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).
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
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