Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

doi:10.1016/j.biopsych.2015.01.005

Biological Psychiatry

Volume 78, Issue 5, 1 September 2015, Pages 344-353

https://doi.org/10.1016/j.biopsych.2015.01.005 Get rights and content

Abstract

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). Although its diagnostic features have been recently reclassified with the emergence of the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition, the disorder remains characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the etiology and maintenance of PTSD. Translational research spanning the past few decades has revealed several potential avenues for the identification of diagnostic biomarkers for PTSD. These include, but are not limited to, monoaminergic transmitter systems, the hypothalamic-pituitary-adrenal axis, metabolic hormonal pathways, inflammatory mechanisms, psychophysiological reactivity, and neural circuits. The current review provides an update to the literature with regard to the most promising putative PTSD biomarkers, with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression. Such biomarkers will most likely be identified by multi-dimensional models derived from comprehensive descriptions of molecular, neurobiological, behavioral, and clinical phenotypes.

Section snippets

Monoamine Systems In PTSD

PTSD is characterized by increased sympathetic nervous system tone that is coincident with augmented levels of catecholamine secretion (12). Urinary and central levels of norepinephrine (NE) are heightened in individuals with PTSD (13) and in child trauma victims (14), and peripheral and central levels of NE in response to threatening stimuli are also elevated in PTSD (15, 16). Recent evidence suggests that this increase in NE in PTSD is due to attenuated levels of the NE transporter within the

Neuroendocrine Biomarkers of PTSD

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is present in PTSD and has been extensively characterized (Figure 1) [for review see (31)]. Evidence suggests that individuals with PTSD have attenuated levels of basal cortisol (31) and that a low level of cortisol in trauma survivors is associated with increased risk for subsequent development of PTSD (32, 33). However, findings on baseline cortisol levels have been mixed, and a recent meta-analysis concluded that there are no

Biomarkers of Heightened Inflammation In PTSD

The high comorbidity between PTSD, physical illness (7) , and inflammation spanning cardiovascular (72) and metabolic disease (73) has led to investigations of the relationship between inflammatory markers and PTSD symptomology (Table 2). Pro-inflammatory cytokines (i.e., proteins), including interleukin (IL)-6 (74), IL-1β (75), and IL-2 (76), are elevated in individuals with PTSD and peripheral levels of inflammatory markers correlate positively with PTSD symptomology (Figure 1) (77).

Genetic and Epigenetic Biomarkers of PTSD

Genetic loci within genes critical for the neuroendocrine regulation of the HPA axis and emotional behavior have been associated with increased risk for PTSD [see review (5)]. However, these genetic loci have been associated with other psychiatric conditions as well, indicating that these genetic polymorphisms are not specific to PTSD but rather may serve as biomarkers for stress-induced psychopathology in general or common underlying symptoms. There are several recent genomic reviews of PTSD

Psychophysiological Biomarkers of PTSD

Hyperarousal symptoms, which include some of the longstanding, hallmark symptoms of PTSD, can be strongly influenced by an individual’s autonomic response following trauma; the output of the autonomic nervous system can be indexed noninvasively via psychophysiological assessments of peripheral targets, such as heart rate (HR), blood pressure, skin conductance (SC), respiration rate, muscle contractions using electromyography (EMG) (e.g., startle), and body temperature. However, the use of these

Neuroanatomical and Neuroactivational Biomarkers of PTSD

Neuroimaging data gathered during the last decade demonstrate that PTSD is associated with greater amygdala activation compared with control subjects (126). Functional magnetic resonance imaging (fMRI) studies have shown that trauma-relevant words increase amygdala activation in PTSD subjects more than in control subjects (127, 128, 129, 130). Exaggerated fear responses observed in PTSD may be due to a weakened inhibitory control of the amygdala by the medial prefrontal cortex (mPFC). A large

Summary and Conclusions

To date, an array of putative biomarkers associated with PTSD risk and symptom progression have been identified across distinct biological domains, including, but not limited to, alterations and differences in monoaminergic systems, neuroendocrinology, inflammation, genomics, psychophysiology, and neuroanatomy. However, the heterogeneity inherent in PTSD symptom presentation and the common comorbidity with other psychiatric and general medical conditions represent formidable obstacles in the

Acknowledgments and Disclosures

This work was funded in part by the Brain and Behavior Foundation (formerly National Alliance for Research on Schizophrenia and Depression) (SDN and TJ); the Department of Defense/Congressionally Directed Medical Research Program (Award # W81XWH-08-2-0170) (SDN); the Emory University Research Committee; a Public Health Service Grant (UL1 RR025008) from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources (SDN); and National

References (149)

A.L. Roberts et al.
Posttraumatic stress disorder across two generations: Concordance and mechanisms in a population-based sample
Biol Psychiatry
(2012)
P.R. Zoladz et al.
Current status on behavioral and biological markers of PTSD: A search for clarity in a conflicting literature
Neurosci Biobehav Rev
(2013)
S.M. Southwick et al.
Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder
Biol Psychiatry
(1999)
D.L. Delahanty et al.
Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims
Psychoneuroendocrinology
(2005)
T.D. Geracioti et al.
Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder
Psychoneuroendocrinology
(2008)
E.I. Martin et al.
The neurobiology of anxiety disorders: Brain imaging, genetics, and psychoneuroendocrinology
Psychiatr Clin North Am
(2009)
R.C. Arora et al.
Paroxetine binding in the blood platelets of post-traumatic stress disorder patients
Life Sci
(1993)
M. Maes et al.
Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression
Neuropsychopharmacology
(1999)
J.W. Murrough et al.
Reduced amygdala serotonin transporter binding in posttraumatic stress disorder
Biol Psychiatry
(2011)
R.V. Parsey et al.
Altered serotonin 1A binding in major depression: A [carbonyl-C-11]WAY100635 positron emission tomography study
Biol Psychiatry
(2006)

K. Walsh et al.

Cortisol at the emergency room rape visit as a predictor of PTSD and depression symptoms over time

Psychoneuroendocrinology

(2013)

J. Mouthaan et al.

The role of acute cortisol and DHEAS in predicting acute and chronic PTSD symptoms

Psychoneuroendocrinology

(2014)

J.D. Bremner et al.

Cortisol response to a cognitive stress challenge in posttraumatic stress disorder (PTSD) related to childhood abuse

Psychoneuroendocrinology

(2003)

B.M. Freidenberg et al.

Women with PTSD have lower basal salivary cortisol levels later in the day than do men with PTSD: A preliminary study

Physiol Behav

(2010)

I.R. Galatzer-Levy et al.

Cortisol response to an experimental stress paradigm prospectively predicts long-term distress and resilience trajectories in response to active police service

J Psychiatr Res

(2014)

G. Matic et al.

Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD

Prog Neuropsychopharmacol Biol Psychiatry

(2013)

R. Yehuda et al.

Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder

Biol Psychiatry

(2004)

R. Yehuda et al.

Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks

Biol Psychiatry

(2009)

M. van Zuiden et al.

Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: A prospective study

Biol Psychiatry

(2012)

R.A. Bryant et al.

The association between menstrual cycle and traumatic memories

J Affect Disord

(2011)

E.M. Glover et al.

Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder

Biol Psychiatry

(2012)

S.E. Hammack et al.

Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior

Psychoneuroendocrinology

(2009)

H. Ghzili et al.

Role of PACAP in the physiology and pathology of the sympathoadrenal system

Front Neuroendocrinol

(2008)

A.M. Rasmusson et al.

Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder

Biol Psychiatry

(2006)

J.J. Mulchahey et al.

Cerebrospinal fluid and plasma testosterone levels in post-traumatic stress disorder and tobacco dependence

Psychoneuroendocrinology

(2001)

A. Reijnen et al.

The effect of deployment to a combat zone on testosterone levels and the association with the development of posttraumatic stress symptoms: A longitudinal prospective Dutch military cohort study

Psychoneuroendocrinology

(2015)

A.M. Rasmusson et al.

Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD

Biol Psychiatry

(2000)

C.A. Morgan et al.

Trauma exposure rather than posttraumatic stress disorder is associated with reduced baseline plasma neuropeptide-Y levels

Biol Psychiatry

(2003)

C.A. Morgan et al.

Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: Replication and extension of previous report

Biol Psychiatry

(2002)

M.N. Rao et al.

Hyperinsulinemic response to oral glucose challenge in individuals with posttraumatic stress disorder

Psychoneuroendocrinology

(2014)

M.N. Hill et al.

Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks

Psychoneuroendocrinology

(2013)

C.S. de Kloet et al.

Elevated plasma arginine vasopressin levels in veterans with posttraumatic stress disorder

J Psychiatr Res

(2008)

T. Weiss et al.

Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population

Gen Hosp Psychiatry

(2011)

M. Maes et al.

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events

Biol Psychiatry

(1999)

B. Spivak et al.

Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder

Biol Psychiatry

(1997)

R. von Kanel et al.

Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder

J Psychiatr Res

(2007)

R.J. Miller et al.

C-reactive protein and interleukin 6 receptor in post-traumatic stress disorder: A pilot study

Cytokine

(2001)

L. Plantinga et al.

Association between posttraumatic stress disorder and inflammation: A twin study

Brain Behav Immun

(2013)

N. Rohleder et al.

Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder

Neurosci Biobehav Rev

(2010)

N. Rohleder et al.

Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder

Biol Psychiatry

(2004)

T.W. Pace et al.

Increased peripheral NF-kappaB pathway activity in women with childhood abuse-related posttraumatic stress disorder

Brain Behav Immun

(2012)

C.L. Raison et al.

Cytokines sing the blues: Inflammation and the pathogenesis of depression

Trends Immunol

(2006)

H.P. Söndergaard et al.

The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder

Clin Chim Acta

(2004)

R. von Känel et al.

Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder

J Psychiatr Res

(2007)

E.C. McCanlies et al.

C-reactive protein, interleukin-6, and posttraumatic stress disorder symptomology in urban police officers

Cytokine

(2011)

S.L. Klein

Hormones and mating system affect sex and species differences in immune function among vertebrates

Behav Processes

(2000)

K. Skelton et al.

PTSD and gene variants: New pathways and new thinking

Neuropharmacology

(2012)

E.A. Dedert et al.

Posttraumatic stress disorder, cardiovascular, and metabolic disease: A review of the evidence

Ann Behav Med

(2010)

R.C. Kessler et al.

Posttraumatic stress disorder in the National Comorbidity Survey

Arch Gen Psychiatry

(1995)

N. Breslau

The epidemiology of posttraumatic stress disorder: What is the extent of the problem?

J Clin Psychiatry

(2001)

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ReviewDiagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

Abstract

Section snippets

Monoamine Systems In PTSD

Neuroendocrine Biomarkers of PTSD

Biomarkers of Heightened Inflammation In PTSD

Genetic and Epigenetic Biomarkers of PTSD

Psychophysiological Biomarkers of PTSD

Neuroanatomical and Neuroactivational Biomarkers of PTSD

Summary and Conclusions

Acknowledgments and Disclosures

Biol Psychiatry

Neurosci Biobehav Rev

Biol Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

Psychiatr Clin North Am

Life Sci

Neuropsychopharmacology

Biol Psychiatry

Biol Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

Psychoneuroendocrinology

Physiol Behav

J Psychiatr Res

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

J Affect Disord

Biol Psychiatry

Psychoneuroendocrinology

Front Neuroendocrinol

Biol Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

J Psychiatr Res

Gen Hosp Psychiatry

Biol Psychiatry

Biol Psychiatry

J Psychiatr Res

Cytokine

Brain Behav Immun

Neurosci Biobehav Rev

Biol Psychiatry

Brain Behav Immun

Trends Immunol

Clin Chim Acta

J Psychiatr Res

Cytokine

Behav Processes

Neuropharmacology

Posttraumatic stress disorder, cardiovascular, and metabolic disease: A review of the evidence

Ann Behav Med

Posttraumatic stress disorder in the National Comorbidity Survey

Arch Gen Psychiatry

The epidemiology of posttraumatic stress disorder: What is the extent of the problem?

J Clin Psychiatry

Review
Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research