,potentiate or add to a complex biology underlying enduring effects of trauma as we strive to identify the biological mechanisms of PTSD itself. Norman et al. (pages 542–551) present a review of the current under- standing of the incidence, treatment and etiology of substance abuse disorders in PTSD patients. In parallel, Logrip, et al. (pages 552–564) describe pre-clinical models of 3 different types of stress effects on addiction behavior (developmental, adult social and adult non-social), and how the neural circuits and neuropeptide systems underlying stress responses alter reward processing and circuitry to support drug seeking. This review is very timely given the mounting support for developmental trauma, such as childhood neglect, inter- acting with the development of stress systems to increase risk for development of PTSD (see below). There is also significant co- morbidity between PTSD and depression, (Cerdá et al., 2010) and in this special issue Hammack et al. (pages 565–575) compare two preclinical models of depression and PTSD (learned helplessness and social defeat), discussing the orthogonal and common system mechanisms underlying their effects on anxiety and depressive behaviors. Nappi and colleagues (pages 576–585) review the current understanding of PTSD and co-morbid sleep disorders and their treatment, arguing that sleep disorder treatment is likely critical for full resolution of symptoms and for efficacy of pharmacotherapeutic treatments. This is an exciting area of PTSD research which has been relatively unexplored in pre-clinical models. The co-morbidity of chronic pain in PTSD is a relatively new field that is discussed in depth in Moeller-Bertram and Strigo (pages 586–597), both in terms of treatment as well as underlying circuit and neurochemical mecha- nisms underlying increased pain perception in this population. Finally, many traumatic events also involve head injuries (e.g. combat blast injury, transportation accident), but it is not well understood how traumatic brain injury impacts PTSD pathology and outcome. In this issue, Simmons and Matthews (598–606) present a meta- analysis of imaging studies describing how brain injury can affect emotional regulation and trauma processing in PTSD patients.

2. Current pharmacological and psychological approaches to PTSD treatment: where are we now and where are we going?

Bomyea and colleagues (pages 606–616) review the literature on psychosocial approaches to treating PTSD and, in so doing,

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emphasize that there is much more work to be done in improving the effectiveness of existing treatments, tailoring them to specific populations, and developing new approaches for treating individ- uals who cannot access or do not benefit from traditional treat- ments. They also point to the need for our field to become more adept at matching patients to treatments to which they are most likely to benefit, i.e., the holy grail of personalization of treatments for PTSD (and other mental disorders).

Steckler and Risbrough (pages 617–627) provide a brief review of current pharmacological treatments for PTSD, followed by an extensive review of current development efforts of new compounds targeted toward stress response systems. They also cover the emerging literature on the use of pharmacological agents to facilitate therapies that depend on new learning (i.e., most psychosocial therapies). This overview clearly demonstrates the promise of new pharmacotherapies to come, and points to the need for clinical trials to move many of these new compounds from bench to bedside.

3. Risk and resilience to enduring effects of trauma: genetic, epigenetic and environmental factors

First, the review from Skelton et al. (pages 628–637) describes the current understanding of genetics of PTSD risk from single gene mutations. They then discuss a translational approach of using PTSD-related phenotypes that are measurable across animal and human models to uncover novel gene pathways and validate candidates from association studies. This topic is then tackled in more depth specifically as related to fear-learning endopheno- types by Johnson and colleagues (pages 638–646). They describe how models of Pavlovian fear associations in animals have been exploited to identify gene pathways and neural circuits under- lying the etiology of PTSD. Another approach to understanding genetics of PTSD that is especially useful for testing the “chicken or the egg” hypothesis of PTSD associated phenotypes is utiliza- tion of twin studies, reviewed by Kremen et al. (pages 467– 653). The authors show that a number of limbic circuit and cogni- tive abnormalities in PTSD may be attributed to pre-existing factors that may confer risk to PTSD, while other phenotypes such as arousal and anterior cingulate abnormalities may be a function of trauma exposure. Such understanding of trait vs. state PTSD-associated pathology will be critical in refining our current animal models of pathology and “risk” (see animal models section below). Finally, in order to understand the genetic underpinnings of PTSD, it will be essential to account for interac- tions of candidate genes with environmental factors, not only the trauma itself (G � E), but also many well understood environ- mental factors that can confer additional risk to later trauma responses through epigenetic mechanisms (e.g. developmental stressors, G � E � E). The complexities and challenges of identifying and adequately designing experiments to answer this question are many, as described by Mehta and Binder (pages 654–662). They suggest utilization of a candidate gene approach (e.g. HPA axis genes) in conjunction with endophenotypes as one way to solve the puzzle of the etiology of PTSD.

4. PTSD etiology: neurochemical and neural circuit abnormalities

In this special issue we also have a number of reviews that present novel hypotheses of the etiology of PTSD and its pathology. Baker et al. (pages 663–673) review the expanding body of literature on immune system mediators in the periphery

and the central nervous system (CNS) in chronic PTSD along with the evidence for increased peripheral inflammation in these indi- viduals. Acheson et al. (pages 674–685) review the evidence for structural and functional abnormalities of the hippocampus in PTSD subjects and present the hypothesis that this pathology can lead to reduced contextual control of conditioned fear associ- ations, leading to unrestrained simple conditioned cue responses across multiple environments, a facet of PTSD symptoms. Aup- perle and colleagues (pages 686–694) present a review of the deficits in executive function and frontal cortex circuitry under- lying these functions in PTSD patients. They then present a theo- retical model concerning how dysfunction in response inhibition and attention regulation may play a role in the development of PTSD symptoms and treatment outcome in PTSD. Jovanovic et al. (pages 695–704) review the findings of reduced safety signal learning in PTSD patients, discussing the reverse translational methods that their group has used in primates to delineate the neural substrates underlying this process and how they relate to neural circuit abnormalities in PTSD patients. Finally, Hauger and colleagues (pages 705–714) provide an extensive review of cell signaling pathways linked to stress responding, and present a novel hypothesis of reduced G-protein coupled receptor desen- sitization in stress pathways as a potential candidate mechanism for PTSD development after severe trauma.

5. Animal models of PTSD: focus on predator stress

Although the other reviews in this issue give a broad picture of the translational methods of pavlovian fear conditioning as a model for the intrusive memories and avoidance of trauma reminders domains of PTSD symptoms, others have taken a different approach in modeling the effects of a single acute trauma in creating enduring generalized anxiety-like and increased arousal behaviors in animals. Predator stress models have been found to have predic- tive, face and construct validity for PTSD symptoms, pathology and treatment response. First, Cohen and colleagues (pages 715–724) review the validity of the predator stress model for PTSD, and the unique approach that their group has used with this model to identify “at risk” populations and the mechanisms underlying this risk for enduring anxiety after acute trauma. Second, Adamec and colleagues (pages 725–736) present a research paper on the commonality of predator stress and other stressors to alter neuronal activation in brainstem regions, and reports that sero- tonin neuron activation in the dorsal raphe was linked to stress responsivity. Lastly, Bakshi et al. (pages 737–748) describe a novel effect of predator stress – disruption of sensorimotor gating – that requires activation of corticotropin releasing factor receptors but is not dependent upon HPA activation. These data suggest a potential neuropeptide mechanism for the sensorimotor gating deficits described in some PTSD patients.

We trust that this state-of-the-art compilation of papers covering many aspects of the field of trauma-related disorders, with an emphasis on PTSD, will be of considerable utility to any reader interested in learning more about the present and future understanding and management of this highly prevalent, serious set of conditions.

References

Cerdá, M., Sagdeo, A., Johnson, J., Galea, S., 2010 Oct. Genetic and environmental influences on psychiatric comorbidity: a systematic submitted for publication. J. Affect Disord. 126 (1–2), 14–38. Epub 2009 Dec 11. Review.

Committee on treatment of posttraumatic stress disorder, I.o.M.o.t.N.A., 2007. Treat- ment of Posttraumatic Stress Disorder: An Assessment of the Evidence. The National Academies Press, Washington D.C.

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Kessler, R.C., Chiu, W.T., Demler, O., Merikangas, K.R., Walters, E.E., 2005. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627.

Nock, N.K., Hwang, I., Sampson, N.A., Kessler, R.C., 2010. Mental disorders, comor- bidity and suicidal behavior: results from the National Comorbidity Survey Replication. Mol. Psychiatry 15, 868–876.

Victoria B. Risbrough*, Murray B. Stein University of California San Diego, Department of Psychiatry, 9500 Gilman Drive, La Jolla, CA 92093-0804, United States

* Corresponding author. E-mail address: [email protected] (V.B. Risbrough)