Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder

Abstract

The catecholamine norepinephrine is a critical effector of the mammalian stress response and has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD)-a syndrome intrinsically related to the experience of extraordinary stress. Symptom-linked hypernoradrenergic derangements have been observed in PTSD and several studies have examined the potential therapeutic effects of agents that dampen the centrally hyperactive noradrenergic state. These agents include compounds that decrease norepinephrine release (e.g. centrally acting alpha(2) agonists such as clonidine) and those which block post-synaptic norepinephrine receptors (e.g. centrally acting alpha(1) or beta receptor antagonists such as prazosin or propranolol). In this article, we review studies of central noreadrenergic hyperactivity under both basal and challenge conditions and explore the evidence for these derangements as potential psychopharmacologic targets in patients with PTSD. Given the significant involvement of CNS norepinephrine hyperactivity in PTSD, and its link to intrusive and hyperarousal symptoms, it is not surprising that interventions directed at this system have therapeutic potential in PTSD. The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

“…This leads to reexperiencing memories of the original trauma and causes early hyperaroused psychophysiological responses and, with time, turns into a late ''numbing'' experience (when circulating NE and cortisol are actually low perhaps due to a ''burn-out'' state). [48] The efficacy of the a1 antagonist prazosin, the a2 agonist clonidine, and the b antagonist propanolol in the clinical treatment of early PTSD provide the evidence of an involvement of a dysfunctional central NE system in early trauma-related syndromes. [48][49][50][51] There is substantial evidence to show that the sleep problems and nightmares that are seen in PTSD may be secondary to hyperactivity of the noradrenergic systems during the earlier acute stages of the trauma and thus prazosin, a selective a1 noradrenergic antagonist, was shown to provide clinical benefit.…”

“…[48] The efficacy of the a1 antagonist prazosin, the a2 agonist clonidine, and the b antagonist propanolol in the clinical treatment of early PTSD provide the evidence of an involvement of a dysfunctional central NE system in early trauma-related syndromes. [48][49][50][51] There is substantial evidence to show that the sleep problems and nightmares that are seen in PTSD may be secondary to hyperactivity of the noradrenergic systems during the earlier acute stages of the trauma and thus prazosin, a selective a1 noradrenergic antagonist, was shown to provide clinical benefit. [52][53][54][55] Taken together, these findings suggest that traumatic stress results in a hyperactive central NE system and exaggerated central nervous system responses (i.e., sensitization) to noradrenergic activation.…”

“…[52][53][54][55] Taken together, these findings suggest that traumatic stress results in a hyperactive central NE system and exaggerated central nervous system responses (i.e., sensitization) to noradrenergic activation. [48,49,56] …”

Pharmacologic Considerations for Youth with Posttraumatic Stress Disorder

“…Given that research has consistently demonstrated increased noradrenergic tone in both adults (for review see) 16) and youth with PTSD, 17) several investigators have explored the efficacy of anti-adrenergic agents for the prevention and treatment of PTSD. Propranolol is a centrally-acting, long-chain β-blocker that is used primarily for hypertension, and has been used off-label for the treatment of situational anxiety, such a stage fright or performance anxiety.…”

Understanding Resilience

“…The noradrenergic system is activated upon stress, resulting in increased release of norepinephrine primarily from the locus coeruleus to its many projection sites that modulate stress responses and emotional behaviors, including the amygdala, hippocampus, hypothalamus and PFC, all of which constitute the LC-NE system (Aston- Jones and Cohen, 2005;Strawn and Geracioti, 2008). The activation of the LC-NE system under acute stress leads to generation and transmission of negative emotional memories starting from the amygdala, a process that can be inhibited by blocking norepinephrine activity (Charney, 2004).…”