Clinical Neuroscience

Posttraumatic stress disorder: From pathophysiology to pharmacology

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Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.1 The prevalence of PTSD varies significantly across countries and by type of trauma (Box1-7).


The prevalence of PTSD

In the general population, the prevalence of posttraumatic stress disorder (PTSD) varies from as low as 0.3% in China to as high as 6.1% in New Zealand1 and 6.8% in the United States.2 These rates are actually much lower than expected when one considers that severe trauma is experienced by 60.7% of men and 51.2% of women.3,4 Although the majority of individuals exposed to trauma experience emotional distress immediately following a traumatic event, most of them do not develop PTSD.5

It appears that the context of trauma is important: 12% to 15% of veterans experience PTSD, compared with 19% to 75% of crime victims and 80% of rape victims.1 The lifetime risk for PTSD is twice as high in women as it is in men,6 and genetic vulnerability may play a role. For example, twin studies showed that approximately 30% of the risk for PTSD may be mediated by genetic predisposition.7

Individuals who develop PTSD experience a wide range of symptoms.8 These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table8). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.8

PTSD-specific symptoms

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.9 Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans10 and in animal models.11 Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.12 These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models15 and in humans,16 but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.17 Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.20 Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.21

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.22 In exploratory studies,23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.25,26 This suggests that we must learn more about this system before we proceed.27

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.28 Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.29 A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.30,31 We need to learn more about BDNF before we proceed.32

Continue to: Serotonin transporter (5-HTT) gene


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